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Compositions for elimination of senescent cells

A technology for senescent cells and compositions, which is applied in the field of selectively removing senescent cell compositions and screening senescent cell lysing agents, and can solve problems such as side effects

Pending Publication Date: 2021-09-03
UNIV FUR BODENKULTUR WIEN +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, many reported senescent cell lysers, such as navitoclax and dasatinib, have severe side effects, and most senescent cell lysers are not universally effective in all cell types

Method used

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  • Compositions for elimination of senescent cells
  • Compositions for elimination of senescent cells
  • Compositions for elimination of senescent cells

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0245] Example 1: Altered Lipid Metabolism in Senescent Cells

Embodiment 1A

[0246] Example 1A: Identification of elevated levels of lysoPC in senescent cells

[0247] As described herein, altered lipid metabolism in senescent cells was discovered and two lyso PCs were identified as novel biomarkers of aging using mass spectrometry. In various primary human cell lines, 1-stearoyl-2-hydroxy-SN-glycerol-3-phosphorylcholine (18:0lyso PC) and 1-palmitoyl-2-hydroxy-SN-glycerol- 3-Phosphorylcholine (16:0lyso PC) is upregulated during aging, whether the inducer is telomere-dependent (replicative senescence) or independent (stress-induced progeria; figure 1 ).

[0248] figure 1 showed elevated lysophosphatidylcholine in senescent cells. figure 1 a shows the lipid profile of human dermal fibroblasts (HDFs) from three different donors at early, mid and late population doubling (PD), where the levels of lysoPC were relative to dipalmitoylphosphatidylcholine (DPPC) Levels are normalized. figure 1 b shows lipid analysis of stress-induced progeria (SIPS) FIDF a...

Embodiment 1B

[0251] Example 1B: Increased production of arachidonic acid (AA) in senescent cells

[0252] The secreted phospholipase A2 receptor (PLA2R1) induces cellular senescence (Augert et al. 2009) and was upregulated in our dataset ( figure 2 ), which was reported to activate PLA2G4A through phosphorylation of MAPK to induce the production of lyso PC and the simultaneous release of arachidonic acid (AA) (Fonteh et al. 2000; Pan et al. 2015; Scott et al. 2006).

[0253] Given the fact that an increase in lyso PC is evident under senescence in all cell lines examined and independent of senescence-inducing agents, it is suggested that altered lipid metabolism can be used as a tool to exploit specificity for senescent cells and thus be useful in the prevention or Targets for cytotoxic therapies for the treatment of age-related diseases and disorders.

[0254] Increased eicosanoid formation has been reported to be associated with cellular senescence and senescence (Currais et al. 2016; ...

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Abstract

The invention relates to a composition comprising one or more inhibitors capable of inhibiting at least two of cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and lipoxygenase or a composition comprising one or more inhibitors capable of inhibiting an enzyme with arachidonate-CoA ligase activity, specifically long-chain-fatty-acid-CoA ligase (ACSL)1, ACSL3, ACSL4, ACSL5, ACSL6, SLC27A2 or ACSBG2, or a combination thereof for use in selectively eliminating senescent cells. The invention further relates to an in vitro method of identifying senescent cells in a subject and to a method of identifying candidate compounds for the selective elimination of senescent cells.

Description

technical field [0001] The invention relates to the field of senolytics, and provides a composition for selectively clearing senolytics and a method for screening compounds of senolytics. Background technique [0002] Senescent cells have been found to accumulate in tissues and organs during the aging process, which is very close to age-related pathology, where senescent cells play a crucial role in the initiation and progression of age-related diseases and disorders. Elimination of senescent cells in mouse models using genetic or pharmacological approaches has been shown to prolong healthspan and prevent or delay the onset of age-related diseases and disorders, as well as the development of frailty. Since then, a variety of pharmacological compounds capable of selectively clearing senescent cells have been identified and are often referred to as "senolytics". [0003] Although cellular senescence is a tumor suppressor mechanism, during embryonic development ( -Espín et a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/196A61K31/403A61K31/405A61K31/616A61P35/00
CPCG01N2500/10A61K31/196A61K31/403A61K31/405A61K31/616A61P35/00A61K31/415A61K31/661A61K45/06G01N33/5308G01N33/56966G01N2510/00G01N2800/7042
Inventor I·拉默曼J·格里拉里V·皮尔斯F·格鲁贝尔M-S·纳茨特
Owner UNIV FUR BODENKULTUR WIEN
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