Compositions and methods for extending longevity

Abstract

To provide a composition that extends the lifespan of a subject and / or reduces or delays the onset of at least one age-related symptom or condition.SOLUTION: In some embodiments, the composition comprises at least one bacterial strain or extract(s) thereof or component(s) thereof and an excipient. In some embodiments, the at least one bacterial strain comprises the genus Gluconobacter, Acetobacter, Gluconoacetobacter, Acidomonas, Ameyamaea, Asaia, Granulibacter, Kozakia, Neoasaia, Neokomagataea, Saccharibacter, Swaminathania, Tanticharoenia, or combinations thereof. Also provided are methods of making and using the compositions disclosed herein.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 909,186, filed October 1, 2019, the entire contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Aging is a complex process that affects all cellular processes and leads to diverse functional changes. Summary of the Invention

[0003] The present disclosure provides compositions comprising at least one bacterial strain or extract(s) or component(s) thereof, and an excipient.

[0004] In some embodiments, the at least one bacterial strain comprises the genus Gluconobacter, Acetobacter, Gluconoacaetobacter, Acidomonas, Ameyamaea, Asaia, Granulibacter, Kozakia, Neoasaia, Neokomagataea, Saccharibacter, Swaminathania, Tanticharoenia, or a combination thereof. In some embodiments, at least one bacterial strain comprises Gluconobacter albidus, Gluconobacter cerinus, Gluconobacter frateruii, Gluconobacter japonicus, Gluconobacter kondonii, Gluconobacter nephelii, Gluconobacter oxydans, Gluconoacetobacter diazotrophicus, Gluconoacetobacter hansenii, Gluconoacetobacter saccharivorans, Acetobacter aceti, Acetobacter malorum, or a combination thereof. In some embodiments, at least one bacterial strain comprises Gluconacetobacter hansenii, Gluconobacter oxydans, Acetobacter aceti, or a combination thereof. In some embodiments, at least one bacterial strain comprises Gluconacetobacter hansenii.

[0005] In some embodiments, the excipient is or includes an inert (e.g., non-biologically active) agent. The excipient may be included in the composition, for example, to provide or contribute a desired consistency or stabilizing effect. In some embodiments, the excipient may include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, or ethanol.

[0006] In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is a food, beverage, feed composition, or dietary supplement. In some embodiments, the composition is a liquid, syrup, tablet, lozenge, gummy, capsule, powder, gel, or film. In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is an enteric-coated formulation.

[0007] In some embodiments, when at least one bacterial strain or extract(s) or component(s) thereof is administered to a C. elegans culture comprising C. elegans animals, the average lifespan of the C. elegans animals in the C. elegans culture is characterized in that it is extended by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% compared to that of C. elegans animals in an equivalent C. elegans culture without the administration of the at least one bacterial strain or extract(s) or component(s) thereof.

[0008] In some embodiments, when at least one bacterial strain or extract(s) or component(s) thereof is administered to a C. elegans culture comprising C. elegans animals, the average pharyngeal pumping activity of the C. elegans animals in the C. elegans culture is characterized in that it is increased by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% compared to that of C. elegans animals in an equivalent C. elegans culture without the administration of the at least one bacterial strain or extract(s) or component(s) thereof.

[0009] In some embodiments, when at least one bacterial strain or extract(s) or component(s) thereof is administered to a C. elegans culture comprising C. elegans animals, the average movement speed of the C. elegans animals in the C. elegans culture is characterized in that it is increased by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% compared to that of C. elegans animals in an equivalent C. elegans culture without the administration of the at least one bacterial strain or extract(s) or component(s) thereof.

[0010] In some embodiments, when at least one bacterial strain or extract(s) or component(s) thereof is administered to a C. elegans culture comprising C. elegans animals, the reproductive ability of the C. elegans animals in the C. elegans culture is characterized in that it is reduced by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% compared to that of C. elegans animals in an equivalent C. elegans culture without the administration of the at least one bacterial strain or extract(s) or component(s) thereof.

[0011] In some embodiments, the at least one bacterial strain or extract(s) or component(s) thereof is characterized in that when a C. elegans culture containing the C. elegans animals is exposed to ultraviolet radiation, the average survival time of C. elegans animals in the C. elegans culture administered with the at least one bacterial strain or extract(s) or component(s) thereof is increased by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% compared to that of C. elegans animals in an equivalent C. elegans culture without the administration of the at least one bacterial strain or extract(s) or component(s) thereof.

[0012] In some embodiments, the at least one bacterial strain, or extract(s) or component(s) thereof, is characterized in that when a C. elegans culture containing the C. elegans animals is exposed to an elevated temperature, the mean survival time of C. elegans animals in the C. elegans culture administered with the at least one bacterial strain, or extract(s) thereof, or component(s) thereof, is increased by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% compared to that of C. elegans animals in an equivalent C. elegans culture without the administration of the at least one bacterial strain, or extract(s) thereof, or component(s). In some embodiments, the elevated temperature is at least 37°C, at least 40°C, at least 45°C, at least 50°C, at least 55°C, at least 60°C, at least 65°C, at least 70°C, at least 75°C, or at least 80°C. In some embodiments, the elevated temperature is between 50°C and 65°C, between 65°C and 80°C, or between 80°C and 120°C.

[0013] In some embodiments, when at least one bacterial strain or extract(s) or component(s) thereof is administered to a C. elegans culture comprising the C. elegans animals, the average amount of intestinal fat observed in the C. elegans animals is characterized in that it is reduced by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% compared to that of C. elegans animals in an equivalent C. elegans culture without the administration of the at least one bacterial strain or extract(s) or component(s) thereof.

[0014] In some embodiments, the C. elegans animal is an adult C. elegans animal. In some embodiments, the C. elegans animal is at least 5 days old.

[0015] The present disclosure provides methods comprising administering a composition described herein to a subject of the composition.

[0016] In some embodiments, the method is a method of extending the lifespan of a subject, hi some embodiments, the lifespan of the subject is extended by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% compared to that of a comparable subject without administration of the composition.

[0017] In some embodiments, the method is a method of reducing or delaying the onset of at least one age-related symptom or condition in a subject. In some embodiments, the at least one age-related symptom or condition is reduced or delayed by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% in the subject compared to that of a comparable subject without administration of the composition. In some embodiments, the at least one age-related symptom or condition is or includes a decline in muscle and / or neuromuscular function in the subject. In some embodiments, the at least one age-related symptom or condition is or includes dysregulation of lipid metabolism.

[0018] In some embodiments, the subject is at least 30 years old, at least 35 years old, at least 40 years old, at least 45 years old, at least 50 years old, at least 55 years old, at least 60 years old, at least 65 years old, at least 70 years old, or at least 75 years old. In some embodiments, the subject is an elderly subject.

[0019] In some embodiments, the subject is a mammal. In some embodiments, the animal is a non-human primate (e.g., a higher primate), a sheep, a dog, a rodent (e.g., a mouse or a rat), a guinea pig, a goat, a pig, a cat, a rabbit, or a cow. In some embodiments, the mammal is a human.

[0020] In some embodiments, the methods include administering a sufficient amount of a microorganism to colonize the microbiota of the subject.

[0021] In some embodiments, the administering step comprises ingesting.

[0022] The present disclosure provides for the use of a composition disclosed herein to extend the lifespan of a subject. The present disclosure provides for the use of at least one bacterial strain, or an extract(s) or component(s) thereof, to extend the lifespan of a subject. In some embodiments, the at least one bacterial strain comprises a species of the genus Gluconobacter, Acetobacter, Gluconoacaetobacter, Acidomonas, Ameyamaea, Asaia, Granulibacter, Kozakia, Neoasaia, Neokomagataea, Saccharibacter, Swaminathania, Tanticharoenia, or a combination thereof. In some embodiments, the at least one bacterial strain comprises Gluconacetobacter hansenii, Gluconobacter oxydans, Acetobacter aceti, or a combination thereof. In some embodiments, the at least one bacterial strain comprises Gluconacetobacter hansenii.

[0023] The present disclosure provides for the use of a composition described herein to reduce or delay the onset of at least one age-related symptom or condition in a subject. The present disclosure provides for the use of at least one bacterial strain, or an extract(s) or component(s) thereof, to reduce or delay the onset of at least one age-related symptom or condition in a subject. In some embodiments, the at least one bacterial strain comprises a species of the genus Gluconobacter, Acetobacter, Gluconoacaetobacter, Acidomonas, Ameyamaea, Asaia, Granulibacter, Kozakia, Neoasaia, Neokomagataea, Saccharibacter, Swaminathania, Tanticharoenia, or a combination thereof. In some embodiments, the at least one bacterial strain comprises Gluconacetobacter hansenii, Gluconobacter oxydans, Acetobacter aceti, or a combination thereof. In some embodiments, the at least one bacterial strain comprises Gluconacetobacter hansenii.

[0024] In some embodiments, at least one age-related symptom or condition is reduced or delayed in a subject by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% compared to that of a comparable subject without administration of the composition.

[0025] In some embodiments, the at least one age-related symptom or condition is or comprises a decline in muscle and / or neuromuscular function in the subject. In some embodiments, the at least one age-related symptom or condition is or comprises dysregulation of lipid metabolism.

[0026] In some embodiments, the subject is at least 30 years old, at least 35 years old, at least 40 years old, at least 45 years old, at least 50 years old, at least 55 years old, at least 60 years old, at least 65 years old, at least 70 years old, or at least 75 years old. In some embodiments, the subject is an elderly subject.

[0027] In some embodiments, the subject is a mammal. In some embodiments, the animal is a non-human primate (e.g., a higher primate), a sheep, a dog, a rodent (e.g., a mouse or a rat), a guinea pig, a goat, a pig, a cat, a rabbit, or a cow. In some embodiments, the mammal is a human.

[0028] The present disclosure provides the use of the compositions described herein for treating a subject who has or is at risk of developing a disease or disorder associated with premature aging.The present disclosure provides the use of at least one bacterial strain, or an extract(s) thereof, or a component(s) thereof, for treating a subject who has or is at risk of developing a disease or disorder associated with premature aging.In some embodiments, the disease or disorder is Bloom's syndrome, Bockayne's syndrome, Hutchinson-Gilford progeria syndrome, mandibular palatal dysplasia with lipodystrophy type A, progeria syndrome, Rothmund-Thomson syndrome, Seip's syndrome, or Werner's syndrome.

[0029] The present disclosure provides a method for characterizing the ability of one or more microbial strains to modify lifespan, age-related symptoms, and / or age-related conditions in a subject, comprising: (a) adding a plurality of microbial strains of a mammalian microbiota to a plurality of C. elegans cultures, wherein a different microbial strain is added to each C. elegans culture, and each culture contains C. elegans animals of the same C. elegans strain; and (b) determining whether each microbial strain of the plurality of microbial strains affects one or more parameters of the C. elegans animals in each culture, wherein the one or more parameters are associated with aging, age-related symptoms, and / or age-related conditions.

[0030] The present disclosure provides for the use of C. elegans animals to characterize the ability of one or more microbial strains to modify lifespan, age-associated symptoms, and / or age-associated conditions in a subject.

[0031] The present disclosure provides methods of making the compositions described herein, comprising combining at least one bacterial strain(s) or extract(s) or component(s) thereof, and an excipient.

[0032] definition The scope of the present invention is defined by the claims appended hereto, and is not limited by the specific embodiments described herein. Those skilled in the art will recognize, upon reading this specification, various modifications that are equivalent to such described embodiments or that may otherwise be within the scope of the claims. Generally, terms used in this specification adhere to the meanings understood in the art unless expressly indicated otherwise. Explicit definitions of certain terms are provided below, and the meaning of these and other terms in specific instances throughout this specification will be apparent to those skilled in the art from the context.

[0033] The use of ordinal terms such as "first," "second," "third," etc. in the claims to modify claim elements does not, in itself, imply any priority, precedence, or order of one claim element relative to another claim element or relative to the chronological order in which the actions of a method are performed, but is used solely as a label to distinguish one claim element with a particular name from another element with the same name (but in which an ordinal term is used) to distinguish between claim elements.

[0034] As used herein, the articles "a" and "an" should be understood to include plural referents unless clearly indicated to the contrary. A claim or specification including "or" between one or more members of a group is deemed satisfied when one, more than one, or all group members are present in, employed in, or otherwise relevant to a particular product or process, unless specified to the contrary or where clear from the context. In some embodiments, exactly one member of a group is present in, employed in, or otherwise relevant to a given product or process. In some embodiments, two or more, or all group members are present in, employed in, or otherwise relevant to a given product or process. It should be understood that the invention encompasses all variations, combinations, and permutations of one or more limitations, elements, clauses, descriptive terminology, etc. from one or more of the enumerated claims that are introduced into other claims that rely on the same base claim (or any other claim, if relevant), unless otherwise indicated in the paragraph or where it is clear to one of ordinary skill in the art that a contradiction or inconsistency would result. Where elements are presented as a list (e.g., in a Markush group or similar format), it is understood that each subgroup of elements is also disclosed, and that any element(s) can be deleted from the group. Generally, when an embodiment or aspect is referred to as "comprising" certain elements, features, etc., it should be understood that the particular embodiment or aspect "consists of" or "consists essentially of" such certain elements, features, etc. For the sake of brevity, these embodiments will not in all instances be specifically described in so many words herein. It is also understood that any embodiment or aspect can be explicitly excluded from the claims, regardless of whether a specific exclusion is set forth in the specification.

[0035] Administration: As used herein, the term "administration" typically refers to the administration of a composition to a subject or system to achieve delivery of an agent to the subject or system. In some embodiments, the agent is or is contained in a composition, and in some embodiments, the agent is produced through metabolism of the composition or one or more components thereof. Those of skill in the art will be aware of the various routes that may be utilized for administration to a subject, e.g., a human, in the appropriate circumstances. For example, in some embodiments, administration may be ocular, oral, parenteral, topical, etc. In certain embodiments, administration can be bronchial (e.g., by bronchial instillation), buccal, transdermal (e.g., can be or include one or more of topical to the dermis, intradermal, interdermal, transdermal), intestinal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, intraspecific organ (e.g., intrahepatic), mucosal, intranasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), intravaginal, or intravitreal. In many embodiments provided by the present disclosure, administration is oral. In some embodiments, administration can include only a single administration. In some embodiments, administration can include the application of a number of doses. In some embodiments, administration can include administration that is intermittent (e.g., multiple doses separated in time) and / or periodic (e.g., individual doses separated by a common period of time) administration. In some embodiments, administration can include continuous dosing (e.g., perfusion) for at least a selected period of time. Administration of cells can be by any suitable route that results in delivery to a desired location in a subject where at least a portion of the delivered cells or cellular components remain viable. Cell survival after administration to a subject can be short-term, such as a few hours, to long-term, such as 24 hours to days, to as long as years, i.e., long-term engraftment. In some embodiments, administration includes delivery of a bacterial extract or preparation that contains one or more bacterial metabolic products and / or by-products, but lacks entirely viable bacterial cells.

[0036] Analog: As used herein, the term "analog" refers to a substance that shares one or more particular structural features, elements, components, or moieties with a reference substance. Typically, an "analog" exhibits significant structural similarity to the reference substance, e.g., sharing a core or consensus structure, but also differs in certain individual ways. In some embodiments, an analog is a substance that can be produced from a reference substance, e.g., by chemical manipulation of the reference substance. In some embodiments, an analog is a substance that can be produced through the implementation of a synthetic process that is substantially similar (e.g., shares multiple steps) to that which produces the reference substance. In some embodiments, an analog is produced, or can be produced, through the implementation of a synthetic process that is different from that used to produce the reference substance.

[0037] Approximately: When applied to one or more values ​​of interest, includes values ​​similar to the stated reference value. In certain embodiments, the term "approximately" or "about" refers to a range of values ​​that is within 10% (greater or lesser) of the stated reference value, unless otherwise stated or clear from the context (except where such number exceeds 100% of possible values).

[0038] Equivalent: As used herein, the term "equivalent" refers to two or more agents, entities, circumstances, sets of conditions, subjects, etc. that may not be identical to one another, but are sufficiently similar to permit a comparison between them where one of skill in the art would understand that conclusions can be reasonably drawn based on the observed differences or similarities. In some embodiments, comparable sets of conditions, circumstances, individuals, or populations are characterized by multiple substantially identical characteristics and one or a few different characteristics. One of skill in the art will understand what degree of identity is required in any given situation for two or more such agents, entities, circumstances, sets of conditions, etc. to be considered equivalent in context. For example, one of skill in the art will understand that sets of circumstances, individuals, or populations are comparable to one another when they are characterized by a sufficient number and type of substantially identical characteristics to warrant a reasonable conclusion that differences in results obtained or phenomena observed under or with different sets of circumstances, individuals, or populations are caused by or indicate variations in those characteristics.

[0039] Conservative: As used herein, refers to an example when describing a conservative amino acid substitution, including the replacement of an amino acid residue with another amino acid residue having a side chain R group with similar chemical properties (e.g., charge or hydrophobicity). Generally, a conservative amino acid substitution will not substantially alter the functional property of interest for the protein, e.g., the ability of a receptor to bind a ligand. Examples of groups of amino acids having side chains with similar chemical properties include aliphatic side chains such as glycine (Gly, G), alanine (Ala, A), valine (Val, V), leucine (Leu, L), and isoleucine (Ile, I); aliphatic hydroxyl side chains such as serine (Ser, S) and threonine (Thr, T); amide-containing side chains such as asparagine (Asn, N) and glutamine (Gln, Q); aromatic side chains such as phenylalanine (Phe, F), tyrosine (Tyr, Y), and tryptophan (Trp, W); basic side chains such as lysine (Lys, K), arginine (Arg, R), and histidine (His, H); acidic side chains such as aspartic acid (Asp, D) and glutamic acid (Glu, E); and sulfur-containing side chains such as cysteine ​​(Cys, C) and methionine (Met, M). Conservative amino acid substitutions include, for example, valine / leucine / isoleucine (Val / Leu / Ile, V / L / I), phenylalanine / tyrosine (Phe / Tyr, F / Y), lysine / arginine (Lys / Arg, K / R), alanine / valine (Ala / Val, A / V), glutamic acid / aspartic acid (Glu / Asp, E / D), and asparagine / glutamine (Asn / Gln, N / Q). In some embodiments, conservative amino acid substitutions can be substitutions of alanine for any naturally occurring residue in a protein, for example, as used in alanine scanning mutagenesis. In some embodiments, conservative substitutions are made that have positive values ​​in the PAM250 log-likelihood matrix disclosed in Gonnet, GH et al., 1992, Science 256:1443-1445, which is incorporated herein by reference in its entirety. In some embodiments, the substitution is a moderately conservative substitution, and the substitution has a non-negative value in the PAM250 log-likelihood matrix. [Table 1]

[0040] Control: As used herein, this refers to the art-understood meaning of "control," a standard against which results are compared. Typically, controls are used to strengthen the integrity of experiments by isolating variables in order to draw conclusions about such variables. In some embodiments, a control is a reaction or assay performed simultaneously with a test reaction or assay to provide a point of comparison. "Control" also includes "control animals." "Control animals" may have a modification as described herein, a different modification than described herein, or no modification (i.e., wild-type animals). In one experiment, the "test" (i.e., the variable being tested) is administered. In a second experiment, the "control" does not receive the variable being tested. In some embodiments, a control is a historical control (i.e., a previously performed test or assay, or a previously known amount or result). In some embodiments, a control is or includes a printed or otherwise kept record. A control can be a positive or negative control.

[0041] Determining, Measuring, Evaluating, Assessing, Assaying, Analyzing, and Analysis: Determining, measuring, evaluating, assessing, assaying, and analyzing are used interchangeably herein to refer to any form of measurement, including determining whether an element is present. These terms include both quantitative and / or qualitative determinations. Assays can be relative or absolute. "Assaying for the presence of" can be determining the amount of something present and / or determining whether it is present or absent.

[0042] Dosage form: Those of skill in the art will understand that the term "dosage form" can be used to refer to a physically discrete unit of an agent (e.g., a therapeutic agent) for administration to a subject. Typically, each such unit contains a predetermined amount of agent. In some embodiments, such amount is a unit dosage (or a whole fraction thereof) appropriate for administration according to a dosing regimen determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., a therapeutic dosing regimen). Those of skill in the art will understand that the total amount of a therapeutic composition or agent to be administered to a particular subject is determined by one or more attending physicians and may involve the administration of multiple dosage forms.

[0043] Dosage regimen: Those skilled in the art will understand that the term "dosage regimen" can be used to refer to a series of unit doses (usually two or more) administered individually to a subject, usually separated by a period of time. In some embodiments, a given medication has a recommended dosing regimen, which can include one or more doses. In some embodiments, a dosing regimen includes multiple doses, each separated in time from the other doses. In some embodiments, the individual doses are separated from each other by periods of equal length, and in some embodiments, a dosing regimen includes multiple doses and at least two different periods separating the individual doses. In some embodiments, all doses within a dosing regimen are the same unit dose amount. In some embodiments, different doses within a dosing regimen are different amounts. In some embodiments, a dosing regimen includes a first dose at a first dose amount, followed by one or more additional doses at a second dose amount that is different from the first dose amount. In some embodiments, a dosing regimen includes a first dose at a first dose amount, followed by one or more additional doses at a second dose amount that is the same as the first dose amount.

[0044] Engineered: In general, the term "engineered" refers to the aspect of having been manipulated by the hand of man. For example, a cell or organism is considered "engineered" if it has been manipulated so that its genetic information has been altered (e.g., by transformation, mating, somatic cell hybridization, transfection, transduction, or other mechanisms, or by which previously present genetic material has been altered or removed, e.g., by substitution or deletion mutation, or by a mating protocol, in which new genetic material not previously present has been introduced, or by which previously present genetic material has been altered or removed, e.g., by changing or removing). As is common practice and understood by those of skill in the art, the progeny of an engineered polynucleotide or cell are typically still referred to as "engineered," despite the actual manipulation that took place on the previous entity.

[0045] Functional: As used herein, a "functional" biomolecule is a biomolecule in a form in which it exhibits a property and / or activity by which it is characterized. A biomolecule can have two functions (i.e., bifunctional) or many functions (i.e., multifunctional).

[0046] Gene: As used herein, refers to a DNA sequence in a chromosome that encodes a product (e.g., an RNA product and / or a polypeptide product). In some embodiments, a gene comprises coding sequence (i.e., a sequence that encodes a specific product). In some embodiments, a gene comprises non-coding sequence. In some specific embodiments, a gene can include both coding (e.g., exonic) and non-coding (e.g., intronic) sequence. In some embodiments, a gene can include one or more regulatory sequences (e.g., promoters, enhancers, etc.) and / or intronic sequences that, for example, can control or influence one or more aspects of gene expression (e.g., cell-type specific expression, inducible expression, etc.). For clarity, as used in this disclosure, the term "gene" generally refers to a portion of a nucleic acid that encodes a polypeptide or fragment thereof; it should be noted that this term can optionally encompass regulatory sequences, as will be clear to one of skill in the art from the context. This definition is not intended to exclude the application of the term "gene" to non-protein-coding expression units, but rather to clarify that, in many cases, the term as used in this document refers to a nucleic acid that encodes a polypeptide.

[0047] Improved, increased, enhanced, inhibited, or reduced: As used herein, the terms "improved," "increased," "enhanced," "inhibited," "reduced," or their grammatical equivalents refer to a value relative to a baseline or other reference measurement. In some embodiments, the value is statistically significantly different from the baseline or other reference measurement. In some embodiments, a suitable reference measurement can be or include a measurement in a particular system (e.g., a single individual) under otherwise equivalent conditions in the absence (e.g., before and / or after) of a particular agent or treatment, or in the presence of an appropriate equivalent reference agent. In some embodiments, a suitable reference measurement can be or include a measurement in an equivalent system known or expected to respond in a particular manner in the presence of the relevant agent or treatment. In some embodiments, a suitable reference is a negative reference; in some embodiments, a suitable reference is a positive reference.

[0048] Isolated: As used herein, refers to a substance and / or entity that (1) has been separated from at least some of the components with which it was originally produced (whether in natural and / or experimental settings) and / or (2) has been designed, created, prepared, and / or manufactured by the hand of man. In some embodiments, an isolated substance or entity may be enriched, and in some embodiments, an isolated substance or entity may be pure. In some embodiments, isolated substances and / or entities are separated from about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% of the other components with which they were originally contained. In some embodiments, an isolated agent is about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99% or greater purity. As used herein, a substance is "pure" if it is substantially free of other components. In some embodiments, as will be understood by those of skill in the art, a substance may still be considered "enriched," "isolated," or even "pure" after being combined with certain other components, such as, for example, one or more carriers or excipients (e.g., buffers, solvents, water, etc.), and in such embodiments, the percent isolation or purity of the substance is calculated without including such carriers or excipients. Those of skill in the art are aware of various techniques for isolating (e.g., enriching or purifying) substances or agents (e.g., using one or more of fractionation, extraction, precipitation, or other separations).

[0049] Pharmaceutical composition: As used herein, the term "pharmaceutical composition" refers to a composition in which an active agent is formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in a unit dosage amount suitable for administration in a treatment regimen that exhibits a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, the pharmaceutical composition may be specially formulated for administration in solid or liquid form, including those adapted for oral administration, such as drenches (aqueous or non-aqueous solutions or suspensions), tablets, buccal, sublingual, and those targeted for systemic absorption, boluses, powders, granules, pastes for application to the tongue, capsules, powders, etc. In some embodiments, the active agent may be or comprise a cell or a population of cells (e.g., a culture, e.g., an EES microorganism), and in some embodiments, the active agent may be or comprise an extract or component of a cell or a population of cells (e.g., a culture). In some embodiments, the active agent may be or comprise an isolated, purified, or pure compound. In some embodiments, the active agent may be synthesized in vitro (e.g., via chemical and / or enzymatic synthesis). In some embodiments, the active agent may be or comprise a natural product (isolated from a natural source or synthesized in vitro).

[0050] Pharmaceutically acceptable: As used herein, the term "pharmaceutically acceptable," which may be used in reference to a carrier, diluent, or excipient used, for example, to formulate a pharmaceutical composition disclosed herein, means a carrier, diluent, or excipient that is compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

[0051] Pharmaceutically acceptable carrier: As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, that is involved in carrying or transporting a compound of interest from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate; excipients such as powdered tragacanth, malt, gelatin, talc, cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar, buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, pH buffer solutions, polyesters, polycarbonates and / or polyanhydrides, and other non-toxic compatible substances used in pharmaceutical formulations.

[0052] Prebiotic: As used herein, "prebiotic" refers to components that enable or promote specific changes in both the composition and / or activity of the gastrointestinal flora that may (or may not) benefit the host. In some embodiments, prebiotics may include one or more of the following: prebiotics include pome fruit extract, berry extract, and walnut extract.

[0053] Prevention: As used herein, the term "prevention" refers to a delay in the onset and / or a reduction in the frequency and / or severity of one or more symptoms of a particular disease, disorder, or condition. In some embodiments, prevention is assessed on a population basis, such that an agent is considered to "prevent" a particular disease, disorder, or condition if a statistically significant reduction in the onset, frequency, and / or intensity of one or more of the disease, disorder, or symptoms is observed in a population susceptible to the disease, disorder, or condition. In some embodiments, prevention may be considered complete, for example, if the onset of the disease, disorder, or condition has been delayed for a predetermined period of time.

[0054] Reference: As used herein, describes a standard or control against which a comparison is made. For example, in some embodiments, a subject agent, animal, individual, population, sample, sequence, or value is compared to a reference or control agent, animal, individual, population, sample, sequence, or value. In some embodiments, the reference or control is tested and / or determined substantially contemporaneously with the subject testing or determination. In some embodiments, the reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as understood by those of skill in the art, a reference or control is determined or characterized under conditions or circumstances comparable to those being evaluated. Those of skill in the art will understand when sufficient similarity exists to justify reliance on and / or comparison to a particular possible reference or control. In some embodiments, the reference is a negative control reference, and in some embodiments, the reference is a positive control reference.

[0055] Risk: As understood from the context, "risk" of a disease, disorder, and / or condition refers to the likelihood that a particular individual will develop the disease, disorder, and / or condition. In some embodiments, risk is expressed as a percentage. In some embodiments, risk is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, to 100%. In some embodiments, risk is expressed as risk compared to the risk associated with a reference sample or group of reference samples. In some embodiments, the reference sample or group of reference samples has a known risk of the disease, disorder, condition, and / or event. In some embodiments, the reference sample or group of reference samples is from an individual comparable to the particular individual. In some embodiments, the relative risk is 0.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more.

[0056] Sample: As used herein, the term "sample" generally refers to an aliquot of material obtained or derived from a source of interest. In some embodiments, the source of interest is a biological or environmental source. In some embodiments, the source of interest can be or include a cell or organism, such as a microorganism, a plant, or an animal (e.g., a human). In some embodiments, the source of interest is or includes a biological tissue or fluid. In some embodiments, the biological tissue or fluid can be or include amniotic fluid, aqueous body fluid, ascites, bile, bone marrow, blood, milk, cerebrospinal fluid, earwax, chyle, chime, semen, endolymph, exudate, feces, gastric acid, gastric juice, lymph, mucus, pericardial fluid, lymph, ascites, pleural fluid, pus, fluid, saliva, serum, semen, serum, smegma, saliva, synovial fluid, sweat, tears, urine, vaginal secretions, vitreous humor, vomit, and / or combinations or components thereof. In some embodiments, the biological fluid may be or include intracellular fluid, extracellular fluid, intravascular fluid (plasma), interstitial fluid, lymph, and / or permeate fluid. In some embodiments, the biological fluid may be or include phytoexudates. In some embodiments, the biological tissue or sample may be obtained, for example, by aspiration, biopsy (e.g., fine needle or tissue biopsy), swab (e.g., oral, nasal, skin, or vaginal swab), scraping, surgery, lavage, or irrigation (e.g., bronchoalveolar, ductal, nasal, ocular, oral, uterine, vaginal, or other lavage or irrigation). In some embodiments, the biological sample is or includes cells obtained from an individual. In some embodiments, the sample is a "primary sample" obtained directly from the source of interest by any suitable means. In some embodiments, as is clear from the context, the term "sample" refers to a preparation obtained by processing the primary sample (e.g., by removing one or more components and / or adding one or more agents), for example, by filtering using a semipermeable membrane.Such a "processed sample" may include, for example, nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to one or more techniques, such as nucleic acid amplification or reverse transcription, isolation and / or purification of specific components, etc.

[0057] Subject: As used herein, the term "subject" refers to an individual to whom the provided treatment is administered. In some embodiments, the subject is an animal. In some embodiments, the subject is a mammal, e.g., a mammal experiencing or susceptible to a disease, disorder, or condition described herein. In some embodiments, the animal is a vertebrate, e.g., a mammal such as a non-human primate (particularly a higher primate), sheep, dog, rodent (e.g., a mouse or rat), guinea pig, goat, pig, cat, rabbit, or cow. In some embodiments, the animal is a non-mammal, such as a chicken, amphibian, reptile, or the invertebrate model C. elegans. In some embodiments, the subject is a human. In some embodiments, the patient is suffering from or susceptible to one or more diseases, disorders, or conditions as described herein. In some embodiments, the patient exhibits one or more symptoms of one or more diseases, disorders, or conditions as described herein. In some embodiments, the patient has been diagnosed with one or more diseases, disorders, or conditions as described herein. In some embodiments, the subject has undergone or is undergoing a particular therapy to diagnose and / or treat a disease, disorder, or condition, hi another embodiment, the subject is an experimental animal or animal surrogate as a disease model.

[0058] Substantially: As used herein, refers to a qualitative condition indicating the entire or nearly entire extent or degree of a characteristic or property of interest. Those skilled in the biological arts will understand that biological and chemical phenomena rarely, if ever, proceed perfectly and / or reach perfection or achieve or avoid absolute results. Thus, the term "substantially" is used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[0059] Symptoms are reduced: According to the present invention, a "symptom is reduced" when the magnitude (e.g., intensity, severity, etc.) and / or frequency of one or more symptoms of a particular disease, disorder, or condition is reduced. For clarity, delaying the onset of a particular symptom is considered a form of reducing the frequency of that symptom.

[0060] Therapeutic regimen: "Therapeutic regimen," as that term is used herein, refers to a dosing regimen, the administration of which across a relevant population can be correlated with a desired or beneficial therapeutic outcome.

[0061] Therapeutically effective amount: As used herein, it refers to an amount that produces a desired effect in a subject to which it is administered. In some embodiments, this term refers to an amount sufficient to treat a disease, disorder, and / or condition when administered to a population suffering from or susceptible to the disease, disorder, and / or condition according to a therapeutic dosing regimen. In some embodiments, a therapeutically effective amount is an amount that reduces the incidence and / or severity of, and / or delays the onset of, one or more symptoms of the disease, disorder, and / or condition. Those skilled in the art will understand that the term "therapeutically effective amount" does not actually require that successful treatment be achieved in a particular individual. Rather, a therapeutically effective amount can be an amount that, when administered to patients in need of such treatment, provides a specific, desired pharmacological response in a substantial number of subjects. In some embodiments, reference to a therapeutically effective amount refers to the amount measured in one or more specific tissues (e.g., tissues affected by a disease, disorder, or condition) or bodily fluids (e.g., blood, saliva, serum, sweat, tears, urine, etc.). Those skilled in the art will appreciate that in some embodiments, a therapeutically effective amount of a particular agent or therapy may be formulated and / or administered in a single dose, while in some embodiments, a therapeutically effective agent may be formulated and / or administered in multiple doses, for example, as part of a dosing regimen.

[0062] Treatment: As used herein, the term "treatment" (or "treat" or "treating") refers to the application of any treatment that partially or completely palliates, improves, reverses, inhibits, delays the onset of, reduces the severity of, and / or reduces the incidence of one or more symptoms, characteristics, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be of subjects who do not exhibit signs of the associated disease, disorder, and / or condition and / or who exhibit only early signs of the disease, disorder, and / or condition. Alternatively, or in addition, such treatment may be of subjects who exhibit one or more established signs of the associated disease, disorder, and / or condition. In some embodiments, treatment may be of subjects who have been diagnosed with the associated disease, disorder, and / or condition. In some embodiments, treatment may be of subjects known to have one or more susceptibility factors that statistically correlate with an increased risk of developing the associated disease, disorder, and / or condition. [Brief explanation of the drawings]

[0063] [Figure 1]This figure contains data demonstrating that administration of Acetobacteraceae increased the lifespan of C. elegans. Panel (A) shows a lifespan assay for C. elegans animals administered either E. coli OP50, Gluconobacter oxydans, Acetobacter aceti, or Gluconacetobacter hansenii. Compared to animals administered E. coli OP50, C. elegans animals administered either Gluconobacter oxydans, Acetobacter aceti, or Gluconacetobacter hansenii had longer lifespans. Panel (B) contains a cumulative hazard plot for C. elegans animals administered either E. coli OP50, Gluconobacter oxydans, Acetobacter aceti, or Gluconacetobacter hansenii. Panel (C) contains the restricted mean lifespan (RMLS) of C. elegans animals administered either E. coli OP50, Gluconobacter oxydans, Acetobacter aceti, or Gluconacetobacter hansenii. Panel (D) contains a statistical analysis of the data shown in panels (A)-(C) of Figure 1. [Figure 2]Panel (A) contains data showing that administration of Acetobacteraceae improved muscle function / activity. Panel (B) contains data obtained by measuring pharyngeal pumping in C. elegans animals administered either E. coli OP50, Gluconobacter oxydans, Acetobacter aceti, or Gluconacetobacter hansenii. Compared to the pharyngeal pumping rate of C. elegans animals administered either E. coli OP50, the pumping rate of C. elegans animals administered either Gluconobacter oxydans, Acetobacter aceti, or Gluconacetobacter hansenii was significantly higher in C. elegans animals on days 6 and 12. The top of each bar indicates the number of C. elegans animals scored. Each bar represents the mean ± SD. Panel (B) contains data obtained by measuring body flexions / minute in C. elegans animals administered either E. coli OP50, Gluconobacter oxydans, Acetobacter aceti, or Gluconacetobacter hansenii. Compared to the number of body flexions / minute in C. elegans animals administered either E. coli OP50, the rate of body flexions / minute in animals administered either Gluconobacter oxydans, Acetobacter aceti, or Gluconacetobacter hansenii was significantly higher in animals on days 6 and 12. NS indicates no significant difference. The top of each bar indicates the number of C. elegans animals scored. Each bar represents the mean ± SD. [Figure 3]Panel (A) contains data showing that administration of Acetobacteraceae improved stress tolerance. Panel (A) contains data obtained from an ultraviolet light tolerance assay of C. elegans animals administered either E. coli OP50, Gluconobacter oxydans, Acetobacter aceti, or Gluconacetobacter hansenii. Compared to UV-irradiated animals administered E. coli OP50, UV-irradiated C. elegans animals administered either Gluconobacter oxydans, Acetobacter aceti, or Gluconacetobacter hansenii had a longer lifespan. The mean ± SD for each measurement is plotted. Panel (B) contains data obtained from a heat tolerance assay of C. elegans animals administered either E. coli OP50, Gluconobacter oxydans, Acetobacter aceti, or Gluconacetobacter hansenii. Compared with C. elegans animals shifted to 37°C that received E. coli OP50, C. elegans animals shifted to 37°C that received either Gluconobacter oxydans, Acetobacter aceti, or Gluconacetobacter hansenii had a longer lifespan. The mean ± sd for each measurement is plotted. [Figure 4] These included data showing that administration of Acetobacteraceae reduced fat deposition. Compared to animals treated with E. coli OP50, C. elegans animals treated with Gluconacetobacter hansenii had reduced fat levels, as revealed by Oil Red O staining. [Figure 5]Panel (A) contains data showing that prx-5 was required for G. hansenii-induced lifespan extension. Panel (A) contains data obtained from lifespan assays of wild-type or prx-5(0) animals administered either E. coli OP50 or Gluconacetobacter hansenii. Compared to C. elegans animals administered either E. coli OP50, C. elegans animals administered either Gluconacetobacter hansenii had a longer lifespan. The lifespan curves of prx-5(0) animals administered either E. coli OP50 or Gluconacetobacter hansenii were similar. Panel (B) contains data obtained from the restricted mean lifespan (RMLS) of wild-type or prx-5(0) C. elegans animals administered either E. coli OP50 or Gluconacetobacter hansenii. Panel (C) contains data from cumulative hazard plots of wild-type or prx-5(0) C. elegans animals administered either E. coli OP50 or Gluconacetobacter hansenii. [Figure 6]Panel (A) contains data showing that tcer-1 and aak-2 were required for G. hansenii-induced lifespan extension. Panel (A) contains data obtained from lifespan assays of wild-type or tcer-1(0) C. elegans animals administered either E. coli OP50 or Gluconacetobacter hansenii. Compared to C. elegans animals administered either E. coli OP50, C. elegans animals administered either Gluconacetobacter hansenii had longer lifespans. The lifespan curves of tcer-1(0) C. elegans animals administered either E. coli OP50 or Gluconacetobacter hansenii are similar. Panel (B) contains data obtained from restricted mean lifespan (RMLS) of wild-type or tcer-1(0) C. elegans animals administered either E. coli OP50 or Gluconacetobacter hansenii. Panel (C) contains data obtained from lifespan assays of wild-type or aak-2(0) C. elegans animals administered either E. coli OP50 or Gluconacetobacter hansenii. Compared to C. elegans animals administered E. coli OP50, animals administered either Gluconacetobacter hansenii had a longer lifespan. The lifespan curves of aak-2(0) C. elegans animals administered either E. coli OP50 or Gluconacetobacter hansenii are similar. Panel (D) contains data obtained from the restricted mean lifespan (RMLS) of wild-type or aak-2(0) C. elegans animals administered either E. coli OP50 or Gluconacetobacter hansenii. [Figure 7]Panel (A) contains data showing that daf-16 was not required for G. hansenii-induced lifespan extension. Panel (B) contains data obtained from lifespan assays of wild-type or daf-16(0) C. elegans animals administered either E. coli OP50 or Gluconacetobacter hansenii. Panel (C) contains data obtained from restricted mean lifespan (RMLS) assays of wild-type or daf-16(0) C. elegans animals administered either E. coli OP50 or Gluconacetobacter hansenii. [Figure 8] Panel (A) contains data showing that hsf-1 was required for the G. hansenii-induced thermotolerance phenotype. Panel (B) contains data showing that administration of G. hansenii does not affect heat shock protein expression. Panel (C) contains data obtained from thermotolerance assays of wild-type or hsf-1(0) C. elegans animals administered either E. coli OP50 or Gluconacetobacter hansenii. [Figure 9] These figures contain data showing an analysis of gene pathways required for the G. hansenii-induced thermotolerance phenotype. Panel (A) contains data obtained from thermotolerance assays of wild-type or tcer-1(0) C. elegans animals challenged with either E. coli OP50 or Gluconacetobacter hansenii. Panel (B) contains data obtained from thermotolerance assays of wild-type or prx-5(0) C. elegans animals challenged with either E. coli OP50 or Gluconacetobacter hansenii. Panel (C) contains data obtained from thermotolerance assays of wild-type or aak-2(0) C. elegans animals challenged with either E. coli OP50 or Gluconacetobacter hansenii. DETAILED DESCRIPTION OF THE INVENTION

[0064] Aging is a complex process that affects numerous cellular processes and leads to diverse functional changes. In some cases, aging is accompanied by a gradual decline in tissue structure and cellular function, which can lead to increased morbidity and mortality risk. Over the past century, human life expectancy has increased dramatically worldwide (Beltran-Sanchez et al., 2015). This increase in life expectancy poses new challenges for the healthcare and well-being of aging populations (Knickman and Snell, 2002). Chronic human diseases associated with aging populations, such as cardiovascular disease, cancer, arthritis, diabetes, and neurodegenerative diseases, are increasing at an alarming rate worldwide (Franceschi et al., 2018) (Lunenfeld and Stratton, 2013) (Frasca et al., 2017). Therefore, the goal of aging research is to identify therapeutic interventions that can delay the decline in cellular function associated with aging and promote longevity.

[0065] The present disclosure provides the recognition that the microbial species present in a subject's microbiota can affect the subject's lifespan. The present disclosure provides insight that certain microorganisms, particularly microorganisms in a microbiota (e.g., a human microbiota), can be adjusted to modify the subject's life expectancy. For example, among other things, the present disclosure provides the recognition that certain microorganisms can be administered to a subject, and can extend the subject's lifespan and / or reduce or delay the onset of age-related symptoms or conditions in the subject.

[0066] The present disclosure further provides that C. elegans is a powerful tool for determining which microbes in the microbiome can extend the lifespan of a subject and / or reduce or delay the onset of age-related symptoms or conditions in a subject. Accordingly, the present disclosure provides techniques for identifying such microbes.

[0067] C. elegans The free-living nematode C. elegans has been widely used as a model system. C. elegans is inexpensive to culture, easily manipulated, and has numerous genetic and molecular tools available for research. C. elegans is a simple multicellular organism. Adults contain approximately 1,000 somatic cells but possess a variety of tissue types, including muscle, nerve, and intestinal cells. C. elegans' short generation time allows for rapid experimentation. C. elegans typically progresses from egg to juvenile to reproductive adult in three days at room temperature. A single adult C. elegans can have 300–1,000 offspring, allowing for the use and rapid replenishment of a significant number of animals in a relatively short time. Due to its sexual dimorphism, C. elegans is useful for genetics. Self-fertilizing hermaphrodites can be maintained as homozygous mutants without the need for mating, and males can be used for genetic crosses. C. elegans is transparent at all stages of its life cycle, providing the ability to view the interior of the organism. This allows for the observation of cellular events and permits the use of phosphorescent, luminescent, and fluorescent reporters. Manipulation of protein expression in C. elegans can also be performed using RNA-mediated interference (RNAi), which can allow for the rapid assessment of gene function. Another advantage of using C. elegans as a model system is that animals can be frozen and recovered, thereby allowing for long-term storage.

[0068] C. elegans can be genetically modified using a number of techniques to generate C. elegans strains. The sexual dimorphism of C. elegans allows for relatively easy genetic manipulations, following known procedures. For example, if a strain needs to be propagated, a single hermaphrodite can be used to self-fertilize and generate a population of offspring. Even if a mutation renders the animal unable to mate, the hermaphrodite can still produce offspring. Another aspect of C. elegans reproduction that makes it an effective genetic tool is the ability to cross male animals with hermaphrodites. For example, crossbreeding experiments allow genetic markers, such as mutations that cause visible phenotypes, to be placed together with unknown mutations in a single organism, facilitating the mapping of the mutation. Hermaphrodites produce only a limited number of sperm and can typically produce approximately 300 self-progeny. Through mating, the number of offspring produced by a single hermaphrodite increases to approximately 1,000 by adding sperm produced by the male. The relatively large number of offspring combined with the short lifespan of C. elegans allows rapid and inexpensive analyses to be performed on the animals.

[0069] In addition to reproductive genetic modification, C. elegans can be genetically modified through the injection of transgenes. Microinjection is an effective method for generating animals and directly introducing various types of molecules into cells. For DNA transformation, one approach is to inject DNA into the distal arm of the C. elegans gonad. The distal germline of C. elegans contains a central nucleus of cytoplasm shared by many germ cell nuclei. Therefore, DNA injected into the distal arm of the C. elegans gonad can be delivered to many offspring. Direct microinjection into the oocyte nucleus can induce chromosomal integration of the transgene, but this technique can be more difficult. C. elegans can also integrate genetic material administered to them.

[0070] C. elegans is relatively easy to culture. It can be grown in either liquid culture or on nematode growth medium (NGM) agar plates in the presence of bacteria. It is possible to grow animals in a chemically defined medium without the addition of bacteria, which can be useful because the components of the medium can be varied to study the animal's nutritional or other chemical requirements. In some embodiments, C. elegans is grown on agar plates. C. elegans can be grown on nematode growth medium (NGM) agar plates. Bacteria can be spread on NGM plates as a food source for the animals. For example, OP50, a leaky E. coli uracil supplement, can be used. OP50 grows slowly and provides nutrients to the animals without overfeeding them. When the animals consume all the food on the plate, holes can be made in the agar, and the "starved" plates can be maintained for several weeks in an incubator at 15°C. Animals can be transferred to fresh agar plates containing bacteria by cutting and removing a small block of agar from the starvation plate with a sterile instrument such as a micropipette tip, by washing the animals off the surface of the plate with sterile water, or by picking one or more individuals onto a fresh plate, resulting in the re-emergence of C. elegans. C. elegans can be cryopreserved at any time. C. elegans prefers to grow at 15°C to 25°C, although temperatures may vary depending on the C. elegans strain and the conditions being tested. In some embodiments, C. elegans can be cultured at temperatures of at least 5°C, at least 10°C, at least 15°C, at least 20°C, at least 25°C, at least 30°C, at least 35°C, or at least 40°C. In some embodiments, C. elegans can be cultured at temperatures up to 65°C, up to 60°C, up to 55°C, up to 50°C, up to 55°C, up to 40°C, up to 35°C, up to 30°C, up to 25°C or up to 20°C.Standard protocols for the manipulation and culture of C. elegans are known, as described, for example, by Stiernagle T. Maintenance of C. elegans. Wormbook, ed. The C. elegans Research Community, WormBook. (February 11, 2006), which is incorporated herein by reference.

[0071] The bacterial nematode Caenorhabditis elegans is an excellent model organism for aging research due to its short lifespan (approximately 15 days). C. elegans is a powerful model for studying genetic pathways that regulate the aging process (Knickman and Snell, 2002), (Johnson, 2003), (Antebi, 2007), (Wilkinson et al., 2012). C. elegans is amenable to forward and reverse genetic approaches, as well as the identification and characterization of small molecule compounds that affect aging (Antebi, 2007), (Collins et al., 2006), (Denzel et al., 2019), (Arey and Murphy, 2017). Studies in C. elegans have uncovered conserved genetic pathways that regulate aging and correspond to pathways involved in human longevity (Bitto et al., 2015) (Collins et al., 2006) (Arey and Murphy, 2017) (Finch and Ruvkun, 2001). These include the insulin / IGF-1-like signaling (IIS) pathway (Tissenbaum and Ruvkun, 1998) (Kenyon, 2011), target of rapamycin (TOR) (Robida-Stubbs et al., 2012) (Johnson et al., 2013), Nrf2 / antioxidant stress response pathway (Blackwell et al., 2015), TGFβ signaling (Kaplan et al., 2015) (Luo et al., 2010), Sirtuins (Dang, 2014) (Guarente, 2007) (Longo and Kennedy, 2006), autophagy (Gelino et al., 2016) (Hansen et al., 2008) (Chang et al., 2017), and the AMP-activated protein kinase (AMPK) pathway (Burkewitz et al., 2014) (Curtis et al., 2014). et al., 2006) (Onken and Driscoll, 2010). Given the similarities between animals, mechanistic pathways that influence lifespan may be conserved throughout animal evolution.

[0072] Interventions that have been demonstrated to delay aging and extend lifespan in C. elegans include disruption of nutrient sensing, dietary restriction, mutations affecting mitochondrial metabolism, mutations affecting ribosomal function, and drugs such as rapamycin (Kapahi et al., 2017), (Finch and Ruvkun, 2001), (Srivastava, 2017), (Pan and Finkel, 2017), (Bansal et al., 2015), (Kenyon, 2005), (Wilkinson et al., 2012). Thus, C. elegans may represent a powerful model for identifying and characterizing interventions that promote healthy aging and may be beneficial in humans (Johnson, 2003).

[0073] Several recent studies have implicated the key role of the human gut microbiota in regulating various aspects of human development, including aging (Vaiserman et al., 2017), (Zapata and Quagliarello, 2015), (Bischoff, 2016). This microbiota directly influences host development by, among other things, providing nutrients and essential metabolic compounds (Choi et al., 2018). Dramatic shifts in microbiota composition have been observed between infants and adults, and between middle-aged and older adults (Choi et al., 2018), (An et al., 2018), (Claesson et al., 2012), (Kim and Jazwinski, 2018), (Gerber, 2014), (Maffei et al., 2017). Changes in microbiota composition have also been suggested as a key factor in several aging-related conditions, including metabolic syndrome and cancer (Tilg and Kaser, 2011). Changes in microbiota composition likely lead to changes in microbial metabolism, but how these changes affect aging is not understood. The majority of metabolites in human plasma are of microbial origin, and the gut microbiota is a likely source. It is unknown whether these microbiota-derived metabolic factors may influence the aging process.

[0074] The techniques provided in this disclosure can be used to identify microorganisms, extracts, or microbiota-derived components (e.g., factors, metabolites, etc.) that modulate the aging process, define conserved signaling pathways by which these microorganisms or microbiota-derived factors influence aging, and develop novel therapeutics based on these factors for beneficial effects on overall human health in old age. Because both C. elegans and bacteria are genetically tractable, the techniques described herein can be used to assess how diet affects aging in an unbiased manner.

[0075] C. elegans is a bacterial nematode that feeds on various bacterial species growing on decaying fruit and vegetation. Many of these microorganisms also colonize the C. elegans gut, serving as its microbiota. In the laboratory, C. elegans are fed exclusively E. coli OP50. E. coli serves as the animal's nutrition, providing essential nutrients that the nematode cannot synthesize de novo. C. elegans has emerged as a powerful model for studying the effects of diet on aging because the standard E. coli diet can be easily replaced with other microorganisms (MacNeil and Walhout, 2013). Recent studies in C. elegans suggest that diffusible metabolites derived from bacteria may directly affect aging in C. elegans (Ezcurra, 2018) (Smith et al., 2008). Animals fed an E. coli mutant unable to synthesize coenzyme Q were found to live longer (Jonassen et al., 2001). The lifespan-extending effect of metformin (widely used to treat diabetes) in C. elegans was found to be due to alterations in bacterial folate and methionine metabolism (Cabreiro et al., 2013) (Onken and Driscoll, 2010). Genetic or pharmacological inhibition of E. coli folate synthesis leads to increased lifespan in C. elegans (Maynard et al., 2018). Strain-specific effects of E. coli on C. elegans lifespan were found to be due to structural differences in lipopolysaccharides (Maier et al., 2010). NO derived from B. subtilis was found to extend lifespan through modulation of the DAF-16 / FOXO and heat shock factor 1 (HSF-1) pathways (Donato et al., 2017).Probiotic bacteria, such as Lactobacillus and Bifidobacterium, can enhance immunity and extend lifespan in C. elegans (Zhao et al., 2013; Fasseas et al., 2013; Grompone et al., 2012; Komura et al., 2013; Martorell et al., 2016; Sugawara and Sakamoto, 2018; Zhao et al., 2017). Studies in C. elegans have also revealed that the effects of genetic mutations on lifespan can depend on the specific bacterial diet (Maier et al., 2010; Brooks et al., 2009; Heintz and Mair, 2014). A TOR complex-2 specific factor Rictor mutant is short-lived when grown on E. coli OP50 bacteria but long-lived when cultured on E. coli HT115 (Soukas et al., 2009). A C. elegans alh-6 (aldehyde dehydrogenase gene) mutant is short-lived when grown on E. coli OP50 bacteria but not on HT115 (Pang and Curran, 2014). The underlying mechanism(s) responsible for these differences are unknown, but metabolites or signals produced by these E. coli strains may be one contributing factor. In summary, these studies represent the beginning of an era of exploration into how the microbiota influences host lifespan. Studies from several laboratories have identified a core set of microorganisms that comprise the natural microbiota of C. elegans (Dirksen et al., 2016) (Felix and Braendle, 2010). Animals collected directly from their native habitat carry a diverse range of bacteria, primarily Proteobacteria, Bacteroidetes, Firmicutes, and Actinobacteria (Samuel et al., 2016). The C. elegans microbiota was found to be distinct from its natural habitat, suggesting selective or preferential gating of microorganisms.Although the effects of feeding individual bacterial species of the C. elegans microbiota on animal development have been investigated, a systematic analysis of the effects of the microbiota on C. elegans aging has not previously been performed.

[0076] composition The present disclosure provides compositions comprising at least one bacterial strain, or extract(s) or component(s) thereof, and an excipient. While the present disclosure provides exemplary microorganisms (e.g., bacterial strains) that affect aging, the present disclosure also provides methods for identifying additional microorganisms that can be used in accordance with the compositions and methods described herein.

[0077] In some embodiments, the at least one bacterial strain comprises the genus Gluconobacter, Acetobacter, Gluconoacaetobacter, Acidomonas, Ameyamaea, Asaia, Granulibacter, Kozakia, Neoasaia, Neokomagataea, Saccharibacter, Swaminathania, Tanticharoenia, or a combination thereof. In some embodiments, at least one bacterial strain comprises Gluconobacter albidus, Gluconobacter cerinus, Gluconobacter frateruii, Gluconobacter japonicus, Gluconobacter kondonii, Gluconobacter nephelii, Gluconobacter oxydans, Gluconoacetobacter diazotrophicus, Gluconoacetobacter hansenii, Gluconoacetobacter saccharivorans, Acetobacter aceti, Acetobacter malorum, or a combination thereof. In some embodiments, at least one bacterial strain comprises Gluconacetobacter hansenii, Gluconobacter oxydans, Acetobacter aceti, or a combination thereof. In some embodiments, at least one bacterial strain comprises Gluconacetobacter hansenii.

[0078] In some embodiments, the composition comprises at least one bacterial strain. In some embodiments, the composition comprises at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least 15, or at least 20 bacterial strains. In some embodiments, the composition comprises up to 100, up to 90, up to 80, up to 70, up to 60, up to 50, up to 40, up to 30, up to 20, up to 10, or up to 5 bacterial strains.

[0079] In some embodiments, the extract(s) of at least one bacterial strain comprise one or more extracts of at least one bacterial strain. In some embodiments, the component(s) of at least one bacterial strain comprise one or more extracts of at least one bacterial strain. Thus, comprising at least one bacterial strain or extract(s) or component(s) thereof described herein can include, for example, two extracts from Gluconobacter oxydans, a component from Acetobacter aceti, and a component from Gluconacetobacter hansenii.

[0080] The compositions described herein may include an excipient. In some embodiments, the excipient is or includes an inert (e.g., non-biologically active) agent. The excipient may be included in the composition, for example, to provide or contribute a desired consistency or stabilizing effect. In some embodiments, the excipient may include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, or ethanol.

[0081] In some embodiments, a composition for use according to the present disclosure is a pharmaceutical composition, e.g., for administration (e.g., oral administration) to a mammal (e.g., a human). Pharmaceutical compositions typically include an active agent (e.g., an individual microbial strain or a combination of microbial strains) and an excipient. The excipient may be a pharmaceutically acceptable carrier, such as saline, solvent, dispersion medium, coating, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc., that are compatible with pharmaceutical administration.

[0082] In some embodiments, compositions or pharmaceutical compositions for use according to the present disclosure may comprise and / or be administered in conjunction with one or more supplemental active compounds; in certain embodiments, such supplemental active compounds may be selected from the group consisting of ginger, curcumin, probiotics (e.g., one or more probiotic strains of the following genera: Lactobacillus, Bifidobacterium, Saccharomyces, Enterococcus, Streptococcus, Pediococcus, Leuconostoc, Bacillus, and / or Escherichia coli (Fijan, Int J Environ Res Public Health. 2014, incorporated herein by reference) May;11(5):4745-4767), prebiotics (non-digestible food ingredients that support the growth of probiotic microorganisms, e.g., fructans such as fructooligosaccharides (FOS) and inulin, galactans such as galactooligosaccharides (GOS), dietary fibers such as resistant starch, pectin, beta-glucans, and xylooligosaccharides (Hutkins et al., Curr Opin Biotechnol. 2016 Feb;37:1-7, incorporated herein by reference), and combinations thereof.

[0083] Compositions or pharmaceutical compositions are usually formulated to be compatible with their intended route of administration. Examples of routes of administration include oral administration. Methods for formulating suitable compositions have been reported, for example, in Remington: The Science and Practice of Pharmacy, 21st ed., 2005, and Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs (Dekker, NY). Oral compositions generally contain an inert diluent or an edible carrier. To name just a few, in some embodiments, oral formulations can be or include syrups, liquids, tablets, lozenges, gummies, capsules (e.g., gelatin capsules), powders, gels, films, etc.

[0084] In some embodiments, compatible binders and / or adjuvant materials may be included as part of the composition (e.g., pharmaceutical composition). In some specific embodiments, the composition may include, for example, any one or more of the following inactive ingredients, or compounds of a similar nature: binders such as microcrystalline cellulose, gum tragacanth, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or cornstarch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavor. In some embodiments, the composition can be consumed as is, sprinkled on, or mixed into food or liquids (e.g., water). In some embodiments, a composition that can be administered to a subject as described herein can be or can comprise an ingestible article (e.g., a food or beverage) that contains (e.g., is supplemented with) an individual microbial strain or a combination of microbial strains (e.g., from a mammalian microbiota), an extract thereof, and / or a component thereof.

[0085] In some embodiments, the food product may be or include one or more of bars, candy, baked goods, cereals, savory snacks, pasta, chocolate, and other solid foods, as well as liquid or semi-solid foods including yogurt, soups, and stews, and beverages such as smoothies, shakes, fruit juices, and other carbonated or non-carbonated beverages. In some embodiments, the food product is prepared by the subject by mixing individual microbial strains or combinations of microbial strains (e.g., from a mammalian microbiota), extracts thereof, and / or components thereof.

[0086] The compositions can be included in a kit, container, pack, or dispenser together with instructions for administration or use in the methods described herein.

[0087] In some embodiments, the at least one microbial (e.g., bacterial) strain is killed (e.g., heat-killed). Alternatively, in some embodiments, the at least one microbial (e.g., bacterial) strain may comprise viable or living cells.

[0088] In some embodiments, the therapeutic methods described herein comprise administering at least one viable or living microbial (e.g., bacterial) strain. In some such embodiments, the at least one viable or living microbial (e.g., bacterial) strain is administered according to a regimen that achieves a population of the subject's microbiota in the administered cells.

[0089] In some embodiments, at least one microbial (e.g., bacterial) strain described herein comprises and / or is formulated through the use of one or more cell cultures and / or supernatants or pellets thereof, and / or powders formed therefrom.

[0090] In some embodiments, the pharmaceutical compositions provided herein are capable of promoting colonization of at least one microbial (e.g., bacterial) strain, particularly a microbial strain(s) that has been identified, characterized, or evaluated as extending lifespan or reducing or delaying the onset of at least one age-related symptom or condition in a subject. In some embodiments, the pharmaceutical compositions provided herein are capable of promoting colonization of at least one microbial (e.g., bacterial) strain, particularly a microbial strain(s) that has been identified, characterized, or evaluated as extending lifespan or reducing or delaying the onset of at least one age-related symptom or condition in a subject.

[0091] In some embodiments, a pharmaceutical composition is tailored to a particular mammal (e.g., a particular human subject) based on the mammal's (e.g., human) microbiota. In some embodiments, a pharmaceutical composition is specific to the microbiota of a mammalian subject (e.g., human). In some embodiments, a pharmaceutical composition is specific to the microbiota of a population of mammals (e.g., humans). A population of mammals can include, but is not limited to, a family, mammals in the same geographic location (e.g., neighborhood, city, state, or country), mammals with the same disease or condition, mammals of a particular age or age range, or mammals consuming a particular diet (e.g., food, food source, or caloric intake).

[0092] In some embodiments, the compositions described herein are formulated for oral administration. In some embodiments, the compositions are food, beverage, feed compositions, or dietary supplements. In some embodiments, the compositions are liquids, syrups, tablets, lozenges, gummies, capsules, powders, gels, or films. In some embodiments, the compositions are pharmaceutical compositions. In some embodiments, the compositions are enteric-coated formulations.

[0093] The compositions described herein can affect aging or the signs of aging. As described above, a model system for characterizing the performance of a microorganism (e.g., a bacterial strain) in a composition can be C. elegans. For example, in some embodiments, when at least one bacterial strain or an extract(s) or component(s) thereof is administered to a C. elegans culture containing C. elegans animals, the average lifespan of the C. elegans animals in the C. elegans culture is characterized by being extended by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% compared to that of C. elegans animals in an equivalent C. elegans culture without the administration of at least one bacterial strain or an extract(s) thereof. Lifespan refers to the period from the birth of a subject to the death of the subject. Lifespan can be the average period from the birth to the death of multiple subjects (e.g., C. elegans, mammals, humans).

[0094] In some embodiments, when at least one bacterial strain or extract(s) or component(s) thereof is administered to a C. elegans culture containing C. elegans animals, the average pharyngeal pumping activity of the C. elegans animals in the C. elegans culture is characterized by an increase of at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% compared to that of C. elegans animals in an equivalent C. elegans culture without the administration of the at least one bacterial strain or extract(s) or component(s). Pharyngeal pumping activity can be measured, for example, by counting grinder movements, e.g., single contractions and relaxations of the C. elegans anterior and / or posterior pharynx. In some embodiments, pharyngeal pumping activity can be measured in pumps (or grinder movements) per minute (ppm). The average pharyngeal pumping activity can be the average number of pumps (eg, per minute) across multiple subjects (eg, C. elegans, mammals, humans).

[0095] In some embodiments, when at least one bacterial strain or extract(s) or component(s) thereof is administered to a C. elegans culture containing C. elegans animals, the average locomotor speed of the C. elegans animals in the C. elegans culture is characterized in that it increases by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% compared to that of C. elegans animals in an equivalent C. elegans culture without the administration of at least one bacterial strain or extract(s) or component(s). In some embodiments, the locomotor speed can be calculated by the number of animal bends per minute. The average locomotor speed can be the average number of animal bends (e.g., per minute) of multiple subjects (e.g., C. elegans, mammals, humans).

[0096] In some embodiments, when at least one bacterial strain or extract(s) or component(s) thereof is administered to a C. elegans culture containing C. elegans animals, the reproductive ability of the C. elegans animals in the C. elegans culture is characterized in that it is reduced by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% compared to that of C. elegans animals in an equivalent C. elegans culture without the administration of the at least one bacterial strain or extract(s) or component(s). In some embodiments, reproductive ability can be determined by the number of reproductive events (e.g., births) that occur. In some embodiments, reproductive ability can be determined by the number of offspring. The average reproductive rate can be the average number of reproductive events or the average number of offspring of a plurality of animals, e.g., C. elegans.

[0097] In some embodiments, the at least one bacterial strain, or extract(s) or component(s) thereof, is characterized in that when a C. elegans culture containing the C. elegans animals is exposed to ultraviolet radiation, the average survival time of the C. elegans animals in the C. elegans culture administered with the at least one bacterial strain, or extract(s) thereof, or component(s) thereof, is increased by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% compared to that of C. elegans animals in a comparable C. elegans culture without the administration of the at least one bacterial strain, or extract(s) thereof, or component(s). In some embodiments, survival time is measured from the time the animals are exposed to UV radiation to the time the animals die.

[0098] In some embodiments, the at least one bacterial strain, or extract(s) or component(s) thereof, is characterized in that when a C. elegans culture containing the C. elegans animals is exposed to an elevated temperature, the mean survival time of C. elegans animals in the C. elegans culture administered with the at least one bacterial strain, or extract(s) thereof, or component(s) thereof, is increased by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% compared to that of C. elegans animals in an equivalent C. elegans culture without the administration of the at least one bacterial strain, or extract(s) thereof, or component(s). In some embodiments, the elevated temperature is at least 37°C, at least 40°C, at least 45°C, at least 50°C, at least 55°C, at least 60°C, at least 65°C, at least 70°C, at least 75°C, or at least 80°C. In some embodiments, the elevated temperature is between 50° C. and 65° C., between 65° C. and 80° C., or between 80° C. and 120° C. In some embodiments, survival time is measured from the time the elevated temperature is reached to the time the animal dies.

[0099] In some embodiments, when at least one bacterial strain or its extract(s) or component(s) is administered to a C. elegans culture containing C. elegans animals, the average amount of intestinal fat observed in the C. elegans animals in the C. elegans culture is characterized by being reduced by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% compared to that of C. elegans animals in a comparable C. elegans culture without the administration of at least one bacterial strain or its extract(s) or component(s). In some embodiments, the amount of intestinal fat is determined by visual observation after staining, for example, with Oil Red O. In some embodiments, the area stained by Oil Red O can be measured, for example.

[0100] In some embodiments, the C. elegans animal is an adult C. elegans animal. In some embodiments, the C. elegans animal is at least 5 days old.

[0101] method The present disclosure provides that the compositions described herein can be useful for extending the life span of subjects, or reducing or delaying age-related symptoms or conditions.The present disclosure provides a method comprising administering the compositions described herein to the subject of the composition.As mentioned above, the compositions can be formulated to be compatible with their intended administration route.

[0102] In some embodiments, the method is a method of extending the lifespan of a subject, hi some embodiments, the lifespan of the subject is extended by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% compared to that of a comparable subject without administration of the composition.

[0103] In some embodiments, the method is a method of reducing or delaying the onset of at least one age-related symptom or condition in a subject. In some embodiments, the at least one age-related symptom or condition is reduced or delayed by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% in the subject compared to that of a comparable subject without administration of the composition. In some embodiments, the at least one age-related symptom or condition is or includes a decline in muscle and / or neuromuscular function in the subject. In some embodiments, the at least one age-related symptom or condition is or includes dysregulation of lipid metabolism. In some embodiments, the at least one age-related symptom or condition is or includes, for example, levels of mitosis, organ function, organ wall thickness, core body temperature fluctuations, bone density, levels of peristalsis, retinal thickness, tympanic membrane thickness, hearing loss, vision loss, or a combination thereof.

[0104] In some embodiments, the subject is at least 30 years old, at least 35 years old, at least 40 years old, at least 45 years old, at least 50 years old, at least 55 years old, at least 60 years old, at least 65 years old, at least 70 years old, or at least 75 years old. In some embodiments, the subject is an elderly subject. However, the subject may be under 30 years old, for example, if the subject suffers from a disease or condition associated with premature aging.

[0105] In some embodiments, the method is a method for treating a subject who has or is at risk of developing a disease or disorder associated with premature aging. In some embodiments, the disease or disorder is Bloom's syndrome, Bockayne's syndrome, Hutchinson-Gilford progeria syndrome, mandibular palatal dysplasia with lipodystrophy type A, progeria syndrome, Rothmund-Thomson syndrome, Seip's syndrome, or Werner's syndrome.

[0106] In some embodiments, the subject is a mammal. In some embodiments, the animal is a non-human primate (e.g., a higher primate), a sheep, a dog, a rodent (e.g., a mouse or a rat), a guinea pig, a goat, a pig, a cat, a rabbit, or a cow. In some embodiments, the mammal is a human.

[0107] In some embodiments, the methods include administering a sufficient amount of a microorganism to colonize the microbiota of the subject.

[0108] Biological effects assessment The present disclosure provides insights that C. elegans can be used to identify, characterize, or evaluate microbial strain(s) of a mammalian microbiota for their ability to extend the lifespan of a subject, or to reduce or delay age-related symptoms and / or conditions by contacting the microbial strain(s) (e.g., feeding, administering the microbial strain(s) to C. elegans). To determine whether a microbial strain or combination of microbial strains extends lifespan or reduces or delays age-related symptoms and / or conditions in C. elegans, parameters can be observed, measured, or assessed in different samples contacted with the microbial strain or combination of microbial strains. As a few examples, parameters can include muscle function / activity, e.g., movement or bending, reproduction, stress resistance, lipid metabolism, or a combination thereof. In some embodiments, parameters may include genetic variations (e.g., the presence of SNPs, deletions, additions, inversions, or repeats in DNA), transcription levels, protein levels, metabolite levels, lipid levels, carbohydrate levels, protein (e.g., enzyme) activity levels, alone or in addition to those previously listed, and can be observed, measured, or assessed to determine whether a microbial strain or combination of microbial strains affects the lifespan of a subject or reduces or delays age-associated symptoms and / or conditions in C. elegans.

[0109] In some embodiments, the methods described herein utilize a first sample and a second sample. In some embodiments, the first sample is a reference sample. In some embodiments, the reference sample can be, for example, a culture of C. elegans contacted (e.g., administered or fed) with OP50. In some embodiments, the reference sample can be a culture of C. elegans contacted (e.g., administered or fed) with a microbial strain or combination of microbial strains from the microbiota of a healthy individual. In some embodiments, the reference sample can be a culture of C. elegans contacted (e.g., administered or fed) with a microbial strain or combination of microbial strains from the microbiota of an individual obtained at a first time point.

[0110] In some embodiments, the second sample can be a test sample. In some embodiments, the test sample can be a C. elegans culture that has been contacted (e.g., administered or fed) with an individual or combination of microbial strains from a mammalian microbiota, for example, a human microbiota. In some cases, the human microbiota is the microbiota of a person suffering from or at risk of a disease or condition, for example, a disease or condition associated with premature aging or delayed aging. In some embodiments, the test sample can be a C. elegans culture that has been contacted (e.g., administered or fed) with a microbial strain or combination of microbial strains from the microbiota of an individual obtained at a second time point (e.g., an elderly subject).

[0111] In some embodiments, the methods described herein include comparing one or more parameters obtained from a test sample with one or more parameters obtained from a reference sample. In some embodiments, by comparing one or more parameters obtained from a test sample with one or more parameters obtained from a reference sample, it can be determined that an individual microbial strain or a combination of microbial strains from a microbiota affects lifespan or reduces or delays age-related symptoms and / or conditions in a C. elegans culture. In some embodiments, by comparing one or more parameters obtained from a test sample with one or more parameters obtained from a reference sample, it can be determined that an individual microbial strain or a combination of microbial strains from a microbiota extends lifespan or reduces or delays age-related symptoms and / or conditions in a cultured C. elegans.

[0112] C. elegans and methods using C. elegans provided herein may be useful for assessing, characterizing, or identifying microbial strains of the microbiota that affect lifespan or reduce or delay age-related symptoms and / or age-related conditions. The present disclosure provides the recognition that C. elegans and methods using C. elegans provided herein can be used to define and / or characterize microbial signatures associated with a subject's lifespan, or one or more age-related symptoms and / or age-related conditions.

[0113] The present disclosure also provides the recognition that C. elegans, and methods using C. elegans provided herein, can be used to monitor age progression.

[0114] The present disclosure also provides insight that C. elegans and methods using C. elegans provided herein can be used to tailor therapeutic agents (e.g., therapies, dietary supplements, and / or probiotics) to individual patients. In some cases, microbial strains within an individual can be evaluated, characterized, or identified to determine whether they affect age-related symptoms and / or age-related conditions. Based on the results, the individual can be administered one or more microbial strains to adjust the microbial strains (and / or components or compounds thereof) in their microbiome. In some cases, this affects the aging of the individual. For example, if an individual is determined to have a relatively low amount of one or more microbial strains determined to extend lifespan, administration of the one or more microbial strains can extend the individual's lifespan.

[0115] Among other things, the present disclosure provides techniques for evaluating one or more microorganisms for the utilities described herein. In some embodiments, techniques for identifying and / or characterizing a microorganism as described herein can include a comparison of observations or measurements made on C. elegans administered the microorganism with an appropriate reference (e.g., with a positive control reference and / or a negative control reference). In some embodiments, the reference can be or include a historical reference, and in some embodiments, the reference can be or include a contemporaneous reference. [Example]

[0116] The following examples are provided to illustrate to one of ordinary skill in the art how to make and use the methods and compositions described herein and are not intended to limit the scope of the disclosure.

[0117] A library of approximately 30 bacterial species was screened for their effects on C. elegans lifespan. Bacterial species were selected based on their abundance in 16s RNA sequencing studies. This screen identified three bacterial species that significantly extended the lifespan of wild-type C. elegans animals. Such screening can be repeated with additional microbial species to determine whether such species affect lifespan, following the techniques described herein.

[0118] Example 1: Administration of Acetobacteraceae increased the lifespan of C. elegans. C. elegans (N2) longevity assays were performed on NGM plates seeded with either E. coli OP50, G. oxydans, A. aceti, or G. hansenii (Figure 1, panels A–D). C. elegans animals treated with either G. oxydans, A. aceti, or G. hansenii had significantly (P<0.00001) extended lifespans compared with animals treated with E. coli OP50 (Figure 1, panel A). Cumulative hazard plot analysis generated using the OASIS2 platform (Han et al., 2016) showed that hazard rates differed between animals treated with E. coli OP50 and those treated with either G. oxydans, A. aceti, or G. hansenii (Figure 1, panel B). Hazard plots for animals receiving G. hansenii compared with animals receiving either G. oxydans or A. aceti were slightly different from each other (Figure 1, panel B). Hazard plots were not different between animals receiving G. oxydans and animals receiving A. aceti (Figure 1, panel B).

[0119] OASIS2 software was used to calculate the restricted mean life span (RMLS) of animals treated with either G. oxydans, A. aceti, or G. hansenii. The RMLS of animals treated with E. coli OP50 for 14.86 ± 0.27 days (RMLS ± SE, n = 104) was significantly different from the RMLS of animals treated with G. oxydans for 20.52 ± 0.39 days (RMLS ± SE, n = 117) with a two-sided p value of <0.0001. Similarly, the RMLS of animals treated with E. coli OP50 for 14.86 ± 0.27 days (RMLS ± SE, n = 104) was significantly different from the RMLS of animals treated with A. aceti for 19.17 ± 0.41 days (RMLS ± SE, n = 124) with a two-sided p value of <0.0001. Similarly, the RMLS of animals treated with E. coli OP50 for 14.86 ± 0.27 (RMLS ± se, n = 104) days was significantly different from the RMLS of animals treated with G. hansenii for 22.95 ± 0.39 (RMLS ± se, n = 103) days, with a two-sided p-value of <0.0001 (Figure 1, Panel C). A smaller but statistically significant difference (two-sided p-value = 0.0181) was observed when the RMLS of animals treated with G. oxydans was compared with the RMLS of animals treated with A. aceti. However, a statistically significant difference (two-sided p-value <0.0001) was observed when the RMLS of animals treated with G. oxydans or A. aceti was compared with the RMLS of animals treated with G. hansenii. Comparing the survival curves of animals administered E. coli OP50 with those administered either G. oxydans, A. aceti, or G. hansenii, significant differences in survival rates were observed (Figure 1, panel D). Smaller but statistically different hazard ratios were observed between animals administered either G. oxydans or A. aceti and those administered G. hansenii (Figure 1, panel D). However, survival rates were not significantly different between animals administered G. oxydans and those administered A. aceti (Figure 1, panel D).These observations indicate that in the context of a lifespan assay, administration of G. hansenii significantly improved the lifespan of animals compared to E. coli OP50, G. oxydans, or A. aceti.

[0120] Example 2: Administration of Acetobacteraceae improved muscle function / activity. Because muscle function / activity declines as animals age, we monitored pharyngeal pumping activity and motor speed in animals treated with E. coli OP50, G. oxydans, A. aceti, or G. hansenii. Pharyngeal pumping activity was significantly reduced in 10-day-old animals treated with E. coli OP50 compared with 5-day-old animals treated with E. coli OP50 (Figure 2, Panel A). However, compared with animals treated with E. coli OP50, animals treated with G. oxydans, A. aceti, or G. hansenii showed improved pharyngeal pumping function, whether 5- or 10-day-old animals (Figure 2, Panel A). This result suggests that muscle function was better preserved in aged animals treated with G. oxydans, A. aceti, or G. hansenii compared with animals treated with E. coli OP50. Pharyngeal pumping rates of 5-day-old animals administered either G. oxydans, A. aceti, or G. hansenii were significantly higher than those of animals administered E. coli OP50, suggesting that a calorie restriction effect can be ruled out because the animals were not starved.

[0121] To analyze the effectiveness of G. oxydans, A. aceti, or G. hansenii in delaying aging, we measured locomotor speed during the aging time course (days 6 and 12 after adulthood). Locomotor speed was significantly reduced in 12-day-old animals treated with E. coli OP50 compared with 6-day-old adults (Figure 2, Panel B, p<0.00001). However, in animals treated with G. oxydans, A. aceti, or G. hansenii, the locomotor rate of 12-day-old animals was significantly higher than that of age-matched animals treated with E. coli OP50 (p<0.00001). Interestingly, the locomotor speed of 6-day-old animals treated with G. oxydans, A. aceti, or G. hansenii was significantly higher than that of age-matched animals treated with E. coli OP50 (Figure 2, Panel B, p<0.00001). These results suggested that neuromuscular function required for locomotion was better preserved in older animals treated with G. hansenii.

[0122] Example 3: Administration of Acetobacteraceae did not affect reproduction Many long-lived C. elegans mutants exhibit reduced fertility (Larsen et al., 1995) (Hughes et al., 2007). Therefore, the effects of G. hansenii on reproduction were examined. The fecundity of animals treated with G. hansenii was slightly lower than that of animals treated with E. coli OP50. The total number of offspring produced in animals treated with G. hansenii was also significantly reduced. Animals treated with E. coli OP50 produced 180 ± 31 (mean ± standard deviation of 15 animals) offspring, whereas 151 ± 32 (mean ± standard deviation of 15 animals) offspring were produced by animals treated with G. hansenii (two-tailed p-value = 0.0188). Measurement of the time course distribution of offspring production revealed no apparent differences in the rate of offspring production.

[0123] Example 4: Administration of Acetobacteraceae improved stress tolerance Because lifespan extension in C. elegans has been linked to stress tolerance, we determined the effects of G. oxydans, A. acetate, or G. hansenii treatment on UV and heat tolerance. Resistance to UV irradiation was significantly increased in animals treated with either G. oxydans, A. acetate, or G. hansenii compared with animals treated with either E. coli OP50 (Figure 3, panel A). Animals treated with either E. coli OP50, G. oxydans, A. acetate, or G. hansenii were exposed to 1,000 J / m 2 The animals were exposed to UV radiation (254 nm) at a dose of 100 mg / kg / day. The number of dead and viable animals was scored daily until all animals died. Animals treated with either G. oxydans, A. aceti, or G. hansenii survived longer than animals treated with E. coli OP50 (Figure 3, Panel A). The mean survival times of wild-type animals treated with either G. oxydans, A. aceti, or G. hansenii were 4.69 ± 0.15 (RMLS ± se, n = 97, p < 0.0001), 4.99 ± 0.14 (RMLS ± se, n = 98, p < 0.0001), and 5.4 ± 0.14 (RMLS ± se, n = 98, p < 0.0001), respectively, compared with 2.79 ± 0.12 (RMLS ± se, n = 99) days for animals treated with E. coli OP50.

[0124] To assess heat shock resistance, animals administered either E. coli OP50, G. oxydans, A. aceti, or G. hansenii were transferred from 20°C to 37°C. Viable and dead nematodes were scored every hour until all animals died. Animals administered G. oxydans, A. aceti, or G. hansenii significantly extended their mean survival time after the transfer to higher temperatures compared with animals administered E. coli OP50. While >60% of wild-type animals administered E. coli OP50 died within 2 hours of the transfer to 37°C, 100% of wild-type animals administered either G. oxydans, A. aceti, or G. hansenii remained alive 4 hours after the transfer (Figure 3, Panel B). Furthermore, 100% of wild-type animals administered E. coli OP50 died within 3 hours of shifting to 37°C, whereas 100% of wild-type animals administered either G. oxydans, A. aceti, or G. hansenii remained dead even 6 hours after shifting to 37°C. Thus, this data suggested that administration of G. oxydans, A. aceti, or G. hansenii confers heat stress tolerance.

[0125] Example 5: Administration of Acetobacteraceae reduced fat deposition Aging may be associated with dysregulation of lipid metabolism in some animals. Therefore, we examined the effect of G. hansenii administration on lipid levels during aging. In E. coli OP50-treated animals, large amounts of intestinal fat were observed by Oil Red O staining, whereas this accumulation was not observed in G. hansenii-treated animals (Figure 4).

[0126] Example 6: prx-5, tcer-1 and aak-2 were involved in G. hansenii-induced lifespan extension. Because administration of G. hansenii had a significant effect on various aspects of aging compared with G. oxydans or A. aceti, G. hansenii was the focus for further study. Insulin / IGF-1-like signaling (IIS) pathway (Tissenbaum and Ruvkun, 1998) (Kenyon, 2011), target of rapamycin (TOR) (Robida-Stubbs et al., 2012) (Johnson et al., 2013), Nrf2 / antioxidant stress response pathway (Blackwell et al., 2015), TGFβ signaling (Kaplan et al., 2015) (Luo et al., 2010), Sirtuins (Dang, 2014) (Guarente, 2007) (Longo and Kennedy, 2006), autophagy (Gelino et al., 2016) (Hansen et al., 2008) (Chang et al., 2017), and AMP-activated protein kinase (AMPK) pathway (Burkewitz et al., 2014) (Curtis et al., 2014). Several conserved pathways have been reported to be involved in determining lifespan in C. elegans, including the prx-5, tcer-1, aak-2, and daf-16 mutants (Onken and Driscoll, 2010). To identify the genetic pathways that G. hansenii traverses to improve lifespan, we performed longevity assays on prx-5, tcer-1, aak-2, and daf-16 mutants.

[0127] prx-5 encodes an orthologue of human PEX5, which is required for peroxisomal import of cytoplasmic proteins containing peroxisomal targeting sequences ( Wang et al., 2013 Peroxisomes are important organelles that play key roles in several metabolic pathways, including lipid metabolism. An age-dependent decrease in peroxisomal protein import has been observed previously (Narayan et al., 2016), and studies in yeast have shown that reduced peroxisomal import reduces chronological lifespan (Lefevre et al., 2013). tcer-1 encodes a putative transcription elongation factor that regulates aging in C. elegans (Amrit et al., 2016) (Ghazi et al., 2009) (McCormick et al., 2012). aak-2 encodes an AMP-activated protein kinase that regulates lifespan in C. elegans (Curtis et al., 2006) (Moreno-Arriola et al., 2016) (Lee et al., 2008) (Apfeld et al., 2004). daf-16 encodes a FOXO family transcription factor that functions downstream of insulin signaling to regulate lifespan in many animals, including C. elegans (Kimura et al., 2016). al., 1997) (Murphy et al., 2003) (Lee et al., 2001).

[0128] Based on the data obtained, G. hansenii-induced lifespan extension required prx-5, tcer-1, and aak-2, whereas daf-16 was not required for the longevity phenotype. For the lifespan assay, we used the prx-5(ku517) strain, in which PRX-5 is produced as a cleavage product (i.e., lacking the last 26 amino acids of the protein (Wang et al., 2013)). This strain is referred to herein as prx-5(0). Comparison of survival curves revealed that the RMLS of G. hansenii-challenged wild-type animals was significantly higher than that of G. hansenii-challenged prx-5(0) animals [21.94 ± 0.34 (n = 109) days vs. 14.86 ± 0.27 (n = 104) days (p < 0.0001)] (Figure 5, panels A-B). The RMLS of prx-5(0) animals treated with G. hansenii was more similar to that of wild-type animals treated with E. coli OP50 [13.52 ± 0.34 (n = 103) days vs. 13.11 ± 0.32 (n = 113) days (p = 0.3805)] (Figure 5, Panels A-B), suggesting that prx-5 is required for G. hansenii-induced lifespan extension. Furthermore, prx-5(0) animals treated with E. coli OP50 had reduced RMLS compared with wild-type animals treated with E. coli OP50, suggesting that prx-5 is required for normal lifespan [9.59 ± 0.29 (n = 108) days vs. 13.11 ± 0.32 (n = 113) days (p < 0.0001)] (Figure 5, Panels A-B). prx-5(0) animals receiving G. hansenii had increased RMLS compared with prx-5(0) animals receiving E. coli OP50 [13.52 ± 0.34 (n = 103) days vs. 9.59 ± 0.29 (n = 108) days (p < 0.0001)] (Figure 5, Panels A-B). This result suggested that the lifespan extension in animals receiving G. hansenii was dependent on prx-5, but G. hansenii also improved the lifespan of prx-5(0) mutants. Similar results were obtained by comparing the cumulative hazard ratios of wild-type and prx-5(0) animals receiving either E. coli OP50 or G. hansenii (Figure 5, Panel C).Lifespan assays of tcer-1(0) animals revealed that administration of G. hansenii prolonged the RMLS of wild-type animals compared to wild-type animals administered E. coli OP50 [22.15 ± 0.37 (n = 110) days vs. 14.43 ± 0.30 (n = 98) days (p < 0.0001)], but administration of G. hansenii did not prolong the RMLS of tcer-1(0) animals compared to those administered E. coli OP50 [15.15 ± 0.29 (n = 97) days vs. 15.24 ± 0.31 (n = 92) days (p < 0.0001)] (Figure 6, Panels A-B). The RMLS of tcer-1(0) animals challenged with G. hansenii was not significantly different from that of wild-type animals challenged with E. coli OP50 [15.15 ± 0.29 (n = 97) days vs. 14.43 ± 0.3 (n = 98) days, p = 0.0861] or from that of tcer-1(0) animals challenged with E. coli OP50 [15.15 ± 0.29 (n = 97) days vs. 15.24 ± 0.31 (n = 92) days, p = 0.8322] (Figure 6, panels A-B). This result suggests that tcer-1 is required for G. hansenii-induced lifespan extension. Lifespan assays of aak-2(0) animals revealed that administration of G. hansenii prolonged the RMLS of wild-type animals compared with wild-type animals administered E. coli OP50 [22.10 ± 0.36 (n = 105) days vs. 13.29 ± 0.31 (n = 89) days (p < 0.0001)], but administration of G. hansenii did not prolong the RMLS of aak-2(0) animals compared with those of aak-2(0) animals administered E. coli OP50 [15.13 ± 0.31 (n = 105) days vs. 14.73 ± 0.30 (n = 110) days (p < 0.3548)] (Figure 6, panels C-D).

[0129] Example 7: daf-16 was not required for G. hansenii-induced lifespan extension. Although G. hansenii-induced lifespan extension phenotypes appeared to require prx-5, tcer-1, or aak-2 animals, results suggested that daf-16 was not required for the longevity phenotype. Lifespan assays revealed that the RMLS of daf-16(0) animals treated with G. hansenii was significantly increased compared to that of daf-16(0) animals treated with E. coli OP50 [22.61 ± 0.26 (n = 97) days vs. 11.51 ± 0.30 (n = 98) days (p < 0.0001)] (Figure 7, panels A-B).

[0130] Example 8: hsf-1 was involved in the G. hansenii-induced thermotolerance phenotype. Thermotolerance in C. elegans has been linked to the expression of heat shock proteins under the control of the heat shock factor-1 (HSF-1) transcription factor (Hajdu-Cronin et al., 2004) (Link et al., 1999). Therefore, we examined G. oxydans, A. aceti, and G. hansenii treatment to determine whether such treatment induces hsp-16.2::gfp expression. hsp-16.2 is a heat shock protein induced by heat stress under the control of the heat shock factor-1 (HSF-1) transcription factor. 2.5 ± 1.1% (n = 225) of animals administered E. coli OP50 and grown at 20°C showed hsp-16.2::gfp GFP induction, whereas 86.6 ± 8.3% (n = 252) of animals administered E. coli OP50 and shifted to 35°C for 1 hour had hsp-16.2::gfp expression. Animals administered either G. oxydans, A. aceti, or G. hansenii and grown at 20°C did not show induction of hsp-16.2::gfp expression, suggesting that induction of heat shock protein expression is not required for the thermotolerant phenotype. When animals challenged with either G. oxydans, A. aceti, or G. hansenii were shifted to 35°C for 1 hour, expression of hsp-16.2::gfp was observed in 94.1 ± 4.3% (n = 243), 88.9 ± 2.4% (n = 220), and 90.2 ± 1.3% (n = 216) of the animals, respectively (Fig. 8). This result suggested that challenge with either G. oxydans, A. aceti, or G. hansenii did not affect the induction of heat shock response genes.

[0131] Although we did not observe induction of heat-responsive genes in animals challenged with G. hansenii and grown at 20°C, the thermotolerance phenotype was found to be dependent on HSF-1. While 100% of wild-type animals challenged with G. hansenii survived a 3-hour shift to 37°C, 100% of hsf-1(0) animals challenged with G. hansenii died (Figure 8, Panel B). Furthermore, 25.6 ± 4.7% (n = 300) of wild-type animals challenged with E. coli OP50 survived 2 hours after the shift to 37°C, whereas 100 ± 0% (n = 300) of hsf-1(0) animals challenged with E. coli OP50 died within 2 hours of the shift, suggesting that HSF-1 is required for thermotolerance (Figure 8, Panel B). Compared with hsf-1(0) animals administered E. coli OP50 and shifted to 37°C, survival was higher in hsf-1(0) animals administered G. hansenii and shifted to 37°C (Fig. 8, panel B), suggesting that HSF-1-independent pathways may also exist.

[0132] The results suggested that the thermotolerance phenotype was dependent on HSF-1 and HSF-1-independent pathways, even though G. hansenii challenge did not induce hsp-16.2::gfp. To test whether the thermotolerance phenotype of G. hansenii-challenged animals depended on PRX-5, TCER-1, or AAK-2, we performed thermotolerance assays in tcer-1(0), prx-5(0), or aak-2(0) mutants. The survival curves of tcer-1(0) animals challenged with G. hansenii were similar to those of wild-type animals challenged with G. hansenii, suggesting that TCER-1 is not required for the thermotolerance phenotype (Figure 9, panel A). prx-5(0) animals were found to be hypersensitive to heat stress compared to wild-type animals. On the other hand, 22 ± 1% (n = 300) of wild-type animals challenged with E. coli OP50 survived 2 hours after being shifted to 37°C, whereas 100 ± 0% (n = 300) of prx-5(0) animals challenged with E. coli OP50 died within 2 hours of being shifted to 37°C, suggesting that PRX-5 is required for thermotolerance (Figure 9, panel B). Furthermore, 100% of wild-type animals challenged with G. hansenii survived a 3-hour shift to 37°C, whereas 100% of prx-5(0) animals challenged with G. hansenii died (Figure 8, panel B), suggesting that PRX-5 is required for the thermotolerance phenotype of G. hansenii-challenged animals. AAK-2 was found to be required for the thermotolerance phenotype of G. hansenii-challenged animals. The survival rate of aak-2(0) animals challenged with G. hansenii was significantly reduced compared with that of wild-type animals challenged with G. hansenii (Figure 9, panel C). The survival curve of aak-2(0) animals challenged with E. coli OP50 was similar to that of wild-type animals challenged with E. coli OP50, suggesting that AAK-2 is not required for normal thermotolerance (Figure 9, panel C).

[0133] Other embodiments It should be understood by those skilled in the art that various changes, modifications, and improvements to the present disclosure may be readily made by those skilled in the art. Such changes, modifications, and improvements are intended to be part of this disclosure and are intended to be within the spirit and scope of the invention. Accordingly, the foregoing description and drawings are by way of example only, and any inventions described in this disclosure as more particularly described by the following claims.

[0134] Those of ordinary skill in the art will understand the typical basis for deviation or error attributable to values ​​obtained in the assays or other processes described herein. Publications, websites, and other reference materials referred to herein to describe the background of the invention or to provide additional details regarding its practice are hereby incorporated by reference in their entirety.

[0135] While embodiments of the invention have been described in conjunction with the detailed description thereof, it should be understood that the foregoing description is intended to illustrate, but not limit, the scope of the invention, which is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

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Claims

1. (a) at least one bacterial strain, or an extract thereof, or a component thereof, wherein the at least one bacterial strain comprises a species of the genus Gluconobacter, Acetobacter, Gluconoacaetobacter, Acidomonas, Ameyamaea, Asaia, Granulibacter, Kozakia, Neoasaia, Neokomagataea, Saccharibacter, Swaminathania, Tanticharoenia, or a combination thereof; (b) an excipient.

2. 10. The composition of claim 1, wherein the at least one bacterial strain comprises Gluconacetobacter hansenii, Gluconobacter oxydans, Acetobacter aceti, or a combination thereof.

3. 3. The composition of claim 1 or 2, wherein the at least one bacterial strain comprises Gluconacetobacter hansenii.

4. 4. The composition according to any one of claims 1 to 3, characterized in that when the at least one bacterial strain, or an extract thereof, or a component thereof, is administered to a C. elegans culture comprising C. elegans animals, the average lifespan of the C. elegans animals in the C. elegans culture is extended by at least 20% compared to that of C. elegans animals in a comparable C. elegans culture without administration of the at least one bacterial strain, or an extract thereof, or a component thereof.

5. The composition according to any one of claims 1 to 4, characterized in that when the at least one bacterial strain, or an extract thereof, or a component thereof, is administered to a C. elegans culture comprising C. elegans animals, the average pharyngeal pumping activity of the C. elegans animals in the C. elegans culture is increased by at least 20% compared to that of C. elegans animals in an equivalent C. elegans culture without administration of the at least one bacterial strain, or an extract thereof, or a component thereof.

6. 6. The composition according to any one of claims 1 to 5, wherein when the at least one bacterial strain or an extract thereof or a component thereof is administered to a C. elegans culture comprising C. elegans animals, the average movement speed of the C. elegans animals in the C. elegans culture is increased by at least 20% compared to that of C. elegans animals in an equivalent C. elegans culture without administration of the at least one bacterial strain or an extract thereof or a component thereof.

7. 7. The composition according to any one of claims 1 to 6, characterized in that when the at least one bacterial strain, or an extract thereof, or a component thereof, is administered to a C. elegans culture comprising C. elegans animals, the reproductive ability of the C. elegans animals in the C. elegans culture is reduced by at least 20% compared to that of C. elegans animals in an equivalent C. elegans culture without administration of the at least one bacterial strain, or an extract thereof, or a component thereof.

8. 8. The composition according to any one of claims 1 to 7, wherein the at least one bacterial strain, or an extract thereof, or a component thereof, is administered to C. elegans animals in a C. elegans culture, when the C. elegans animals are exposed to ultraviolet radiation, the mean survival time of the C. elegans animals in the C. elegans culture to which the at least one bacterial strain, or an extract thereof, or a component thereof, has been administered is increased by at least 20% compared to that of C. elegans animals in a comparable C. elegans culture without the administration of the at least one bacterial strain, or an extract thereof, or a component thereof.

9. 9. The composition according to any one of claims 1 to 8, wherein the at least one bacterial strain, or an extract thereof, or a component thereof, is administered to C. elegans animals in a C. elegans culture containing the C. elegans animals, and the at least one bacterial strain, or an extract thereof, or a component thereof, when the C. elegans culture is exposed to an elevated temperature, the mean survival time of the C. elegans animals in the C. elegans culture to which the at least one bacterial strain, or an extract thereof, or a component thereof is administered is increased by at least 20% compared to that of the C. elegans animals in an equivalent C. elegans culture without the administration of the at least one bacterial strain, or an extract thereof, or a component thereof.

10. 10. The composition of claim 9, wherein the elevated temperature is at least 37°C.

11. The composition according to any one of claims 1 to 10, characterized in that when the at least one bacterial strain or an extract thereof or a component thereof is administered to a C. elegans culture comprising C. elegans animals, the average amount of intestinal fat observed in the C. elegans animals in the C. elegans culture is reduced by at least 20% compared to that of C. elegans animals in a comparable C. elegans culture without administration of the at least one bacterial strain or an extract thereof or a component thereof.

12. 12. The composition of any one of claims 4 to 11, wherein the C. elegans animal is an adult C. elegans animal.

13. 13. The composition of any one of claims 4 to 12, wherein the C. elegans animal is at least 5 days old.

14. The composition of any one of claims 1 to 13, wherein the composition is formulated for oral administration.

15. The composition of any one of claims 1 to 14, wherein the composition is a food, beverage, feed composition, or dietary supplement.

16. The composition of any one of claims 1 to 15, wherein the composition is a liquid, syrup, tablet, lozenge, gummy, capsule, powder, gel, or film.

17. The composition according to any one of claims 1 to 16, wherein the composition is a pharmaceutical composition.

18. The composition according to any one of claims 1 to 17, wherein the composition is an enteric coated formulation.

19. A method comprising administering to a subject a composition according to any one of claims 1 to 18.

20. 20. The method of claim 19, wherein the method is a method of extending the lifespan of a subject.

21. 21. The method of claim 20, wherein the lifespan of the subject is extended by at least 20% compared to that of a comparable subject without administration of the composition.

22. 20. The method of claim 19, wherein the method is a method of reducing or delaying the onset of at least one age-related symptom or condition in a subject.

23. 23. The method of claim 22, wherein the at least one age-related symptom or condition is reduced or delayed by at least 20% in the subject compared to that of a comparable subject without administration of the composition.

24. 24. The method of claim 22 or 23, wherein the at least one age-related symptom or condition is or comprises a decline in muscle and / or neuromuscular function in the subject.

25. 25. The method of any one of claims 22 to 24, wherein the at least one age-related symptom or condition is or comprises dysregulation of lipid metabolism.

26. 26. The method of any one of claims 19 to 25, wherein the subject is at least 30 years old.

27. The method of any one of claims 19 to 26, wherein the subject is an elderly subject.

28. The method of any one of claims 19 to 27, wherein the subject is a mammal.

29. The method of any one of claims 19 to 28, wherein the subject is a human.

30. 30. The method of any one of claims 19 to 29, comprising administering a sufficient amount of a microorganism to colonize the microbiota of the subject.

31. 1. Use of at least one bacterial strain, or an extract or component thereof, for extending the lifespan of a subject, wherein the at least one bacterial strain comprises a bacterium of the genus Gluconobacter, Acetobacter, Gluconoacaetobacter, Acidomonas, Ameyamaea, Asaia, Granulibacter, Kozakia, Neoasaia, Neokomagataea, Saccharibacter, Swaminathania, Tanticharoenia, or a combination thereof.

32. 32. The use of claim 31 , wherein the at least one bacterial strain comprises Gluconacetobacter hansenii, Gluconobacter oxydans, Acetobacter aceti, or a combination thereof.

33. 33. The use of claim 31 or 32, wherein the at least one bacterial strain comprises Gluconacetobacter hansenii.

34. 1. Use of at least one bacterial strain, or an extract or component thereof, to reduce or delay the onset of at least one age-related symptom or condition in a subject, wherein the at least one bacterial strain comprises a bacterium of the genus Gluconobacter, Acetobacter, Gluconoacaetobacter, Acidomonas, Ameyamaea, Asaia, Granulibacter, Kozakia, Neoasaia, Neokomagataea, Saccharibacter, Swaminathania, Tanticharoenia, or a combination thereof.

35. 35. The use of claim 34, wherein the at least one bacterial strain comprises Gluconacetobacter hansenii, Gluconobacter oxydans, Acetobacter aceti, or a combination thereof.

36. 36. The use according to claim 34 or 35, wherein the at least one bacterial strain comprises Gluconacetobacter hansenii.

37. 35. The use of claim 34, wherein the at least one age-related symptom or condition is reduced or delayed by at least 20% in the subject compared to that of a comparable subject without administration of the composition.

38. 38. The use according to any one of claims 34 to 37, wherein the at least one age-related symptom or condition is or comprises a decline in muscle and / or neuromuscular function in the subject.

39. 39. The use according to any one of claims 34 to 38, wherein the at least one age-related symptom or condition is or comprises dysregulation of lipid metabolism.

40. 40. The use according to any one of claims 34 to 39, wherein the subject is at least 30 years old.

41. The use according to any one of claims 34 to 40, wherein the subject is an elderly subject.

42. The use according to any one of claims 34 to 41, wherein the subject is a mammal.

43. The use according to any one of claims 34 to 42, wherein the subject is a human.

44. 1. A method for characterizing the ability of one or more microbial strains to modify longevity, age-associated symptoms, and / or age-associated conditions in a subject, comprising: (a) adding a plurality of microbial strains of a mammalian microbiota to a plurality of C. elegans cultures, wherein a different microbial strain is added to each C. elegans culture, and each culture contains C. elegans animals of the same C. elegans strain; (b) determining whether each microbial strain of the plurality of microbial strains affects one or more parameters of the C. elegans animals in each culture, wherein the one or more parameters are associated with aging, age-related symptoms, and / or age-related conditions.

45. Use of C. elegans animals to characterize the ability of one or more microbial strains to modify lifespan, age-associated symptoms, and / or age-associated conditions in a subject.

46. A method of making a composition according to any one of claims 1 to 18, comprising combining at least one bacterial strain or an extract or component thereof and said excipient.

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