Novel cells and methods

Abstract

The present invention relates to an induced pluripotent stem cell (iPSC) or a somatic cell derived from an iPSC by forward programming or directed differentiation constitutively expressing an alternative splice form of Lamin A. The cells comprise an expression cassette comprising a coding sequence for the alternative Lamin A splice form operably linked to a cumate operator (CuO) sequence and a constitutive promoter. Also provided is the use of the cells described herein in a method of identifying a gene or combination of genes involved in the reversal of an ageing phenotype or in the maintenance of a non-aged phenotype. Methods of rejuvenating somatic cells, treating diseases or disorders associated with ageing, and modulating ageing (e.g. age-modulating methods and uses), including in vivo, are also provided, said methods comprising modulating the expression and / or activity of the gene / combination of genes identified herein.

Description

[0001]CLO-C-P3598PCT NOVEL CELLS AND METHODS FIELD OF THE INVENTION The present invention relates to an induced pluripotent stem cell (iPSC) or a somatic cell derived from an iPSC by forward programming or directed differentiation constitutively expressing an alternative splice form of Lamin A. The cells comprise an expression cassette comprising a coding sequence for the alternative Lamin A splice form operably linked to a cumate operator (CuO) sequence and a constitutive promoter. Also provided is the use of the cells described herein in a method of identifying a gene or combination of genes involved in the reversal of an ageing phenotype or in the maintenance of a non-aged phenotype. Methods of rejuvenating somatic cells, treating diseases or disorders associated with ageing, and modulating ageing (e.g. age-modulating methods and uses), including in vivo, are also provided, said methods comprising modulating the expression and / or activity of the gene / combination of genes identified herein. BACKGROUND OF THE INVENTION Ageing is the shared risk factor of a multitude of diseases, ranging from cancer to dementia (Niccoli and Partridge (2012) Curr. Biol.). However, a number of findings demonstrated that the ageing trajectory can be modulated, e.g. by dietary interventions (Longo and Mattson (2014) Cell Metab.; Longo et al. (2021) Nat. Ageing), drugs (Kennedy and Pennypacker (2014) Tranl. Res.; Guilbert et al. (2021) Methods), and genetic manipulation (Simpson et al. (2021) Clin Epigenetics; Zhang et al. (2020) Nat Rev Mol Cell Biol). Most importantly, reprogramming of somatic cells into induced pluripotent stem cells is able to reverse many hallmarks of ageing (Lapasset et al. (2011) Genes Dev.). Hence, there exist mechanisms that are able to modulate ageing, which deserve further investigation. Whilst the process of ageing is still poorly understood, it affects cells in multiple ways. Otin et al. (2013) Cell have provided a comprehensive review of “The Hallmarks of Ageing”, which include mitochondrial changes, senescence, altered intracellular communication, genomic instability, telomere shortening, epigenetic changes, and deregulation of nutrient pathways. These may lead to changes in cellular function, such as a reduced ability of immune cells to survey cancerogenic events, which ultimately contribute to the plethora of age-related diseases. Stem cells provide scalable model systems to study the biology of a species. However, modelling late-onset disorders using pluripotent stem cells (PSCs) such as embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) technology holds a challenge due to the CLO-C-P3598PCT embryonic nature of pluripotent stem cells and in particular the cellular rejuvenation during iPSC reprogramming (Lapasset et al. (2011) Genes Dev.; Maherali et al. (2007) Cell Stem Cell; Studer et al. (2015) Stem Cell, 16:591-600). Moreover, hallmarks of ageing are often related to disease associated degenerative processes. Independently, they have been associated with a gradual deterioration in structure and function. Some of these hallmarks have been identified as nuclear blebbing and folding, shortening of dendrite length (in the case of neurons), telomere attrition, reduced proteostasis and the accumulation of DNA damage and mitochondrial reactive oxygen species (ROS) (Lopez-Otin et al. (2013) Cell; Miller et al. (2013) Cell Stem Cell; Studer et al. (2015) Stem Cell). In addition, changes in gene expression profile have been observed in neurons (Arancio (2019) GeroScience; Mertens et al. (2015) Cell Stem Cell, 17:705-718) and in the human brain in general (Dillman et al. (2017) Sci. Rep.). These findings further corroborate the need for generating faithful iPSC models of human disease and have therefore inspired two main strategies to induce cellular ageing. The first approach involves manipulating the cellular environment by introducing toxic stressors such as reactive oxygen species (Davalli et al. (2016) Oxid. Med. Cell. Longev.), or by inflammatory cytokines to mimic the general overall inflammatory state associated with ageing. The second approach involves introducing intrinsic changes to the cells to induce ageing. That was accomplished by promoting telomere shortening through pharmacological inhibition of telomerase, the enzyme involved in maintaining telomere length (Vera et al. (2016) Cell Rep.). In this study, similar age- and disease-related phenotype changes such as an increase in mitochondrial ROS production, DNA damage and loss tyrosine hydroxylase expression were reported in Parkinsonian midbrain dopaminergic neurons. However, the study remains preliminary, as the effect on other cellular processes was not looked at. There is therefore a need to develop tools to study ageing and which will allow the use of systematic methods to identify genes and regulatory networks that contribute to ageing and the reversal of ageing in iPSCs which may subsequently be applied to somatic cells. SUMMARY OF THE INVENTION According to a first aspect of the invention, there is provided an induced pluripotent stem cell (iPSC), stem cell or a somatic cell derived from an iPSC by forward programming or directed differentiation comprising an expression cassette, said expression cassette comprising a coding sequence for an alternative splice form of Lamin A operably linked to a cumate operator CLO-C-P3598PCT (CuO) sequence and a constitutive promoter, thereby yielding constitutive expression of the alternative splice form of Lamin A in the cell. In particular embodiments, the cell does not comprise a sequence coding for a cumate repressor protein (CymR). In further embodiments, the alternative splice form of Lamin A is progerin or a progerin-like truncated form of Lamin A. In one embodiment, the presence of the expression cassette and absence of a CymR coding sequence yields constitutive expression of the alternative splice form of Lamin A in the cell. In a further embodiment, the cell chronically displays an ageing phenotype. According to a further aspect, there is provided a use of the iPSC, stem cell or somatic cell described herein in a method of identifying a gene or a combination of genes involved in the reversal of an ageing phenotype or in the maintenance of a non-aged phenotype in the cell. In a certain embodiment, the method of identifying a gene or combination of genes comprises the steps of: (i) culturing the iPSC, stem cell or somatic cell as described herein; (ii) optionally performing a loss-of-function, inhibitory, knock-out, gain-of-function or combinatorial screen in the cell; (iii) measuring an ageing phenotype in the cell; and (iv) identifying a gene or combination of genes as being involved in the reversal of an ageing phenotype or maintenance of a non-aged phenotype when the ageing phenotype is altered when the loss-of-function, inhibitory, knock-out, gain-of-function or combinatorial screen is performed compared to when the cell is not subjected to the screen. In further embodiments, the ageing phenotype measured in step (iii) is the same ageing phenotype chronically displayed by the cell. In yet further embodiments, the cell is an iPSC or stem cell and is forward programmed or differentiated to a somatic cell, or the cell is a somatic cell derived from an iPSC or a stem cell by forward programming or directed differentiation, and the forward programming / directed differentiation is performed before and / or after the identification of the gene or combination of genes, such as wherein forward programming / directed differentiation is performed in culturing step (i) and / or after performing the screen of step (ii). In a yet further aspect of the invention, there is provided a method of rejuvenating a somatic cell comprising modulating the expression and / or activity of one or more gene or combination of genes identified by the use described herein. CLO-C-P3598PCT In another aspect, there is provided an age-modulating method for use in a method of treating a disease or disorder associated with ageing in a subject, said age-modulating method comprising modulating the expression and / or activity of a gene or a combination of genes identified by the use as described herein. In a still further aspect, there is provided a method of modulating ageing in vivo, said method comprising the age-modulating method described herein. According to another aspect of the invention, there is provided a method of treating a disease or disorder associated with ageing, said method comprising the age-modulating method described herein. BRIEF DESCRIPTION OF THE FIGURES Figure 1: TetOn inducible system to overexpress Progerin. A) Scheme of the 2 vectors used to generate progerin overexpressing hiPSCs. The rtTA cassette was introduced into the ROSA26 genomic safe harbour (GSH) site while the expression cassette was introduced into the AAVS1 GSH, to allow a stable expression of progerin. Progerin was linked to GFP to allow visualisation of expression. B) The GFP-progerin expression cassette was introduced into BobC and KOLF2 human iPSCs backgrounds. Expression of GFP-progerin was observed based on fluorescence microscopy imaging. Scale bars: 250µm, left panels; 75µm, right panels. C) mRNA levels of progerin based on qRT-PCR in BobC (top panel) and KOLF2 (bottom panel) iPSCs. Data is presented as means ± SEM, Student t-test. **p< 0.01, ****p<0.0001. Figure 2: Doxycycline dose response assay in human iPSCs-GFP-Progerin line. A) Fluorescence microscopy images for the nucleic acid marker Hoechst (blue, top panels) and for GFP-progerin (green, bottom panels). KOLF2-GFP-progerin human iPSCs were treated with ranging dox concentrations (0-2µg / mL). Cell viability was compromised when doxycycline concentration was above 0.05µg / mL. Scale bars, 250µm. B) The number of cells per cm2was calculated per doxycycline concentration after 5 days of doxycycline treatment. A concentration above 0.05µg / mL showed to significantly reduce the number of cells. Data normalised to untreated cells (0µg / mL doxycycline). Data is presented as means ± SEM, One Way Anova with Tukey’s multiple comparisons test, ***p< 0.001, ****p<0.0001. C) Phase images of KOLF2-GFP-progerin human iPSCs that were treated with ranging dox concentrations (0-2µg / mL). Cell death was observed for dox concentration above 0.05µg / mL. Scale bars, 250µm. Figure 3: Genomic instability is shown by increased DNA damage in aged iPSCs. CLO-C-P3598PCT A-B) Fluorescence microscopy images for the DNA double strand breaks marker γH2AX (white) and the nucleic acid marker DAPI (blue) in both KOLF2 (A) and BOBC (B) hiPSCs treated (aged) or not treated (non-aged) with doxycycline. The number of foci was significantly higher for the aged group. Scale bars, 10µm. Data is presented as means ± SEM, student t- test, **p< 0.01. Figure 4: Telomere attrition is shown by reduced length and activity in aged iPSCs. A) Quantitative RT-PCR analysis-based assessment of relative telomere length demonstrates shortening in aged iPSCs compared to non-aged iPSCs. B) Volcano plots analysis, based on bulk RNA sequencing data, demonstrating differential expression of genes involved in telomere regulation and senescence. Figure 5: Epigenetic alterations are shown by reduced intensity of peripheral heterochromatin markers in aged iPSCs. A-B) Fluorescence microscopy images for the peripheral heterochromatin marker H3K9me3 (green) and the nucleic acid marker DAPI (blue) in both KOLF2 (A) and BOBC (B) iPSCs treated (aged) or not treated (non-aged) with doxycycline. H3K9ME3 intensity was significantly reduced in the aged group. Scale bars, 25µm. Data is presented as means ± SEM, student t-test, ****p< 0.0001. Figure 6: Loss of proteostasis is shown by activation of stress response pathways in aged iPSCs. A-C) Volcano plots analysis, based on bulk RNA sequencing data, demonstrating activation (upregulation) of genes involved in the main stress response pathways involved with proteostasis: oxidative stress response (ROS), unfolded protein response (UPR) and heat shock response (HSR). Figure 7: Disabled macroautophagy is shown by changes in autophagic flux in aged iPSCs. A) Autophagic flux measured by dye labelling autophagic vacuoles in live cells. Analysis indicates an increased autophagic flux in the aged iPSCs compared to non-aged iPSCs. Data is normalized to non-aged iPSCs levels and is presented as means ± SD, student t-test, ****p< 0.0001. B) Volcano plots analysis, based on bulk RNA sequencing data, demonstrating differential expression of genes involved in autophagy. BNIP3 that is known to be downregulated in ageing, was also found to be downregulated based on this analysis. Figure 8: Downregulated nutrient-sensing is shown by downregulation of selected DEGs and proteins in aged iPSCs. A) Western blot analysis of nutrient-sensing pathways in aged iPSCs shows a decrease of PGC1α and FOXO3 proteins and an increase (activation) of mTOR, characteristics of deregulation in ageing cells. B) Volcano plots analysis, based on bulk RNA sequencing data, demonstrating downregulation of differentially expressed genes related to nutrient-sensing in aged iPSCs, i.e. insulin pathway. Figure 9: Mitochondrial dysfunction is shown by reduced oxygen levels in aged iPSCs. A) Seahorse flux analysis demonstrating reduced oxygen consumption rates (OCRs) in aged iPSCs. Data is presented as means ± SD, student t-test, ns=not significant. B) CLO-C-P3598PCT Increased mitochondria (evident by MitoTracker Red marker) and signalling (evident by MitoSOX marker), indicate an increase in both parameters. Data is normalized to non-aged iPSCs levels and is presented as means ± SD, student t-test, **p<0.01, ****p< 0.0001. Figure 10: Cellular senescence is shown by increased β-galactosidase activity in aged iPSCs. A-B) Brightfield microscopy images for β-galactosidase (β-Gal) staining in both KOLF2 (A) and BOBC (B) iPSCs treated (aged) or not treated (non-aged) with doxycycline. β-Gal intensity was significantly increased in the aged group, indicating more are present. Scale bars, 250µm. Data is presented as means ± SEM, student t-test, 0.0001. Figure 11: Stem cell exhaustion is shown by reduced proliferation rate in aged iPSCs. A) Proliferation rate assay was conducted in progerin expressing iPSCs, showing to decrease their proliferation rate. B) Volcano plots analysis, based on bulk RNA sequencing data, demonstrating differential expression of genes related to proliferation, i.e. downregulation of proliferation-inducing genes (i.e. LHX5, APC2 and FGFR3) and upregulation of genes negatively affecting proliferation (i.e. INHBE). Figure 12: Design of a chronic ageing model in human iNeurons. A) A dual inducible system to overexpress NGN2 via the TetOn inducible system and GFP-progerin via the Cumate switch system. The rtTA cassette was introduced into the ROSA26 genomic safe harbour (GSH) site while the reprogramming cassette was introduced into the AAVS1 GSH, to allow a stable expression of both NGN2 and Progerin. The cumate system was modified to exclude the cumate repressor (CymR), allowing a constitutive expression of GFP-progerin. B) Scheme of the experimental procedure to generate chronically aged cortical glutamatergic iNeurons. Aged human iPSCs are treated with 2µg / mL doxycycline for a week to overexpress NGN2, resulting in aged iNeurons (iNs). Progerin is constitutively expressed in the background. iNeuron induction is based on a previous protocol by Pawlowski et al. (2017). Figure 13: Constitutive expression of Progerin does not affect iPSCs viability. A) Phase (bottom panels) and fluorescence (top panels) images of human aged iPSCs NGN2- GFP-Progerin line over a time course of 7 days. HiPSCs expressing progerin were plated as single cells and were stained each day for the nuclear DNA marker Hoechst (blue, top panels). No indications of cell death were observed. Scale bars: 250µm. B) The number of cells per cm2was measured each day for 7 days, showing an exponential increase, as expected from pluripotent cells. C) Immunocytochemistry for the pluripotency marker NANOG (red, far-left panel), for GFP-progerin (green, middle panel), and for the nuclear DNA marker DAPI (blue, right panel). Scale bar: 25µm. D) mRNA levels of GFP based on quantitative RT-PCR analysis. Aged iPSCs (’N2P caiPSCs’) show significantly higher levels of GFP than control NGN2-iPSCs (‘NGN2 iPSCs’) that do not express GFP. Data is presented as mean ± SD. Student t-test. ****p<0.0001. CLO-C-P3598PCT Figure 14: Induction of chronically aged iNeurons from aged iPSCs. A-B) mRNA levels of the pluripotency markers OCT4 and NANOG (A) are downregulated in the aged iNs while the neuronal markers, MAP2, Synapsin-1 and PSD95 (B) are upregulated compared to iPSCs. Analysis based on quantitative RT-PCR in chronically aged iNs (caiNs) and iPSCs (caiPSCs). Data is presented as mean ± SD. Student t-test. * p<0.05, **p<0.01. Figure 15: Constitutive expression of Progerin to force age iNeurons. A) Immunocytochemistry for the nuclear membrane protein Lamin-A (red, left far panel), for GFP- progerin (green, middle panel) and for the nuclear DNA marker DAPI (blue). Images are showing expression of GFP-progerin in the induced neurons without adding the cumate molecule to the neuronal cultures, indicating progerin is constitutively expressed. Scale bars: left, 25µm; right, 10µm. B) mRNA levels of GFP based on quantitative RT-PCR analysis in NGN2-iNs and in chronically aged iNs (N2P caiNs). Data is presented as mean ± SD. Student t-test. **p<0.01. C) Phase images of the chronically aged iNs at day 7, 14 and 21 post induction. Scale bar 100µm. D) Immunocytochemistry for the axonal marker β3-tubulin (grey, middle panel), for the dendritic marker MAP2 (red, far left panel) and for the nuclear DNA marker DAPI (blue). Scale bar 50µm. Figure 16: Multi electrode area analysis in chronically aged iNeurons. A) Weighted mean firing rate was measured in both non-aged NGN2 iNs and chronically aged iNs (N2P caiNs) showing similar rates. Data is presented as mean ± SEM in an XY points plot. B) The burst duration in the aged iNs group seemed to be decreasing at later stages of neuronal culture and maturation. Data is presented as mean ± SEM in an XY points plot. Figure 17: Mitochondrial dysfunction in chronically aged iNeurons. A) Scheme of the oxygen consumption rate ‘Mito Stress’ assay parameters. B) Oxygen consumption rates (OCRs) in aged iNeurons (N2P caiNs) are reduced, indicating on mitochondrial dysfunction. Data is presented as mean ± SEM in an XY points plot. C) Analysis of the different parameters (basal respiration, maximal respiration, and ATP production) showing significant reduction in aged iNeurons (N2P caiNs). Data is presented as mean ± SEM. One- way Anova. ** p<0.01, ***p<0.001. D) Energetic profile based on the assay measurements in control NGN2 iNs and chronically aged iNs, providing important parameters of cell energy metabolism: baseline phenotype, stressed phenotype, and metabolic potential (shown by lines d1 and d2). Figure 18: DNAmAge prediction based on epigenetic clock analysis. DNA methylation from non-aged (iNs) and constitutively aged (caiNs) neurons was measured. Epigenetic clock analysis based on Steve Horvath clock (Horvath 2013 Genome Biol 14, 3156, doi: https: / / doi.org / 10.1186 / gb-2013-14-10-r115) showed an increase in the biological age of the caiNs. Data is presented in box plots with min to max range, student t-test, *p<0.05. CLO-C-P3598PCT Figure 19: Shannon entropy analysis. DNA methylation analysis based on the number of methylated CpG sites showed higher entropy in caiNs compared to non-aged iNeurons. Data is presented in box plots with min to max range, student t-test, ****p<0.0001. DETAILED DESCRIPTION OF THE INVENTION The present invention is based, in part, on the previous discovery by the inventors that the unique regenerative capacity of stem cells (e.g. induced pluripotent stem cells; iPSCs) allows them to actively reverse induced ageing phenotypes. Such findings and methods for inducing ageing for a period of time are disclosed in PCT / GB2023 / 051123, and are hereby specifically incorporated by reference in their entirety. The present invention builds on these findings by providing an iPSC which stably expresses the ageing-inducing factor progerin, an alternative splice form of Lamin A, and thus chronically displays an ageing phenotype. The regenerative capacity of iPSCs enables them to tolerate the stable progerin expression and chronic ageing phenotype. Thus, in a first aspect of the invention there is provided an induced pluripotent stem cell (iPSC), stem cell or a somatic cell derived from an iPSC by forward programming or directed differentiation comprising an expression cassette, said expression cassette comprising a coding sequence for an alternative splice form of Lamin A coupled to a weak promoter sequence, thereby yielding low level constitutive expression of the alternative splice form of Lamin A in the cell while maintaining cell viability. The term “constitutive” is used herein in its normal context in the field of biology, namely that expression is continuous in the cell and is thus not inducible or regulated. In particular embodiments, the expression of the alternative splice form of Lamin A (e.g. progerin) is constitutive, i.e. the cell continuously expresses the alternative splice form. According to these embodiments, expression of the Lamin A alternative splice form is not inducible in the cell. In further embodiments, the constitutive expression of the Lamin A alternative splice form (e.g. progerin) is at a low level in the cell. A “low level” of expression as demonstrated herein provides a level in the cell sufficient to provide an effect (i.e. display of an aging phenotype) but not at such a level that the viability of the cell is affected. Thus, the cell expresses the Lamin A alternative splice form (e.g. progerin) at a level whereby an ageing phenotype as described herein is displayed (in particular chronically) but no or minimal cell death is caused. In yet further embodiments, the low level expression of the Lamin A alternative splice form does not affect the cell function, such as the regeneration function or regenerative capacity of stem cells as described herein (i.e. when the cell is an iPSC or a stem cell). Thus, in one embodiment the cell is an iPSC or a stem cell and expresses the Lamin A alternative splice CLO-C-P3598PCT form at a level whereby cellular regeneration functions are maintained. In a further embodiment, the cell is an iPSC and it retains a regenerative capacity. According to these embodiments, an ageing phenotype caused by expression of the Lamin A alternative splice form may be displayed following forward programming or directed differentiation of said iPSC or stem cell to a somatic cell, in particular only following / after said forward programming / directed differentiation (i.e. the iPSC / stem cell does not display an ageing phenotype, while the somatic cell derived therefrom does display an ageing phenotype). For example, such a display of the ageing phenotype only following forward programming / directed differentiation may be due to the expression level of the Lamin A alternative splice form being such (i.e. sufficiently low) that the regenerative capacity of the iPSC or stem cell is maintained, and / or because the regenerative capability of the iPSC / stem cell may thus be sufficient to overcome the level of Lamin A alternative splice form expression and prevent any display of an ageing phenotype in said cell. However, following / after forward programming or directed differentiation the resulting somatic cell, which does not comprise regeneration functions or regenerative capacity, will display an ageing phenotype. As such, in a still further embodiment the cell may be a somatic cell forward programmed or differentiated from an iPSC or a stem cell as described herein constitutively expressing a low level of Lamin A alternative splice form which displays an ageing phenotype following said forward programming or directed differentiation. According to this embodiment, the iPSC or stem cell from which the somatic cell is derived does not display the ageing phenotype. This is in contrast to that normally expected by expression of a factor which causes major cellular changes (i.e. an ageing- inducing factor, such as the Lamin A alternative splice form, progerin), wherein a chronically displayed ageing phenotype would normally be expected to cause or be correlated with cell death, low cell viability and loss of cellular function (e.g. loss of regenerative capacity in the case of stem cells / iPSCs). Such low level expression while maintaining cell viability and / or cellular regeneration functions is achieved by the present invention by the use of a “weak promoter” to drive expression of the Lamin A alternative splice form. The term “weak promoter” as used herein includes constitutive transcriptional promoters which are known in the art to be weak, as well as strong constitutive promoters which are coupled (e.g. operably linked) to a repressor sequence. Transcriptional repressor sequences (referred to herein simply as “repressor sequences” for brevity, and are also known as transcriptional repressor recognition sequences by virtue of the fact they are bound by transcriptional repressor proteins) therefore reduce the expression driven by a strong constitutive promoter. However, other methods of achieving low level expression of the Lamin A alternative splice form would be readily recognised by the skilled person and are encompassed by the present invention. For example, an exogenous substance which drives expression from an inducible promoter as described herein (e.g. doxycycline in the Tet-On system) may be administered / provided CLO-C-P3598PCT constitutively at a low level / dose to the cell to drive low level expression of the Lamin A alternative splice form. Said low dose constitutive administration / provision of the exogenous substance would achieve the same result as demonstrated herein, namely low level constitutive expression of the Lamin A alternative splice form in the cell leading to the chronic display of an ageing phenotype as described herein. In some embodiments the low level constitutive expression of the Lamin A alternative splice form is driven by a weak constitutive promoter. Accordingly, in a further embodiment the weak promoter is a weak constitutive promoter. While it will be appreciated by the skilled person that the relative strength of a promoter will vary depending on the cell type and possibly the location in the genome, some examples in mammalian cells of weak constitutive promoters include, but are not limited to: the promoter from the human ubiquitin C gene (UPC), which provides ubiquitous (i.e. constitutive expression); and the promoter from phosphoglycerate kinase gene (PGK) which gives widespread expression in different mammalian cell types and has been reported to resist promoter down regulation due to methylation or deacetylation. Thus, in some embodiments the weak constitutive promoter may be selected from the UPC (SEQ ID NO: 1) or the PGK promoter (SEQ ID NO: 2). In other embodiments, the weak constitutive promoter may be a fragment of the UPC (SEQ ID NO: 1) or the PGK (SEQ ID NO: 2) promoters, such as a functional variant or fragment thereof. Functional variants and fragments of promoters described herein may be portions of said sequences which make up enhancer elements, or which exclude enhancer elements, such that expression is still driven / provided by the promoter sequence (i.e. function is retained). GGTGCAGCGGCCTCCGCGCCGGGTTTTGGCGCCTCCCGCGGGCGCCCCCCTCCTCA CGGCGAGCGCTGCCACGTCAGACGAAGGGCGCAGGAGCGTTCCTGATCCTTCCGCCC GGACGCTCAGGACAGCGGCCCGCTGCTCATAAGACTCGGCCTTAGAACCCCAGTATCA GCAGAAGGACATTTTAGGACGGGACTTGGGTGACTCTAGGGCACTGGTTTTCTTTCCA GAGAGCGGAACAGGCGAGGAAAAGTAGTCCCTTCTCGGCGATTCTGCGGAGGGATCT CCGTGGGGCGGTGAACGCCGATGATTATATAAGGACGCGCCGGGTGTGGCACAGCTA GTTCCGTCGCAGCCGGGATTTGGGTCGCGGTTCTTGTTTGTGGATCGCTGTGATCGTC ACTTGGTGAGTTGCGGGCTGCTGGGCTGGCCGGGGCTTTCGTGGCCGCCGGGCCGC TCGGTGGGACGGAAGCGTGTGGAGAGACCGCCAAGGGCTGTAGTCTGGGTCCGCGA GCAAGGTTGCCCTGAACTGGGGGTTGGGGGGAGCGCACAAAATGGCGGCTGTTCCCG AGTCTTGAATGGAAGACGCTTGTAAGGCGGGCTGTGAGGTCGTTGAAACAAGGTGGGG GGCATGGTGGGCGGCAAGAACCCAAGGTCTTGAGGCCTTCGCTAATGCGGGAAAGCT CTTATTCGGGTGAGATGGGCTGGGGCACCATCTGGGGACCCTGACGTGAAGTTTGTCA CTGACTGGAGAACTCGGGTTTGTCGTCTGGTTGCGGGGGCGGCAGTTATGCGGTGCC CLO-C-P3598PCT GTTGGGCAGTGCACCCGTACCTTTGGGAGCGCGCGCCTCGTCGTGTCGTGACGTCAC CCGTTCTGTTGGCTTATAATGCAGGGTGGGGCCACCTGCCGGTAGGTGTGCGGTAGG CTTTTCTCCGTCGCAGGACGCAGGGTTCGGGCCTAGGGTAGGCTCTCCTGAATCGACA GGCGCCGGACCTCTGGTGAGGGGAGGGATAAGTGAGGCGTCAGTTTCTTTGGTCGGT TTTATGTACCTATCTTCTTAAGTAGCTGAAGCTCCGGTTTTGAACTATGCGCTCGGGGTT GGCGAGTGTGTTTTGTGAAGTTTTTTAGGCACCTTTTGAAATGTAATCATTTGGGTCAAT ATGTAATTTTCAGTGTTAGACTAGTAAA (SEQ ID NO: 1). TTCTACCGGGTAGGGGAGGCGCTTTTCCCAAGGCAGTCTGGAGCATGCGCTTTAGCAG CCCCGCTGGGCACTTGGCGCTACACAAGTGGCCTCTGGCCTCGCACACATTCCACATC CACCGGTAGGCGCCAACCGGCTCCGTTCTTTGGTGGCCCCTTCGCGCCACCTTCTACT CCTCCCCTAGTCAGGAAGTTCCCCCCCGCCCCGCAGCTCGCGTCGTGCAGGACGTGA CAAATGGAAGTAGCACGTCTCACTAGTCTCGTGCAGATGGACAGCACCGCTGAGCAAT GGAAGCGGGTAGGCCTTTGGGGCAGCGGCCAATAGCAGCTTTGCTCCTTCGCTTTCTG GGCTCAGAGGCTGGGAAGGGGTGGGTCCGGGGGCGGGCTCAGGGGCGGGCTCAGG GGCGGGGCGGGCGCCCGAAGGTCCTCCGGAGGCCCGGCATTCTGCACGCTTCAAAA GCGCACGTCTGCCGCGCTGTTCTCCTCTTCCTCATCTCCGGGCCTTTCGACCT (SEQ ID NO: 2). In alternative embodiments, the low level constitutive expression of the Lamin A alternative splice form is driven by a strong constitutive promoter coupled to a transcriptional repressor sequence. Thus, in a yet further embodiment the weak promoter is a strong constitutive promoter coupled to a transcriptional repressor sequence. Examples of strong constitutive promoters in mammalian cells which may be used coupled to a repressor sequence include, but are not limited to: the human elongation factor 1α (EF1A) promoter, which has been shown to provide consistent expression regardless of cell type or physiology; the cytomegalovirus immediate-early (CMV) promoter which may contain an enhancer region but has been shown to be silenced in some cell types; the chicken β-Actin promoter coupled with CMV early enhancer (CAG / CAGG) which contains the CMV enhancer, chicken beta actin promoter, and rabbit beta-globin splice acceptor; the simian virus 40 early (SV40) promoter which may additionally include an enhancer element; the β-actine gene promoter which provides ubiquitous expression and may be either the human or chicken sequence; RNA polymerase III promoters such as H1, U6 and 7SK, which have been shown to give good expression in particular in neuronal cells (in the case of H1) and for which either the human or murine sequence can be used; and the Ca2+ / calmodulin-dependent protein kinase II (CaMKIIa) promoter, which provides neuronal expression and may be modulated by calcium and calmodulin. Further examples of promoters which may find utility herein are described in Qin CLO-C-P3598PCT et al. (2010; PLoS One, 5(5):e10611, doi: https: / / doi.org / 10.1371%2Fjournal.pone.0010611), the promoters and sequences of which are hereby specifically incorporated by reference. Thus, in some embodiments the weak constitutive promoter may be selected from the EF1A (SEQ ID NO: 3), CMV (SEQ ID NO: 4 or SEQ ID NO: 5), CAG / CAGG (SEQ ID NO: 6), SV40 (SEQ ID NO: 7), H1 (full: SEQ ID NO: 8; or ‘core’: SEQ ID NO: 9), U6 or 7SK promoters, or a variant or functional fragment / variant thereof. GGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTG GGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTG GGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTAT ATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACA GGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGC GTGCCTTGAATTACTTCCACCTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGT TGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGC TTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCT TCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGC TGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTG GTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACAT GTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCT CAAGCTGGCCGGCCTGCTCTGGTGCCTGGTCTCGCGCCGCCGTGTATCGCCCCGCCC TGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTT CCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGC GGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGT GACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGA GTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGA GTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTG CCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTT TTCTTCCATTTCAGGTGTCGTGA (SEQ ID NO: 3). TAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCG CGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCA TTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACG TCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATA TGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGC CCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCG CTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGAC TCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCA CLO-C-P3598PCT AAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCG GTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACCGTCAGAT C (SEQ ID NO: 4). GTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGAT TTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGG GACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTG TACGGTGGGAGGTCTATATAAGCAGAGCT (SEQ ID NO: 5). ACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTC CGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCC CATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGA CGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCA TATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTAT GCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCAT CGCTATTACCATGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCATCTCCCCC CCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCGATGGGG GCGGGGGGGGGGGGGGGGCGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGGGCG GGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTCCGA AAGTTTCCTTTTATGGCGAGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAGCGCG CGGCGGGCGGGGAGTCGCTGCGACGCTGCCTTCGCCCCGTGCCCCGCTCCGCCGCC GCCTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGG CGGGACGGCCCTTCTCCTCCGGGCTGTAATTAGCGCTTGGTTTAATGACGGCTTGTTT CTTTTCTGTGGCTGCGTGAAAGCCTTGAGGGGCTCCGGGAGGGCCCTTTGTGCGGGG GGAGCGGCTCGGGGGGTGCGTGCGTGTGTGTGTGCGTGGGGAGCGCCGCGTGCGGC TCCGCGCTGCCCGGCGGCTGTGAGCGCTGCGGGCGCGGCGCGGGGCTTTGTGCGCT CCGCAGTGTGCGCGAGGGGAGCGCGGCCGGGGGCGGTGCCCCGCGGTGCGGGGGG GGCTGCGAGGGGAACAAAGGCTGCGTGCGGGGTGTGTGCGTGGGGGGGTGAGCAGG GGGTGTGGGCGCGTCGGTCGGGCTGCAACCCCCCCTGCACCCCCCTCCCCGAGTTGC TGAGCACGGCCCGGCTTCGGGTGCGGGGCTCCGTACGGGGCGTGGCGCGGGGCTCG CCGTGCCGGGCGGGGGGTGGCGGCAGGTGGGGGTGCCGGGCGGGGCGGGGCCGC CTCGGGCCGGGGAGGGCTCGGGGGAGGGGCGCGGCGGCCCCCGGAGCGCCGGCG GCTGTCGAGGCGCGGCGAGCCGCAGCCATTGCCTTTTATGGTAATCGTGCGAGAGGG CGCAGGGACTTCCTTTGTCCCAAATCTGTGCGGAGCCGAAATCTGGGAGGCGCCGCC GCACCCCCTCTAGCGGGCGCGGGGCGAAGCGGTGCGGCGCCGGCAGGAAGGAAATG GGCGGGGAGGGCCTTCGTGCGTCGCCGCGCCGCCGTCCCCTTCTCCCTCTCCAGCCT CGGGGCTGTCCGCGGGGGGACGGCTGCCTTCGGGGGGGACGGGGCAGGGCGGGGT CLO-C-P3598PCT TCGGCTTCTGGCGTGTGACCGGCGGCTCTAGAGCCTCTGCTAACCATGTTCATGCCTT CTTCTTTTTCCTACAGCTCCTGGGCAACGTGCTGGTTATTGTGCTGTCTCATCATTTTGG CAAAGAATTC (SEQ ID NO: 6). CTGTGGAATGTGTGTCAGTTAGGGTGTGGAAAGTCCCCAGGCTCCCCAGCAGGCAGAA GTATGCAAAGCATGCATCTCAATTAGTCAGCAACCAGGTGTGGAAAGTCCCCAGGCTC CCCAGCAGGCAGAAGTATGCAAAGCATGCATCTCAATTAGTCAGCAACCATAGTCCCG CCCCTAACTCCGCCCATCCCGCCCCTAACTCCGCCCAGTTCCGCCCATTCTCCGCCCC ATGGCTGACTAATTTTTTTTATTTATGCAGAGGCCGAGGCCGCCTCTGCCTCTGAGCTA TTCCAGAAGTAGTGAGGAGGCTTTTTTGGAGGCCTAGGCTTTTGCAAAAAGCT (SEQ ID NO: 7). GAACGCTGACGTCATCAACCCGCTCCAAGGAATCGCGGGCCCAGTGTCACTAGGCGG GAACACCCAGCGCGCGTGCGCCCTGGCAGGAAGATGGCTGTGAGGGACAGGGGAGT GGCGCCCTGCAAATATTTGCATGTCGCTATGTGTTCTGGGAAATCACCATAAACGTGAA ATGTCTTTGGATTTGGGAATCTTATAAGTTCTGTATGAGACCACTCTTTCCC (SEQ ID NO: 8). ATATTTGCATGTCGCTATGTGTTCTGGGAAATCACCATAAACGTGAAATGTCTTTGGATT TGGGAATCTTATAAGTTCTGTATGAGACCACTCTTTCCC (SEQ ID NO: 9). Any of the promoters to be used herein may comprise (e.g. additionally comprise) an enhancer sequence. Thus, in a still further embodiment the CMV promoter may additionally comprise the CMV enhancer of the sequence of SEQ ID NO: 10. CGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCA TTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACG TCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATA TGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGC CCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCG CTATTACCATG (SEQ ID NO: 10). Thus, in a certain embodiment the constitutive promoter comprises the CMV promoter / enhancer and comprises the sequence of SEQ ID NO: 11. CGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCA TTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACG CLO-C-P3598PCT TCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATA TGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGC CCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCG CTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGAC TCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCA AAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCG GTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCT (SEQ ID NO: 11). In a yet further embodiment, the constitutive promoter comprises a sequence about 60%, about 70%, about 80%, about 90% or about 100% identical to any of SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 10 or SEQ ID NO: 11. In still further embodiments, the constitutive promoter comprises a sequence about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% identical to any of SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 10 or SEQ ID NO: 11. In another embodiment, the constitutive promoter consists of SEQ ID NO: 4, SEQ ID NO: 5 or SEQ ID NO: 11. Transcriptional repressor sequences are known in the art and any endogenous, exogenous or engineered repressor sequence may be used coupled to a strong constitutive promoter as described herein. The term “coupled to” refers to the functional linkage of the repressor sequence and strong constitutive promoter whereby the repressor sequence affects (i.e. represses / reduces) transcription from the otherwise strong constitutive promoter. Wherein the repressor sequence and strong constitutive promoter are coupled, the repressor sequence need not be in the same contiguous sequence as the strong constitutive promoter and Lamin A alternative splice form coding sequence. For example, wherein the repressor sequence is endogenous to the iPSC, stem cell or derived somatic cell, the repressor sequence is not part of the expression cassette comprised in the cell. Thus, according to this embodiment the repressor sequence and the strong constitutive promoter become operably linked only after insertion of the expression cassette in the cell. Examples of endogenous transcriptional repressor sequences (which may be included exogenously) include those bound and regulated by Kruppel associated box (KRAB) domain-containing proteins (e.g. KRAB-zinc finger proteins), and such repressors have been shown to be involved in many cellular and organism-wide processes, including embryonic development, cell development and differentiation, cell proliferation, autophagy, apoptosis, neoplastic transformation and cell cycle regulation. In certain preferred circumstances, “coupled to” may also refer herein to the operable linkage of an exogenous and / or engineered repressor sequence and strong constitutive promoter. Thus, in preferred embodiments the repressor sequence is exogenous. Wherein the exogenous repressor sequence and strong constitutive promoter are operably CLO-C-P3598PCT linked, they are contained within the expression cassette together with the Lamin A alternative splice form coding sequence. In other words, the operably linked repressor sequence and strong constitutive promoter sequence are in the same contiguous sequence of the expression cassette introduced into the cell. Thus, according to these embodiments the exogenous repressor sequence and strong constitutive promoter are operably linked in the expression cassette. Further examples of repressor sequences which may be introduced as exogenous repressors include, but are not limited to: the lac operon repressor (lacZYA operon); the met operon repressor; the L-arabinose operon repressor; the cumate operator (CuO) sequence; and the tet operator (TetO) sequence. In the presence of their corresponding repressor proteins which recognise and bind to these sequences, transcription is blocked. However, as used herein in the absence of their repressor proteins (e.g. no cumate repressor protein (CymR) is expressed in the cell when the CuO sequence is used) transcription is allowed to proceed but it is reduced / at a lower level than would be expected from the strong constitutive promoter if used alone. Thus, in a particularly preferred embodiment the transcriptional repressor sequence is exogenous and is operably linked to the strong constitutive promoter such that the weak promoter sequence coupled to the Lamin A alternative splice form coding sequence comprises a cumate operator (CuO) sequence and a strong constitutive promoter. Whether the repressor sequence is endogenous or exogenous will affect the orientation of elements within the expression cassette, when relevant (e.g. when an endogenous repressor sequence is used, it may not be present in the expression cassette and is instead upstream of the genomic location where the expression cassette is inserted). In one embodiment, the expression cassette comprises the coding sequence for the alternative splice form of Lamin A coupled to (e.g. operably linked to) a weak constitutive promoter in the following order / orientation: 5’-weak constitutive promoter-coding sequence-3’. In another embodiment, the expression cassette comprises the coding sequence for the alternative splice form of Lamin A coupled to (e.g. operably linked to) a strong constitutive promoter in the following order / orientation: 5’-strong constitutive promoter-coding sequence-3’. According to this embodiment, an endogenous transcription repressor sequence is located upstream of the genomic location where the expression cassette is inserted. In a yet other embodiment, the expression cassette comprises the coding sequence for the alternative splice form of Lamin A coupled to (e.g. operably linked to) a transcriptional repressor sequence and a strong constitutive promoter in the following order / orientation: CLO-C-P3598PCT 5’-strong constitutive promoter-repressor sequence-coding sequence-3’. In an alternative embodiment, the expression cassette comprises the coding sequence for the alternative splice form of Lamin A coupled to (e.g. operably linked to) a transcriptional repressor sequence and a constitutive promoter in the following order / orientation: 5’-repressor sequence-strong constitutive promoter-coding sequence-3’. In some embodiments, the constitutive expression of the Lamin A alternative splice form (e.g. progerin) in the cell is because the cell does not comprise a repressor protein which recognises and / or binds the transcription repressor sequence. In one embodiment, the repressor protein absent in the cell is the corresponding repressor protein for the repressor sequence. Thus, in a further embodiment the cell does not comprise said repressor protein and / or a sequence encoding it. In yet further embodiments, the constitutive expression of the Lamin A alternative splice form (e.g. progerin) in the cell is because the cell does not comprise a sequence encoding for the cumate repressor protein (CymR). Thus, in one embodiment the cell does not comprise a sequence coding for a cumate repressor protein (CymR). In a further embodiment, the cell does not comprise the cumate repressor protein (CymR). The absence of CymR in the cell allows expression from the expression cassette encoding the Lamin A alternative splice form and the constitutive promoter. While the expression cassette comprises a cumate operator (CuO) operably linked to the Lamin A alternative splice form coding sequence, the absence of CymR allows expression. Thus, in a yet further embodiment the presence of the expression cassette and absence of a CymR coding sequence yields constitutive expression of the alternative splice form of Lamin A in the cell. The cumate switch was discovered in Pseudomonas putida and was developed as a method of inducible gene expression where transcription is reversibly mediated in the presence of the cumate, by virtue of binding of the CymR to CuO sequences in the absence of cumate. The system comprising both CuO sequences and CymR is available in both activator and repressor configurations, where the presence of cumate leads to the repression of transcription or activation of transcription, respectively. The repressor configuration is the naturally occurring configuration and regulation is mediated by the binding of the repressor (CymR) to the operator site (CuO), placed downstream of a constitutive promoter and upstream of an operably linked coding sequence. Addition of cumate, a small molecule, releases CymR from CuO sequences and relieves the repression, allowing transcription to proceed. In the activator configuration, an engineered chimeric transactivator (cTA) protein, formed by the fusion of CymR with the activation domain of VP16, is able to activate transcription when bound to the CuO operator site, placed upstream of the constitutive promoter. Cumate addition to the activator system abrogates DNA binding and therefore transactivation by cTA, stopping transcription. CLO-C-P3598PCT According to the present invention, while CymR (or any CymR coding sequences) is not present in the cell, the CuO sequences are comprised in the expression cassette according to the repressor configuration, i.e. downstream of a constitutive promoter and upstream of the operably linked coding sequence for the Lamin A alternative splice form. However, in the absence of CymR, no repression of expression occurs. Thus, in one embodiment the expression cassette comprises the coding sequence for the alternative splice form of Lamin A operably linked to a CuO sequence and a promoter as described herein in the following order / orientation: 5’-promoter-CuO-coding sequence-3’. In another embodiment, the expression cassette comprises the coding sequence for the alternative splice form of Lamin A operably linked to a CuO sequence and a promoter as described herein in the following order / orientation: 5’-CuO-promoter-coding sequence-3’. In one embodiment, the expression cassette comprises the sequence of SEQ ID NO: 12. CGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCA TTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACG TCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATA TGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGC CCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCG CTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGAC TCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCA AAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCG GTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTATGACCATTCGGGGTCTCTC CCTGCTAGCATCAGGGTTATTGTATCATGAGCGGATACATATGTCAATGTACCGGAACA AACAGACAATCTGGTCTGTTTGTACATGGTTGACGGATCGCCGCGAAGCCGCTAACTG CGCCGGTTAACAAACAGACAATCTGGTCTGTTTGTAACTAGTAGAGGAAGCTTCCGCGC CACCATGGTGAGCAAGGGCGCCGAGCTGTTCACCGGCATCGTGCCCATCCTGATCGA GCTGAATGGCGATGTGAATGGCCACAAGTTCAGCGTGAGCGGCGAGGGCGAGGGCGA TGCCACCTACGGCAAGCTGACCCTGAAGTTCATCTGCACCACCGGCAAGCTGCCTGTG CCCTGGCCCACCCTGGTGACCACCCTGAGCTACGGCGTGCAGTGCTTCTCACGCTACC CCGATCACATGAAGCAGCACGACTTCTTCAAGAGCGCCATGCCTGAGGGCTACATCCA GGAGCGCACCATCTTCTTCGAGGATGACGGCAACTACAAGTCGCGCGCCGAGGTGAA GTTCGAGGGCGATACCCTGGTGAATCGCATCGAGCTGACCGGCACCGATTTCAAGGAG GATGGCAACATCCTGGGCAATAAGATGGAGTACAACTACAACGCCCACAATGTGTACAT CLO-C-P3598PCT CATGACCGACAAGGCCAAGAATGGCATCAAGGTGAACTTCAAGATCCGCCACAACATC GAGGATGGCAGCGTGCAGCTGGCCGACCACTACCAGCAGAATACCCCCATCGGCGAT GGCCCTGTGCTGCTGCCCGATAACCACTACCTGTCCACCCAGAGCGCCCTGTCCAAGG ACCCCAACGAGAAGCGCGATCACATGATCTACTTCGGCTTCGTGACCGCCGCCGCCAT CACCCACGGCATGGATGAGCTGTACAAGN(n)ATGGAGACCCCGTCCCAGCGGCGCGCC ACCCGCAGCGGGGCGCAGGCCAGCTCCACTCCGCTGTCGCCCACCCGCATCACCCG GCTGCAGGAGAAGGAGGACCTGCAGGAGCTCAATGATCGCTTGGCGGTCTACATCGA CCGTGTGCGCTCGCTGGAAACGGAGAACGCAGGGCTGCGCCTTCGCATCACCGAGTC TGAAGAGGTGGTCAGCCGCGAGGTGTCCGGCATCAAGGCCGCCTACGAGGCCGAGCT CGGGGATGCCCGCAAGACCCTTGACTCAGTAGCCAAGGAGCGCGCCCGCCTGCAGCT GGAGCTGAGCAAAGTGCGTGAGGAGTTTAAGGAGCTGAAAGCGCGCAATACCAAGAA GGAGGGTGACCTGATAGCTGCTCAGGCTCGGCTGAAGGACCTGGAGGCTCTGCTGAA CTCCAAGGAGGCCGCACTGAGCACTGCTCTCAGTGAGAAGCGCACGCTGGAGGGCGA GCTGCATGATCTGCGGGGCCAGGTGGCCAAGCTTGAGGCAGCCCTAGGTGAGGCCAA GAAGCAACTTCAGGATGAGATGCTGCGGCGGGTGGATGCTGAGAACAGGCTGCAGAC CATGAAGGAGGAACTGGACTTCCAGAAGAACATCTACAGTGAGGAGCTGCGTGAGACC AAGCGCCGTCATGAGACCCGACTGGTGGAGATTGACAATGGGAAGCAGCGTGAGTTTG AGAGCCGGCTGGCGGATGCGCTGCAGGAACTGCGGGCCCAGCATGAGGACCAGGTG GAGCAGTATAAGAAGGAGCTGGAGAAGACTTATTCTGCCAAGCTGGACAATGCCAGGC AGTCTGCTGAGAGGAACAGCAACCTGGTGGGGGCTGCCCACGAGGAGCTGCAGCAGT CGCGCATCCGCATCGACAGCCTCTCTGCCCAGCTCAGCCAGCTCCAGAAGCAGCTGG CAGCCAAGGAGGCGAAGCTTCGAGACCTGGAGGACTCACTGGCCCGTGAGCGGGACA CCAGCCGGCGGCTGCTGGCGGAAAAGGAGCGGGAGATGGCCGAGATGCGGGCAAGG ATGCAGCAGCAGCTGGACGAGTACCAGGAGCTTCTGGACATCAAGCTGGCCCTGGAC ATGGAGATCCACGCCTACCGCAAGCTCTTGGAGGGCGAGGAGGAGAGGCTACGCCTG TCCCCCAGCCCTACCTCGCAGCGCAGCCGTGGCCGTGCTTCCTCTCACTCATCCCAGA CACAGGGTGGGGGCAGCGTCACCAAAAAGCGCAAACTGGAGTCCACTGAGAGCCGCA GCAGCTTCTCACAGCACGCACGCACTAGCGGGCGCGTGGCCGTGGAGGAGGTGGATG AGGAGGGCAAGTTTGTCCGGCTGCGCAACAAGTCCAATGAGGACCAGTCCATGGGCA ATTGGCAGATCAAGCGCCAGAATGGAGATGATCCCTTGCTGACTTACCGGTTCCCACC AAAGTTCACCCTGAAGGCTGGGCAGGTGGTGACGATCTGGGCTGCAGGAGCTGGGGC CACCCACAGCCCCCCTACCGACCTGGTGTGGAAGGCACAGAACACCTGGGGCTGCGG GAACAGCCTGCGTACGGCTCTCATCAACTCCACTGGGGAAGAAGTGGCCATGCGCAAG CTGGTGCGCTCAGTGACTGTGGTTGAGGACGACGAGGATGAGGATGGAGATGACCTG CTCCATCACCACCATGGCTCCCACTGCAGCAGCTCGGGGGACCCCGCTGAGTACAAC CTGCGCTCGCGCACCGTGCTGTGCGGGACCTGCGGGCAGCCTGCCGACAAGGCATCT CLO-C-P3598PCT GCCAGCGGCTCAGGAGCCCAGAGCCCCCAGAACTGCAGCATCATGTAA (SEQ ID NO: 12), wherein N(n)represents a non-coding sequence of any length of any nucleic acids. In a yet further embodiment, the expression cassette comprises a sequence about 60%, about 70%, about 80%, about 90% or about 100% identical to SEQ ID NO: 12. In still further embodiments, the expression cassette comprises a sequence about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% identical to SEQ ID NO: 12. In another embodiment, the expression cassette consists of SEQ ID NO: 12. In a still further embodiment, the expression cassette further and / or additionally comprises a poly A sequence, such as an SV40 poly A sequence. Further additional sequences may also be inserted between the coding and poly A sequences, such as restriction enzyme sites used in the construction of the cassette or any other non-coding spacer sequence of any length of any nucleic acids (and may thus be represented as N(n)). In particular, the expression cassette may comprise the poly A sequence (e.g. the SV40 poly A sequence) 3’ of the coding sequence, such that orientation of the expression cassette is as follows: 5’-weak constitutive promoter-coding sequence-poly A-3’. 5’-strong constitutive promoter-coding sequence-ploy A-3’. 5’-strong constitutive promoter-repressor sequence-coding sequence-poly A-3’. 5’-repressor sequence-strong constitutive promoter-coding sequence-poly A-3’. In one embodiment, the poly A sequence is the SV40 poly A sequence comprising the sequence of SEQ ID NO: 13. AACTTGTTTATTGCAGCTTATAATGGTTACAAATAAAGCAATAGCATCACAAATTTCACAA ATAAAGCATTTTTTTCACTGC (SEQ ID NO: 13). In one embodiment, a CuO repressor sequence is derived from the p-cmt and / or p-cym operons in Pseudomonas putida. In a further embodiment, the CuO sequence is a variant and / or a functional fragment of the p-cmt and / or p-cym operons. Such functional fragments include any variants or portions of the operons that may still be bound by CymR and thus function as CuO sequences. In particular, functional fragments and variants still provide the level of expression of the Lamin A alternative splice form from the expression cassette described herein in the absence of CymR compared to the full p-cmt and / or p-cym operons. In a further embodiment, the CuO sequence comprises the sequence of SEQ ID NO: 14. CLO-C-P3598PCT ATGACCATTCGGGGTCTCTCCCTGCTAGCATCAGGGTTATTGTATCATGAGCGGATACA TATGTCAATGTACCGGAACAAACAGACAATCTGGTCTGTTTGTACATGGTTGACGGATC GCCGCGAAGCCGCTAACTGCGCCGGTTAACAAACAGACAATCTGGTCTGTTTGTAACT AGTAGAGGAAGCTTCCGC (SEQ ID NO: 14) In a yet further embodiment, the CuO sequence variant or functional fragment comprises a sequence about 60%, about 70%, about 80%, about 90% or about 100% identical to SEQ ID NO: 14. In still further embodiments, the variant or functional fragment comprises a sequence about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% identical to SEQ ID NO: 14. In another embodiment, the CuO sequence consists of SEQ ID NO: 14. Induced pluripotent stem cells (iPSCs) are cells that have been reprogrammed to an embryonic stem cell-like state by being forced to express genes and factors important for maintaining the defining properties of embryonic stem cells. In 2006, it was shown that overexpression of four specific transcription factors could convert adult cells into pluripotent stem cells. Oct-3 / 4 and certain members of the Sox gene family have been identified as potentially crucial transcriptional regulators involved in the induction process. Additional genes including certain members of the Klf family, the Myc family, Nanog, and Lin28, may increase the induction efficiency. Examples of the genes which may be used as reprogramming factors to generate iPSCs include Oct3 / 4, Sox2, Sox1, Sox3, Sox15, Sox17, Klf4, Klf2, c-Myc, N-Myc, L-Myc, Nanog, Lin28, Fbx15, ERas, ECAT15-2, Tcl1, beta-catenin, Lin28b, Sall4, Esrrb, Tbx3 and Glis1, GATA3, GATA6 and these reprogramming factors may be used singly, or in combination of two or more kinds thereof. In particular, the reprogramming factors may comprise at least the Yamanaka factors, i.e. Oct3 / 4, Sox2, Klf4 and c-Myc. Thus, according to the disclosures herein any stem cell may be used in the methods described herein or may comprise the expression cassette as described herein, such as a pluripotent stem cell, an induced pluripotent stem cell (iPSC), a germline stem cell, a multipotent stem cell, an oligopotent stem cell, a unipotent stem cell or a tissue-specific / tissue- resident stem cell. Thus, it will be appreciated that cells suitable for the disclosures herein may include any type of stem cell. For example, the stem cells may be pluripotent stem cells, for example iPSCs, embryonic stem cells or pluripotent stem cells derived by nuclear transfer or cell fusion. It may be preferred that the embryonic stem cell is derived without destruction of the embryo, particularly where the cells are human. In some embodiments, the stem cells are not derived from human or animal embryos, i.e. the invention does not extend to any methods or uses which involve the destruction of human or animal embryos. The stem cells may also include multipotent stem cells, oligopotent stem cells or unipotent stem cells. The CLO-C-P3598PCT stem cells may also include foetal stem cells or adult stem cells, such as hematopoietic stem cells, mesenchymal stem cells, neural stem cells, epithelial stem cells or skin stem cells. In certain aspects, the stem cells may be isolated from umbilical, placenta, amniotic fluid, chorion villi, blastocysts, bone marrow, adipose tissue, brain, peripheral blood, cord blood, menstrual blood, blood vessels, skeletal muscle, skin and liver. In a particular embodiment, the cell is an iPSC. In an alternative embodiment, the cell is a somatic cell derived from a reprogrammed iPSC or a stem cell. Such derivation of the somatic cell may be by forward programming or directed differentiation of the iPSC / stem cell using methods known in the art and as described herein. In one embodiment, the somatic cell is a neuron (e.g. motor neuron, sensory neuron, GABAergic neuron, glutamatergic neuron or dopaminergic neuron), glia cell, blood cell (e.g. erythrocyte), immune cell (e.g. T cell, B cell, Macrophage, NK cell, neutrophil or granulocyte), liver cell (e.g. hepatocyte, Kupffer cell or stromal cell), muscle cell (e.g. smooth muscle cell), myocyte (e.g. cardiomyocyte), fibroblast, skin cell (e.g. keratinocyte), bone cell, cartilage cell, epithelial cell, endothelial cell or adipocyte. In a further embodiment the cell, is a neuron derived from an iPSC or a stem cell by forward programming or directed differentiation. The term “somatic cell” as used herein includes any type (i.e. lineage) of cell that makes up the body of an organism, excluding germ cells and undifferentiated stem cells. Somatic cells may therefore include, for example and without limitation, neurons, glia cells, blood cells (e.g. leucocytes), liver cells (e.g. hepatocytes), muscle cells (e.g. myocytes) or fibroblasts. The somatic cell may be an adult cell or a cell derived from an adult which displays one or more detectable characteristics of an adult or non-embryonic cell. References herein to a somatic cell “derived from an iPSC or a stem cell by forward programming or directed differentiation” refer to cells which comprise the phenotype and / or characteristics of a somatic cell as defined herein (e.g. the surface phenotype and / or functional characteristics associated with a particular lineage) and have been forward programmed or differentiated from a pluripotent stem cell which has previously been reprogrammed as described herein, i.e. an iPSC. Forward programming of an iPSC or a stem cell to a somatic cell comprises the introduction of lineage-specific factors, such as transcription factors, or nucleic acids which encode said lineage-specific factors, for example in the form of mRNA or expression cassettes. Alternatively, forward programming may comprise increasing the expression of lineage- specific factors (e.g. lineage-specific transcription factors), such as by increasing the expression of said lineage-specific factor genes and / or their protein expression. The expression of an exogenous or endogenous (in particular an exogenous) transcription factor may be increased. In one embodiment, forward programming comprises introducing into the CLO-C-P3598PCT iPSC / stem cell a nucleic acid or protein preparation which encodes or provides a lineage- specific transcription factor or combinations thereof, and culturing the cell under conditions suitable for reprogramming the cell into a somatic cell. Directed differentiation comprises culturing the iPSC / stem cell in conditions to direct differentiation towards a particular somatic cell fate, such as by using exogenous factors to mimic developmental signals which would be encountered by the cell during physiological development. Directed differentiation factors may include signalling molecules and / or extracellular structures, scaffolds and / or matrices which promote cell adhesion and tissue-like structures. Such factors may be altered over time (e.g. in their type or structure, or in their dose / amount) to mimic the changing environment seen by the cell during development. In one embodiment, the iPSC, stem cell or somatic cell is from a mammal. In a further embodiment, the mammal is a human. Thus, in a particular embodiment the iPSC, stem cell or somatic cell is from a human and is a human iPSC, stem cell or a human somatic cell, such as a somatic cell forward programmed or differentiated from a re-programmed human iPSC or stem cell. In an alternative embodiment, the mammal is a mouse, optionally such that the iPSC, stem cell or somatic cell is a mouse iPSC, stem cell or a mouse somatic cell, such as a somatic cell forward programmed or differentiated from a re-programmed mouse iPSC / stem cell. It will be understood that increasing the expression of lineage-specific factors, such as transcription factors, in the iPSCs or stem cells to be forward programmed or differentiated into somatic cells may include any method known in the art, for example, by induction of expression of one or more expression cassettes previously introduced into the cells, or by introduction of nucleic acids (such as DNA or RNA), polypeptides or small molecules to the cells. Increasing the expression of certain endogenous but transcriptionally repressed genes may also reverse the silencing or inhibitory effect on the expression of these genes by regulating the upstream transcription factor expression or epigenetic modulation. Therefore, methods of the invention may involve culturing the cell population under conditions to artificially increase the expression level of one or more lineage-specific transcription factors. In particular embodiments, the lineage-specific transcription factors are provided by an expression cassette. Thus, in certain embodiments the cell comprises a further expression cassette comprising one or more coding sequences for one or more lineage-specific transcription factors operably linked to an inducible promoter. According to these embodiments, the cell comprising this further expression cassette may be forward programmed by inducing expression of the one or more lineage-specific transcription factors. CLO-C-P3598PCT Suitable inducible promoters are known in the art and include, without limitation the Tet system. However, as will be readily appreciated by the presence of a CuO sequence in the expression cassette encoding the Lamin A alternative splice form, any further expression cassette (including comprising lineage-specific transcription factor coding sequences) will not use a cumate inducible promoter. Thus, in certain embodiments the inducible promoter comprised in the further expression cassette is different to that in the expression cassette encoding the Lamin A alternative splice form. This inducible promoter imparts the ability to control expression of the one or more lineage-specific transcription factors. In particular, the “inducible promoter” herein comprises an operator sequence for the transcriptional regulator protein (e.g. a tetracycline operator (TetO) sequence) and a constitutive promoter. In this system, the activity of the constitutive promoter is supressed until transcription is allowed / activated from the operator sequence. Controlled Expression In one embodiment, expression of the lineage-specific transcription factors is under controlled transcription. In this aspect of the invention, the transcription and translation (expression) of the transcription factors may be controlled within the cell. This permits overexpression of the transcription factors, if required. The further exogenous expression cassette carrying the lineage-specific transcription factors may comprise an externally inducible transcriptional regulatory element (i.e. an inducible promoter) for inducible expression of the transcription factors. Said inducible expression cassette may be controlled by addition of an exogenous substance. Whatever culturing conditions are used, the exogenous substance will control expression of the genetic sequence within the inducible expression cassette; and may either be supplied continuously and then withdrawn in order to induce transcription or supplied as transcription is required, dependent upon its mode of action. Thus, in some embodiments the inducible promoter is regulated by a transcriptional regulator protein and said transcriptional regulator protein is controlled by an exogenously supplied substance. In a further embodiment, upon exposure of the cell to the exogenously supplied substance (e.g. tetracycline or a derivate thereof), the one or more lineage-specific transcription factors are expressed. A transcriptional regulator protein is a protein that binds to DNA, preferably sequence- specifically to a DNA site located in or near a promoter, and either facilitating the binding of the transcription machinery to the promoter, and thus transcription of the DNA sequence (a transcriptional activator) or blocks this process (a transcriptional repressor). CLO-C-P3598PCT The DNA sequence that a transcriptional regulator protein binds to is called a transcription factor-binding site or response element, and these are found in or near the promoter of the regulated DNA sequence. Transcriptional activator proteins bind to the response element and promote gene expression. Such activator proteins are preferred in the methods of the present invention for controlling inducible cassette expression. Transcriptional repressor proteins bind to the response element and prevent gene expression. Transcriptional regulator proteins may be activated or deactivated by a number of mechanisms including binding of a substance, interaction with other transcription factors (e.g. homo- or hetero-dimerisation) or coregulatory proteins, phosphorylation, and / or methylation. The transcriptional regulator protein may be controlled by activation or deactivation. If the transcriptional regulator protein is a transcriptional activator protein, it is preferred that the transcriptional activator protein requires activation. This activation may be through any suitable means, but it is preferred that the transcriptional regulator protein is activated through the addition of an exogenous substance to the cell. The supply of an exogenous substance to the cell can be controlled, and thus the activation of the transcriptional regulator protein can be controlled. Alternatively, an exogenous substance can be supplied in order to deactivate a transcriptional regulator protein, and then supply withdrawn in order to activate the transcriptional regulator protein. If the transcriptional regulator protein is a transcriptional repressor protein, it is preferred that the transcriptional repressor protein requires deactivation. Thus, a substance is supplied to prevent the transcriptional repressor protein repressing transcription, and thus transcription is permitted. Any suitable transcriptional regulator protein may be used, preferably one that may be activated or deactivated. It is preferred that an exogenous substance may be supplied to control the transcriptional regulator protein. Such transcriptional regulator proteins are also called inducible transcriptional regulator proteins. Tetracycline-Controlled Transcriptional Activation is a method of inducible gene expression where transcription is reversibly turned on or off in the presence of the antibiotic tetracycline or one of its derivatives (e.g. doxycycline which is more stable). In this system, the transcriptional activator protein is tetracycline-responsive transcriptional activator protein (rtTa) or a derivative thereof. The rtTA protein is able to bind to DNA at specific TetO operator CLO-C-P3598PCT sequences. Several repeats of such TetO sequences are placed upstream of a minimal constitutive promoter (such as the CMV promoter), which together form a tetracycline response element (TRE). There are two forms of this system, depending on whether the addition of tetracycline or a derivative activates (Tet-On) or deactivates (Tet-Off) the rtTA protein. In a Tet-Off system, tetracycline or a derivative thereof binds rtTA and deactivates the rtTA, rendering it incapable of binding to TRE sequences, thereby preventing transcription of TRE- controlled genes. This system was first described in Gossen et al. (1992). The Tet-On system is composed of two components; (1) the constitutively expressed tetracycline-responsive transcriptional activator protein (rtTa) and the rtTa-sensitive inducible promoter (Tet Responsive Element, TRE). This may be bound by tetracycline or its more stable derivatives, including doxycycline (dox), resulting in activation of rtTa, allowing it to bind to TRE sequences and inducing expression of TRE-controlled genes. The use of this may be preferred in the method of the invention. Thus, the transcriptional regulator protein may be a tetracycline-responsive transcriptional activator (rtTa) protein, which can be activated or deactivated by tetracycline or one of its derivatives, which are supplied exogenously. If the transcriptional regulator protein is rtTA, then the expression cassette comprising an inducible promoter includes a tetracycline operator (TetO) sequence and a constitutive promoter, such as to make up a tetracycline response element (TRE). The exogenously supplied substance is tetracycline or one of its derivatives. Variants and modified rtTa proteins may also be used in the methods of the invention, these include Tet-On Advanced transactivator (also known as rtTA2S-M2) and Tet- On 3G (also known as rtTA-V16, derived from rtTA2S-S2). Thus, in one embodiment the transcriptional regulator protein is an rtTa and the exogenously supplied substance is tetracycline or a derivative thereof, such as doxycycline. The tetracycline response element (TRE) generally consists of 7 repeats of the 19bp bacterial TetO sequence separated by spacer sequences, together with a minimal promoter. Variants and modifications of the TRE sequence are possible, since the minimal promoter can be any suitable promoter. Preferably the minimal promoter shows no or minimal expression levels in the absence of rtTa binding, but upon rtTa binding provides constitutive expression. The inducible promoter may thus comprise a TRE. In a further embodiment, upon exposure of the cell to the exogenously supplied substance expression from the expression cassette comprising the inducible promoter occurs. In a particular embodiment, upon exposure of the CLO-C-P3598PCT cell to the exogenously supplied substance (e.g. tetracycline or a derivate thereof), the one or more lineage-specific transcription factors are expressed. A modified system based upon tetracycline control is the T-REX System (Thermo-Fisher Scientific), in which the transcriptional regulator protein is a transcriptional repressor protein, TetR. The components of this system include an inducible promoter comprising a strong human cytomegalovirus immediate-early (CMV) promoter and two tetracycline operator 2 (TetO2) sites, and a Tet repressor (TetR). In the absence of tetracycline, the Tet repressor forms a homodimer that binds with extremely high affinity to each TetO2 sequence in the inducible promoter, and prevents transcription from the promoter. Once added, tetracycline binds with high affinity to each Tet repressor homodimer rendering it unable to bind to the Tet operator. The Tet repressor:tetracycline complex then dissociates from the Tet operator and allows induction of expression. In this instance, the transcriptional regulator protein is TetR and the inducible promoter comprises two TetO2 sites. The exogenously supplied substance is tetracycline or a derivative thereof (e.g. doxycycline). The cumate switch is another method of inducible gene expression where transcription is reversibly turned on or off in the presence of the cumate. This system is available in both activator and repressor configurations, where the presence of cumate leads to the repression of transcription or activation of transcription, respectively. In the repressor configuration, regulation is mediated by the binding of the repressor (CymR) to the operator site (CuO), placed downstream of a constitutive promoter. Addition of cumate, a small molecule, relieves the repression and allows transcription to proceed. In the activator configuration, a chimeric transactivator (cTA) protein, formed by the fusion of CymR with the activation domain of VP16, is able to activate transcription when bound to the CuO operator site, placed upstream of the constitutive promoter. Cumate addition abrogates DNA binding and therefore transactivation by cTA, stopping transcription. However, as will be readily appreciated a cumate switch is not used for controlling the expression of the one or more lineage-specific transcription factors in the present invention because the expression of the Lamin A alternative splice form is already under the control of CuO sequences (but not the activity / DNA-binding status of CymR). Thus, in some embodiments the transcriptional regulator protein may be a Tet-responsive transcriptional activator protein (rtTA). In one embodiment, expression of the lineage-specific transcription factors is under the control of a Tet-responsive element. Thus in a further embodiment, the expression cassette comprising the coding sequence for the one or more lineage-specific transcription factors comprises a Tet-response element (TRE). In a yet further embodiment, expression of the sequences encoding the lineage-specific transcription factors CLO-C-P3598PCT is controlled, such as induced, by exogenous addition of tetracycline or a derivative thereof (e.g. doxycycline). In one embodiment, the Tet-response element (TRE) comprises the sequence of SEQ ID NO: 15. GAGTTTACTCCCTATCAGTGATAGAGAACGTATGAAGAGTTTACTCCCTATCAGTGATA GAGAACGTATGCAGACTTTACTCCCTATCAGTGATAGAGAACGTATAAGGAGTTTACTC CCTATCAGTGATAGAGAACGTATGACCAGTTTACTCCCTATCAGTGATAGAGAACGTAT CTACAGTTTACTCCCTATCAGTGATAGAGAACGTATATCCAGTTTACTCCCTATCAGTGA TAGAGAACGTATGTCGAGGTAGGCGTGTACGGTGGGCGCCTATAAAAGCAGAGCTCGT TTAGTGAACCGTCAGATCGCCTGGAGCAATTCCACAACACTTTTGTCTTATACTT (SEQ ID NO: 15). In another embodiment, the TRE consists of a sequence of SEQ ID NO: 15. In an alternative embodiment, the TRE comprises a sequence with about 60%, about 70%, about 80%, about 90% or about 100% identity to SEQ ID NO: 15. Other inducible expression systems are known and can be used in the present invention. These include the Complete Control Inducible system from Agilent Technologies. This is based upon the insect hormone ecdysone or its analogue ponasterone A (ponA) which can activate transcription in mammalian cells which are transfected with both the gene for the Drosophila melanogaster ecdysone receptor (EcR) and an inducible promoter comprising a binding site for the ecdysone receptor. The EcR is a member of the retinoid-X-receptor (RXR) family of nuclear receptors. In humans, EcR forms a heterodimer with RXR that binds to the ecdysone-responsive element (EcRE). In the absence of PonA, transcription is repressed by the heterodimer. Other examples of repressor protein-comprising transcriptional regulator systems are also known and can include those using an ecdysone receptor or a derivative thereof. Particular examples include the VgEcR synthetic receptor from Agilent technologies which is a fusion of EcR, the DNA binding domain of the glucocorticoid receptor and the transcriptional activation domain of Herpes Simplex Virus VP16. The inducible promoter comprises the EcRE sequence or modified versions thereof together with a minimal promoter. Modified versions include the E / GRE recognition sequence of Agilent Technologies, in which mutations to the sequence have been made. The E / GRE recognition sequence comprises inverted half-site recognition elements for the retinoid-X-receptor (RXR) and GR binding domains. In all permutations, the exogenously supplied substance is ponasterone A, which CLO-C-P3598PCT removes the repressive effect of EcR or derivatives thereof on the inducible promoter, and allows transcription to take place. Expression of the one or more lineage-specific transcription factors described herein may be increased using the dual cassette expression system described in WO 2018 / 096343, which is hereby specifically incorporated herein by reference in its entirety. This system targets genetic safe harbour (GSH) sites which provides a reduced risk of epigenetic silencing of the inserted genetic material. Therefore, in one embodiment an expression cassette comprising one or more sequences coding for lineage-specific transcription factors as described herein are introduced into the iPSC, stem cell or somatic cell using a method comprising: - targeted insertion of a gene encoding a transcriptional regulator protein into a genetic safe harbour (GSH) site of the cell; and - targeted insertion of an inducible cassette into a further GSH of the cell, wherein said inducible cassette comprises said transcription factor sequences operably linked to an inducible promoter, and said promoter is regulated by the transcriptional regulator protein. These embodiments of the invention provide a dual expression cassette system. The insertion of the gene encoding a transcriptional regulator protein into one GSH provides the control mechanism for the expression of the inducible cassette which is operably linked to the inducible promoter and inserted into a further GSH site. In one embodiment, the GSH are different. In a further embodiment, the lineage-specific transcription factor encoding expression cassette is inserted into the same GSH as the expression cassette encoding the Lamin A alternative splice form, with the transcriptional regulator protein encoding sequence inserted into a further GSH. According to this embodiment, the Lamin A alternative splice form and lineage-specific transcription factor encoding expression cassettes may be inserted into a first GSH, and the transcriptional regulator protein is inserted into a second GSH. In an alternative embodiment, the lineage-specific transcription factor encoding expression cassette is inserted into a different GSH as the expression cassette encoding the Lamin A alternative splice form, with the transcriptional regulator protein encoding sequence inserted into a yet further GSH. According to this embodiment, the Lamin A alternative splice form encoding expression cassette may be inserted into a first GSH, the lineage-specific transcription factor encoding expression cassette inserted into a second GSH, and the transcriptional regulator protein is inserted into a third GSH. The use of the terms “first”, “second”, “third” and the like herein are merely for ease of distinction and are intended solely to distinguish one potential GSH site or expression cassette from another, wherein a “first” GSH differs from a “second” CLO-C-P3598PCT GSH and a “first” expression cassette differs from a “second” expression cassette, and so on. The use of these numerical terms is not intended to be limiting or an indication as to the order of insertion, expression or use. A GSH site is a locus within the genome wherein a gene or other genetic material may be inserted without any deleterious effects on the cell or on the inserted genetic material. Most beneficial is a GSH site in which expression of the inserted gene sequence is not perturbed by any read-through expression from neighbouring genes and expression of the inducible cassette minimises interference with the endogenous transcription programme. More formal criteria have been proposed that assist in the determination of whether a particular locus is a GSH site in future (Papapetrou et al. (2011)). These criteria include a site that is: (i) 50 kb or more from the 5’ end of any gene; (ii) 300 kb or more from any gene related to cancer; (iii) 300 kb or more from any microRNA (miRNA); (iv) located outside a transcription unit; and (v) located outside ultraconserved regions (UCR). It may not be necessary to satisfy all of these proposed criteria, since GSH already identified do not fulfil all of the criteria. It is thought that a suitable GSH will satisfy at least 2, 3, 4 or all of these criteria. Any suitable GSH site may be used in the present invention, on the basis that the site allows insertion of genetic material without deleterious effects to the cell and permits transcription of the inserted genetic material. Those skilled in the art may use these simplified criteria to identify a suitable GSH, and / or the more formal criteria set out above. In one embodiment, the genetic safe harbour sites (GSHs) are selected from (in particular any two) of the hROSA26 locus, the AAVS1 locus, the DBI locus, the CLYBL gene, the CCR5 gene or the HPRT gene. In particular, the GSHs may be the hROSA26 locus, the AAVS1 locus and the DBI locus. Insertions specifically within genetic safe harbour sites is preferred over random genome integration, since this is expected to be a safer modification of the genome, and is less likely to lead to unwanted side effects such as silencing natural gene expression or causing mutations that lead to cancerous cell types. In another embodiment, the single genetic safe harbour site is selected from any GSH described herein. The adeno-associated virus integration site 1 locus (AAVS1) is located within the protein phosphatase 1, regulatory subunit 12C (PPP1R12C) gene on human chromosome 19, which is expressed uniformly and ubiquitously in human tissues. AAVS1 has been shown to be a favourable environment for transcription, since it comprises an open chromatin structure and native chromosomal insulators that enable resistance of the inducible cassettes against silencing. There are no known adverse effects on the cell resulting from disruption of the CLO-C-P3598PCT PPP1R12C gene. Moreover, an inducible cassette inserted into this site remains transcriptionally active in many diverse cell types. The hROSA26 site has been identified on the basis of sequence analogy with a GSH from mice (ROSA26 – reverse oriented splice acceptor site #26). The hROSA26 locus is on chromosome 3 (3p25.3) and can be found within the Ensembl database (GenBank: CR624523). The integration site lies within the open reading frame (ORF) of the THUMPD3 long non-coding RNA (reverse strand). Since the hROSA26 site has an endogenous promoter, the inserted genetic material may take advantage of that endogenous promoter, or alternatively may be inserted operably linked to a promoter. Intron 2 of the Citrate Lyase Beta-like (CLYBL) gene, on the long arm of Chromosome 13, was identified as a suitable GSH since it is one of the identified integration hot-spots of the phage derived phiC31 integrase. Studies have demonstrated that randomly inserted inducible cassettes into this locus are stable and expressed. It has been shown that insertion of inducible cassettes at this GSH do not perturb local gene expression (Cerbini et al. (2015)). CLYBL thus provides a GSH which may be suitable for use in the present invention. CCR5, which is located on chromosome 3 (position 3p21.31) is a gene which codes for HIV-1 major co-receptor. Interest in the use of this site as a GSH arises from the null mutation in this gene that appears to have no adverse effects, but predisposes to HIV-1 infection resistance. Zinc-finger nucleases that target the third exon have been developed, thus allowing for insertion of genetic material at this locus. The hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene encodes a transferase enzyme that plays a central role in the generation of purine nucleotides through the purine salvage pathway. GSH in other organisms have been identified and include ROSA26, HRPT and Hipp11 (H11) loci in mice. Mammalian genomes may include GSH sites based upon pseudo attP sites. For such sites, hiC31 integrase, the Streptomyces phage-derived recombinase, has been developed as a non-viral insertion tool, because it has the ability to integrate an inducible cassette-containing plasmid carrying an attB site into pseudo attP sites. Technically, the insertions into the first and / or second GSH may occur on one chromosome, or on both chromosomes. The GSH exists at the same genetic loci on both chromosomes of diploid organisms. Insertion within both chromosomes is advantageous since it may enable CLO-C-P3598PCT an increase in the level of transcription from the inserted genetic material within the inducible cassette, thus achieving particularly high levels of transcription. Specific insertion of genetic material into the particular GSH based upon customised site- specific generation of DNA double-strand breaks at the GSH may be achieved. The genetic material may then be introduced using any suitable mechanism, such as homologous recombination. Any method of making a specific DSB in the genome may be used, but preferred systems include CRISPR / Cas9 and modified versions thereof, zinc finger nucleases and the TALEN system. One or more genetic sequences may be controllably transcribed from within the second and / or further GSH or from within the single GSH. Indeed, the inducible cassette may contain 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 genetic sequences which it is desired to insert into the GSH and the transcription of which be controllably induced. Therefore, the several (e.g. two) lineage- specific transcription factors may be included within the same cassette introduced into the second / further genetic safe harbour site. For example, the several lineage-specific transcription factors may be included in several mono-cistronic constructs or one or more bi- cistronic or tri-cistronic construct as required. It will be understood that similar combinations of constructs may be used to achieve higher orders of expression. In one embodiment, the lineage-specific transcription factors and the one or more ageing-inducing factor are included in one bi-cistronic construct. Site-Specific Delivery & Targeting Any suitable technique for insertion of a nucleic acid sequence (i.e. an expression cassette) into a specific sequence may be used, and several are described in the art. Suitable techniques include any method which introduces a break at the desired location and permits recombination of the vector into the gap. Thus, a crucial first step for targeted site-specific genomic modification is the creation of a double-strand DNA break (DSB) at the genomic locus to be modified. Distinct cellular repair mechanisms can be exploited to repair the DSB and to introduce the desired sequence, and these are non-homologous end joining repair (NHEJ), which is more prone to error; and homologous recombination repair (HR) mediated by a donor DNA template, that can be used to insert inducible cassettes. Several techniques exist to allow customised site-specific generation of DSB in the genome. Many of these involve the use of customized endonucleases, such as zinc finger nucleases, TALENs or the clustered regularly interspaced short palindromic repeats / CRISPR associated protein (CRISPR / Cas9) system. CLO-C-P3598PCT Zinc finger nucleases are artificial enzymes which are generated by fusion of a zinc-finger DNA-binding domain to the nuclease domain of the restriction enzyme FokI. The latter has a non-specific cleavage domain which must dimerise in order to cleave DNA. This means that two zinc finger nuclease monomers are required to allow dimerisation of the FokI domains and to cleave the DNA. The DNA binding domain may be designed to target any genomic sequence of interest, and is a tandem array of Cys2His2 zinc fingers, each of which recognises three contiguous nucleotides in the target sequence. The two binding sites are separated by 5-7bp to allow optimal dimerization of the FokI domains. The enzyme thus is able to cleave DNA at a specific site, and target specificity is increased by ensuring that two proximal DNA- binding events must occur to achieve a double-strand break. Transcription activator-like effector nucleases, or TALENs, are dimeric transcription factor / nucleases. They are made by fusing a TAL effector DNA-binding domain to a DNA cleavage domain (a nuclease). Transcription activator-like effectors (TALEs) can be engineered to bind practically any desired DNA sequence, so when combined with a nuclease, DNA can be cut at specific locations. TAL effectors are proteins that are secreted by Xanthomonas bacteria, the DNA binding domain of which contains a repeated highly conserved 33–34 amino acid sequence with divergent 12th and 13th amino acids. These two positions are highly variable and show a strong correlation with specific nucleotide recognition. This straightforward relationship between amino acid sequence and DNA recognition has allowed for the engineering of specific DNA-binding domains by selecting a combination of repeat segments containing appropriate residues at the two variable positions. TALENs are thus built from arrays of 33 to 35 amino acid modules, each of which targets a single nucleotide. By selecting the array of the modules, almost any sequence may be targeted. Again, the nuclease used may be FokI or a derivative thereof. Three types of CRISPR mechanisms have been identified, of which type II is the most studied. The CRISPR / Cas9 system (type II) utilises the Cas9 nuclease to make a double-stranded break in DNA at a site determined by a short guide RNA. The CRISPR / Cas system is a prokaryotic immune system that confers resistance to foreign genetic elements. CRISPR are segments of prokaryotic DNA containing short repetitions of base sequences. Each repetition is followed by short segments of “protospacer DNA” from previous exposures to foreign genetic elements. CRISPR spacers recognise and cut the exogenous genetic elements using RNA interference. The CRISPR immune response occurs through two steps: CRISPR-RNA (crRNA) biogenesis and crRNA-guided interference. CrRNA molecules are composed of a variable sequence transcribed from the protospacer DNA and a CRISPR repeat. Each crRNA CLO-C-P3598PCT molecule then hybridizes with a second RNA, known as the trans-activating CRISPR RNA (tracrRNA) and together these two eventually form a complex with the nuclease Cas9. The protospacer DNA encoded section of the crRNA directs Cas9 to cleave complementary target DNA sequences, if they are adjacent to short sequences known as protospacer adjacent motifs (PAMs). This natural system has been engineered and exploited to introduce DSB breaks in specific sites in genomic DNA, amongst many other applications. In particular, the CRISPR type II system from Streptococcus pyogenes may be used. At its simplest, the CRISPR / Cas9 system comprises two components that are delivered to the cell to provide genome editing: the Cas9 nuclease itself and a guide RNA (gRNA). The gRNA is a fusion of a customised, site-specific crRNA (directed to the target sequence) and a standardised tracrRNA. Once a DSB has been made, a donor template with homology to the targeted locus is supplied; the DSB may be repaired by the homology-directed repair (HDR) pathway allowing for precise insertions to be made. Derivatives of this system are also possible. Mutant forms of Cas9 are available, such as Cas9D10A with only nickase activity. This means it cleaves only one DNA strand and does not activate NHEJ. Instead, when provided with a homologous repair template, DNA repairs are conducted via the high-fidelity HDR pathway only. Cas9D10A may be used in paired Cas9 complexes designed to generate adjacent DNA nicks in conjunction with two sgRNAs complementary to the adjacent area on opposite strands of the target site, which may be particularly advantageous. The elements for making the double-strand DNA break may be introduced in one or more vectors, such as plasmids, for expression in the stem or somatic cell described herein. Thus, any method of making specific, targeted double strand breaks in the genome in order to affect the insertion of a gene / inducible cassette and / or expression cassettes described herein may be used in the present invention. It may be preferred that the method for inserting the gene / inducible cassette utilises any one or more of zinc finger nucleases, TALENs and / or CRISPR / Cas9 systems or any derivative thereof. Once the DSB has been made by any appropriate means, the gene / inducible cassette and / or expression cassettes for insertion may be supplied in any suitable fashion as described herein. The cassette and associated genetic material form the donor DNA for repair of the DNA at the CLO-C-P3598PCT DSB and are inserted using standard cellular repair machinery / pathways. How the break is initiated will alter which pathway is used to repair the damage, as noted above. Ageing Factors & Ageing Phenotypes As will be appreciated, the constitutive expression of the ageing-inducing factor, an alternative splice form of Lamin A, in the iPSC, stem cell or somatic cell derived from an iPSC or a stem cell by forward programming or directed differentiation leads to the chronic display of an ageing phenotype by said cell. Thus, in a particular embodiment the cell (i.e. the iPSC, stem cell or somatic cell derived from an iPSC / stem cell by forward programming or directed differentiation) chronically displays an ageing phenotype. The term “chronic” is used herein in its normal meaning and context, namely that that the cell displays or has an ageing phenotype for a prolonged period of time. The ageing phenotype may also be described as persistent or permanent. Such prolonged period of time / persistence is relative to the life-time of the cell and to any active steps which may be taken to change the phenotype of the cell, including its ageing phenotype or lineage identity. It is also relative to the time in culture of said cell, such as the ageing phenotype is chronically displayed for the duration that the cell is in culture. However, as will be readily appreciated since display of the ageing phenotype is caused by constitutive expression of the Lamin A alternative splice form, any alteration in this expression will result in a change in the ageing phenotype displayed. For example, if a CymR is expressed or otherwise provided to the cell, expression of the Lamin A alternative splice form will be reduced and thus so will the ageing phenotype. The terms “age” and “ageing” as used herein refer to the phenotypic changes associated with age which restrict functionality and can be considered to be a consequence of ageing. These ageing phenotypes can be distinct from ageing DNA correlates such as epigenetic changes and double strand breaks for which the causality with ageing has not yet been established and reversal of which may not lead to a reversal of ageing or maintenance of a non-aged phenotype. However, it will be appreciated that these correlates may be measured in the present invention as alternative / further ageing phenotypes. Examples of cellular phenotypes associated with ageing are: mitochondrial dysfunction, senescence, altered intracellular communication, genomic instability, telomere shortening, epigenetic changes, and deregulation of nutrient pathways (Otin et al. (2013) Cell “The Hallmarks of Ageing”). Other ageing phenotypes include: reduced proliferation, changes in cell and / or nuclear morphology, changes in gene expression, and alterations in Lamin-A and / or Lamin-C nuclear protein expression. Thus, “age” and “ageing” may refer to any ageing phenotype herein and in certain embodiments refer to the phenotype of the cell (e.g. the ageing phenotype), such as the CLO-C-P3598PCT phenotype of the cell observed upon constitutive expression of the Lamin A alternative splice form and / or measured as part of a method of identifying a gene or combination of genes involved in the reversal or maintenance of a non-aged phenotype as described herein. In one embodiment, the ageing phenotype may be selected from one or more of: proliferation, senescence, loss of proteostasis, changes in cell and / or nuclear morphology, mitochondrial function, changes in gene expression, altered expression of Lamin-A and / or Lamin-C nuclear protein, in particular upregulation, epigenetic marks associated with ageing, altered DNA or histone methylation, altered methylation entropy, DNA double strand breaks, telomere length, and a transcriptomic and / or epigenetic clock. In a further embodiment, the ageing phenotype is a transcriptomic signature associated with an aged phenotype (e.g. as described in US 63 / 545,973). In a yet further embodiment, the ageing phenotype is reduced proliferation and / or increased senescence. In another embodiment, the changes in nuclear morphology are folding abnormalities, blebbing and / or loss of nuclear circularity. In a further embodiment, the mitochondrial function is reduced oxygen consumption and / or increased mitochondrial reactive oxygen species (ROS). In a yet further embodiment, the changes in gene expression are selected from one or more of: differential expression of somatic cell lineage identity genes, differential expression of mitochondrial genes, differential expression of apoptosis- and / or senescence-related genes, differential expression of autophagy-associated genes, differential expression of inflammation response-related genes, differential expression of altered intracellular communication-related genes, deregulated nutrient-sensing-related genes, and differential expression of DNA damage-related genes. In a still further embodiment, the changes in gene expression are selected from one or more of: downregulation of somatic cell lineage identity genes, downregulation of mitochondrial genes, upregulation of apoptosis- and / or senescence-related genes, downregulation / upregulation of autophagy-associated genes, differential expression of inflammation response-related genes, differential expression of altered intracellular communication-related genes, deregulated nutrient-sensing-related genes, and upregulation of DNA damage-related genes. In another embodiment, the epigenetic marks associated with ageing are selected from one or more of: reduced heterochromatin trimethylated H3K9 (H3K9me3), reduced heterochromatin trimethylated H3K27 (H3K27me3), reduced HP1γ, and increased γH2AX. In a further embodiment, the telomere length is shortened. In a yet further embodiment, the transcriptomic and / or epigenetic clock is a single cell transcriptomic and / or epigenetic clock. In a certain embodiment, the ageing phenotype is a transcriptomic clock, such as a transcriptomic signature associated with an aged phenotype. In a further embodiment, the ageing phenotype is a single cell transcriptomic clock, such as a transcriptomic signature associated with an aged phenotype. In a still further embodiment, the ageing phenotype, such as the ageing CLO-C-P3598PCT phenotype of the cell, is a combination of one or more of the ageing phenotypes described herein. In one embodiment, the “age” of the cell or whether the cell is “aged” is determined using an the Horvath epigenetic clock (Horvath, S (2013) Genome Biol., doi: 2013-14-10-r115). Thus, in a further embodiment the ageing phenotype is age according to an epigenetic clock, such as the Horvath epigenetic clock. The Horvath epigenetic clock can be used as an age estimation method based on DNA methylation at CpG dinucleotide motifs in the DNA. DNA methylation age (further known as a “predicted age”) is characterised by the following properties: it is close to zero for ES and iPS cells; it correlates with cell passage number; it gives rise to a highly heritable measure of age acceleration; and it is applicable to chimpanzee tissues as well as to tissue from other species. The DNA methylation age of blood has been shown to predict all-cause mortality in later life, even after adjusting for known risk factors, suggesting that it is related to processes that cause ageing. Similarly, markers of physical and mental fitness have been associated with the epigenetic clock. One particular feature of the Horvath epigenetic clock is its high accuracy and applicability to a broad spectrum of tissues and cell types. Since it allows one to contrast the ages of different tissues and cells from the same subject (including a forward programmed or differentiated somatic cell with a non-iPSC or non-stem cell derived somatic cell of the same lineage or a pluripotent cell, such as an iPSC), it can be used to identify tissues and cells that show evidence of accelerated age due to disease. Furthermore, the Horvath epigenetic clock may be used to identify any change in DNA methylation age caused by treatment, such as reprogramming or forward programming / directed differentiation. In another embodiment, “age” is determined using a transcriptomic clock, such as a single cell transcriptomic clock. Thus, in a further embodiment the ageing phenotype is age according to a transcriptomic clock. In some embodiments, the transcriptomic clock comprises a transcriptomic signature associated with an aged phenotype of the cell. One example of transcriptomic clocks is described in Fleischer et al. (2018) Genome Biol. 19, 221 (doi: https: / / doi.org / 10.1186 / s13059-018-1599-6). Previously known ageing clocks trained on single cell RNA sequencing signatures typically suffer from: i) restriction to particular cell types; ii) lower accuracy than epigenetic-based ageing clocks; and iii) high variance of age measurements. However, these may be overcome in the methods described herein using a novel bioinformatic approach which yields single cell transcriptomic clocks that: i) are cell type independent; ii) exhibit accuracy rivalling epigenetic ageing clocks; and iii) have minimal variance in age measurements. Said bioinformatic approach may also be applied to multiomic data where data sets such as genomic, proteomic and epigenomic data sets are combined. CLO-C-P3598PCT In a further embodiment, a transcriptomic clock, such as a single cell transcriptomic clock, may be combined with any ageing phenotype described herein. For example, in some embodiments age is determined using a combination of a single cell transcriptomic clock with changes in cell and / or nuclear morphology, epigenetic clock measurements, mitochondrial function, epigenetic marks associated with ageing, altered methylation entropy, gene expression or any combination thereof. An ageing phenotype according to an epigenetic and / or transcriptomic clock as described herein comprises an “older” age as determined by said epigenetic and / or transcriptomic clock (i.e. so that a quantifiable change can be detected) upon constitutive expression of the Lamin A alternative splice form, compared to the cell prior to said constitutive expression or compared to a cell not constitutively expressing the Lamin A alternative splice form (i.e. the methylation and / or transcriptomic age is older than a non-aged cell). In further embodiments, “age” is determined using any suitable molecular signature, including those suitable for use as a biological clock. Such biological clocks may therefore be used to determine biological age. Further examples of biological clocks to those mentioned hereinbefore are known in the art and include the measurement of telomere length, the proteomic clock, the metabolomic clock and the ribosomal clock which measures the methylation status of CpG sites within ribosomal DNA (rDNA; Wang & Lemos (2019) Genome Res, doi: http: / / www.genome.org / cgi / doi / 10.1101 / gr.241745.118). It will be readily appreciated that any of these and other molecular signatures / biological clocks may be used independently or in combination (e.g. the epigenetic and transcriptomic clocks may be used together in combination to determine age, or either / both the epigenetic and transcriptomic clocks may be used together with a further biological clock, such as the ribosomal clock). In the context of biological clocks, making a cell “older” will therefore comprise a detectable and quantifiable change in the age determined by these clocks, such as an rDNA methylation (rDNAm) age which is older, upon constitutive expression of the Lamin A alternative splice form, compared to the cell prior to said constitutive expression or compared to a cell not constitutively expressing the Lamin A alternative splice form. In certain embodiments, the ageing phenotype is specific to the cell, such as to the cell type and / or lineage. For example, and without limitation, wherein the cell is a stem cell, such as a pluripotent stem cell, an induced pluripotent stem cell (iPSC), a germline stem cell, a multipotent stem cell, an oligopotent stem cell, a unipotent stem cell or a tissue-specific / tissue- resident stem cell, the ageing phenotype may be reduced proliferation. Alternatively or in addition, wherein the cell is a stem cell, the ageing phenotype may be increased senescence. CLO-C-P3598PCT If the cell is an immune cell, such as a T cell forward programmed or differentiated from an iPSC / stem cell, the ageing phenotype may be increased senescence. If the cell is a cell of the nervous system, such as a neuron or a glia cell forward programmed or differentiated from an iPSC / stem cell, the ageing phenotype may be a phenotype of a neurological degenerative disease, such as reduced process density and / or connectivity, reduced average dendritic length, reduced neurite diameter, downregulation of neuronal marker genes, loss of cell identity or reduced electrophysiological activity. Thus, in one embodiment wherein the cell is a neuron forward programmed or differentiated from an iPSC / stem cell, the ageing phenotype is a phenotype of a neurological degenerative disease, such as those described herein. If the cell is a muscle cell, such as a myocyte in the heart forward programmed or differentiated from an iPSC / stem cell, the ageing phenotype may be reduced electrophysiological activity or reduced mitochondrial function. It will be appreciated that the Lamin A alternative splice form is herein used as an “ageing- inducing factor”. In a particular embodiment, the Lamin A alternative splice form is progerin or a progerin-like truncated form of Lamin A. Such progerin-like protein may alter nuclear morphology, in particular loss of nuclear circularity, in a similar manner to progerin. Progerin is a nuclear lamina protein associated with Hutchinson-Gilford Progeria Syndrome (HGPS) and is a mutant form of Lamin A lacking 50 amino acids of the C-terminus which prevents removal of a farnesyl group and leads to accumulation of the protein at the nuclear rim / lamina. Thus, an example of a progerin-like protein is a truncated form of Lamin A which may comprise a deletion of the C-terminal truncation site leading to the improper processing of the protein and failure to integrate into the nuclear lamina, causing morphological alterations in the cell which are similar to those caused by progerin. In one embodiment, the Lamin A alternative splice form is progerin and comprises an amino acid sequence of SEQ ID NO: 16. METPSQRRATRSGAQASSTPLSPTRITRLQEKEDLQELNDRLAVYIDRVRSLETENAGLRLR ITESEEVVSREVSGIKAAYEAELGDARKTLDSVAKERARLQLELSKVREEFKELKARNTKKE GDLIAAQARLKDLEALLNSKEAALSTALSEKRTLEGELHDLRGQVAKLEAALGEAKKQLQDE MLRRVDAENRLQTMKEELDFQKNIYSEELRETKRRHETRLVEIDNGKQREFESRLADALQE LRAQHEDQVEQYKKELEKTYSAKLDNARQSAERNSNLVGAAHEELQQSRIRIDSLSAQLSQ LQKQLAAKEAKLRDLEDSLARERDTSRRLLAEKEREMAEMRARMQQQLDEYQELLDIKLAL DMEIHAYRKLLEGEEERLRLSPSPTSQRSRGRASSHSSQTQGGGSVTKKRKLESTESRSS FSQHARTSGRVAVEEVDEEGKFVRLRNKSNEDQSMGNWQIKRQNGDDPLLTYRFPPKFTL KAGQVVTIWAAGAGATHSPPTDLVWKAQNTWGCGNSLRTALINSTGEEVAMRKLVRSVTV CLO-C-P3598PCT VEDDEDEDGDDLLHHHHGSHCSSSGDPAEYNLRSRTVLCGTCGQPADKASASGSGAQSP QNCSIM (SEQ ID NO: 16). In a further embodiment, the Lamin A alternative splice form is a variant and / or functional fragment of the amino acid sequence of SEQ ID NO: 16, such as a sequence about 60%, about 70%, about 80%, about 90% or about 100% identical to SEQ ID NO: 16. The term “functional fragment” as used herein refer to fragment of the specified sequence that still retain a substantial amount of the function of the full length sequence. For example, a functional fragment of SEQ ID NO: 16 (e.g. a progerin-like protein) will alter nuclear morphology in a similar manner and to a similar amount to progerin as described herein, and / or results in the ageing of a cell as described herein upon expression in said cell. In still further embodiments, the Lamin A alternative splice form comprises a sequence about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% identical to SEQ ID NO: 16. In another embodiment, the Lamin A alternative splice form consists of SEQ ID NO: 16. In other embodiments, the Lamin A alternative splice form comprises an amino acid sequence encoded by SEQ ID NO: 17. ATGGAGACCCCGTCCCAGCGGCGCGCCACCCGCAGCGGGGCGCAGGCCAGCTCCAC TCCGCTGTCGCCCACCCGCATCACCCGGCTGCAGGAGAAGGAGGACCTGCAGGAGCT CAATGATCGCTTGGCGGTCTACATCGACCGTGTGCGCTCGCTGGAAACGGAGAACGCA GGGCTGCGCCTTCGCATCACCGAGTCTGAAGAGGTGGTCAGCCGCGAGGTGTCCGGC ATCAAGGCCGCCTACGAGGCCGAGCTCGGGGATGCCCGCAAGACCCTTGACTCAGTA GCCAAGGAGCGCGCCCGCCTGCAGCTGGAGCTGAGCAAAGTGCGTGAGGAGTTTAAG GAGCTGAAAGCGCGCAATACCAAGAAGGAGGGTGACCTGATAGCTGCTCAGGCTCGG CTGAAGGACCTGGAGGCTCTGCTGAACTCCAAGGAGGCCGCACTGAGCACTGCTCTCA GTGAGAAGCGCACGCTGGAGGGCGAGCTGCATGATCTGCGGGGCCAGGTGGCCAAG CTTGAGGCAGCCCTAGGTGAGGCCAAGAAGCAACTTCAGGATGAGATGCTGCGGCGG GTGGATGCTGAGAACAGGCTGCAGACCATGAAGGAGGAACTGGACTTCCAGAAGAACA TCTACAGTGAGGAGCTGCGTGAGACCAAGCGCCGTCATGAGACCCGACTGGTGGAGA TTGACAATGGGAAGCAGCGTGAGTTTGAGAGCCGGCTGGCGGATGCGCTGCAGGAAC TGCGGGCCCAGCATGAGGACCAGGTGGAGCAGTATAAGAAGGAGCTGGAGAAGACTT ATTCTGCCAAGCTGGACAATGCCAGGCAGTCTGCTGAGAGGAACAGCAACCTGGTGGG GGCTGCCCACGAGGAGCTGCAGCAGTCGCGCATCCGCATCGACAGCCTCTCTGCCCA GCTCAGCCAGCTCCAGAAGCAGCTGGCAGCCAAGGAGGCGAAGCTTCGAGACCTGGA GGACTCACTGGCCCGTGAGCGGGACACCAGCCGGCGGCTGCTGGCGGAAAAGGAGC CLO-C-P3598PCT GGGAGATGGCCGAGATGCGGGCAAGGATGCAGCAGCAGCTGGACGAGTACCAGGAG CTTCTGGACATCAAGCTGGCCCTGGACATGGAGATCCACGCCTACCGCAAGCTCTTGG AGGGCGAGGAGGAGAGGCTACGCCTGTCCCCCAGCCCTACCTCGCAGCGCAGCCGT GGCCGTGCTTCCTCTCACTCATCCCAGACACAGGGTGGGGGCAGCGTCACCAAAAAG CGCAAACTGGAGTCCACTGAGAGCCGCAGCAGCTTCTCACAGCACGCACGCACTAGC GGGCGCGTGGCCGTGGAGGAGGTGGATGAGGAGGGCAAGTTTGTCCGGCTGCGCAA CAAGTCCAATGAGGACCAGTCCATGGGCAATTGGCAGATCAAGCGCCAGAATGGAGAT GATCCCTTGCTGACTTACCGGTTCCCACCAAAGTTCACCCTGAAGGCTGGGCAGGTGG TGACGATCTGGGCTGCAGGAGCTGGGGCCACCCACAGCCCCCCTACCGACCTGGTGT GGAAGGCACAGAACACCTGGGGCTGCGGGAACAGCCTGCGTACGGCTCTCATCAACT CCACTGGGGAAGAAGTGGCCATGCGCAAGCTGGTGCGCTCAGTGACTGTGGTTGAGG ACGACGAGGATGAGGATGGAGATGACCTGCTCCATCACCACCATGGCTCCCACTGCAG CAGCTCGGGGGACCCCGCTGAGTACAACCTGCGCTCGCGCACCGTGCTGTGCGGGAC CTGCGGGCAGCCTGCCGACAAGGCATCTGCCAGCGGCTCAGGAGCCCAGAGCCCCCA GAACTGCAGCATCATGTAA (SEQ ID NO: 17). In further embodiments, the Lamin A alternative splice form is a variant or functional fragment of the amino acid sequence encoded by SEQ ID NO: 17, such as a variant sequence encoded by a sequence about 60%, about 70%, about 80%, about 90% or about 100% identical to SEQ ID NO: 17. In still further embodiments, the Lamin A alternative splice form comprises a sequence about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% identical to an amino acid encoded by SEQ ID NO: 17. In another embodiment, the Lamin A alternative splice form consists of an amino acid sequence encoded by SEQ ID NO: 17. Uses & Screening Methods In a further aspect of the invention, there is provided the use of the iPSC, stem cell or somatic cell derived from an iPSC or a stem cell by forward programming or directed differentiation described herein in a method of identifying a gene or a combination of genes involved in the reversal of an ageing phenotype or in the maintenance of a non-aged phenotype in the cell. Such uses are based on the previous observations by the inventors that artificially ageing iPSCs and then optionally reversing said ageing can be used with loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screens to identify genes / combinations of genes involved in the regenerative capacity of iPSCs and stem cell. To do this, an iPSC is aged and then subjected to the screen (or vice versa) and by measuring the changes in an ageing phenotype or the progression of said ageing phenotype compared to in an aged iPSC CLO-C-P3598PCT not subjected to the screen, the involvement of the knocked out, inhibited or activated gene / combination in the reversal of the ageing phenotype or the maintenance of the non-aged state can be identified. Alternatively, the reversal of ageing can be used to identify genes / combinations of genes by subsequently introducing the repressor protein which recognises the transcriptional repressor sequence described hereinbefore (e.g. the CymR protein) or a coding sequence thereof into the cells, thereby preventing the expression of the Lamin A alternative splice form and allowing the cell to reverse the previously chronically displayed ageing phenotype. According to this alternative screening method whereby the reversal of an ageing phenotype is measured, the changes of ageing phenotype are the ability of the cell (in particular an iPSC) to reverse the ageing phenotype following the loss-of- function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen. As will be readily appreciated, in all screening embodiments described herein the cell subjected to the screen and in which the ageing phenotype is measured is compared to a cell in which the screen has not been performed, i.e. a control cell. The control cell will be subjected to the same ageing factor and process as described herein (i.e. it is a cell constitutively expressing the Lamin A alternative splice form as described herein), such that the ageing phenotype can be measured and compared to that displayed by the cell in which the screen has been performed. Thus, in some embodiments screening step (ii) of the identification method described herein may be described as optional (i.e. it is performed on one cell and not on another, control, cell). Identification of genes and combinations of genes may be by sequencing. For example, genes or combinations of genes involved in reversal of an ageing phenotype or maintenance of a non-aged phenotype which have been targeted may be identified by transcriptome sequencing to determine the expression, such as the expression level, following targeting. Alternatively, said genes or combinations of genes may be identified by detecting the agent used to target said gene(s), e.g. the guide RNA that was present in a cell in which the ageing phenotype has been altered. In one embodiment, identification of genes or combinations of genes involved in reversal of an ageing phenotype or maintenance of a non-aged phenotype is by detection of the guide RNA used to target said gene or detection of the multiple guide RNAs used to target said combination of genes. In a further embodiment, the detection of the guide RNA is by sequencing. In a yet further embodiment, the guide RNA comprises a barcode sequence and detection of the guide RNA is by sequencing using said barcode sequence. Thus, in one embodiment the method of identifying a gene or combination of genes comprises the steps of: CLO-C-P3598PCT (i) culturing the iPSC, stem cell or somatic cell as described herein; (ii) performing a loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen in the cell; (iii) measuring an ageing phenotype in the cell; and (iv) identifying a gene or combination of genes as being involved in the reversal of an ageing phenotype or maintenance of a non-aged phenotype when the ageing phenotype is altered when the loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen is performed. As described hereinbefore, step (iv) may comprise comparing the cell in which the screen has been performed to a cell not subjected to the screen (a control cell). Thus, in one embodiment step (ii) is optional (i.e. it is performed in one cell and not in another, control, cell). In another embodiment, the reversal of an ageing phenotype in the cell following the loss-of- function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen is measured. Thus, in a further embodiment the method of identifying a gene / combination of genes comprises additional step (iib) of introducing into the cell a repressor protein which recognises the transcriptional repressor sequence described hereinbefore (e.g. CymR) or expressing in the cell said repressor protein, thereby downregulating expression of the Lamin A alternative splice form. According to this embodiment the control cell may be a cell in which no repressor protein has been introduced / expressed and thus in which no reversal of the ageing phenotype occurs. This control cell may be in addition to or an alternative to the cell in which no loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen has been performed. In a yet further embodiment, the method of identifying a gene or combination of genes comprises the steps of: (i) culturing the iPSC, stem cell or somatic cell as described herein; (ii) performing a loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen in the cell; (iib) introducing into the cell or expressing in the cell a transcription repressor protein, thereby downregulating expression of the Lamin A alternative splice form; (iii) measuring an ageing phenotype in the cell; and (iv) identifying a gene or combination of genes as being involved in the reversal of an ageing phenotype or maintenance of a non-aged phenotype when the ageing phenotype is altered when the loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen is performed. CLO-C-P3598PCT Introduction or expression of the transcription repressor protein (e.g. CymR) may be by any suitable method described herein or known to the skilled person. For example, expression of the repressor protein may be from a transiently transfected plasmid or from an expression cassette introduced into the cell. If expression is from an introduced expression cassette, said expression could be controlled by an exogenous substance as described hereinbefore. Genes / combinations of genes may be identified as having a “pro-ageing” effect when the loss- of-function, knock-out or inhibition of such genes / combinations leads to a reduction of the ageing phenotype, such as the reduction in its severity and / or a reduction in the effects of the ageing phenotype seen in the cell. Conversely, a gain-of-function or activation of these pro- ageing genes / combinations will lead to the increase of the ageing phenotype, such as increased / enhanced severity. As will be appreciated, since the cells of the present invention chronically display an ageing phenotype, no alteration in the progression or development of said phenotype is likely to be observed as it is already present / developed. However, such changes in development and / or progression are not excluded since it will be known that some ageing phenotypes may develop or progress (such as in their severity) further over time. Genes / combinations can also be identified as having pro-ageing effects if their knock-out, loss-of-function or inhibition leads to an increase in the reversal of an ageing phenotype, or their gain-of-function or activation leads to a decrease in the reversal of an ageing phenotype. Such reversal may be in the presence of the Lamin A alternative splice form (i.e. when step (iib) is not performed), or alternatively following downregulation of the Lamin A alternative splice form expression when step (iib) is performed in the identification method. Thus, according to these alternatives the pro-ageing gene / combination may have a strong, direct or active effect in driving ageing (e.g. the ageing phenotype), or may have a weak, indirect or passive effect in ageing / on the ageing phenotype, respectively. Genes / combinations of genes may alternatively be identified as having an “anti-ageing” effect when the loss-of-function, knock-out or inhibition of such genes / combinations leads to an increase of the ageing phenotype, such as an increase in its severity and / or an increase in the effects of the ageing phenotype in the cell. Conversely, a gain-of-function or activation of anti- ageing genes / combinations will lead to a decrease of the ageing phenotype, such as decreased / reduced severity. Genes / combinations may also be identified as having anti- ageing effects if their knock-out, loss-of-function or inhibition leads to a decrease in the reversal of an ageing phenotype, or their gain-of-function or activation leads to an increase in the reversal of an ageing phenotype. As described hereinbefore, such reversal may be in the presence of the Lamin A alternative splice form (i.e. when step (iib) is not performed) or CLO-C-P3598PCT following downregulation of its expression when step (iib) is performed. Thus, the anti-ageing gene / combination may have a strong, direct or weak effect in preventing ageing, or may have a weak, indirect or passive effect in ageing / on the ageing phenotype, respectively. The activity and / or expression of pro- and anti-ageing genes / combinations may therefore be modulated as appropriate to alter / modulate ageing, in particular to reduce and / or slow ageing including the reduction and / or slowing of an ageing phenotype. Progression of an ageing phenotype may also be reduced and / or slowed. In particular, in order to reduce and / or slow ageing, the activity and / or expression of pro-ageing genes / combinations can be reduced and / or inhibited. Alternatively or in addition / combination, the activity and / or expression of anti- ageing genes / combinations can be increased and / or enhanced to reduce and / or slow ageing. Conversely, if ageing is to be increased and / or accelerated the activity and / or expression of pro-ageing genes / combinations can be increased / enhanced and / or the activity / expression of anti-ageing genes / combinations can be decreased / reduced. Any method, compound or substance known in the art may be used to alter the activity and / or expression of the identified pro- or anti-ageing genes / combinations described herein. For example and without limitation, small molecule inhibitors or activators, antagonists / blocking agents or agonists / trans- activators (e.g. co-factors), post-transcriptional inhibition or enhancement (e.g. RNAi or saRNA). Further methods for altering the activity and / or expression of genes are known, and include gene editing methods, such as CRISPR (e.g. CRISPR-ko, CRISPRi and / or CRISPRa). In the context of a combination of genes, activity and / or expression of one gene or set of genes may be increased / enhanced / promoted while the activity / expression of another gene or set of genes is inhibited / reduced. In certain embodiments, the ageing phenotype measured in the identification method is the same ageing phenotype as chronically displayed by the cell. In one embodiment, the ageing phenotype measured is the transcriptomic clock of the cell, optionally in combination with one or more further biological clock as described hereinbefore. In a further embodiment, the ageing phenotype measured is the morphology of the cell, optionally in combination with the transcriptomic clock as described hereinbefore. In one embodiment, the loss-of-function, inhibitory, knock-out, gain-of-function, activatory or combinatorial screen comprises nucleic acids, polypeptides (e.g. proteins, such as antibodies), aptamers and / or small molecules (e.g. small molecule compounds). Such nucleic acids, polypeptides, aptamers and small molecules include those which act as activators / agonists as well as those which act as inhibitors / antagonists. Thus, it will be appreciated that the methods described herein find utility in screening any modulator (e.g. CLO-C-P3598PCT modulators of expression or activity) of a gene or a combination of genes involved in the reversal of an ageing phenotype or in the maintenance of a non-aged phenotype in a cell. In another embodiment, the loss-of-function, inhibitory, knock-out or combinatorial screen comprises a whole-genome screen. Such whole-genome screens, also known as genome- wide screens, aim to elucidate the relationship between genotype and phenotype by altering the expression or activity of a gene or gene product on a genome-wide scale and studying the resulting phenotypic alterations, such as in steps (ii) and (iii) of the method described herein. As their name suggests, loss-of-function, inhibitory or knock-out screens perturb the expression of genes, preventing them from functioning as normal. Thus, when loss-of- function, inhibitory or knock-out screens are performed, a gene or combination of genes will be identified as being involved in the reversal of an ageing-phenotype when said ageing- phenotype persists for longer or is not reversed in an artificially aged cell following induction of ageing compared to an artificially aged cell in which no loss-of-function, inhibition or knock- out of the gene or combination of genes has occurred. Alternatively, when loss-of-function, inhibitory or knock-out screens are performed, a gene or combination of genes will be identified as being involved in the maintenance of a non-aged phenotype when said phenotype is lost in an artificially aged cell, i.e. the cell displays an aged-phenotype, following induction of ageing compared to an artificially aged cell in which no loss-of-function, inhibition or knock- out of the gene or combination of genes has occurred. Gain-of-function screens enhance the activity or expression of a gene or gene product. If gain-of-function screens are used, a gene or combination of genes may be identified as being involved in the reversal of an ageing- phenotype when said ageing-phenotype is reversed more quickly or persists for a shorter period of time in an artificially aged cell following induction of ageing compared to an artificially aged cell in which no gain-of-function of the gene or combination of genes has occurred. Alternatively, a gene or combination of genes may be identified as being involved in the maintenance of a non-aged phenotype when said phenotype persists in an artificially aged cell, i.e. the cell does not display an aged phenotype, following induction of ageing compared to an artificially aged cell in which no gain-of-function of the gene or combination of genes has occurred. A combinatorial screen comprises a combination of one or more of loss-of-function, inhibitory and knock-out as described herein. Such combinatorial screens allow the accurate identification of combinations of genes involved in the reversal of an ageing phenotype or maintenance of a non-aged phenotype. In another embodiment, a combinatorial screen may also comprise a combination of a loss-of-function / inhibitory and an activatory / gain-of-function screen, e.g. by combining CRISPR-ko or CRISPRi with CRISPRa. CLO-C-P3598PCT In a specific embodiment, a CRISPR screen is combined with single-cell RNA sequencing to read out an mRNA signature that captures ageing or age reversal. Several approaches are known to the skilled person, e.g. CROP-seq which reads out the sgRNA directly (Datlinger et al. (2017) Nat. Methods, 14(3):297-301, doi: seq (Dixit et al. (2016) Cell, 167(7):1853-1866.e17, doi: j.cell.2016.11.038) which reads out the sgRNA indirectly via a barcode. In a particular embodiment, the 5’ chemistry of 10X Genomics may be used as published previously (Replogle et al. (2020) Nat. Biotechnol., 38(8):954-961, doi: https: / / doi.org / 10.1038 / s41587- 020-0470-y) to capture sgRNAs during a template switch reaction. Methods of performing whole-genome screens are known in the art and any such method will be appreciated to find utility in the methods described herein. However, of particular utility are screens performed using CRISPR as described herein. Thus, in one embodiment, the loss- of-function, inhibitory, knock-out, activatory or combinatorial screen is performed using CRISPR. In a further embodiment, wherein the screen is a loss-of-function or inhibitory screen the CRISPR is CRISPRi. CRISPRi can sterically repress transcription by blocking either transcriptional initiation or elongation. This is accomplished by designing single guide RNA (sgRNA) complementary to the promoter, the transcriptional start site (TSS) or exonic sequences of the gene to be transcriptionally inhibited or repressed. Depending on the nature of the CRISPR effector, targeting either the template or non-template strand leads to stronger repression. For example, with dCas9, repression is stronger when the guide RNA (gRNA) is complementary to the non-template strand. Unlike transcription elongation block, inhibition / repression by CRISPRi is independent of the targeted DNA strand when targeting the transcriptional start site. In some embodiments, the dCas9 may be fused to a transcriptional repressor, such as a KRAB domain. Multiple KRAB domains have been used in the published literature (Alerasool et al. (2020) Nat. Methods, 17(11):1093-1096, doi: https: / / doi.org / 10.1038 / s41592-020-0966-x). In a yet further embodiment, wherein the screen is a knock-out screen the CRISPR is CRISPR-ko and uses the active Cas9 nuclease. CRISPR-ko involves the introduction of a DNA double strand break (DSB) at the target site and the subsequent insertion or deletion of bases upon repair of DSBs created by the Cas9 nuclease in genes to which it has been targeted by a gRNA. Following creation of the DSB, the imprecise non-homologous end joining repair (NHEJ) pathway is used but results in inserted or deleted bases, thus creating indels or producing gene knockouts. Gain-of-function screens may use CRISPR activation. CRISPR activation (CRISPRa) uses modified versions of CRISPR effectors which do not have endonuclease activity but comprise added transcriptional activators, such as VP64 or VPR, on dCas9 and / or the gRNAs. The transcriptional activators fused to the CRISPRa components therefore increase expression of CLO-C-P3598PCT genes of interest following targeting to the gene by the gRNA. In a still further embodiment, wherein the screen is a combinatorial screen the CRISPR is a combination of: CRISPRi, and CRISPR-ko, i.e. a combination of two or more of any of the above mentioned CRISPR techniques. According to these embodiments, Cas9 protein may be used in the CRISPR methods. Thus, in one embodiment Cas9 protein is introduced into the iPSC, stem cell or somatic cell using an expression cassette comprising a sequence coding for the Cas9 protein. The expression cassette may be as described hereinbefore, and when other expression cassettes are used for integration of the ageing-inducing factor and / or the transcriptional regulator, may be referred to as a third expression cassette. In a further embodiment the Cas9 coding sequence is operably linked to a ubiquitous promoter. In a certain embodiment, the promoter is the CAG promoter as described hereinbefore. In a yet further embodiment, the expression cassette is integrated into the genome of the iPSC or stem cell at a GSH site, examples of which are described herein. In certain embodiments, the expression cassette comprising the Cas9 coding sequence is integrated at a third GSH site. As described hereinbefore, the use of the term “third” is not intended to be limiting but merely to distinguish the GSH site for integration of the Cas9 coding expression cassette from the GSH sites optionally used for integration of the Lamin A alternative splice form coding expression cassette and / or the transcriptional regulator coding expression cassette, as well as to distinguish from said expression cassettes. In a still further embodiment, the third GSH is the CYBL locus. Thus, in one embodiment the expression cassette comprising the Cas9 coding sequence is integrated into the CYBL locus. In some embodiments, the use to identify genes / combinations of genes involved in ageing comprises forward programming or directed differentiation of the iPSC or stem cell to a somatic cell. Such forward programming or directed differentiation may be performed as described hereinbefore, e.g. using lineage-specific transcription factors. In one embodiment, said forward programming or directed differentiation is performed before identification of the gene or combination of genes. In another embodiment, forward programming or directed differentiation is performed after identification. For example, forward programming or directed differentiation may be performed in culturing step (i) and / or may be performed after the screen of step (ii). Additionally or alternatively, forward programming or directed differentiation can be performed concurrently with measuring step (iii). Thus, in one embodiment the identification of the gene / combination of genes comprises the steps of: CLO-C-P3598PCT (i) culturing the iPSC or stem cell as described herein and forward programming or differentiating said iPSC or stem cell to a somatic cell; (ii) performing a a loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen in the cell; (iii) measuring an ageing phenotype in the cell; and (iv) identifying a gene or combination of genes as being involved in the reversal of an ageing phenotype or maintenance of a non-aged phenotype when the ageing phenotype is altered when the loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen is performed. In a further embodiment, identification comprises the steps of: (i) culturing the iPSC or stem cell as described herein; (ii) performing a loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen in the cell, followed by forward programming or differentiating the iPSC or stem cell to a somatic cell; (iii) measuring an ageing phenotype in the cell; and (iv) identifying a gene or combination of genes as being involved in the reversal of an ageing phenotype or maintenance of a non-aged phenotype when the ageing phenotype is altered when the loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen is performed. In a yet further embodiment, identification comprises the steps of: (i) culturing the iPSC or stem cell as described herein; (ii) performing a loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen in the cell; (iii) forward programming or differentiating the iPSC or stem cell to a somatic cell and measuring an ageing phenotype in the cell; and (iv) identifying a gene or combination of genes as being involved in the reversal of an ageing phenotype or maintenance of a non-aged phenotype when the ageing phenotype is altered when the loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen is performed. In another embodiment, identification comprises the steps of: (i) culturing the iPSC or stem cell as described herein and forward programming or differentiating said iPSC or stem cell to a somatic cell; (ii) performing a loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen in the cell; CLO-C-P3598PCT (iib) introducing into the cell or expressing in the cell a transcription repressor protein, thereby downregulating expression of the Lamin A alternative splice form; (iii) measuring an ageing phenotype in the cell; and (iv) identifying a gene or combination of genes as being involved in the reversal of an ageing phenotype or maintenance of a non-aged phenotype when the ageing phenotype is altered when the loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen is performed. In a still further embodiment, identification comprises the steps of: (i) culturing the iPSC or stem cell as described herein; (ii) performing a loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen in the cell, followed by forward programming or differentiating the iPSC or stem cell to a somatic cell; (iib) introducing into the cell or expressing in the cell a transcription repressor protein, thereby downregulating expression of the Lamin A alternative splice form; (iii) measuring an ageing phenotype in the cell; and (iv) identifying a gene or combination of genes as being involved in the reversal of an ageing phenotype or maintenance of a non-aged phenotype when the ageing phenotype is altered when the loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen is performed. In a yet further embodiment, identification comprises the steps of: (i) culturing the iPSC or stem cell as described herein; (ii) performing a loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen in the cell; (iib) introducing into the cell or expressing in the cell a transcription repressor protein, thereby downregulating expression of the Lamin A alternative splice form; (iii) forward programming or differentiating the iPSC or stem cell to a somatic cell and measuring an ageing phenotype in the cell; and (iv) identifying a gene or combination of genes as being involved in the reversal of an ageing phenotype or maintenance of a non-aged phenotype when the ageing phenotype is altered when the loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen is performed. In particular embodiments, identification is performed in an iPSC, stem cell or a somatic cell derived from an iPSC or a stem cell by forward programming or directed differentiation as described herein. Thus, in further embodiments the use of the iPSC, stem cell or somatic cell CLO-C-P3598PCT as described herein is in vitro, in vivo or ex vivo. In vitro includes in culture, such as in an in vitro cell culture of, for example primary cells obtained from a subject or cell lines as may be known in the art. The terms in vivo and ex vivo are used according to their normal meaning and context. In a certain embodiment, the use in in vitro. In a further embodiment, identifying a gene or combination of genes is performed in vitro. It may be preferred that the iPSC or stem cell is derived without destruction of an embryo, particularly where the cells are human. In some embodiments, the iPSCs or stem cells are not derived from human or animal embryos, i.e. the invention does not extend to any methods or uses which involve the destruction of human or animal embryos. Methods of Rejuvenation, Therapeutic Uses & Methods of Treatment In another aspect of the invention, there is provided a method of rejuvenating a cell comprising altering the expression and / or activity of one or more gene or combination of genes identified by the methods / use described herein. In one embodiment, the cell to be rejuvenated is a somatic cell. In a further embodiment, the cell is a tissue-specific stem cell. It will be appreciated that references herein to “a” or “the” cell, such as a or the somatic cell, include a single or small number of cells, as well as to a population of cells, which may be large in number. Thus, it will be appreciated that any references herein, including any aspect or embodiment, to singular include plural and vice versa, unless explicitly stated otherwise. The term “rejuvenating” as used herein refers to the reversal or maintenance of an ageing phenotype, such as those described herein. Such rejuvenation will therefore be appreciated to maintain a cell in a younger or non-aged stated compared to a cell in a non-rejuvenated state, or will alter the age of a cell so that it is younger or in a less-aged state than prior to rejuvenation. Rejuvenation will also or alternatively reduce and / or slow the progression or development of an ageing phenotype. Thus, in one embodiment the rejuvenated cell comprises a reduced and / or slowed ageing phenotype, such as reduced and / or slowed progression of the ageing phenotype. Whether a cell is “younger”, “non-aged” or “less-aged” may be determined using any ageing phenotype described herein, in particular using an epigenetic and / or transcriptomic clock. For example, a rejuvenated cell may display fewer alterations in cellular and / or nuclear morphology compared to cell in a non-rejuvenated state. Therefore, in one embodiment the rejuvenated cell comprises a methylation age (e.g. as determined using an epigenetic clock) of younger or less than prior to rejuvenation or than a cell in a non-rejuvenated state (i.e. a non-rejuvenated cell). In a further embodiment, the rejuvenated cell comprises a transcriptomic age (e.g. as determined using a transcriptomic clock) of younger or less than prior to rejuvenation or than a non-rejuvenated cell. In another embodiment, the younger or less-aged methylation age corresponds to that of a cell from an CLO-C-P3598PCT earlier point in the life cycle of the tissue or organism from which the iPSC or stem cell was obtained. In a further embodiment, the younger or less-aged transcriptomic age corresponds to that of a cell from an earlier point in the life cycle of the tissue or organism from which the iPSC or stem cell was obtained. In yet further embodiments, the rejuvenated cell comprises, with respect to an ageing phenotype as described herein, the phenotype of a reprogrammed stem cell, such as a pluripotent stem cell and / or an iPSC. In some embodiments, the rejuvenated cell comprises a methylation age or a transcriptomic age corresponding to that of a reprogrammed stem cell, such as a pluripotent stem cell and / or an iPSC. Thus, in one embodiment the rejuvenated cell comprises a methylation age or a transcriptomic age of a pluripotent stem cell. In a further embodiment, the rejuvenated cell comprises a methylation age or a transcriptomic age of an iPSC or a stem cell. In a yet further embodiment, the rejuvenated cell comprises a methylation age and a transcriptomic age of pluripotent stem cell. In a still further embodiment, the rejuvenated cell comprises a methylation age and a transcriptomic age of an iPSC or a stem cell. Any method of altering the activity and / or expression of identified genes as described hereinbefore may be used in the rejuvenation methods. In particular, in order to reduce and / or slow ageing, the activity and / or expression of pro-ageing genes / combinations can be reduced and / or inhibited. Alternatively or in addition / combination, the activity and / or expression of anti- ageing genes / combinations can be increased and / or enhanced to reduce and / or slow ageing. In further alternatives, genes and combinations of genes identified in iPSCs as pro- or anti- ageing using the methods described herein, may have the reverse effects in somatic cells, such as pro-ageing genes identified in iPSCs may have anti-ageing effects in somatic cells and / or anti-ageing genes identified in iPSCs may have pro-ageing effects in somatic cells. According to this alternative, in order to reduce and / or slow ageing in somatic cells, the activity and / or expression of pro-ageing genes / combinations may be reduced and / or inhibited, while the activity and / or expression of anti-ageing genes / combinations may be increased and / or enhanced to reduce and / or slow ageing in somatic cells. Any method, compound or substance known in the art and as described hereinbefore may be used to alter the activity and / or expression of the identified pro- or anti-ageing genes / combinations described herein. The rejuvenation methods and methods of altering the activity and / or expression of the identified genes / combinations of genes as described herein will be appreciated to find utility in the reduction and / or slowing of ageing, such as in an age-modulating method, in particular the slowing and / or reduction of ageing in a subject (e.g. an aged subject). CLO-C-P3598PCT The terms “modulating ageing”, “age-modulating / modulation methods” and “rejuvenation” may therefore be interchangeably and refer to the alteration (e.g. reversal) or maintenance of an ageing phenotype, such as any of those described herein. In the context of rejuvenation, age- modulating methods may maintain a cell in a younger or non-aged state compared to a non- rejuvenated cell, or will alter the age of a cell so that it is younger or in a less-aged state than prior to rejuvenation. Subjects suffering from age-related diseases or disorders will also benefit since it would be expected that by reducing and / or slowing ageing, the disease or disorder, its effects and / or its progression would also be reduced and / or slowed. Thus, in a further aspect of the invention there is provided an age-modulating and / or rejuvenation method for use in a method of treating a disease or disorder associated with ageing in a subject, said age-modulating / rejuvenating method comprising modulating the expression and / or activity of a gene or a combination of genes identified as described herein. Thus, in certain embodiments there is provided the alteration of the activity and / or expression of the genes / combinations of genes identified herein for use in a method of treating a disease or disorder associated with ageing in a subject. The term “in a subject” herein may be used interchangeably with or in addition to “in vivo”. In another aspect, there is provided a method of modulating ageing in vivo and / or an in vivo rejuvenation method, said method comprising the age-modulating method described herein (i.e. comprising modulating the activity and / or expression of the gene / combinations of genes identified herein). In a further aspect, there is provided a method of treating a disease or disorder associated with ageing, said method comprising the age-modulating method described herein (i.e. comprising modulating the activity and / or expression of the gene / combinations of genes identified herein). As will be readily appreciated, the in vivo age-modulating / rejuvenation methods and methods of treatment herein may comprise administration of a modulator of the activity and / or expression of a gene or combination of genes identified herein. For example, wherein ageing (or a disease / disorder associated with ageing) is to be reduced and / or slowed in a subject, an inhibitor, an antagonist, a blocking agent and / or negative post-transcriptional regulator of a pro-ageing gene or combination of pro-ageing genes may be administered. An inhibitor may include a small-molecule inhibitor, an siRNA or an antibody targeting the gene product of interest as described hereinbefore. Alternatively or additionally, an agonist, a trans-activator and / or a post-transcriptional enhancer of an anti-ageing gene or combination of anti-ageing genes may be administered. Such administration may be systemically, e.g. enteral or CLO-C-P3598PCT parenteral, such as via intravenous infusion, or locally, such as directly into the tissue or organ to be treated / rejuvenated, e.g. by topical administration. In some embodiments, the modulator of the activity and / or expression of a gene or combination of genes identified herein is comprised in a pharmaceutical composition, optionally further comprising one or more pharmaceutically acceptable carriers, diluents and / or excipients. Thus, according to a further aspect, there is provided a pharmaceutical composition comprising the modulator of the activity and / or expression of a gene or combination of genes identified herein for use in the age-modulating / rejuvenation methods and / or in a method of treating a disease or disorder associated with ageing in a subject. The disease or disorder associated with ageing may be a degenerative disease or disorder, including without limitation of the pancreas (e.g. type 2 diabetes), of the blood and / or bone marrow, of the heart (e.g. cardiovascular disease, cardiomyopathy, ischaemic heart disease, cardiac arrhythmia or heart failure), of the skin, or a neurological disease or disorder (e.g. a neurodegenerative disease / disorder). Examples of neurodegenerative diseases and disorders include, without limitation amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy and prion diseases. Thus, in some embodiments the age-modulating / rejuvenation method is performed in the skin, liver, pancreas, heart, brain, central nervous system, peripheral nervous system, blood and / or bone marrow, such as in a cell comprised in any of said tissues or organs. In further embodiments, the age-modulating method can be considered to rejuvenate said tissue, organ and / or cell in which the method is performed. It will be appreciated that references herein to a patient or subject relate equally to animals and humans and that the invention finds particular utility in veterinary treatment of any of the above mentioned diseases, disorders and conditions which are also present in said animals. It will be appreciated that references herein to “treatment” include such terms as “amelioration”, “prevention”, “reversal”, “suppression” and the like. Furthermore, such references include administration of the modulator of the activity and / or expression of a gene or combination of genes as described herein or composition comprising the modulator as defined herein prior to the onset of the disease or disorder. Administration may also be anticipated after the induction event of the disease or disorder, either before clinical presentation of said disease or disorder, or after symptoms manifest. CLO-C-P3598PCT Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs. As used herein, the term “about” when used herein includes up to and including 10% greater and up to and including 10% lower than the value specified, suitably up to and including 5% greater and up to and including 5% lower than the value specified, especially the value specified. The term “between” as used herein includes the values of the specified boundaries. It will be understood that all embodiments described herein may be applied to all aspects of the invention and vice versa. Other features and advantages of the present invention will be apparent from the description provided herein. It should be understood, however, that the description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications will become apparent to those skilled in the art. CLAUSES A set of clauses defining the invention, its aspects and embodiments is as follows: 1. An induced pluripotent stem cell (iPSC), stem cell or a somatic cell derived from an iPSC or stem cell by forward programming or directed differentiation comprising an expression cassette, said expression cassette comprising a coding sequence for an alternative splice form of Lamin A coupled to a weak promoter sequence, thereby yielding low level constitutive expression of the alternative splice form of Lamin A in the cell while maintaining cell viability. 2. The iPSC, stem cell or somatic cell of clause 1, wherein the weak promoter sequence is a weak constitutive promoter. 3. The iPSC, stem cell or somatic cell of clause 1, wherein the weak promoter sequence is a strong constitutive promoter coupled to a transcriptional repressor sequence. 4. The iPSC, stem cell or somatic cell of clause 3, wherein the transcriptional repressor sequence is an endogenous repressor sequence or is exogenous. 5. The iPSC, stem cell or somatic cell of clause 4, wherein the transcriptional repressor sequence is exogenous and is operably linked to the strong constitutive promoter, CLO-C-P3598PCT 6. The iPSC, stem cell or somatic cell of clause 5, wherein the weak promoter sequence comprises a cumate operator (CuO) sequence and a strong constitutive promoter. 7. The iPSC, stem cell or somatic cell of any one of clauses 4 to 6, wherein the cell does not comprise a sequence coding for a repressor protein which recognises the exogenous repressor sequence. 8. The iPSC, stem cell or somatic cell of clause 6 or clause 7, wherein the cell does not comprise a sequence coding for a cumate repressor protein (CymR). 9. The iPSC, stem cell or somatic cell of clause 7 or clause 8, wherein the presence of the expression cassette comprising an exogenous repressor sequence operably linked to a strong constitutive promoter and the absence of sequence coding for a repressor protein which recognises said exogenous repressor sequence, such as a CymR coding sequence, yields constitutive expression of the alternative splice form of Lamin A in the cell. 10. The iPSC, stem cell or somatic cell of any one of clauses 1 to 9, wherein the alternative splice form of Lamin A is progerin or a progerin-like truncated form of Lamin A. 11. The iPSC, stem cell or somatic cell of clause 10, wherein the progerin comprises the amino acid sequence of SEQ ID NO: 16, or a variant or functional fragment thereof, and / or comprises an amino acid sequence encoded by SEQ ID NO: 17, or a variant or functional fragment thereof. 12. The iPSC, stem cell or somatic cell of any one of clauses 1 to 11, wherein the expression cassette comprises the coding sequence for the alternative splice form of Lamin A operably linked to a weak promoter in the following order: 5’-weak promoter-coding sequence-3’, such as: 5’-weak constitutive promoter-coding sequence-3’; 5’-strong constitutive promoter-repressor sequence-coding sequence-3’; or 5’-repressor sequence-strong constitutive promoter-coding sequence-3’. 13. The iPSC, stem cell or somatic cell of any one of clauses 1 to 12, wherein the cell chronically displays an ageing phenotype. 14. The iPSC, stem cell or somatic cell of clause 13, wherein the ageing phenotype is selected from any one or more of: proliferation, senescence, changes in cell and / or nuclear CLO-C-P3598PCT morphology, mitochondrial function, changes in gene expression, altered expression of Lamin- A and / or Lamin-C nuclear protein, in particular upregulation, epigenetic marks associated with ageing, altered DNA or histone methylation, methylation entropy, DNA double strand breaks, telomere length, and an epigenetic clock and / or further transcriptomic clock, in particular changes in cell and / or nuclear morphology and / or a further transcriptomic clock, such as a transcriptomic signature associated with an aged phenotype. 15. The iPSC, stem cell or somatic cell of clause 14, wherein the ageing phenotype is reduced proliferation and / or increased senescence, wherein the changes in nuclear morphology are folding abnormalities, blebbing and / or loss of nuclear circularity, wherein the mitochondrial function is reduced oxygen consumption and / or increased mitochondrial reactive oxygen species (ROS), wherein the changes in gene expression are selected from one or more of: differential / altered expression of somatic cell lineage identity genes, differential expression of mitochondrial genes, differential expression of apoptosis- and / or senescence-related genes, differential expression of autophagy-associated genes, differential expression of inflammation response-related genes, differential expression of altered intracellular communication-related genes, deregulated nutrient-sensing-related genes, and differential expression of DNA damage-related genes, such as one or more of: downregulation of somatic cell lineage identity genes, downregulation of mitochondrial genes, upregulation of apoptosis- and / or senescence- related genes and downregulation / upregulation of autophagy-associated genes, wherein the epigenetic marks associated with ageing are selected from one or more of: reduced heterochromatin trimethylated H3K9 (H3K9me3), reduced HP1γ, and increased γH2AX, wherein the telomere length is shortened, and / or wherein the transcriptomic and / or epigenetic clock is a single cell transcriptomic and / or epigenetic clock. 16. The iPSC, stem cell or somatic cell of any one of clauses 1 to 15, wherein the cell comprises a further expression cassette comprising one or more coding sequences for one or more lineage-specific transcription factors operably linked to an inducible promoter. 17. The iPSC, stem cell or somatic cell of clause 16, wherein the inducible promoter comprises a tetracycline operator (TetO) sequence and a constitutive promoter. CLO-C-P3598PCT 18. The iPSC, stem cell or somatic cell of clause 16 or clause 17, wherein the inducible promoter is regulated by a transcriptional regulator protein and said transcriptional regulator protein is controlled by an exogenously supplied substance. 19. The iPSC, stem cell or somatic cell of clause 18, wherein the transcriptional regulator protein is a tetracycline-responsive transcriptional activator protein (rtTa) and the exogenously supplied substance is tetracycline or a derivate thereof, such as doxycycline. 20. The iPSC, stem cell or somatic cell of clause 18 or clause 19, wherein upon exposure of the cell to the exogenously supplied substance (e.g. tetracycline or a derivate thereof), the one or more lineage-specific transcription factors are expressed. 21. Use of the iPSC, stem cell or somatic cell of any one of clauses 1 to 20 in a method of identifying a gene or a combination of genes involved in the reversal of an ageing phenotype or in the maintenance of a non-aged phenotype in the cell. 22. The use of clause 21, wherein the method of identifying a gene or combination of genes comprises the steps of: (i) culturing the iPSC, stem cell or somatic cell of any one of clauses 1 to 20; (ii) performing a loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen in the cell; (iii) measuring an ageing phenotype in the cell; and (iv) identifying a gene or combination of genes as being involved in the reversal of an ageing phenotype or maintenance of a non-aged phenotype when the ageing phenotype is altered when the loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen is performed. 23. The use of clause 21, wherein the method of identifying a gene or combination of genes comprises the steps of: (i) culturing the iPSC, stem cell or somatic cell as described herein; (ii) performing a loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen in the cell; (iib) introducing into the cell or expressing in the cell a transcription repressor protein, thereby downregulating expression of the Lamin A alternative splice form; (iii) measuring an ageing phenotype in the cell; and (iv) identifying a gene or combination of genes as being involved in the reversal of an ageing phenotype or maintenance of a non-aged phenotype when the ageing phenotype is CLO-C-P3598PCT altered when the loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen is performed. 23. The use of clause 22 or 23, wherein the ageing phenotype measured in step (iii) is the same ageing phenotype chronically displayed by the cell according to any one of clauses 13 to 15. 24. The use of any one of clauses 21 to 23, wherein the cell is an iPSC or a stem cell and is forward programmed or differentiated to a somatic cell, or wherein the cell is a somatic cell derived from an iPSC or a stem cell by forward programming or directed differentiation, and wherein the forward programming or differentiation is performed before and / or after the identification of the gene or combination of genes. 25. The use of clause 24, wherein forward programming or directed differentiation is performed in culturing step (i) and / or after performing the screen of step (ii). 26. The use of clause 24 or clause 25, wherein the method of identifying the gene / combination of genes comprises the steps of: (i) culturing the iPSC or stem cell as described herein and forward programming or differentiating said iPSC or stem cell to a somatic cell; (ii) performing a a loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen in the cell; (iii) measuring an ageing phenotype in the cell; and (iv) identifying a gene or combination of genes as being involved in the reversal of an ageing phenotype or maintenance of a non-aged phenotype when the ageing phenotype is altered when the loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen is performed. 27. The use of clause 24 or clause 25, wherein the method of identifying the gene / combination of genes comprises the steps of: (i) culturing the iPSC or stem cell as described herein; (ii) performing a loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen in the cell, followed by forward programming or differentiating the iPSC or stem cell to a somatic cell; (iii) measuring an ageing phenotype in the cell; and (iv) identifying a gene or combination of genes as being involved in the reversal of an ageing phenotype or maintenance of a non-aged phenotype when the ageing phenotype is CLO-C-P3598PCT altered when the loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen is performed. 28. The use of clause 24 or clause 25, wherein the method of identifying the gene / combination of genes comprises the steps of: (i) culturing the iPSC or stem cell as described herein; (ii) performing a loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen in the cell; (iii) forward programming or differentiating the iPSC or stem cell to a somatic cell and measuring an ageing phenotype in the cell; and (iv) identifying a gene or combination of genes as being involved in the reversal of an ageing phenotype or maintenance of a non-aged phenotype when the ageing phenotype is altered when the loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen is performed. 29. The use of clause 24 or clause 25, wherein the method of identifying the gene / combination of genes comprises the steps of: (i) culturing the iPSC or stem cell as described herein and forward programming or differentiating said iPSC or stem cell to a somatic cell; (ii) performing a loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen in the cell; (iib) introducing into the cell or expressing in the cell a transcription repressor protein, thereby downregulating expression of the Lamin A alternative splice form; (iii) measuring an ageing phenotype in the cell; and (iv) identifying a gene or combination of genes as being involved in the reversal of an ageing phenotype or maintenance of a non-aged phenotype when the ageing phenotype is altered when the loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen is performed. 30. The use of clause 24 or clause 25, wherein the method of identifying the gene / combination of genes comprises the steps of: (i) culturing the iPSC or stem cell as described herein; (ii) performing a loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen in the cell, followed by forward programming or differentiating the iPSC or stem cell to a somatic cell; (iib) introducing into the cell or expressing in the cell a transcription repressor protein, thereby downregulating expression of the Lamin A alternative splice form; CLO-C-P3598PCT (iii) measuring an ageing phenotype in the cell; and (iv) identifying a gene or combination of genes as being involved in the reversal of an ageing phenotype or maintenance of a non-aged phenotype when the ageing phenotype is altered when the loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen is performed. 31. The use of clause 24 or clause 25, wherein the method of identifying the gene / combination of genes comprises the steps of: (i) culturing the iPSC or stem cell as described herein; (ii) performing a loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen in the cell; (iib) introducing into the cell or expressing in the cell a transcription repressor protein, thereby downregulating expression of the Lamin A alternative splice form; (iii) forward programming or differentiating the iPSC or stem cell to a somatic cell and measuring an ageing phenotype in the cell; and (iv) identifying a gene or combination of genes as being involved in the reversal of an ageing phenotype or maintenance of a non-aged phenotype when the ageing phenotype is altered when the loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen is performed. 32. The use of any one of clauses 21 to 31, wherein the use is in vitro and / or the method of identifying a gene or combination of genes is performed in vitro. 33. A method of rejuvenating a somatic cell comprising modulating the expression and / or activity of one or more gene or combination of genes identified by the use of any one of clauses 21 to 32. 34. The method of clause 33, wherein the rejuvenated cell comprises a reduced and / or slowed progression of an ageing phenotype compared to a non-rejuvenated cell, and wherein the ageing phenotype is as defined in clause 14 or clause 15. 35. An age-modulating method for use in a method of treating a disease or disorder associated with ageing in a subject, said age-modulating method comprising modulating the expression and / or activity of a gene or a combination of genes identified by the use of any one of clauses 21 to 32. CLO-C-P3598PCT 36. A method of modulating ageing in vivo, said method comprising the age-modulating method of clause 35. 37. A method of treating a disease or disorder associated with ageing, said method comprising the age-modulating method of clause 35. 38. The method of clause 36 or clause 37, wherein the method comprises administering a modulator of the expression and / or activity of the gene or combination of genes identified by the use of any one of clauses 21 to 32. The invention will now be described using the following, non-limiting examples: EXAMPLES Materials & Methods hiPSC Culture Human induced pluripotent stem cells cultures were performed as previously described (Pawlowski et al. (2017) Stem Cell Reports, 8(4):803-812, doi: and Vallier, L (2011) Methods Mol. Biol., 690:57- 66, doi: 1-60761-962-8_3). Briefly, cells were plated on Geltrex (Thermo Fisher Scientific) coated culture dishes and cultured in StemFlex medium (Life Technologies). Cells were passaged in small clumps using ReLeSR (StemCell Technologies) every 6-7 days. Ageing of hiPSCs expressing progerin under control of the tetracycline system was introduced on day 2 post splitting for 5 days using 0.075μg / mL doxycycline. Generation of iNeurons from hiPSCs NGN2-iPSCs and NGN2-GFP-Progerin-iPSCs were dissociated into single cells using Accutase and plated onto Geltrex coated dishes at a density of 50,000 cells per cm2. Forward programming was initiated 24 hours post splitting. The induction was performed in DMEM / F- 12 supplemented with Glutamax (100x), Non-Essential Amino Acids (100x), 50μM 2- Mercaptoethanol (Gibco), 1% Penicillin / Streptomycin, 1μg / mL Doxycycline. After 2 days of induction, the medium was switched to Neurobasal-medium supplemented with Glutamax (100x), B27 (50x), 10ng / mL BDNF (Peprotech), 10ng / mL NT3 (R&D Systems), 1% Penicillin / Streptomycin, and 1μg / mL Doxycycline. On day 3 post induction, cells were dissociated into single cells and plated onto PDL / Geltrex coated plates at a density of 30,000 cells per cm2for final plating in the above Neurobasal medium. Doxycycline was withdrawn at day 7. CLO-C-P3598PCT Multi-Electrode Array (MEA) Recordings Non-aged iNs (NGN2 iNs), and chronically aged iNs (N2P caiNs) were dissociated into single cells at day 3 post induction and replated on PDL / Geltrex coated wells of CytoView MEA 48 (Axion Biosystems) with or without rat cortical astrocytes, at a ratio of 1:1. Co-cultures were maintained in Neurobasal medium for the duration of the recordings. Recordings were performed using the Maestro Pro MEA system (Axion Biosystems). Dose Response and Proliferation Assays GFP-Progerin targeted iPSCs were dissociated into single cells using Accutase and plated at a density of 10,000 cells per cm2in StemFlex medium. For dose response assay, cells were incubated each day with Hoechst (Thermo Fisher Scientific) for 10 minutes and imaged using Evos M5000 microscope system (Thermo Fisher Scientific). For proliferation assay, cells were dissociated each day and counted using Countess II (Thermo Fisher Scientific). Image analysis and cell counting was conducted using Image J. A total of 3 biological replicates was used for the analysis. Western Blot To prepare total protein lysates, aged and non-aged GFP-Progerin targeted hiPSCs were harvested by scraping in PBS (1% BSA), centrifuged at 350g for 10 minutes at 4oC, and re- suspended in ice-cold RIPA buffer (Sigma) supplemented with cOmplete Protease Inhibitor (Roche). Lysates were incubated for 30 minutes at 4oC on a rotating wheel and then clarified by centrifugation at 16000g for 10 minutes at 4oC. The supernatants were transferred to new tubes, and the protein concentration was assessed using Qubit 4 Fluorometer (Thermo Fisher Scientific). Samples were prepared for Western Blot analysis by adding Laemmli buffer (final concentration of 30mM Tris-HCl pH 6.8, 6% glycerol, 2% sodium dodecyl sulphate / SDS, 0.02% bromophenol blue, and 0.25% β-mercaptoethanol), and were denatured at 95oC for 5 minutes. 20µg of proteins were loaded and run on 4-12% NuPAGE Bis-Tris Precast Gels (Invitrogen), then transferred to polyvinylidene fluoride (PVDF) membranes by liquid transfer using NuPAGE Transfer buffer (Invitrogen). Membranes were blocked for 1h at RT in PBS 0.05% Tween-20 (PBST) supplemented with 4% non-fat dried milk and incubated overnight at 4oC on a rotating wheel with the primary antibody diluted in the same blocking buffer. After three washes in PBST, membranes were incubated for 1h at RT with horseradish peroxidase (HRP)-conjugated secondary antibodies diluted in blocking buffer, then further washed three times with PBST before being incubated with Pierce ECL2 Western Blot Substrate (Thermo Fisher) and exposed to Amersham HyperfilmTM (GE Healthcare). Total protein was measured using Licor REVERT total protein stain and wash solution kit. CLO-C-P3598PCT Mitochondrial Assays Measurement of cellular oxygen consumption rate (OCR): Cellular oxygen consumption rate was measured using a XF24 extracellular flux analyser (Seahorse Biosciences, Denmark). Human iPSCs at a density of 2,000 cells / well or human iNeurons (aged and non- aged) at a density of 30,000 cells / well were seeded in XFp miniplates (Agilent Technologies) and were cultured under the conditions described above for ageing or non-ageing conditions. Cells were incubated in assay medium (DMEM without sodium bicarbonate and phenol red) for at least 30 min prior to the assay. OCR was measured every 5 minutes for three times under basal conditions and then after the sequential injection of 0.5 µM oligomycin (inhibitor of ATP synthase), 8.1 µM carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP; uncoupler of mitochondrial inner membrane allowing maximum electron flux through the ETC), and 10 µM rotenone + 10 µM antimycin A (inhibitors of mitochondrial complex I and III, respectively). At least 3 biological replicates were performed, with at least 3 technical replicates per sample. Basal respiration was measured by subtracting non-mitochondrial respiration from the last rate measurement before Oligomycin injection. Maximal respiration was measured by subtracting the non-mitochondrial respiration from the maximum rate measurement after FCCP injection. ATP production was measured by the minimum rate measurement after Olygomycin injection from the last rate measurement before Oligomycin injection. MitoTracker and MitoSOX assays: Human iPSCs were plated on 96 well plates at a density of 2000 cells / well and were cultured under the conditions described above for ageing or non- ageing conditions. On the day of the assay (day 5 of ageing), cells were washed once with PBS, and stained for 25 minutes at 37°C with a mix of MitoSOX Red (ThermoFisher) and MitoTracker Deep Red (ThermoFisher) dyes. Cells were washed twice with FluoroBrite DMEM before being scanned. Cells were stained with Hoechst for cell density normalization, according to the manufacturer’s instructions. Fluorescence was measured using the CLARIOstar microplate reader at 510 / 610 nm and 644 / 665 nm, and the DAPI filter at 340 / 480nm. At least 3 biological replicates were performed, with at least 3 technical replicates per sample. Data analysis was performed by division of the dye signal by Hoechst signal of each well, to normalise to cell count. Afterwards, the dye signal / DAPI ratio of all samples was divided by the average of the untreated group, to normalise samples against it. Data were exported to GraphPad Prism and plotted. Autophagy Assay Autophagic activity of iPSCs was assessed on day 5 of ageing. Briefly, hiPSCs were plated on 96 well plates at a density of 2,000 cells / well and were cultured under the conditions CLO-C-P3598PCT described above for ageing or non-ageing conditions. Live cells were stained using the Autophagy assay kit (ab139484, Abcam) to quantify autophagic vacuoles and monitor autophagic flux. The dye used leads to minimal staining of lysosomes, and bright fluorescence upon incorporation into pre-autophagosomes, autophagosomes, and autolysosomes (autophagolysosomes). Cells were stained with Hoechst for cell density normalization, according to the manufacturer’s instructions. Fluorescence was measured using the CLARIOstar microplate reader with the FITC filter (480 / 530nm), and the DAPI filter (340 / 480nm). At least 3 biological replicates were performed, with at least 3 technical replicates per sample. Data analysis was performed by division of FITC signal by Hoechst signal of each well, to normalise to cell count. Afterwards, the FITC / DAPI ratio of all samples was divided by the average FITC / DAPI of the untreated group, to normalise samples against it. Data were exported to GraphPad Prism and plotted. Senescence Associated Beta-Galactosidase (SA-β-gal) Staining SA-β-gal staining was performed using a Cell Signaling Technology kit according to the manufacturer’s protocol. Colour images of SA-β-gal- stained cells were captured using an Evos microscope (Life Technologies). SA-β-gal intensity was measured using ImageJ software. Immunocytochemistry Cells were fixed in 4% paraformaldehyde (Alfa Aesar) for 15 minutes at room temperature and subsequently washed three times with PBS. The cells were then permeabilized with 0.1% Triton-X-100 for 15 minutes at room temperature. Then, blocked with 10% goat or donkey serum (abcam) and 0.3% Triton X-100 (diluted in PBS) for 30-45 minutes at room temperature. Subsequently, cells were incubated with appropriately diluted primary antibodies (Table 1) in 2% goat or donkey serum and 0.1% Triton X-100 (diluted in PBS) at 4°C overnight. After three washes with PBS, the cells were incubated for 1 hour at room temperature with corresponding secondary antibodies in PBS supplemented with 1% goat or donkey serum. Nuclei were visualized with 4',6-diamidino-2-phenylindole (DAPI, Thermo Fisher Scientific). Images were acquired using a Zeiss LSM 710 confocal microscope (Leica). DNA damage foci analysis (based on ^H2AX staining) was conducted using Image J (version 2.00, NIH). Number of γH2Ax foci was calculated manually and was plotted into a bar graph. H3K9me3 intensity was measured by quantifying cellular fluorescence intensity. Images were processed using ImageJ software. Corrected total cell fluorescence (CTCF) was assessed from cells for each of the tested markers and presented in bar graphs. CLO-C-P3598PCT Table 1: List of Primary Antibodies Used Primary Antibodies Company / Supplier Host ^3-tubulinProteintech Mouse^H2AX Millipore Mouse GFP Abcam Chicken H3K9me3 Abcam Rabbit Lamin A Abcam Rabbit MAP2 Abcam Chicken Nanog Novus Biologicals Goat RNA Extraction Total RNA was extracted from hiPSCs and iNeurons for each condition using GenElute mammalian total RNA miniprep kit (Sigma-Aldrich) with On-Column DNaseI Digestion Set (Sigma-Aldrich). Quantitative Real-Time PCR (qRT-PCR) cDNA synthesis was performed with the Maxima First Strand cDNA Synthesis Kit (Thermo Fisher Scientific). PowerUp SYBR Green Master Mix (Thermo Fisher Scientific) was used for RT-PCR. Samples were run on the QuantStudio 6 Flex Real-Timer PCR System machine (Applied Biosystems). All samples were analysed in technical duplicates or triplicates and normalized to the house-keeping gene Porphobilinogen Deaminase 1 (PBGD1). Results were analysed with the ΔΔCt method. See Table 2 for a full list of primer sequences. Table 2: List of Primers Used for qRT-PCR Analysis. Gene Forward Sequence Reverse Sequence GFP ATCTACTTCGGCTTCGTGACC CTGGGACGGGGTCTCCAT (SEQ ID NO: 18) (SEQ ID NO: 19) MAP2 AGACTGCAGCTCTGCCTTTAG AGGCTGTAAGTAAATCTTCCTCC (SEQ ID NO: 20) (SEQ ID NO: 21) NANOG AGCAGATGCAAGAACTCTCCAA TGAGGCCTTCTGCGTCACAC (SEQ ID NO: 22) (SEQ ID NO: 23) OCT4 GTGGAGGAAGCTGACAACAA ATTCTCCAGGTTGCCTCTCA (SEQ ID NO: 24) (SEQ ID NO: 25) Progerin ACGACGAGGATGAGGATGGA TTCTGGGGGCTCTGGGCTC (SEQ ID NO: 26) (SEQ ID NO: 27) PSD-95 GGCAGCCCTGAAGAACACGTATGA CCCAGGTAGCTGCTGTGACTGATC CLO-C-P3598PCT (SEQ ID NO: 28) (SEQ ID NO: 29) Synapsin-1 CCCTGGGTGTTTGCCCAGAT ACCACGGGGTACGTTGTACT (SEQ ID NO: 30) (SEQ ID NO: 31) Telomere Length Analysis Genomic DNA was extracted from non-aged and aged iPSCs samples using Wizard SV genomic DNA purification system kit (Promega) according to manufacturer’s protocol. Telomere length measurement was based on previously published protocol with some Front. Physiol., 13:1007418, doi: https: / / doi.org / . qPCR was performed in 20μL final volume reactions including 12ng per reaction genomic DNA. Reaction mixture consisted of Fast SYBR Green master mix (Thermo Fisher Scientific), 300nM of primer Tel forward (CGGTTTGTTTGGGTTTGGGTTTGGGTTTGGGTTTGGGTT (SEQ ID NO: 32)), 900nM of primer Tel reverse (GGCTTGCCTTACCCTTACCCTTACCCTT ACCCTTACCCT (SEQ ID NO: 33)) or 500nM of primer 36B4 single gene forward (CAGCAA GTGGGAAGGTGTAATCC (SEQ ID NO: 34)) and 500nM of primer 36B4 single gene reverse (CCCATTCTATCATCAACGGGTACAA (SEQ ID NO: 35)). Reactions were carried out using QuantStudio 6 Flex Real-Timer PCR System machine. Amplification cycling was set in two stages: 10 minutes at 95°C followed by 45 cycles of 15 seconds at 95°C and 2 minutes at 54°C for telomere reactions or 10 minutes at 95°C followed by 45 cycles of 15 seconds at 95°C and 1 minute at 58°C for single gene reactions. Telomere length was calculated as telomere to single copy gene ratio (T / S ratio) and based on the calculation of the ΔCt [Ct (telomeres) / Ct (single gene)]. Telomere length is expressed as the relative T / S ratio, which is normalized to the average T / S ratio of reference sample [2−(ΔCtx − ΔCtr) = 2−ΔΔCT]. Bulk RNA Sequencing Prior to differential expression analysis, raw reads were evaluated for quality check in terms of sequencing quality and contamination. Paired-end bulk RNA-seq data were obtained in FASTQ format generated from GFP-Progerin aged and non-aged iPSCs samples, 3 biological replicates each. Reads initial quality assessment was done by using the FQSTQC and MultiQC tools. Adapter sequences and low-quality bases from reads were trimmed using Trimmomatic (v.0.39). Trimmed reads were mapped to the Homo sapiens genome (GRCh38.105 assembly) using STAR (2.7.10b) mapper. With uniquely mapped read, read counts for features (exons) were generated using the featureCounts function from the Subread package (v 1.6.1) using the Ensembl Known Gene models (version GRCh38.105) as reference annotations. CLO-C-P3598PCT The differentially expressed genes (DEGs) (at P value (FDR) < 0.05) obtained by “Aged” and “Non-aged” control from GFP-Progerin iPSCs. Next, genes involved in the pathways of interest were obtained from the KEGG pathways database. Based on this, volcano plots were generated for each pathway of interest using “ggrepel” and “ggplot2” R packages. Statistical Analysis Statistical analysis was performed with GraphPad Prism (v10). The number of replicates, the statistical test used, and the test results are described in the figure legends. Unless stated otherwise data is presented as mean ± SD. For comparisons between two groups, the unpaired student t-test was used. For multiple comparisons, the one-way analysis of variance (ANOVA) was used with Dunnett’s or Tukey’s multiple comparisons test. DNA Methylation and Epigenetic Clock Analysis Genomic DNA was extracted using Qiagen DNeasy Blood and Tissue kit according to the manufacturer protocol. Samples were sent to ‘Clock Foundation’ for DNA methylation processing and data analysis. Shannon Entropy Analysis Shannon entropy analysis was performed as previously described (Hannum et al. 2013, Molecular Cell, 49:359–67). The following formula was used: ^ ^^^^^^^ = ^ ^∗^^^ (∑^[^^^ ∗ log(^^^)+(1 − ^^^)∗ log(1 − ^^^)] , ^) where MFi is the methylation fraction of the ithmethylation marker and N is the number of markers. Example 1: Overexpression of Progerin in hiPSCs under Doxycycline Control In order to force age human iPSCs, an inducible system was designed, based on the TetOn system (Baron & Bujard (2000) Meth. in Enzymol., 327:401-421, doi: https: / / doi.org / 10.1016 / S0076-6879(00)27292-3), which allowed overexpression of progerin under doxycycline control. The inducible system was targeted into 2 genome safe harbour (GSH) sites. The rtTA cassette was introduced into the ROSA26 locus, while the second cassette, overexpressing GFP-Progerin, was introduced into the AAVS1 locus (Figure 1A). Two different iPSCs background were tested, BOBC (A1ATD-iPSCs) and KOLF2 (HPSI0114i). Both lines demonstrated expression of GFP (which was tagged to Progerin) following doxycycline treatment (Figure 1B). Quantitative RT-PCR analysis based on mRNA levels of progerin also confirmed overexpression of progerin in the ‘Aged’ group which was CLO-C-P3598PCT treated with doxycycline (Figure 1C). Doxycycline dose response assay demonstrated that the standard doxycycline concentrations (2μg / mL) used in most induction protocols with the TetOn system, resulted in a complete cell death (Figure 2A). Thus, doxycycline concentration had to be titrated. A concentration of ^ ^0.05μg / mL, 40,000 times lower, was found to have minor effect on cell viability while still allowing sufficient and detectable expression of progerin in the cells (Figures 2B-C). Example 2: Phenotypic Changes Associated with Ageing in hiPSCs Overexpressing Progerin Using the TetOn System Multiple ageing phenotypes were assessed in the hiPSCs which had been force-aged by progerin overexpression under the control of doxycycline (Example 1). Ageing of the hiPSCs led to increased genomic instability (Figure 3), reduced telomere length and differential expression of genes involved in telomere regulation (Figure 4), epigenetic changes associated with age (reduced H3K9me3; Figure 5), loss of proteostasis (Figure 6), altered autophagic flux (Figure 7), downregulated nutrient sensing (Figure 8), mitochondrial dysfunction (Figure 9), increased cellular senescence (Figure 10) and reduced proliferation rate indicating stem cell exhaustion (Figure 11). Example 3: Constitutive Overexpression of Progerin in Induced Neurons To allow both the induction of neurons from human iPSCs and to age the cells, a dual inducible system was designed. This dual system included a combination of the TetOn inducible system, to overexpress (Mullick et al. (2006) BMC Biotechnol., 6:43, doi: (2020) Analytical Biochemistry, 599:113748, doi: and Seo and Biotechnol., 103(1):303-313, doi: to overexpress GFP-Progerin. To allow a constitutive expression of GFP-Progerin, the cumate repressor (CymR) was excluded from the initial vector cloning and only the rtTA was introduced into the ROSA26 locus (Figure 12A). In this way, CymR does not bind to the cumate operator to repress progerin expression. The reprogramming cassette included both NGN2 under doxycycline control, and a constitutive GFP-progerin expression under the cumate operator (CuO). This new system allowed: 1) to remove the necessity / dependency of the system in the cumate molecule; 2) a constitutive expression of progerin to force age the cells; 3) to allow a stable and a low expression of progerin due to a weak promoter; and 4) to prevent cell death due to progerin toxicity. This new line of aged iPSCs / iNs was referred to as chronically aged. CLO-C-P3598PCT To assess whether the viability of the resulting aged hiPSCs were affected by the constitutive overexpression of progerin, a proliferation assay was conducted. The chronically aged iPSCs showed to extend (Figure 13A) and proliferate (Figure 13B) at normal rates as controls, reaching to a plateau after 7 days in culture. No indication of cell death was observed. Chronically aged iPSCs were kept in culture (while passaged once a week) for up to 4 months, while remaining viable and proliferative (data not shown). To support the proliferation assay, immunocytochemistry (ICC) staining for the pluripotency marker, NANOG, was performed (Figure 13C). GFP was not detectable using ICC methods, however, a quantitative analysis of mRNA levels of GFP showed expression of GFP-Progerin in the aged iPSCs (Figure 13D). To validate the generation of chronically aged iNeurons, the previously published protocol for inducing neurons was used (Baranes et al. (2017) Glia, 71(8):1870-1889, doi: https: / / doi.org / 10.1002 / GLIA.24372; Pawlowskit et al. (2017) Stem Cell Reports, 8(4):803- 812, doi: https: / / doi.org / 10.1016 / j.stemcr.2017.02.016; and Tourigny et al. (2018) BioRxiv, 363671, doi: https: / / doi.org / 10.1101 / 363671; Figure 12B). The aged iNs showed to downregulate pluripotency markers (OCT4 and NANOG) compared to iPSCs, while upregulating neuronal markers such as the dendritic marker MAP2 and the pre- and post- synaptic markers Synapsin-1 and PSD95, respectively (Figure 14). Additionally, both ICC staining and qRT-PCR analysis confirmed expression of GFP in the aged cells (Figures 15A- B). Although, the aged iNs developed neuronal network similarly as was shown before for NGN2-iNs, the dendritic architecture was shown to be less complex with thinner processes and less neurite bundles (Figures 15C-D). An electrophysiological analysis for the spontaneous neuronal activity in the cells, based on multi electrode area analysis, confirmed firing rates activity in the aged iNs similarly as in non-aged iNs (Figure 16). However, burst duration in the aged iNs was compromised at later stages of neuronal culture and maturity. Mitochondrial dysfunction, a well-known hallmark of ageing, was validated based on oxygen consumption rates (OCRs) analysis (Figure 17A). Aged iNeurons showed to have reduced OCR levels compared to control iNeurons (Figure 17B), characterised with significantly reduced basal respiration, maximal respiration, and ATP production rates (Figure 17C). Furthermore, the energetic profile of the aged and non-aged iNeurons was assessed by measuring mitochondrial respiration and glycolysis under baseline and stressed conditions (Oligomycin + FCCP injections) (Figure 17D). In comparison to the aged cells, non-aged iNeurons exhibited a more energetic and aerobic baseline metabolic profile. The aged cells, on the other hand, displayed a comparatively quiescent metabolism. When subjected to stress conditions, both non-aged and aged iNeurons exhibited an upregulation of the glycolytic pathway, potentially compensating for a decline in mitochondrial respiration. However, it is CLO-C-P3598PCT worth noting that the aged iNeurons showed a diminished metabolic capacity, as evidenced by their reduced ability to meet energy demands (d2<d1). While the data presented here is for neurons forward programmed from aged iPSCs (chronically aged iNeurons), it is expected that these can be extrapolated to any other somatic cell type forward programmed or differentiated from the aged iPSCs and stem cells described herein. As will be appreciated, the specific phenotypic changes associated with ageing (less complex dendritic architecture and compromised burst duration seen in aged iNeurons), will depend on the somatic cell type and may be selected from any one or more of those previously described. Example 4: Epigenetic Alterations in caiNs Epigenetic alterations were assessed using established epigenetic clock models, including the DNAmAge prediction clock developed by Steve Horvath (Horvath 2013 Genome Biol 14, 3156, doi: https: / / doi.org / 10.1186 / gb-2013-14-10-r115). The analysis revealed an increase in the predicted biological age of caiNs compared to non-aged iNs (Figure 18). In addition to the epigenetic clock assessment, the level of methylated CpG sites was analyzed to measure Shannon entropy. This analysis demonstrated higher entropy in caiNs relative to non-aged iNs, indicating that caiNs exhibit a more advanced biological age (Figure 19).

Claims

CLO-C-P3598PCT CLAIMS 1. An induced pluripotent stem cell (iPSC), stem cell or a somatic cell derived from an iPSC or a stem cell by forward programming or directed differentiation comprising an expression cassette, said expression cassette comprising a coding sequence for an alternative splice form of Lamin A coupled to a weak promoter sequence, thereby yielding low level constitutive expression of the alternative splice form of Lamin A in the cell while maintaining cell viability.

2. The iPSC, stem cell or somatic cell of claim 1, wherein the weak promoter sequence is a weak constitutive promoter.

3. The iPSC, stem cell or somatic cell of claim 1, wherein the weak promoter sequence is a strong constitutive promoter coupled to a transcriptional repressor sequence.

4. The iPSC, stem cell or somatic cell of claim 3, wherein the transcriptional repressor sequence is an endogenous repressor sequence or is exogenous.

5. The iPSC, stem cell or somatic cell of claim 4, wherein the transcriptional repressor sequence is exogenous and is operably linked to the strong constitutive promoter, such as wherein the weak promoter sequence comprises a cumate operator (CuO) sequence and a strong constitutive promoter.

6. The iPSC, stem cell or somatic cell of claim 4 or claim 5, wherein the cell does not comprise a sequence coding for a repressor protein which recognises the exogenous repressor sequence, such as a sequence coding for a cumate repressor protein (CymR).

7. The iPSC, stem cell or somatic cell of claim 6, wherein the presence of the expression cassette comprising an exogenous repressor sequence operably linked to a strong constitutive promoter and the absence of sequence coding for a repressor protein which recognises said exogenous repressor sequence, such as a CymR coding sequence, yields constitutive expression of the alternative splice form of Lamin A in the cell.

8. The iPSC, stem cell or somatic cell of any one of claims 1 to 7, wherein the alternative splice form of Lamin A is progerin or a progerin-like truncated form of Lamin A,CLO-C-P3598PCT optionally wherein the progerin comprises the amino acid sequence of SEQ ID NO: 16, or a variant or functional fragment thereof, and / or comprises an amino acid sequence encoded by SEQ ID NO: 17, or a variant or functional fragment thereof.

9. The iPSC, stem cell or somatic cell of any one of claims 1 to 8, wherein the expression cassette comprises the coding sequence for the alternative splice form of Lamin A operably linked to a weak promoter in the following order: 5’-constitutive promoter-coding sequence-3’, such as: 5’-constitutive promoter-repressor sequence-coding sequence-3’, or 5’-repressor sequence-constitutive promoter-coding sequence-3’..

10. The iPSC, stem cell or somatic cell of any one of claims 1 to 9, wherein the cell is an iPSC or a stem cell and cellular regeneration functions are maintained, optionally wherein an ageing phenotype is displayed following forward programming or directed differentiation of said iPSC or stem cell to a somatic cell.

11. The iPSC, stem cell or somatic cell of any one of claims 1 to 10, wherein the cell chronically displays an ageing phenotype.

12. The iPSC, stem cell or somatic cell of claim 11, wherein the ageing phenotype is selected from any one or more of: proliferation, senescence, changes in cell and / or nuclear morphology, mitochondrial function, changes in gene expression, altered expression of Lamin- A and / or Lamin-C nuclear protein, in particular upregulation, epigenetic marks associated with ageing, altered DNA or histone methylation, methylation entropy, DNA double strand breaks, telomere length, and an epigenetic clock and / or further transcriptomic clock, in particular changes in cell and / or nuclear morphology and / or a further transcriptomic clock, such as a transcriptomic signature associated with an aged phenotype.

13. The iPSC, stem cell or somatic cell of claim 12, wherein the ageing phenotype is reduced proliferation and / or increased senescence, wherein the changes in nuclear morphology are folding abnormalities, blebbing and / or loss of nuclear circularity, wherein the mitochondrial function is reduced oxygen consumption and / or increased mitochondrial reactive oxygen species (ROS), wherein the changes in gene expression are selected from one or more of: differential / altered expression of somatic cell lineage identity genes, differential expression of mitochondrial genes, differential expression of apoptosis- and / or senescence-related genes,CLO-C-P3598PCT differential expression of autophagy-associated genes, differential expression of inflammation response-related genes, differential expression of altered intracellular communication-related genes, deregulated nutrient-sensing-related genes, and differential expression of DNA damage-related genes, such as one or more of: downregulation of somatic cell lineage identity genes, downregulation of mitochondrial genes, upregulation of apoptosis- and / or senescence- related genes and downregulation / upregulation of autophagy-associated genes, wherein the epigenetic marks associated with ageing are selected from one or more of: reduced heterochromatin trimethylated H3K9 (H3K9me3), reduced HP1γ, and increased γH2AX, wherein the telomere length is shortened, and / or wherein the transcriptomic and / or epigenetic clock is a single cell transcriptomic and / or epigenetic clock.

14. The iPSC, stem cell or somatic cell of any one of claims 1 to 13, wherein the cell comprises a further expression cassette comprising one or more coding sequences for one or more lineage-specific transcription factors operably linked to an inducible promoter, optionally wherein the inducible promoter comprises a tetracycline operator (TetO) sequence and a constitutive promoter.

15. The iPSC, stem cell or somatic cell of claim 14, wherein the inducible promoter is regulated by a transcriptional regulator protein and said transcriptional regulator protein is controlled by an exogenously supplied substance, optionally wherein the transcriptional regulator protein is a tetracycline-responsive transcriptional activator protein (rtTa) and the exogenously supplied substance is tetracycline or a derivate thereof, such as doxycycline.

16. The iPSC, stem cell or somatic cell of claim 15, wherein upon exposure of the cell to the exogenously supplied substance (e.g. tetracycline or a derivate thereof), the one or more lineage-specific transcription factors are expressed.

17. Use of the iPSC, stem cell or somatic cell of any one of claims 1 to 16 in a method of identifying a gene or a combination of genes involved in the reversal of an ageing phenotype or in the maintenance of a non-aged phenotype in the cell.

18. The use of claim 17, wherein the method of identifying a gene or combination of genes comprises the steps of: (i) culturing the iPSC, stem cell or somatic cell of any one of claims 1 to 16;CLO-C-P3598PCT (ii) performing a loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen in the cell; (iii) measuring an ageing phenotype in the cell; and (iv) identifying a gene or combination of genes as being involved in the reversal of an ageing phenotype or maintenance of a non-aged phenotype when the ageing phenotype is altered when the loss-of-function, inhibitory, knock-out, activatory, gain-of-function or combinatorial screen is performed.

19. The use of claim 17 or claim 18, wherein the ageing phenotype measured in step (iii) is the same ageing phenotype chronically displayed by the cell according to any one of claims 11 to 13.

20. The use of any one of claims 17 to 19, wherein the cell is an iPSC or a stem cell and is forward programmed or differentiated to a somatic cell, or wherein the cell is a somatic cell derived from an iPSC or a stem cell by forward programming or directed differentiation, and wherein the forward programming or differentiation is performed before and / or after the identification of the gene or combination of genes, such as wherein forward programming or directed differentiation is performed in culturing step (i) and / or after performing the screen of step (ii).

21. The use of any one of claims 17 to 20, wherein the use is in vitro and / or the method of identifying a gene or combination of genes is performed in vitro.

22. A method of rejuvenating a somatic cell comprising modulating the expression and / or activity of one or more gene or combination of genes identified by the use of any one of claims 17 to 21, optionally wherein the rejuvenated cell comprises a reduced and / or slowed progression of an ageing phenotype compared to a non-rejuvenated cell, and wherein the ageing phenotype is as defined in claim 12 or claim 13.

23. An age-modulating method for use in a method of treating a disease or disorder associated with ageing in a subject, said age-modulating method comprising modulating the expression and / or activity of a gene or a combination of genes identified by the use of any one of claims 17 to 21.

24. A method of modulating ageing in vivo, said method comprising the age-modulating method of claim 23, andCLO-C-P3598PCT optionally comprising administering a modulator of the expression and / or activity of the gene or combination of genes identified by the use of any one of claims 17 to 21.

25. A method of treating a disease or disorder associated with ageing, said method comprising the age-modulating method of claim 23, and optionally comprising administering a modulator of the expression and / or activity of the gene or combination of genes identified by the use of any one of claims 17 to 21.

Images