Extending Healthy Life Span—From Yeast to Humans
Eat Less, Live Long
Studies in several model organisms have shown that dietary restriction without malnutrition, or manipulation of nutrient-sensing pathways through mutations or drugs, can increase life span and reduce age-related disease. Fontana et al. (p. 321) review the ways in which nutrient-sensing pathways are central to aging. Studies of yeast, worms, rodents, and primates show that these pathways are conserved during evolution. Although data on the effects of dietary restriction in primates are very limited, in humans, the protective effects of dietary restriction against cancer, cardiovascular disease, and diabetes must be judged against potentially negative long-term effects. More work is needed to determine whether dietary restriction and the modulation of anti-aging pathways through drugs can extend life span and reduce pathologies in humans.
Abstract
When the food intake of organisms such as yeast and rodents is reduced (dietary restriction), they live longer than organisms fed a normal diet. A similar effect is seen when the activity of nutrient-sensing pathways is reduced by mutations or chemical inhibitors. In rodents, both dietary restriction and decreased nutrient-sensing pathway activity can lower the incidence of age-related loss of function and disease, including tumors and neurodegeneration. Dietary restriction also increases life span and protects against diabetes, cancer, and cardiovascular disease in rhesus monkeys, and in humans it causes changes that protect against these age-related pathologies. Tumors and diabetes are also uncommon in humans with mutations in the growth hormone receptor, and natural genetic variants in nutrient-sensing pathways are associated with increased human life span. Dietary restriction and reduced activity of nutrient-sensing pathways may thus slow aging by similar mechanisms, which have been conserved during evolution. We discuss these findings and their potential application to prevention of age-related disease and promotion of healthy aging in humans, and the challenge of possible negative side effects.
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References and Notes
1
Anderson R. M., Shanmuganayagam D., Weindruch R., Caloric restriction and aging: studies in mice and monkeys. Toxicol. Pathol. 37, 47 (2009).
2
Fontana L., Klein S., Aging, adiposity, and calorie restriction. JAMA 297, 986 (2007).
3
Piper M. D., Partridge L., Dietary restriction in Drosophila: delayed aging or experimental artefact? PLoS Genet. 3, e57 (2007).
4
Kaeberlein M., et al., Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310, 1193 (2005).
5
Powers R. W., Kaeberlein M., Caldwell S. D., Kennedy B. K., Fields S., Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev. 20, 174 (2006).
6
Wei M., et al., Tor1/Sch9-regulated carbon source substitution is as effective as calorie restriction in life span extension. PLoS Genet. 5, e1000467 (2009).
7
Pan Y., Shadel G. S., Extension of chronological life span by reduced TOR signaling requires down-regulation of Sch9p and involves increased mitochondrial OXPHOS complex density. Aging 1, 131 (2009).
8
Steffen K. K., et al., Yeast life span extension by depletion of 60s ribosomal subunits is mediated by Gcn4. Cell 133, 292 (2008).
9
Fabrizio P., Pozza F., Pletcher S. D., Gendron C. M., Longo V. D., Regulation of longevity and stress resistance by Sch9 in yeast. Science 292, 288 (2001).
10
Lin S. J., Defossez P. A., Guarente L., Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289, 2126 (2000).
11
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).
12
Wei M., et al., Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9. PLoS Genet. 4, e13 (2008).
13
Fabrizio P., et al., Sir2 blocks extreme life-span extension. Cell 123, 655 (2005).
14
Burtner C. R., Murakami C. J., Kennedy B. K., Kaeberlein M., A molecular mechanism of chronological aging in yeast. Cell Cycle 8, 1256 (2009).
15
Longo V. D., Ellerby L. M., Bredesen D. E., Valentine J. S., Gralla E. B., Human Bcl-2 reverses survival defects in yeast lacking superoxide dismutase and delays death of wild-type yeast. J. Cell Biol. 137, 1581 (1997).
16
Smith D. L., McClure J. M., Matecic M., Smith J. S., Calorie restriction extends the chronological lifespan of Saccharomyces cerevisiae independently of the Sirtuins. Aging Cell 6, 649 (2007).
17
Kaeberlein M., Burtner C. R., Kennedy B. K., Recent developments in yeast aging. PLoS Genet. 3, e84 (2007).
18
Johnson T. E., Caenorhabditis elegans 2007: The premier model for the study of aging. Exp. Gerontol. 43, 1 (2008).
19
Doonan R., et al., Against the oxidative damage theory of aging: superoxide dismutases protect against oxidative stress but have little or no effect on life span in Caenorhabditis elegans. Genes Dev. 22, 3236 (2008).
20
Libina N., Berman J. R., Kenyon C., Tissue-specific activities of C. elegans DAF-16 in the regulation of lifespan. Cell 115, 489 (2003).
21
Hansen M., et al., A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet. 4, e24 (2008).
22
Piper M. D., Selman C., McElwee J. J., Partridge L., Separating cause from effect: how does insulin/IGF signalling control lifespan in worms, flies and mice? J. Intern. Med. 263, 179 (2008).
23
Chen D., Thomas E. L., Kapahi P., Mango S. E., HIF-1 modulates dietary restriction-mediated lifespan extension via IRE-1 in Caenorhabditis elegans. PLoS Genet. 5, e1000486 (2009).
24
Mehta R., et al., Proteasomal regulation of the hypoxic response modulates aging in C. elegans. Science 324, 1196 (2009).
25
Mair W., Dillin A., Aging and survival: the genetics of life span extension by dietary restriction. Annu. Rev. Biochem. 77, 727 (2008).
26
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 (2009).
27
Smith E. D., et al., Age- and calorie-independent life span extension from dietary restriction by bacterial deprivation in Caenorhabditis elegans. BMC Dev. Biol. 8, 49 (2008).
28
Steinkraus K. A., et al., Dietary restriction suppresses proteotoxicity and enhances longevity by an hsf-1-dependent mechanism in Caenorhabditis elegans. Aging Cell 7, 394 (2008).
29
Tullet J. M., et al., Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell 132, 1025 (2008).
30
McElwee J. J., et al., Evolutionary conservation of regulated longevity assurance mechanisms. Genome Biol. 8, R132 (2007).
31
Groenke S., Clarke D. F., Broughton S., Andrews T. D., Partridge L., PLoS Genet. 6, e1000857 (2010).
32
Broughton S. J., et al., Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands. Proc. Natl. Acad. Sci. U.S.A. 102, 3105 (2005).
33
Kapahi P., et al., Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr. Biol. 14, 885 (2004).
34
Bjedov I., et al., Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 11, 35 (2010).
35
Chapman T., Partridge L., Female fitness in Drosophila melanogaster: an interaction between the effect of nutrition and of encounter rate with males. Proc. Biol. Sci. 263, 755 (1996).
36
Bass T. M., et al., Optimization of dietary restriction protocols in Drosophila. J. Gerontol. A Biol. Sci. Med. Sci. 62, 1071 (2007).
37
Wong R., Piper M. D., Blanc E., Partridge L., Pitfalls of measuring feeding rate in the fruit fly Drosophila melanogaster. Nat. Methods 5, 214 (2008).
38
Grandison R. C., Piper M. D., Partridge L., Amino-acid imbalance explains extension of lifespan by dietary restriction in Drosophila. Nature 462, 1061 (2009).
39
Libert S., et al., Regulation of Drosophila life span by olfaction and food-derived odors. Science 315, 1133 (2007).
40
Giannakou M. E., Goss M., Partridge L., Role of dFOXO in lifespan extension by dietary restriction in Drosophila melanogaster: not required, but its activity modulates the response. Aging Cell 7, 187 (2008).
41
Min K. J., Yamamoto R., Buch S., Pankratz M., Tatar M., Drosophila lifespan control by dietary restriction independent of insulin-like signaling. Aging Cell 7, 199 (2008).
42
Bartke A., Minireview: role of the growth hormone/insulin-like growth factor system in mammalian aging. Endocrinology 146, 3718 (2005).
43
Brown-Borg H. M., Hormonal regulation of longevity in mammals. Aging Res. Rev. 6, 28 (2007).
44
Yan L., et al., Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell 130, 247 (2007).
45
Harrison D. E., et al., Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392 (2009).
46
Selman C., et al., Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326, 140 (2009).
47
Amador-Noguez D., et al., Alterations in xenobiotic metabolism in the long-lived Little mice. Aging Cell 6, 453 (2007).
48
Ikeno Y., et al., Reduced incidence and delayed occurrence of fatal neoplastic diseases in growth hormone receptor/binding protein knockout mice. J. Gerontol. A Biol. Sci. Med. Sci. 64A, 522 (2009).
49
Garcia A. M., et al., Effect of Ames dwarfism and caloric restriction on spontaneous DNA mutation frequency in different mouse tissues. Mech. Aging Dev. 129, 528 (2008).
50
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 (2008).
51
Bass T. M., Weinkove D., Houthoofd K., Gems D., Partridge L., Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans. Mech. Aging Dev. 128, 546 (2007).
52
Enns L. C., et al., Disruption of protein kinase A in mice enhances healthy aging. PLoS ONE 4, e5963 (2009).
53
Shimokawa I., et al., Diet and the suitability of the male Fischer 344 rat as a model for aging research. J. Gerontol. 48, B27 (1993).
54
Pearson K. J., et al., Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction. Proc. Natl. Acad. Sci. U.S.A. 105, 2325 (2008).
55
Patel N. V., et al., Caloric restriction attenuates Abeta-deposition in Alzheimer transgenic models. Neurobiol. Aging 26, 995 (2005).
56
Cohen E., et al., Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. Cell 139, 1157 (2009).
57
Raffaghello L., et al., Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy. Proc. Natl. Acad. Sci. U.S.A. 105, 8215 (2008).
58
Reed M. J., et al., Enhanced cell proliferation and biosynthesis mediate improved wound repair in refed, caloric-restricted mice. Mech. Ageing Dev. 89, 21 (1996).
59
Kristan D. M., Calorie restriction and susceptibility to intact pathogens. Age (Dordr.) 30, 147 (2008).
60
Shevah O., Laron Z., Patients with congenital deficiency of IGF-I seem protected from the development of malignancies: a preliminary report. Growth Horm. IGF Res. 17, 54 (2007).
61
Gourmelen M., Perin L., Binoux M., Effects of exogenous insulin-like growth factor I on insulin-like growth factor binding proteins in a case of growth hormone insensitivity (Laron-type). Acta Paediatr. Scand. Suppl. 377, 115 (1991).
62
Oliveira J. L., et al., Congenital growth hormone (GH) deficiency and atherosclerosis: effects of GH replacement in GH-naive adults. J. Clin. Endocrinol. Metab. 92, 4664 (2007).
63
Suh Y., et al., Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc. Natl. Acad. Sci. U.S.A. 105, 3438 (2008).
64
Bonafè M., et al., Polymorphic variants of insulin-like growth factor I (IGF-I) receptor and phosphoinositide 3-kinase genes affect IGF-I plasma levels and human longevity: cues for an evolutionarily conserved mechanism of life span control. J. Clin. Endocrinol. Metab. 88, 3299 (2003).
65
Kuningas M., et al., Haplotypes in the human Foxo1a and Foxo3a genes; impact on disease and mortality at old age. Eur. J. Hum. Genet. 15, 294 (2007).
66
Colman R. J., et al., Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325, 201 (2009).
67
Fontana L., Meyer T. E., Klein S., Holloszy J. O., Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proc. Natl. Acad. Sci. U.S.A. 101, 6659 (2004).
68
Fontana L., Weiss E. P., Villareal D. T., Klein S., Holloszy J. O., Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans. Aging Cell 7, 681 (2008).
69
Bonkowski M. S., et al., Disruption of growth hormone receptor prevents calorie restriction from improving insulin action and longevity. PLoS ONE 4, e4567 (2009).
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Science
Volume 328 | Issue 5976
16 April 2010
16 April 2010
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Copyright © 2010, American Association for the Advancement of Science.
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Published in print: 16 April 2010
Acknowledgments
We thank M. Wei for careful reading of the manuscript. This work was supported in part by a grant from the American Federation for Aging Research, Bakewell Foundation, and by NIH grants AG20642, AG025135, and GM075308 (to V.D.L.). Support was also provided by the National Center for Research Resources (grant UL1 RR024992) and the National Institute of Diabetes and Digestive and Kidney Diseases (grant P30DK056341); by grants from Istituto Superiore di Sanità/National Institutes of Health Collaboration Program, Ministero della Salute, the Longer Life Foundation (an RGA/Washington University Partnership), and the Bakewell Foundation; and by a donation from the Scott and Annie Appleby Charitable Trust (to L.F.).
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