Portal de Periódicos da CAPES

Molecular basis of ageing

2007; Springer Nature; Volume: 8; Issue: 10 Linguagem: Inglês

10.1038/sj.embor.7401066

1469-3178

Matt Kaeberlein,

Adipose Tissue and Metabolism

Meeting Report7 September 2007free access Molecular basis of ageing Matt Kaeberlein Matt Kaeberlein Department of Pathology, University of Washington, Seattle, Washington, 98195, USA Search for more papers by this author Matt Kaeberlein Matt Kaeberlein Department of Pathology, University of Washington, Seattle, Washington, 98195, USA Search for more papers by this author Author Information Matt Kaeberlein1 1Department of Pathology, University of Washington, Seattle, Washington, 98195, USA EMBO Reports (2007)8:907-911https://doi.org/10.1038/sj.embor.7401066 PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info The 94th Annual Boehringer Ingelheim Fonds International Titisee Conference was held at the Schwarzwald hotel in Titisee, Germany, from 11 to 15 April 2007. The conference was co-chaired by J. Hoeijmakers and J. Campisi, and was organized by H. Frolich. Introduction The 94th Annual Boehringer Ingelheim Fonds International Titisee Conference brought scientists from around the world together to discuss recent progress in studies of the basic biology of ageing (biogerontology). The field of biogerontology has seen a marked growth in scientific and popular interest over the past few years, leading to an influx of new investigators working on diverse aspects of cellular and organismal ageing. This diversity was well represented at the conference, where topics included the molecular causes of ageing, cell senescence and apoptosis, stem cells, cancer, the genetics of longevity and anti-ageing interventions, among others. Although the range of topics was broad, the meeting gave rise to potential models through which this diversity might coalesce into a more comprehensive understanding of how and why we age. One theme underlying much of the discussion at the conference was which approaches—both current and future—might facilitate the transition from basic research to therapeutic treatments for age-associated diseases. The potential benefits of successfully accomplishing such a transition are considerable. For example, it has been estimated that a single intervention to slow ageing in humans—such as dietary restriction (DR), which is now routine in mice—would increase life expectancy in the United States to a greater extent than simultaneously curing cancer, cardiovascular disease and diabetes (Miller, 2002; Olshansky et al, 1990). The molecular basis of ageing was therefore a timely and exciting topic for the 2007 Boehringer Ingelheim Fonds International Titisee Conference. Molecular causes of ageing At a fundamental level, biological ageing can be thought of as a progressive decline in the function of the cells of an organism, ultimately resulting in senescence. Despite much study, a clear understanding of the molecular causes of ageing has remained elusive. Although it is generally recognized that ageing is associated with the accumulation of cellular damage—for example, owing to the production of oxidative radicals (Harman, 1956)—there remains a lack of consensus in the field about the extent to which the accumulation of different types of damage drives the ageing process. Therefore, major themes of the conference were the potential molecular causes of ageing and the roles that many different factors might have in contributing to cell loss and tissue decline with age. The conference opened with the keynote address by G. Martin (Seattle, WA, USA), who gave an overview of the pathobiology of ageing, with an emphasis on the classes of gene action that have escaped the force of natural selection. He concluded that, in contrast to the crucial role of the constitutional genome in the modulation of inter-specific variation in rates of ageing, stochastic events (possibly epigenetic in origin) are likely to be the main modulators of intra-specific variation in rates and patterns of ageing. D. Sinclair (Boston, MA, USA) also touched on this idea by proposing that DNA damage might be a cause of the stochastic loss of gene regulation with age due to global changes in histone acetylation. Telomere shortening The telomere hypothesis of ageing has been an important human model for nearly 20 years (Harley et al, 1992). This hypothesis posits that many age-associated phenotypes are caused by cellular senescence in response to one or more crucially shortened telomeres. In most human cells, telomere length is reduced with each cell division because the enzyme responsible for replacing the telomere ends, telomerase, is unexpressed or expressed at low levels. Replicative senescence of human cells in culture can be rescued by the expression of telomerase, demonstrating that it is sufficient to prevent cell senescence in vitro (Bodnar et al, 1998). The extent to which telomere shortening is relevant to cellular senescence and ageing in vivo, however, remains unknown. J. Shay (Dallas, TX, USA) expressed optimism that telomerase inhibitors will be potent anti-cancer therapies. Shay discussed two classes of therapeutic telomerase inhibitor that are under development. The first is a synthetic telomerase peptide vaccine that is designed to elicit an immune response against a telomerase peptide present on the surface of cancerous cells. The second is an oligonucleotide complementary to the RNA component of telomerase that acts as a direct enzyme inhibitor. L. Rudolph (Hannover, Germany) discussed the possibility that telomere attrition in stem-cell populations is a key feature of ageing tissues. He proposed that transient activation of telomerase might be sufficient to replenish stem-cell telomeres without promoting tumorigenesis. Rudolph also showed data from experiments in telomerase-deficient mice (Rudolph et al, 1999), indicating that cell senescence and apoptosis in cells with crucially short telomeres can be prevented by interfering with a DNA-damage-response pathway. DNA damage and oxidative stress The accumulation of macromolecular damage has long been thought to underlie ageing at a fundamental level. One potentially important type of age-associated damage might be mutagenic damage to nuclear or mitochondrial DNA. J. Vijg (Novato, CA, USA) described a system for quantifying the frequency of different types of nuclear DNA mutation in vivo in flies and mice. Vijg reported that mutation rates were elevated in the liver in one short-lived mouse model and were reduced in the kidneys in two long-lived models: Ames dwarf mice and DR mice. V. Bohr (Baltimore, MD, USA) argued that mitochondrial base-excision repair has an important role in protecting against oxidative damage to mitochondrial DNA and noted that DR induces this type of repair. Meeting co-chair J. Hoeijmakers (Rotterdam, The Netherlands) described progeroid and cancer phenotypes observed in several lines of knockout mice that are deficient for nucleotide-excision repair. Many human diseases, some with characteristics suggestive of premature ageing—such as Cockayne syndrome and trichothiodystrophy—are caused by these types of mutation (Andressoo et al, 2006). On the basis of gene-expression analysis in DNA-repair-deficient mice, Hoeijmakers speculated that nuclear DNA damage might invoke a longevity response by influencing insulin-like growth factor 1 (IGF1) and growth hormone (GH) signalling, which are known to have important roles in determining longevity from studies in model organisms. Cancer and senescence Several talks at the meeting underscored a growing recognition that cancer and ageing might be two sides of the same coin. Cancer is held in check by tumour-suppressing mechanisms that limit unregulated cell division early in life. However, these same anti-cancer pathways also lead to cellular senescence and apoptosis, which might ultimately drive age-related decline in tissue and organ function. Too little tumour-suppressing activity leads to an increased risk of cancer, whereas too much tumour-suppressing activity results in cell depletion and phenotypes consistent with premature ageing. Much of the discussion at the meeting on this topic was centred on the p53 pathway and its role in age-associated disease. Meeting co-chair J. Campisi (Berkeley, CA, USA) discussed the importance of p53 in promoting senescence to prevent cancer. A large body of work from the Campisi laboratory and others has described the detrimental effects that factors secreted by senescent cells have on the surrounding tissues, which, paradoxically, might contribute to elevated cancer incidence and chronic inflammation with age (Campisi, 2005). Campisi reported that, as well as promoting cell senescence, p53 is crucial for keeping the secretion of these factors by senescent cells in check. Therefore, p53 apparently functions as a tumour suppressor both cell-autonomously and non-autonomously. Ageing phenotypes in mice with altered p53 activity were also discussed at the meeting. M. Perry (Bethesda, MD, USA) described mice with a hypomorphic allele of the p53 inhibitor mouse double minute 2 (Mdm2). Too little Mdm2 is lethal, but reduced Mdm2 in transgenic mice leads to enhanced p53 activity, increased apoptosis and decreased cancer formation in at least one cancer-prone model. Interestingly, although cancer incidence is reduced, lifespan is unchanged (Mendrysa et al, 2006). H. Scrable (Charlottesville, VA, USA) described her work with mice that lack the primary p53 isoform but are still able to make an alternative isoform, p44 (Maier et al, 2004). Although these mice do not get cancer, they do seem to undergo accelerated ageing. She also described data indicating a role for p44 in the interaction of p53 with insulin/IGF1 signalling (IIS), and proposed that it might have a function in determining the ageing rate much earlier than had previously been thought—perhaps as early as embryogenesis. Sinclair presented data indicating that increased expression of the silent information regulator 2 homologue 1 (SirT1) protein deacetylase confers protection against colon cancer in mice. SirT1 has been previously reported to modulate p53 activity (Luo et al, 2001; Vaziri et al, 2001) and has been proposed to mediate some aspects of DR (Guarente & Picard, 2005; Kaeberlein & Powers, 2007; Longo & Kennedy, 2006). Sinclair also mentioned ongoing studies to determine whether mice overexpressing SirT1 are long-lived—a topic of great interest to the field. Depletion of stem cells Several talks at the meeting emphasized a growing recognition of the importance of stem cells in ageing. One hypothesis is that stem-cell depletion in mitotically active tissues leads to many of the phenotypes associated with ageing. This hypothesis is attractive because it provides a potential synthesis explaining how all of the proposed causes of age-associated cell loss (DNA damage, telomere shortening, mitochondrial dysfunction and so on) could converge to lead to widespread stem-cell depletion as an organism ages. An important prediction of this hypothesis is that stem-cell abundance or proliferative potential decreases with age. L. Jones (La Jolla, CA, USA) provided experimental evidence for such depletion, showing that germline stem cells are lost with age in the fruit fly (Fig 1). Figure 1.Age-related loss of germline stem cells. Immunostaining for the germ-cell-specific RNA helicase Vasa (green) and the cell-surface protein fasciclin III (red) to mark the hub in young (1-day-old) and old (50-day-old) flies. Germline stem cells reside at the tip of the testis surrounding and in contact with the hub. Each germline stem cell is indicated by a white dot. Image courtesy of L. Jones. Download figure Download PowerPoint C. López-Otin (Oviedo, Spain) presented data indicating a potential link between stem-cell defects and the human progeroid disease, Hutchinson–Gilford progeria syndrome (HGPS). HGPS is caused by defective splicing of the lamin A/C gene, which results in the accumulation of unprocessed lamin A (De Sandre-Giovannoli et al, 2003; Eriksson et al, 2003). Mice that lack the zinc metallopeptidase STE24 homologue (Zmpste24) gene, which codes for a protease that cleaves lamin A, similarly accumulate an unprocessed form of lamin A and show features of premature ageing (Pendas et al, 2002). These mice also had elevated p53 activity, accumulated quiescent stem cells and reduced stem-cell proliferation. López-Otin suggested that stem-cell therapy might prove useful for HGPS patients in the future. Interventions that increase longevity One of the great promises of biogerontology is the development of therapies to combat age-associated diseases. Interventions that slow ageing are likely to delay the onset of many important diseases, including cancer, diabetes, cardiovascular disease and neurodegenerative diseases. Indeed, in rodents, DR seems to have precisely this effect (Masoro, 2005; Weindruch & Walford, 1988). Several talks at the meeting focused on interventions that increase lifespan in model organisms and the potential to translate these discoveries into treatments for humans. Dietary restriction Although new models of enhanced longevity in mammals continue to be described, it was clear that DR remains the gold standard against which these models are compared. Known to increase lifespan in yeast, worms, flies and rodents, DR is the best studied anti-ageing intervention. Much discussion at the meeting centred on the pathways that are thought to mediate DR and the development of DR mimetics—chemicals designed to target these pathways to provide the health and longevity benefits of DR, without requiring reduced food consumption. S. Spindler (Riverside, CA, USA) described an approach for identifying DR mimetics that involves gene-expression profiling. He mentioned published data (Dhahbi et al, 2005) showing that metformin, which is an anti-diabetic compound already known to increase lifespan in mice (Dilman & Anisimov, 1980), recapitulates most of the gene-expression changes associated with DR. One target of metformin is adenosine-monophosphate-activated protein kinase (AMPK), which is known to regulate metabolic and mitochondrial function in response to nutrients (Zhou et al, 2001). Interestingly, AMPK is also activated by resveratrol (Dasgupta & Milbrandt, 2007; Zang et al, 2006), which is a putative DR mimetic that has recently gained much attention for its reported ability to improve the health and median survival of mice fed a high-fat diet (Baur et al, 2006; Lagouge et al, 2006). M. Kaeberlein (Seattle, WA, USA) and T. Johnson (Boulder, CO, USA) both presented data from experiments in the nematode Caenorhabditis elegans indicating that DR increases survival and reduces mortality even when initiated late in life. These observations are similar to the effect of DR in fruit flies (Mair et al, 2003). Spindler also discussed published data in mice indicating that DR initiated late in adulthood rapidly reduced mortality, and caused a shift in gene expression to a pattern similar to that seen in mice placed on a DR diet early in life (Dhahbi et al, 2004). Therefore, a consensus seems to be emerging that, at least in model organisms, DR initiated later in life still has beneficial results for health and longevity. Although it remains to be determined to what extent DR slows ageing in humans, these studies provide hope that DR mimetics will be effective against age-associated disease in middle-aged adults. Growth hormone and insulin/IGF1 signalling GH supplementation has received notoriety as a potential anti-ageing treatment, but so far has not been proven to be effective in this regard (Perls, 2004). J. Kopchick (Athens, OH, USA) made the case that, although GH supplementation is therapeutic for individuals suffering from GH deficiency, in healthy adults it might have adverse consequences, including an increased risk of cancer. Kopchick and A. Bartke (Springfield, IL, USA) both noted that in several rodent models, including GH-receptor-knockout mice, Ames dwarf mice and Snell dwarf mice (Brown-Borg et al, 1996; Coschigano et al, 2000; Flurkey et al, 2001), reduced GH signalling, rather than elevated GH activity, is correlated with increased longevity. Although reduced GH signalling correlates with increased lifespan in mice, simply inhibiting GH activity might not be sufficient to slow ageing. Kopchick reported that mice treated with a peptide GH antagonist are not long-lived. This might be owing to effects specific to the GH agonist used in these studies or it could indicate that other hormonal factors in addition to GH are crucial for the enhanced longevity of the dwarf mice. As the detailed mechanisms accounting for lifespan extension in GH-receptor-knockout and dwarf animals are uncovered, more-targeted therapies to alter GH activity might prove useful against a wide range of age-associated diseases. In addition to reduced levels of GH, one feature that long-lived dwarf mice and mice subjected to DR have in common is reduced insulin and IGF1 levels (Bartke, 2005). Reduced IIS is known to increase the lifespan of worms and flies, which points to an evolutionarily conserved mechanism of action (Longo & Finch, 2003). Surprisingly, genetic evidence has indicated that IIS and DR act in parallel genetic pathways, based on additive increases in lifespan observed when DR is imposed on C. elegans mutants with reduced IIS (Houthoofd et al, 2003; Kaeberlein et al, 2006; Lakowski & Hekimi, 1998; Lee et al, 2006) or Ames dwarf mice (Bartke et al, 2001). Bartke discussed the relationship between reduced GH or IIS signalling and DR, and concluded that they are related, but not identical. This idea fits with data from R. Miller (Ann Arbor, MI, USA), which showed that fibroblasts from Ames dwarf, Snell dwarf or GH-receptor-knockout mice are resistant to a range of stresses in culture, but that a similar phenotype is not observed in fibroblasts from DR animals (Harper et al, 2006). Bartke presented data consistent with the idea that insulin sensitivity is an important predictor of longevity in rodents. Although GH-receptor-knockout mice and Ames dwarf mice respond differently to DR with respect to longevity, in each case a strong correlation between insulin sensitivity and lifespan was observed. R. Westendorp (Leiden, The Netherlands) described a similar correlation in long-lived humans and their offspring, and suggested that human longevity might be associated with more-efficient glucose handling. Bartke also presented evidence that decreased GH or IIS could promote longevity in part by reducing signalling through the nutrient-responsive target of rapamycin (TOR) kinase pathway, which is known to increase lifespan in yeast, worms and flies (Jia et al, 2004; Kaeberlein et al, 2005; Kapahi et al, 2004; Powers et al, 2006; Vellai et al, 2003). TOR signalling has been proposed to mediate lifespan extension from DR in simple eukaryotes (Kapahi & Zid, 2004), and might provide an important molecular link between GH, IIS and DR in mammals. Conclusion The 94th Annual Boehringer Ingelheim Fonds International Titisee Conference on the molecular basis of ageing demonstrated both the complexity and the potential rewards of biogerontology. Although much remains to be discovered, patterns and connections are emerging, and biogerontologists are generally optimistic that effective interventions targeting age-associated disease are on the horizon. Indeed, some of the studies discussed in Titisee are already being translated into potential therapies for specific age-associated diseases. Although efficacy has yet to be demonstrated for any ‘anti-ageing’ intervention, it is likely that the process of moving from basic biogerontology to therapeutic applications will accelerate. It will be interesting to follow the stories told at Titisee and to see which make this transition. Will stem-cell therapies be useful for targeting age-associated diseases? Are DR mimetics feasible and will they be beneficial to humans? Can telomerase activity or GH signalling be effectively modulated in humans to influence ageing and cancer? These questions and many others of importance to the field will probably be answered in the next few years. We therefore look towards the future of biogerontological research, and the next Boehringer Ingelheim Fonds Conference on the molecular mechanisms of ageing, with anticipation and enthusiasm. Acknowledgements The meeting was sponsored by the Boehringer Ingelheim Fonds Foundation for Basic Research in Medicine. I thank G. Martin for helpful discussions and comments on this meeting report. Many thanks to J. Hoeijmakers, J. Campisi and H. Frolich for their efforts organizing the conference, and to all the participants for their outstanding presentations and discussions. I apologize to those participants who could not be included in this review because of space constraints. Biography Matt Kaeberlein References Andressoo JO, Hoeijmakers JH, Mitchell JR (2006) Nucleotide excision repair disorders and the balance between cancer and aging. Cell Cycle 5: 2886–2888CrossrefCASPubMedWeb of Science®Google Scholar Bartke A (2005) Minireview: role of the growth hormone/insulin-like growth factor system in mammalian aging. Endocrinology 146: 3718–3723CrossrefCASPubMedWeb of Science®Google Scholar Bartke A, Wright JC, Mattison JA, Ingram DK, Miller RA, Roth GS (2001) Extending the lifespan of long-lived mice. Nature 414: 412CrossrefCASPubMedWeb of Science®Google Scholar Baur JA et al (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444: 337–342Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay JW, Lichtsteiner S, Wright WE (1998) Extension of life-span by introduction of telomerase into normal human cells. Science 279: 349–352CrossrefCASPubMedWeb of Science®Google Scholar Brown-Borg HM, Borg KE, Meliska CJ, Bartke A (1996) Dwarf mice and the ageing process. Nature 384: 33CrossrefCASPubMedWeb of Science®Google Scholar Campisi J (2005) Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120: 513–522CrossrefCASPubMedWeb of Science®Google Scholar Coschigano KT, Clemmons D, Bellush LL, Kopchick JJ (2000) Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. Endocrinology 141: 2608–2613CrossrefCASPubMedWeb of Science®Google Scholar Dasgupta B, Milbrandt J (2007) Resveratrol stimulates AMP kinase activity in neurons. Proc Natl Acad Sci USA 104: 7217–7222CrossrefCASPubMedWeb of Science®Google Scholar De Sandre-Giovannoli A et al (2003) Lamin a truncation in Hutchinson–Gilford progeria. Science 300: 2055CrossrefCASPubMedWeb of Science®Google Scholar Dhahbi JM, Kim HJ, Mote PL, Beaver RJ, Spindler SR (2004) Temporal linkage between the phenotypic and genomic responses to caloric restriction. Proc Natl Acad Sci USA 101: 5524–5529CrossrefCASPubMedWeb of Science®Google Scholar Dhahbi JM, Mote PL, Fahy GM, Spindler SR (2005) Identification of potential caloric restriction mimetics by microarray profiling. Physiol Genomics 23: 343–350CrossrefCASPubMedWeb of Science®Google Scholar Dilman VM, Anisimov VN (1980) Effect of treatment with phenformin, diphenylhydantoin or L-dopa on life span and tumour incidence in C3H/Sn mice. Gerontology 26: 241–246CrossrefCASPubMedWeb of Science®Google Scholar Eriksson M et al (2003) Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome. Nature 423: 293–298CrossrefCASPubMedWeb of Science®Google Scholar Flurkey K, Papaconstantinou J, Miller RA, Harrison DE (2001) Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Natl Acad Sci USA 98: 6736–6741CrossrefCASPubMedWeb of Science®Google Scholar Guarente L, Picard F (2005) Calorie restriction: the SIR2 connection. Cell 120: 473–482CrossrefCASPubMedWeb of Science®Google Scholar Harley CB, Vaziri H, Counter CM, Allsopp RC (1992) The telomere hypothesis of cellular aging. Exp Gerontol 27: 375–382CrossrefCASPubMedWeb of Science®Google Scholar Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11: 298–300CrossrefCASPubMedWeb of Science®Google Scholar Harper JM, Salmon AB, Chang Y, Bonkowski M, Bartke A, Miller RA (2006) Stress resistance and aging: influence of genes and nutrition. Mech Ageing Dev 127: 687–694CrossrefCASPubMedWeb of Science®Google Scholar Houthoofd K, Braeckman BP, Johnson TE, Vanfleteren JR (2003) Life extension via dietary restriction is independent of the Ins/IGF-1 signalling pathway in Caenorhabditis elegans. Exp Gerontol 38: 947–954CrossrefCASPubMedWeb of Science®Google Scholar Jia K, Chen D, Riddle DL (2004) The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development 131: 3897–3906CrossrefCASPubMedWeb of Science®Google Scholar Kaeberlein M, Powers RW (2007) Sir2 and calorie restriction in yeast: a skeptical perspective. Ageing Res Rev 6: 128–140CrossrefCASPubMedWeb of Science®Google Scholar Kaeberlein M, Powers RW, Steffen KK, Westman EA, Hu D, Dang N, Kerr EO, Kirkland KT, Fields S, Kennedy BK (2005) Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310: 1193–1196CrossrefCASPubMedWeb of Science®Google Scholar Kaeberlein TL, Smith ED, Tsuchiya M, Welton KL, Thomas JH, Fields S, Kennedy BK, Kaeberlein M (2006) Lifespan extension in Caenorhabditis elegans by complete removal of food. Aging Cell 5: 487–494Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Kapahi P, Zid B (2004) TOR pathway: linking nutrient sensing to life span. Sci Aging Knowledge Environ 2004: PE34CrossrefPubMedGoogle Scholar Kapahi P, Zid BM, Harper T, Koslover D, Sapin V, Benzer S (2004) Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol 14: 885–890CrossrefCASPubMedWeb of Science®Google Scholar Lagouge M et al (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127: 1109–1122CrossrefCASPubMedWeb of Science®Google Scholar Lakowski B, Hekimi S (1998) The genetics of caloric restriction in Caenorhabditis elegans. Proc Natl Acad Sci USA 95: 13091–13096CrossrefCASPubMedWeb of Science®Google Scholar Lee GD, Wilson MA, Zhu M, Wolkow CA, de Cabo R, Ingram DK, Zou S (2006) Dietary deprivation extends lifespan in Caenorhabditis elegans. Aging Cell 5: 515–524Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Longo VD, Finch CE (2003) Evolutionary medicine: from dwarf model systems to healthy centenarians? Science 299: 1342–1346CrossrefPubMedWeb of Science®Google Scholar Longo VD, Kennedy BK (2006) Sirtuins in aging and age-related disease. Cell 126: 257–268CrossrefCASPubMedWeb of Science®Google Scholar Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A, Guarente L, Gu W (2001) Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 107: 137–148CrossrefCASPubMedWeb of Science®Google Scholar Maier B, Gluba W, Bernier B, Turner T, Mohammad K, Guise T, Sutherland A, Thorner M, Scrable H (2004) Modulation of mammalian life span by the short isoform of p53. Genes Dev 18: 306–319CrossrefCASPubMedWeb of Science®Google Scholar Mair W, Goymer P, Pletcher SD, Partridge L (2003) Demography of dietary restriction and death in Drosophila. Science 301: 1731–1733CrossrefCASPubMedWeb of Science®Google Scholar Masoro EJ (2005) Overview of caloric restriction and ageing. Mech Ageing Dev 126: 913–922CrossrefCASPubMedWeb of Science®Google Scholar Mendrysa SM, O'Leary KA, McElwee MK, Michalowski J, Eisenman RN, Powell DA, Perry ME (2006) Tumor suppression and normal aging in mice with constitutively high p53 activity. Genes Dev 20: 16–21CrossrefCASPubMedWeb of Science®Google Scholar Miller RA (2002) Extending life: scientific prospects and political obstacles. Milbank Q 80: 155–174Wiley Online LibraryPubMedWeb of Science®Google Scholar Olshansky SJ, Carnes BA, Cassel C (1990) In search of Methuselah: estimating the upper limits to human longevity. Science 250: 634–640CrossrefCASPubMedWeb of Science®Google Scholar Pendas AM et al (2002) Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice. Nat Genet 31: 94–99CrossrefCASPubMedWeb of Science®Google Scholar Perls TT (2004) Anti-aging quackery: human growth hormone and tricks of the trade: more dangerous than ever. J Gerontol A Biol Sci Med Sci 59: 682–691CrossrefPubMedWeb of Science®Google Scholar Powers RW, Kaeberlein M, Caldwell SD, Kennedy BK, Fields S (2006) Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev 20: 174–184CrossrefCASPubMedWeb of Science®Google Scholar Rudolph KL, Chang S, Lee HW, Blasco M, Gottlieb GJ, Greider C, DePinho RA (1999) Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96: 701–712CrossrefCASPubMedWeb of Science®Google Scholar Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA, Pandita TK, Guarente L, Weinberg RA (2001) hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107: 149–159CrossrefCASPubMedWeb of Science®Google Scholar Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Muller F (2003) Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 426: 620CrossrefCASPubMedWeb of Science®Google Scholar Weindruch RH, Walford RL (1988) The Retardation of Aging and Disease by Dietary Restriction. Springfield, IL, USA: ThomasCrossrefGoogle Scholar Zang M, Xu S, Maitland-Toolan KA, Zuccollo A, Hou X, Jiang B, Wierzbicki M, Verbeuren TJ, Cohen RA (2006) Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes 55: 2180–2191CrossrefCASPubMedWeb of Science®Google Scholar Zhou G et al (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108: 1167–1174CrossrefCASPubMedWeb of Science®Google Scholar Previous ArticleNext Article Volume 8Issue 101 October 2007In this issue FiguresReferencesRelatedDetailsLoading ...