Claims
- 1. A method for identifying a compound that modulates aging, the method comprising the steps of:
(i) contacting the compound with a polypeptide, wherein the polypeptide is encoded by a nucleic acid that hybridizes under stringent conditions to a nucleic acid encoding a polypeptide comprising an amino acid sequence selected from the group consisting of: cytochrome C1 (SEQ ID NO: 1), NADH oxidoreductase (SEQ ID NO: 2), ATP synthase (SEQ ID NO: 3), cytochrome C oxidase (SEQ ID NO: 4), phosphoglucose isomerase (SEQ ID NO: 5), GTPase (SEQ ID NO: 6), LLW-1 (SEQ ID NO: 7), LLW-2 (SEQ ID NO: 8), LLW-3 (SEQ ID NO: 9), LLW-4 (SEQ ID NO: 10) and HSF-1 (SEQ ID NO: 11), and human homologues thereof; and (ii) determining the functional effect of the compound upon the polypeptide.
- 2. The method of claim 1, wherein the polypeptide is encoded by a nucleic acid that hybridizes under stringent conditions to a nucleic acid encoding a polypeptide comprising an amino acid sequence selected from the group consisting of: cytochrome C1 (SEQ ID NO: 1), NADH oxidoreductase (SEQ ID NO: 2), ATP synthase (SEQ ID NO: 3), cytochrome C oxidase (SEQ ID NO: 4), phosphoglucose isomerase (SEQ ID NO: 5), GTPase (SEQ ID NO: 6), LLW-1 (SEQ ID NO: 7), LLW-2 (SEQ ID NO: 8), LLW-3 (SEQ ID NO: 9), and LLW-4, (SEQ ID NO: 10) or human homologues thereof.
- 3. The method of claim 1, wherein the polypeptide is encoded by a nucleic acid that hybridizes under stringent conditions to a nucleic acid encoding a polypeptide comprising an amino acid sequence of HSF-1 (SEQ ID NO: 11), or human homologues thereof.
- 4. The method of claim 1, wherein the functional effect is determined in vitro.
- 5. The method of claim 4, wherein the functional effect is determined by measuring enzymatic activity.
- 6. The method of claim 4, wherein the functional effect is determined by measuring ligand, substrate, or cofactor binding to the polypeptide.
- 7. The method of claim 4, wherein the functional effect is determined by measuring binding to a promoter sequence by the polypeptide.
- 8. The method of claim 1, wherein the polypeptide is expressed in a mitochondrial extract or an isolated mitochondrial membrane.
- 9. The method of claim 1, wherein the polypeptide is expressed in a eukaryotic host or host cell and the polypeptide is contacted with the compound in a living cell.
- 10. The method of claim 9, wherein the host cell is derived from C. elegans, mouse, rat, or human.
- 11. The method of claim 9, wherein the host is C. elegans, mouse, rat, or human.
- 12. The method of claim 9, wherein the functional effect is a determined by measuring ligand, substrate, or cofactor binding to the polypeptide.
- 13. The method of claim 9, wherein the functional effect is determined by measuring transcriptional activation.
- 14. The method of claim 9, wherein the functional effect is determined by evaluating age-associated parameters.
- 15. The method of claim 9, wherein the functional effect is determined by evaluating expression of an age-associated gene.
- 16. The method of claim 14, wherein the age-associated parameter is lifespan.
- 17. The method of claim 1, wherein the modulation is inhibition of aging.
- 18. The method of claim 17, wherein inhibition of aging occurs by activation of an HSF polypeptide encoded by a nucleic acid that hybridizes under stringent conditions to a nucleic acid encoding a polypeptide comprising an amino acid sequence of HSF-1 (SEQ ID NO: 11), or human homologues thereof.
- 19. The method of claim 17, wherein inhibition of aging occurs by inhibition of a polypeptide encoded by a nucleic acid that hybridizes under stringent conditions to a nucleic acid encoding a polypeptide comprising an amino acid sequence selected from the group consisting of: cytochrome C1 (SEQ ID NO: 1), NADH oxidoreductase (SEQ ID NO: 2), ATP synthase (SEQ ID NO: 3), cytochrome C oxidase (SEQ ID NO: 4), phosphoglucose isomerase (SEQ ID NO: 5), GTPase (SEQ ID NO: 6), LLW-1 (SEQ ID NO: 7), LLW-2 (SEQ ID NO: 8), LLW-3 (SEQ ID NO: 9), and LLW-4 (SEQ ID NO: 10) or human homologues thereof.
- 20. The method of claim 1 wherein the polypeptide is recombinant.
- 21. The method of claim 1, wherein the compound is an antibody, an antisense molecule, or a small molecule.
- 22. A method for identifying a compound that modulates aging, the method comprising the steps of:
(i) contacting the compound with a polypeptide, wherein the polypeptide is encoded by a nucleic acid that hybridizes under stringent conditions to a nucleic acid encoding a polypeptide comprising an amino acid sequence selected from the group consisting of: cytochrome C1 (SEQ ID NO: 1), NADH oxidoreductase (SEQ ID NO: 2), ATP synthase (SEQ ID NO: 3), cytochrome C oxidase (SEQ ID NO: 4), phosphoglucose isomerase (SEQ ID NO: 5), GTPase (SEQ ID NO: 6), LLW-1 (SEQ ID NO: 7), LLW-2 (SEQ ID NO: 8), LLW-3 (SEQ ID NO: 9), LLW-4 (SEQ ID NO: 10) and HSF-1 (SEQ ID NO: 11), and human homologues thereof, (ii) determining the functional effect of the compound upon the polypeptide; and (iii) contacting a host or host cell expressing the protein and evaluating an age-associated parameter in a host or host cell, thereby identifying a compound that modulates aging.
- 23. The method of claim 22, wherein the polypeptide is recombinant.
- 24. The method of claim 22, wherein the functional effect is a physical effect.
- 25. The method of claim 22, wherein the functional effect is a chemical effect.
- 26. The method of claim 22, wherein the functional effect is a phenotypic effect.
- 27. The method of claim 22, wherein the functional effect is determined in vitro.
- 28. The method of claim 22, wherein the functional effect is determined in a eukaryotic host organism or host cell.
- 29. The method of claim 22, wherein the age-associated parameter is lifespan.
- 30. A method for identifying a compound that modulates aging, the method comprising the steps of:
(i) contacting the compound with a polypeptide that is a component of the mitochondrial respiratory chain; and (ii) determining the functional effect of the compound upon the polypeptide.
- 31. The method of claim 30, wherein the polypeptide is expressed in a mitochondrial extract or an isolated mitochondrial membrane.
- 32. A method for identifying a compound that modulates aging, the method comprising the steps of:
(i) contacting the compound with a polypeptide, wherein the polypeptide is encoded by a nucleic acid that hybridizes under stringent conditions to a nucleic acid listed in Table 5 or Table 6, or a nucleic acid encoding a polypeptide listed in Table 5 or Table 6, or human homologues thereof; and (ii) determining the functional effect of the compound upon the polypeptide.
- 33. A method for identifying a compound that modulates aging, the method comprising the steps of:
(i) contacting the compound with a polypeptide, wherein the polypeptide is encoded by a nucleic acid that hybridizes under stringent conditions to a nucleic acid listed in Table 5 or Table 6, or a nucleic acid encoding a polypeptide listed in Table 5 or Table 6, or human homologues thereof (ii) determining the functional effect of the compound upon the polypeptide; and (iii) contacting a host or host cell expressing the protein and evaluating an age-associated parameter in a host or host cell, thereby identifying a compound that modulates aging.
- 34. A compound that modulates an aging process, wherein the compound is identified by the method of claim 1.
- 35. The compound of claim 34, wherein the compound is an antibody, an antisense molecule, or a small molecule.
- 36. The compound of claim 34, wherein the compound is antimycin or an analog thereof.
- 37. A method of increasing lifespan or treating premature aging in a subject, the method comprising the step of administering to the subject an effective amount of a compound identified using the method of claim 1.
- 38. The method of claim 37, wherein the compound is antimycin.
- 39. A method of increasing lifespan or treating premature aging in a subject, the method comprising the step of administering to the subject an effective amount of a compound that modulates the expression of a polypeptide comprising an amino acid sequence selected from the group consisting of: cytochrome C1 (SEQ ID NO: 1), NADH oxidoreductase (SEQ ID NO: 2), ATP synthase (SEQ ID NO: 3), cytochrome C oxidase (SEQ ID NO: 4), phosphoglucose isomerase (SEQ ID NO: 5), GTPase (SEQ ID NO: 6), LLW-1 (SEQ ID NO: 7), LLW-2 (SEQ ID NO: 8), LLW-3 (SEQ ID NO: 9), LLW-4 (SEQ ID NO: 10) and HSF-1 (SEQ ID NO: 11), and human homologues thereof.
- 40. The method of claim 37 or 39, wherein the aging process is abnormal.
- 41. The method of claim 40, wherein the abnormal aging process is selected from Werner syndrome, Hutchinson-Guilford disease, Bloom's syndrome, Cockayne's syndrome, ataxia telangiectasia, and Down's syndrome.
- 42. The method of claim 37 or 39, wherein the aging process is normal.
- 43. The method of claim 37 or 39, further comprising the step of evaluating an age-associated parameter of the subject.
- 44. A method of identifying a gene or gene product that modulates aging, the method comprising the steps of:
(i) providing a library of nucleic acids, each nucleic acid of the library comprising a segment of a gene of an organism; and (ii) for each member of the library,
(a) generating double-stranded RNA (dsRNA) from the respective member of the library, (b) providing the dsRNA to a cell or one or more cells of the organism to provide a ds-RNA treated cell or ds-RNA treated organism, and (b) monitoring an age-associated parameter of the ds-RNA treated cell or the ds-RNA treated organism.
- 45. A method of identifying a gene or gene product that modulates aging, the method comprising the steps of:
(i) evaluating a relationship between presence or abundance for each species of a plurality of RNA or protein species with respect to age of a cell or organism; (ii) producing or delivering a double-stranded RNA to a cell or one or more cells of an organism, the RNA corresponding to a species whose presence or abundance is correlated with age; and (iii) monitoring an age-associated parameter of the cell or the one or more cells or the organism.
- 46. A method of identifying a compound that modulates aging, the method comprising the steps of:
(i) contacting a test compound to a living or biochemical system that comprising a C. elegans target protein selected from the group consisting of: a respiratory chain component, a heat shock promoter activator, LLW-1, LLW-2, LLW-3, LLW-4, a small GTPase, a protein in Table 5, and a protein in Table 6; and (ii) evaluating a property associated with the target protein; and (iii) evaluating an aging-associated parameter of a C. elegans organism contacted with the test compound.
- 47. A method of identifying a gene or gene product that modulates aging, the method comprising the steps of:
(i) providing a nematode in which activity of a target protein is reduced in the organism by RNA interference; (i) expressing a gene encoding a candidate mammalian protein that is heterologous to the organism; and (iii) evaluating an age associated parameter of the organism.
- 48. A C. elegans nematode that (1) expresses a heterologous gene in at least some cells, the heterologous gene encoding a respiratory chain component or glycolysis component that is non-identical to the corresponding endogenous respiratory chain component or glycolysis component, or a functional domain thereof; and (2) is deficient in at least some cells for an endogenous activity provided by the corresponding endogenous respiratory chain component or glycolysis component.
- 49. A method comprising: assessing an age-associated parameter of the nematode of claim 48.
- 50. A C. elegans nematode that (1) has a deficiency in at least some cells for an endogenous activity, the deficiency generated by dsRNA in the cells, and (2) has an average lifespan of at least 40% greater than an otherwise identical nematode without the deficiency.
- 51. A method of identifying a gene or gene product that modulates aging, the method comprising the steps of:
(i) providing the nematode of claim 50;(ii) introducing a heterologous gene that encodes a heterologous polypeptide into the nematode; (iii) expressing the heterologous gene in the nematode or a progeny of the nematode under conditions wherein the heterologous polypeptide is produced; and (iv) monitoring an age-associated parameter of the nematode or the progeny of the nematode.
- 52. The method of claim 51, further comprising contacting a test compound to the nematode or the progeny prior to or during the monitoring.
CROSS REFERENCES TO RELATED APPLICATIONS
[0001] The present application is related to U.S. Serial No. 60/300,577, filed Jun. 22, 2001, U.S. Serial No. 60/301,052, filed Jun. 25, 2001, and U.S. Serial No. 60/373,975, filed Apr. 18, 2002, each herein incorporated by reference in their entirety.
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
[0002] This invention was made with government support under Grant No. NIH AG11816, awarded by the NIH. The government has certain rights in this invention.
Provisional Applications (3)
|
Number |
Date |
Country |
|
60300577 |
Jun 2001 |
US |
|
60301052 |
Jun 2001 |
US |
|
60373975 |
Apr 2002 |
US |