The genetics of ageing

Colman, R. J. et al. Dietary restriction delays disease onset and mortality in rhesus monkeys. Science 325, 201–204 (2009).

Mair, W., Goymer, P., Pletcher, S. D. & Partridge, L. Demography of dietary restriction and death in Drosophila . Science 301, 1731–1733 (2003).

Hansen, M. et al. Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans . Aging Cell 6, 95–110 (2007).

Kaeberlein, M. et al. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310, 1193–1196 (2005).

Kapahi, P. et al. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr. Biol. 14, 885–890 (2004).

Greer, E. L. et al. An AMPK–FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans . Curr. Biol. 17, 1646–1656 (2007).

Rogina, B. & Helfand, S. L. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc. Natl Acad. Sci. USA 101, 15998–16003 (2004).

Li, Y., Xu, W., McBurney, M. W. & Longo, V. D. SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons. Cell Metab. 8, 38–48 (2008).

Honjoh, S., Yamamoto, T., Uno, M. & Nishida, E. Signalling through RHEB-1 mediates intermittent fasting-induced longevity in C. elegans . Nature 457, 726–730 (2009).

Arum, O., Bonkowski, M. S., Rocha, J. S. & Bartke, A. The growth hormone receptor gene-disrupted (GHR-KO) mouse fails to respond to an intermittent fasting (IF) diet. Aging Cell 8, 756–760 (2009).

Greer, E. L. & Brunet, A. Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans . Aging Cell 8, 113–127 (2009). This paper shows that different pathways extend lifespan in response to different methods of dietary restriction.

Shama, S., Lai, C. Y., Antoniazzi, J. M., Jiang, J. C. & Jazwinski, S. M. Heat stress-induced life span extension in yeast. Exp. Cell Res. 245, 379–388 (1998).

Lithgow, G. J., White, T. M., Melov, S. & Johnson, T. E. Thermotolerance and extended life-span conferred by single-gene mutations and induced by thermal stress. Proc. Natl Acad. Sci. USA 92, 7540–7544 (1995).

Apfeld, J., O'Connor, G., McDonagh, T., DiStefano, P. S. & Curtis, R. The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans . Genes Dev. 18, 3004–3009 (2004).

Heidlelr, T., Hartwig, K., Daniel, H. & Wenzel, U. Caenorhabditis elegans lifespan extension caused by treatment with an orally active ROS-generator is dependent on DAF-16 and SIR-2.1. Biogerontology doi:10.1007/s10522-009-9239-x (2009).

Alcedo, J., Maier, W. & Ch'ng, Q. in Protein Metabolism and Homeostasis in Aging (ed. Tavernarakis, N.) (Landes Bioscience, 2010); available at < http://www.landesbioscience.com/curie/chapter/4546 >.

Lee, S. J. & Kenyon, C. Regulation of the longevity response to temperature by thermosensory neurons in Caenorhabditis elegans . Curr. Biol. 19, 715–722 (2009).

Kenyon, C. A pathway that links reproductive status to lifespan in Caenorhabditis elegans . Ann. NY Acad. Sci. (in the press).

Kenyon, C. The plasticity of aging: insights from long-lived mutants. Cell 120, 449–460 (2005). Most of the pioneering studies in the field are cited in this review.

Dell'agnello, C. et al. Increased longevity and refractoriness to Ca2+-dependent neurodegeneration in Surf1 knockout mice. Hum. Mol. Genet. 16, 431–444 (2007).

Copeland, J. M. et al. Extension of Drosophila life span by RNAi of the mitochondrial respiratory chain. Curr. Biol. 19, 1591–1598 (2009).

Pan, K. Z. et al. Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans . Aging Cell 6, 111–119 (2007).

Hamilton, B. et al. A systematic RNAi screen for longevity genes in C. elegans . Genes Dev. 19, 1544–1555 (2005).

Syntichaki, P., Troulinaki, K. & Tavernarakis, N. eIF4E function in somatic cells modulates ageing in Caenorhabditis elegans . Nature 445, 922–926 (2007).

Garigan, D. et al. Genetic analysis of tissue aging in Caenorhabditis elegans: a role for heat-shock factor and bacterial proliferation. Genetics 161, 1101–1112 (2002).

Herndon, L. A. et al. Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans . Nature 419, 808–814 (2002). This paper lays out a clear case for stochastic determinants of ageing.

Tullet, J. M. et al. Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans . Cell 132, 1025–1038 (2008).

Wang, M. C., O' Rourke, E. J. & Ruvkun, G. Fat metabolism links germline stem cells and longevity in C. elegans . Science 322, 957–960 (2008).

Curran, S. P., Wu, X., Riedel, C. G. & Ruvkun, G. A soma-to-germline transformation in long-lived Caenorhabditis elegans mutants. Nature 459, 1079–1084 (2009).

Melendez, A. et al. Autophagy genes are essential for dauer development and life-span extension in C. elegans . Science 301, 1387–1391 (2003). This study first linked autophagy to lifespan extension.

Hansen, M. et al. A role for autophagy in the extension of lifespan by dietary restriction in C. elegans . PLoS Genet. 4, e24 (2008).

Murphy, C. T., Lee, S. J. & Kenyon, C. Tissue entrainment by feedback regulation of insulin gene expression in the endoderm of Caenorhabditis elegans . Proc. Natl Acad. Sci. USA 104, 19046–19050 (2007).

Bishop, N. A. & Guarente, L. Two neurons mediate diet-restriction-induced longevity in C. elegans . Nature 447, 545–549 (2007).

Bartke, A. Insulin and aging. Cell Cycle 7, 3338–3343 (2008).

Yuan, R. et al. Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels. Aging Cell 8, 277–287 (2009).

Kappeler, L. et al. Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism. PLoS Biol. 6, e254 (2008).

Selman, C. et al. Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice. FASEB J. 22, 807–818 (2008).

Suh, Y. et al. Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc. Natl Acad. Sci. USA 105, 3438–3442 (2008).

Kojima, T. et al. Association analysis between longevity in the Japanese population and polymorphic variants of genes involved in insulin and insulin-like growth factor 1 signaling pathways. Exp. Gerontol. 39, 1595–1598 (2004).

Pawlikowska, L. et al. Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. Aging Cell 8, 460–472 (2009).

Willcox, B. J. et al. FOXO3A genotype is strongly associated with human longevity. Proc. Natl Acad. Sci. USA 105, 13987–13992 (2008).

Anselmi, C. V. et al. Association of the FOXO3A locus with extreme longevity in a southern Italian centenarian study. Rejuvenation Res. 12, 95–104 (2009).

Flachsbart, F. et al. Association of FOXO3A variation with human longevity confirmed in German centenarians. Proc. Natl Acad. Sci. USA 106, 2700–2705 (2009).

Li, Y. et al. Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations. Hum. Mol. Genet. 18, 4897–4904 (2009).

Lunetta, K. L. et al. Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham Study. BMC Med. Genet. 8 (suppl. 1), S13 (2007).

Kenyon, C., Chang, J., Gensch, E., Rudner, A. & Tabtiang, R. A. C. elegans mutant that lives twice as long as wild type. Nature 366, 461–464 (1993).

Clancy, D. J., Gems, D., Hafen, E., Leevers, S. J. & Partridge, L. Dietary restriction in long-lived dwarf flies. Science 296, 319 (2002).

Grandison, R. C., Piper, M. D. & Partridge, L. Amino-acid imbalance explains extension of lifespan by dietary restriction in Drosophila . Nature 462, 1061–1064 (2009).

Kalaany, N. Y. & Sabatini, D. M. Tumors with PI3K activation are resistant to dietary restriction. Nature 458, 725–731 (2009).

Libert, S. et al. Regulation of Drosophila life span by olfaction and food-derived odors. Science 315, 1133–1137 (2007).

Lee, S.-J., Murphy, C. & Kenyon, C. Glucose shortens the lifespan of C. elegans by down-regulating DAF-16/FOXO activity and aquaporin gene expression. Cell Metab. 10, 379–391 (2009).

Jia, K., Chen, D. & Riddle, D. L. The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development 131, 3897–3906 (2004).

Vellai, T. et al. Genetics: influence of TOR kinase on lifespan in C. elegans . Nature 426, 620 (2003).

Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009). This is one of the most exciting demonstrations of lifespan extension by a drug that inhibits a genetically defined lifespan pathway.

Sheaffer, K. L., Updike, D. L. & Mango, S. E. The target of rapamycin pathway antagonizes pha-4/FoxA to control development and aging. Curr. Biol. 18, 1355–1364 (2008).

Medvedik, O., Lamming, D. W., Kim, K. D. & Sinclair, D. A. MSN2 and MSN4 link calorie restriction and TOR to sirtuin-mediated lifespan extension in Saccharomyces cerevisiae . PLoS Biol. 5, e261 (2007).

Zid, B. M. et al. 4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila . Cell 139, 149–160 (2009). This study shows that selective translation of respiratory-chain components contributes to lifespan extension by TOR inhibition and dietary restriction.

Selman, C. et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326, 140–144 (2009).

Steffen, K. K. et al. Yeast life span extension by depletion of 60s ribosomal subunits is mediated by Gcn4. Cell 133, 292–302 (2008).

Um, S. H. et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 43, 200–205 (2004).

Toth, M. L. et al. Longevity pathways converge on autophagy genes to regulate life span in Caenorhabditis elegans. Autophagy 4, 330–338 (2008).

Bjedov, I. et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster . Cell Metab. 11, 35–46 (2010).

Anisimov, V. N. et al. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle 7, 2769–2773 (2008).

Lakowski, B. & Hekimi, S. The genetics of caloric restriction in Caenorhabditis elegans . Proc. Natl Acad. Sci. USA 95, 13091–13096 (1998).

Panowski, S. H., Wolff, S., Aguilaniu, H., Durieux, J. & Dillin, A. PHA-4/Foxa mediates diet-restriction-induced longevity of C. elegans . Nature 447, 550–555 (2007).

Kaeberlein, M. & Powers, R. W. Sir2 and calorie restriction in yeast: a skeptical perspective. Ageing Res. Rev. 6, 128–140 (2007).

Liu, B. et al. The polarisome is required for segregation and retrograde transport of protein aggregates. Cell 140, 257–267 (2010). This paper investigates the Sir2-dependent mechanism of polarized segregation of damaged macromolecules to yeast mother cells.

Dang, W. et al. Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature 459, 802–807 (2009).

Berdichevsky, A., Viswanathan, M., Horvitz, H. R. & Guarente, L. C. elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life span. Cell 125, 1165–1177 (2006).

Hull- Thompson, J. et al. Control of metabolic homeostasis by stress signaling is mediated by the lipocalin NLaz. PLoS Genet. 4, e1000460 (2009).

Griswold, A., Chang, K. T., Runko, A. P., Knight, M. A. & Min, K. T. Sir2 mediates apoptosis through JNK-dependent pathways in Drosophila . Proc. Natl Acad. Sci. USA 105, 8673–8678 (2008).

Pearson, K. J. et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab. 8, 157–168 (2008).

Beher, D. et al. Resveratrol is not a direct activator of SIRT1 enzyme activity. Chem. Biol. Drug Des. 74, 619–624 (2009).

Viswanathan, M., Kim, S. K., Berdichevsky, A. & Guarente, L. A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span. Dev. Cell 9, 605–615 (2005). This is a powerful genetic demonstration that resveratrol does not behave as a simple sirtuin activator.

Smith, D. L. Jr et al. Calorie restriction effects on silencing and recombination at the yeast rDNA. Aging Cell 8, 633–642 (2009).

Riesen, M. & Morgan, A. Calorie restriction reduces rDNA recombination independently of rDNA silencing. Aging Cell 8, 624–632 (2009).

Wang, Y. & Tissenbaum, H. A. Overlapping and distinct functions for Caenorhabditis elegans SIR2 and DAF-16/FOXO. Mech. Ageing Dev. 127, 48–56 (2006).

Li, Y., Xu, W., McBurney, M. W. & Longo, V. D. SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons. Cell Metab. 8, 38–48 (2008).

Kayser, E. B., Sedensky, M. M., Morgan, P. G. & Hoppel, C. L. Mitochondrial oxidative phosphorylation is defective in the long-lived mutant clk-1. J. Biol. Chem. 279, 54479–54486 (2004).

Lapointe, J. & Hekimi, S. Early mitochondrial dysfunction in long-lived Mclk1+/− mice. J. Biol. Chem. 283, 26217–26227 (2008).

Rea, S. L., Ventura, N. & Johnson, T. E. Relationship between mitochondrial electron transport chain dysfunction, development, and life extension in Caenorhabditis elegans . PLoS Biol. 5, e259 (2007).

Kirchman, P. A., Kim, S., Lai, C. Y. & Jazwinski, S. M. Interorganelle signaling is a determinant of longevity in Saccharomyces cerevisiae . Genetics 152, 179–190 (1999).

Cristina, D., Cary, M., Lunceford, A., Clarke, C. & Kenyon, C. A regulated response to impaired respiration slows behavioral rates and increases lifespan in Caenorhabditis elegans . PLoS Genet. 5, e1000450 (2009).

Hsin, H. & Kenyon, C. Signals from the reproductive system regulate the lifespan of C. elegans. Nature 399, 362–366 (1999).

Flatt, T. et al. Drosophila germ-line modulation of insulin signaling and lifespan. Proc. Natl Acad. Sci. USA 105, 6368–6373 (2008).

Parker, W. H. et al. Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nurses' health study. Obstet. Gynecol. 113, 1027–1037.

Tomas- Loba, A. et al. Telomerase reverse transcriptase delays aging in cancer-resistant mice. Cell 135, 609–622 (2008). This paper demonstrates a 'rate limiting' role for telomere length in mammalian longevity.

Pinkston, J. M., Garigan, D., Hansen, M. & Kenyon, C. Mutations that increase the lifespan of C. elegans inhibit tumor growth. Science 313, 971–975 (2006).

Hernebring, M., Brolen, G., Aguilaniu, H., Semb, H. & Nystrom, T. Elimination of damaged proteins during differentiation of embryonic stem cells. Proc. Natl Acad. Sci. USA 103, 7700–7705 (2006).

Fan, W. et al. A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations. Science 319, 958–962 (2008).

Stewart, J. B. et al. Strong purifying selection in transmission of mammalian mitochondrial DNA. PLoS Biol. 6, e10 (2008). References 90 and 91 demonstrate the existence of a quality-control mechanism for inheritance of mitochondrial DNA.

Gems, D. & Doonan, R. Antioxidant defense and aging in C. elegans: is the oxidative damage theory of aging wrong? Cell Cycle 8, 1681–1687 (2009).

Schulz, T. J. et al. Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab. 6, 280–293 (2007).

Budovskaya, Y. V. et al. An elt-3/elt-5/elt-6 GATA transcription circuit guides aging in C. elegans . Cell 134, 291–303 (2008).

Boehm, M. & Slack, F. A developmental timing microRNA and its target regulate life span in C. elegans . Science 310, 1954–1957 (2005). This is the first demonstration that microRNAs affect ageing; interestingly, this microRNA also regulates the timing of developmental events.

Oberdoerffer, P. et al. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 135, 907–918 (2008).

Brack, A. S. et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317, 807–810 (2007).

Gachon, F., Olela, F. F., Schaad, O., Descombes, P. & Schibler, U. The circadian PAR-domain basic leucine zipper transcription factors DBP, TEF, and HLF modulate basal and inducible xenobiotic detoxification. Cell Metab. 4, 25–36 (2006).

Walker, R. F. et al. A case study of 'disorganized development' and its possible relevance to genetic determinants of aging. Mech. Ageing Dev. 130, 350–356 (2009).

Hsu, A. L., Feng, Z., Hsieh, M. Y. & Xu, X. Z. Identification by machine vision of the rate of motor activity decline as a lifespan predictor in C. elegans . Neurobiol. Aging 30, 1498–1503 (2008).

Rea, S. L., Wu, D., Cypser, J. R., Vaupel, J. W. & Johnson, T. E. A stress-sensitive reporter predicts longevity in isogenic populations of Caenorhabditis elegans . Nature Genet. 37, 894–898 (2005).

Ayyadevara, S. et al. C. elegans PI3K mutants reveal novel genes underlying exceptional stress resistance and lifespan. Aging Cell 8, 706–725 (2009).

Davies, B. S., Fong, L. G., Yang, S. H., Coffinier, C. & Young, S. G. The posttranslational processing of prelamin A and disease. Annu. Rev. Genomics Hum. Genet. 10, 153–174 (2009).

Barzilai, N. et al. Unique lipoprotein phenotype and genotype associated with exceptional longevity. J. Am. Med. Assoc. 290, 2030–2040 (2003).