AGING

SPECIAL SECTION

REVIEW

Evolutionary Medicine: From Dwarf Model Systems to Healthy Centenarians?
Valter D. Longo* and Caleb E. Finch
Restriction of the number of calories consumed extends longevity in many organisms. In rodents, caloric restriction decreases the levels of plasma glucose and insulin-like growth factor I (IGF-1) and postpones or attenuates cancer, immunosenescence, and inflammation without irreversible side effects. In organisms ranging from yeast to mice, mutations in glucose or IGF-I–like signaling pathways extend life-span but also cause glycogen or fat accumulation and dwarfism. This information suggests a new category of drugs that could prevent or postpone diseases of aging with few adverse effects. Restriction of caloric intake (CR) extends longevity in organisms from yeast to mice (1, 2) and postpones or prevents a remarkable array of diseases and age-dependent deterioration, without causing irreversible developmental or reproductive defects. By contrast, most genetic manipulations that extend lifespan cause major side effects (Fig. 1). By combining our knowledge of the molecular pathways that regulate longevity and CR, we can begin to develop a novel strategy to prevent diseases such as cancer, Alzheimer’s, and vascular diseases. The molecular pathways involved in the regulation of chronological life-span were identified at about the same time in yeast and worms (3–6 ). Similar to the life-span of higher eukaryotes, the yeast chronological life-span is determined by measuring survival time (7, 8). However, aging in the unicellular yeast is also studied by measuring the number of buds generated by an individual mother cell (replicative lifespan) (9, 10). The down-regulation of glucose-dependent signaling by mutations in the RAS2, CYR1/PKA (11), or SCH9 (12), genes extends the yeast chronological life-span up to 300% and increases resistance to oxidative stress and heat shock (Fig. 2) (7, 13). The down-regulation of the CYR1/PKA pathways also extends the yeast replicative life-span by a mechanism dependent on the silencing protein Sir2 (14). Chronological life-span extension in yeast is mediated by stress-resistance transcription factors Msn2 and Msn4 and mitochondrial superoxide dismutase (SOD2) (7, 13). In the worm Caenorhabditis elegans, the down-regulation of the pathways that includes the DAF-2, AGE-1, and AKT-1/ AKT-2 proteins extends survival up to 300%
Andrus Gerontology Center, Division of Biogerontology, and Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089 – 0191, USA. *To whom correspondence should be addressed. Email: vlongo@usc.edu

(15–17) and increases thermotolerance and antioxidant defenses, through the stress resistance transcription factor DAF-16 (Fig. 2) (5, 18 ). These yeast and worm “longevity pathways” share several homologous proteins, including superoxide dismutases, catalase, heat shock proteins, and the serine threonine kinases SCH9 (yeast) and AKT1/AKT-2 (worm) (Fig. 2) (19 ). The conserved function of longevity genes is also supported by the role of a gene homologous to yeast SIR2 in extending longevity in worms (20). Thus, chronological longevity in yeast and worms is extended by inactivation of pathways that promote growth and, by an increase in protection against oxidative damage, other forms of stress. Systems that repair and replace damaged DNA, proteins, and lipids are also likely to play a major role in extending survival. Conserved genes also regulate longevity in fruit flies. Mutations that decrease the activity of the fly insulin/IGF-I–like pathway cause dwarfism but nearly double longevity (21, 22). These mutations also increase the expression of SOD and the storage of nutrients (Fig. 2) (22). The similarities between

the yeast, worm, and fly longevity regulatory pathways suggest that portions of these pathways have evolved from common ancestors. Because glucose and insulin/IGF-I–like signaling pathways are down-regulated in the absence of nutrients, mutations in these pathways may simulate starvation conditions. A decrease in IGF-I signaling may also extend longevity in mice. Mice homozygous for mutations in the Prop-1 (23) or Pit-1 (24) genes are dwarfs but live 25 to 65% longer than wild-type (25, 26). Prop-1 or Pit-1 homozygotes are deficient in serum growth hormone (GH), thyroid stimulating hormone ( TSH), and prolactin as well as for IGF-I, which is secreted by liver cells upon stimulation with GH. The plasma GH deficiency appears to mediate the effects of Prop-1 and Pit-1 mutations on longevity, because the mice that cannot release GH in response to growth hormone releasing hormone also live longer (27). Furthermore, dwarf mice with high plasma GH but a 90% lower IGF-I [GH receptor/ binding protein (GHR/BP) null mice] (28) live longer than the wild-type mice (29 ). Taken together, these studies suggest that the reduction in plasma IGF-I is responsible for a major portion of the life-span increase in dwarf, GH-deficient, and GHR/BP null mice. Mammals also exhibit an association between stress resistance and reduced IGF-I signaling. The activities of antioxidant enzymes such as superoxide dismutases and catalase are decreased in murine hepatocytes exposed to GH or IGF-I and in transgenic mice overex-

Fig. 1. Wild-type (left specimen) and long-lived dwarf (right specimen) yeast, flies, and mice with mutations that decrease glucose or insulin/IGF-I–like signaling. Yeast sch9 null mutants form smaller colonies (left). sch9 mutants are also smaller in size, grow at a slower rate, and survive three times longer than wild-type yeast. chico homozygous mutant female flies are dwarfs and exhibit an increase in life-span of up to 50% (center) (fly image provided by D. Gems) (21). Chico functions in the fly insulin/IGF-I–like signaling pathway. The GHR/BP mice are dwarfs deficient in IGF-I and exhibit a 50% increase in life-span (right) (mouse images provided by A. Bartke). Other yeast and worm mutants exhibit life-span extension of more than 100% but do not have detectable growth defects.

1342

28 FEBRUARY 2003 VOL 299 SCIENCE www.sciencemag.org

In a small group of healthy nonobese humans. CR acts similarly in most rodent genotypes. By contrast. and Diseases CR has remarkably broad effects on increasing the life-span and attenuating chronic diseases of aging in rodents that are unequaled by any pharmacological intervention. obesity. whereas glycogen provides glucose only during short periods of fasting. mutations or diseases that result in plasma GH or IGF-I deficiencies cause dwarfism. and increase growth and mortality. Since then. flies. but their effect on longevity is unclear. The storage of fat or glycogen is another aspect of the stress response. These changes are homeostatic responses to reduced body stores of fat and the need for increased gluconeogenesis (42 ). In humans. Therefore. Liver adenomas and carcinomas. Laboratory animals have much reduced daily activity as compared to their unlimited food (by not needing to forage) and therefore can be considered as models for sedentary humans who are at high risk for obesity and insulin resistance. and other adverse effects. and mice. Aging. extending their lifespan by slowing mortality rate increases (40) and decreasing strain-specific tumors and other diseases (41 ). and prostate cancer (31 ). In mice. the down-regulation of the Ras2/Cyr1/PKA pathway (where PKA is protein kinase A) results in the accumulation of glycogen. which are deficient in plasma GH and IGF-I. the switch between glycogen storage in yeast and fat storage in metazoans is consistent with the role of longevity regulatory pathways in inducing accumulation of the carbon source that would maximize long-term survival during periods of starvation. insulin. Conserved regulation of longevity. are common in older mice that overexpress GH (34. In yeast and worms. as described above. the intracellular mediators of life-span extension in GH– or IGF-I– deficient mice have not been identified. the increased insulin sensitivity. which is reversed by administration of GH (19 ). the induction of stress-resistance genes is required for pressing GH (Fig. Caloric Restriction. GH/IGF-I and Diseases in Rodents The ability of GH and IGF-I to lower antioxidant defenses in hepatocytes. and chronic pneumonia (39 ). 33). which is the major carbon source catabolized during periods of starvation.org SCIENCE VOL 299 28 FEBRUARY 2003 1343 . Mice with elevated GH and IGF-I instead exhibit severe kidney lesions and a much shorter life-span (29. and flies. lung. Further studies are needed on the role of plasma IGF-I in cognitive decline and neurodegenerative diseases. The role of GH and IGF-I in age-dependent cognitive decline is unclear. kidney disease. as well as indications of reduced mortality (43). McCay’s pioneering work 60 years ago showed that CR increases life-span by about 35% and also results in a lower incidence of tumors. reduce the accumulation of glycogen or fat. In yeast. In yeast. as tumors in Pit-1 or Prop-1 dwarf mice are either reduced or delayed (32. The reduction of plasma GH and IGF-I may also have beneficial therapeutic effects in diabetic nephropathy (37). The small but persistent decreases in blood glucose. and IGF-I. However. Fig. and elevated glucocorticoids may be responsible for the beneficial effects of CR in mice (Table 1).AGING SPECIAL SECTION longevity extension. 30). 35) (although the GH levels are supraphysiological) (36). IGF-I appears to also promote cancer in mice. Silberberg showed that Pit-1 dwarf mice. www. had less osteoarthritis than wild-type mice (30).sciencemag. 2) (19 ). In rats. By contrast. IGF-I deficiency also increases fat accumulation in humans (see “Human GH/IGF-I Deficiency Diseases” section). In mammals fat is the major carbon source during long periods of starvation (hibernation). Infusion of IGF-I into the brains of old rats for 4 weeks partially reverses the age-dependent decline in memory. hormonal. high levels of IGF-I have been associated with increased risk of several human diseases including breast. Monkeys show similar effects of CR on glucose and insulin. Thirty years ago. colorectum. in worms. 2. worms. CR also causes physiologic. Dwarf mutations cause fat accumulation. as well as heart lesions. vascular calcification. IGF-I attenuates cellular stress response and the expression of stress response proteins heat shock protein 72 (HSP72) and hemeoxygenase (19 ). indicates that IGF-I can promote cellular damage and diseases in mammals. Mutations that reduce the activity of these pathways appear to extend longevity by simulating caloric restriction or more severe forms of starvation. IGF-I activates signal transduction pathways analogous to the longevity regulatory pathways in lower eukaryotes and increases mortality. the partially conserved glucose or insulin/IGF-I–like pathways down-regulate antioxidant enzymes and heat shock proteins. 2). and biochemical changes resembling those caused by CR in rodents and monkeys (44). but has no effect on sensorimotor skills (38). Prop-1 dwarf mice show improved cognitive function compared with age-matched normal mice (28). CR has few adverse outcomes for confined animals or sedentary obese humans. CR counteracts the general trend for laboratory rodents and primates to progressively add body fat during aging. the down-regulation of the insulin/IGF-I–like pathways results in the accumulation of fat (Fig.

sciencemag. no available data. Consistent with this notion is the role of IGF-I in reversing the ences in the effects of fat accumulation on mortality. in normal humans. these pathways are inactivated under starvation conditions. resulting in acromegaly. which normally shows prominent activation of microglia-monocytes during aging and in neurodegenerative diseases (52. CR strongly inhibits inflammatory responses of aging. CR increases protein synthesis in liver (45) and probably in skeletal muscle (46). IGF-I– deficient mice (GHR/BP). and increase of free-radical scavenging functions. CR also modulates host defense functions. CR extends further the life-span of Ames dwarf mice. TNF-␣ is well known to inhibit insulin receptor signaling in adipocytes. Human GH/IGF-I and Diseases Diseases that result in either overproduction or reduction of plasma GH and/or IGF-I can be informative for developing therapies that prevent multiple age-related diseases. Human somatotroph adenomas of the pituitary gland can cause chronic secretion of excessive GH. increased prevalence of hypertension. IGF-I. indicating that the activation of antiapoptotic pathways contributes to tumor incidence (62 ). possibly by inhibiting proliferation and decreasing angiogenesis (56). The apparent difference between these two models may be explained by phylogenetic differ- tion on the role of normal levels of GH in cancer and cardiovascular diseases. Blood levels of IL-6 and tumor necrosis factor–␣ (TNF-␣) (which are both involved in acute phase responses) commonly increase during aging in rodents and humans (51 ). which decreases sharply during aging in mice fed ad libitum. blunts the aging changes in T cell functions by maintaining interleukin 2 (IL-2) production (47). a monocyte adhesion molecule (57). including reduced plasma insulin. NSAIDs also reduced the risk of breast. CR may further increase longevity by preventing fat accumulation and reducing mortality associated with obesity. In dwarf mice. Dwarf. CR also enhances the immune responses to influenza during aging (49 ). and IGF-I– deficient (GHR/BP) mice share a number of biochemical and phenotypic characteristics. Mutations in the yeast Ras and worm Daf-2 pathways can extend longevity but can also induce dormant phases that are normally entered during periods of starvation. Microarray analyses confirm that CR attenuates inflammatory gene expression throughout the body (46. and mice suggest that it will be difficult to extend human longevity without causing side effects (Fig. CR may extend lifespan in mammals by attenuating the major inflammatory diseases of aging. Comparison of CR. The similarities of the effects of CR and NSAIDs in diseases of aging is consistent with the role of inflammatory mechanisms in vascular disease. IL-6 stimulates hepatic glucose release (60). Alzheimer’s disease shows remarkable benefits from a broad group of anti-inflammatory drugs. The dwarf phenotype of long-lived yeast. CR. and delays or prevents changes in the proportion of CD4 and CD8 memory cells during aging (50). For example. colon. Long-term reduction of glucose levels may contribute to the decrease in inflammation and diseases in CR mice.AGING SPECIAL SECTION In rodents. and it decreases the load of oxidized proteins (1). and glucose. up to 80% (50). flies. reduced fertility and body size. dwarf mice. These substantial shifts may be due to faster protein turnover (which decreases exposure to endogenous damage). lectin-induced proliferation of splenic lymphocytes. hepatocytes. consistent with a role for CR in protecting against inflammation and neurodegeneration. On the other hand. Long-term use of NSAIDs may be responsible for a reduction in the risk of Alzheimer’s diseases. In vitro. by decreasing glutathione levels and repressing ␥-glutamylcystein synthetase. suggesting that the mechanisms that regulate life-span extension in CR and dwarf mice are not identical (63). the abnormally high GH levels in acromegaly patients provide limited informa- Table 1. dwarf mice have more degenerative cardiopulmonary lesions (32 ). and premature atherosclerosis (68). Thus. reduced muscle and bone mass. is increased twofold by CR at all ages (48). Notably. Thus. Treatment of acromegaly with somatostatin analogs decreases GH and IGF-I. Thus. N/A. High calorie intake is associated with increased risk of Alzheimer’s disease (54). acute hyperglycemia induces Mac-1. 53). Furthermore. GH deficiency in humans can lead to reduced life expectancy and is associated with increased fat mass. and many cancers. In fact. 1). For example. dwarf. CR Dwarf mice IGF-I (mouse) IGF-I (human) mice Glucose regulation Plasma insulin Plasma glucose Somatotropic axis Plasma GH Plasma IGF-I Body size Thyroid function and metabolism Plasma thyroid hormones Body core temperature Reproduction Sexual maturation Fertility Glucocorticoids and adiposity Plasma corticosterone Percent body fat Reduced Reduced Reduced Reduced Reduced Reduced Reduced Delayed Reduced Elevated Reduced Reduced Reduced Absent Greatly reduced Reduced Greatly reduced Reduced Delayed Suppressed Normal Elevated (old) Greatly reduced Modestly reduced Elevated Greatly reduced Reduced Reduced Slightly reduced Delayed Reduced Normal N/A Elevated Reduced Elevated Greatly reduced Reduced N/A N/A Delayed Reduced/normal N/A Elevated protection of CR against carcinogen-induced bladder cancer (62 ). and other cancers. 52. and IGF-1–Deficient Mice CR. resulting in clinical improvements (67). Many of these characteristics are also shared with IGF-I– deficient humans. behavioral problems. insulin resistance. CR has anti-inflammatory effects in brain. decreased production of metabolic toxins. The obesity caused by GH deficiency in humans may promote cardiovascular diseases and age-dependent mortality (65). CR attenuates cellular immune age changes in more than 10 rodent genotypes (47). and skeletal muscle and is implicated in the insulin resistance of aging (59 ). and delayed sexual maturation (Table 1). which is the rate-limiting enzyme of glutathione synthesis (61 ). In flies.org . the reduced levels of plasma IGF-I in dwarf mice may contribute to disease prevention and life-span extension by simulating CR or more severe starvation conditions (Table 1). Although these studies imply a role for GH and IGF-I in diseases of aging. the changes that accompany fat accumulation may counteract the putative beneficial effects of GH/IGF-I 1344 28 FEBRUARY 2003 VOL 299 SCIENCE www. 53). high physiological glucose induces IL-6 and TNF-␣ expression and secretion in monocytes (58). and IGF-I– deficient humans (Laron syndrome) [modified from Bartke and Turyn (80)]. particularly the nonsteroidal anti-inflammatory drugs (NSAIDs) (55). by contrast. dwarf mutations and CR slow aging through overlapping mechanisms (64). which is associated with a major life-shortening from cardiovascular diseases and cancer (66). Alzheimer’s disease. Apoptosis in the tumor is decreased 10-fold in CR mice in which the levels of IGF-I are restored. In fact. Hyperglycemia also alters redox status in muscle cells in vitro.

38. Bronson. Johnson. J. 23. M. 531 (1989). Nature 382.131 13. or (iii) decrease IGF-I signaling by acting on either extracellular or intracellular targets. phagocytes and lymphocytes (77). Sonntag. GH administration also increases the development of diabetes and glucose intolerance in healthy. 39. 21. but are fertile and have normal developmental rates and activity levels (17. http://sageke.sciencemag. 271. Springfield. Bronson. A.org/cgi/content/ full/sageke.sciencemag. E. Mech. Proc. Aging 23 (no. D. Drugs that block IGF-I receptor activation may have a similar effect. but they live longer than littermate control mice (75). GH and IGF-I deficiencies in humans are associated with major defects and diseases. 12275 (1996). (ii) prevent IGF-I release from the liver. 59. E.AGING SPECIAL SECTION deficiency in humans. Neurobiol. R. 908 (1990). S. Morris.to 81-year-old men with low plasma IGF-I concentration (72 ). 68. Roth. 2). J. J. wrinkled skin. GdbGene266 http://sageke. 1319 (1997). tg11 (3 October 2001). Bartke. Mortimer. Nature 410. M. GH treatment can increase body mass and decrease adipose tissue in 61. 20. Acad. E. Cell 105. preliminary data suggest that it is possible. the increased stress resistance and longevity of mice with p66SHC-/. Guarente. G. Borg. longevity may be extended while reducing side effects.sciencemag. and Sch9 as major intracellular pro-senescence proteins (Fig. raising the possibility that the increased mortality observed in hypopituitary patients is caused by ACTH and not GH deficiency. M. H. F. 6. Science’s SAGE KE 2001. Finch. Papaconstantinou. J.org/cgi/content/full/sageke. F. Hum. The increased mortality is observed in GH deficient hypopituitary patients that. Gendron. V. T. Chicago.S. R. D. 2608 (2000). Thomas. References www. M. Kenyon. Soc. Senescence. E. S. Other drugs could target intracellular mediators of pro-senescence hormone and growth factors. University of California Los Angeles (1997). Flurkey. Laron Syndrome is characterized by high GH. 1988). suggesting that reduction of only IGF-I is also associated with some adverse side effects (78). 37. Bartke. 10. Harrison. G. M.sciencemag. S. Kenyon. D. Markowska. Tabtiang. Science 278. R. e. A. 417 (1972). J. 707 (2002). L. 1990). Kenyon. J. Brem et al. mice with very low plasma IGF-I and elevated GH have a fourfold increase in insulin levels and muscle-specific insulin resistance. In summary. Sci. 29. Cell. Studies in simple eukaryotes indicate that IGF-I–like factors activate a major pro-senescence pathway. Weindruch. K. 165 (2001). D. A. N. 23. A. V. 31. but very low plasma IGF-I. D. Jazwinski. Miller. F. G. cerevisiae SCH9. 19). C. K. older women and men (71 ) and increases morbidity and mortality in patients that are clinically ill. 18. Longo. Science’s SAGE KE. C. Science 273. Flyvbjerg. Sohal. Dwarf mice treated transiently in early adult life with GH and thyroid hormone become much larger than untreated dwarf mice. T. K. 35. humans with prop-1 mutations do not lack ACTH. The human Laron Syndrome (LS) is caused by a defect in the GH receptor and resembles GH deficiency clinically and biochemically (70). 1751 (1959). P. C. Genom. Yeast lacking Sch9 activity survive three times longer than wild-type but grow slowly. Science 273. D. J. Pozza. However. R. obesity. U. Genetics 150. 7. R. 17. Therefore. 8. 36. P. C. W. K. Tissenbaum. K. M. Mech. R. E. R. Gralla. Obesity and muscle weakness are other major side effects of GH deficiency that must be prevented before drugs that simulate dwarf mutations can be considered for human studies. 92. L. 34. Meliska. GdbGene131 http://sageke. Rasch. Mol. D..org/cgi/content/full/sageke. Science 249. Inst. Fabrizio. sciencemag. Biol. Landau. V. S. Dwarf mice eat normally and become obese in old age. GH is prescribed extensively as an antiaging hormone (71 ). J. Microbiol. Ageing Dev. K.. Science’s SAGE KE. Finch. J. Fabrizio. D. Clemmons. personal communication. 10. including cancer and kidney diseases in rodents. Defossez. 903 (2002). 24. 18. 9 (2000). Science 289. 14. thesis. L. A.. D. yet they live 50% longer. 2. Rodan. 27. 1472 (2000). F. 33 (1996). chronically high GH levels increase the incidence of diseases. Science 292. Studies in yeast and worms indicate that life-span can be extended without causing growth and reproductive defects. W. Although a mammalian signal transduction pathway that regulates longevity has not been identified. Although studies in rodent models point to GH and IGF-I as promoters of aging and age-related diseases. Kenyon. Wolf et al. 32. S. Science 292. However. Harrison. and increase cardiovascular diseases and cancer in human acromegaly patients. Yu. 521 (1947). 2126 (2000). 461 (1993). By contrast. A. Muller. J. C. and the Genome (University Press. tg1 (27 February 2002). Mattison. also lack adrenocorticotrophic hormone (ACTH). R. E. J. 40. Ruvkun. Trends Genet. T. B.. Natl. Finch. J. 227 (2001). and long-term GH replacement therapy causes some improvements in patients with GH deficiencies (73). W. 536 (1996). Brown-Borg. Tatar et al. T. 76). 18. Nature 408. R. LS causes hypercholesterolemia and glucose intolerance. Snell dwarf mice. K. 559 (1998). Biol. 35 (2003). Bellush. 41.2001/1/tg11. Later in life. Y. K. Longo. L. A. in most cases. J. E. A. Guarente. Ingram. Worm age-1 (hx546) and certain daf-2 mutants can survive up to 150% longer than wild-type worms. Fabrizio et al. and differentiation in cells. Nature 384. (2002). 288 (2001). Mol. Because GH can directly stimulate growth. Aging Assoc. 54 (1996). V.A. Patel. Am. IL. http://sageke. Med. Among the rare prop-1 patients for whom life-span data are available. Segev. Public Health 37. J. 13. C.2001/3/tg13. and impairments in physical and intellectual development (Table 1) (70). J. D. Natl. 19. A. 2.2002/8/tg1. Walford. R.266 12. Muller. Nature 366. P. Mooney. D. it is possible that. Harrison. 19). E. R.org/cgi/genedata/ sagekeGdbGene. cerevisiae CYR1. Rohan. 104 (2001). 6. Gems et al. 5. Dorman. Carter. C. 1. P. A. Am. 42. Longevity. 4. Pathol. 2) (8. D. 9. Chem. Kopchick. 295 (2002). 255 (2000). very short stature. H. 98. 59 (1996). human mutations analogous to the prop-1 mutations that extend longevity in rodents cause defects including dwarfism. The Retardation of Aging and Disease by Dietary Restriction (Charles C. the normal (and possibly longer) life-span of a few individuals with mutations analogous to those that extend longevity in mice suggest that it may be possible to extend human longevity by reducing plasma GH and IGF-I levels. By contrast. Longo. L. Flurkey. Although we do not know whether the longevity effect of dwarf mutations can be separated from the small body size.. Chang.. However. E. Am. G. E. http://sageke. Studies in yeast point to Ras. 107 (2001). 28. Muller. 25. M. M. D. Ageing Dev. 121. Science 292. 123. 33. Endocrinology 141. 71 (1993). Drugs that prevent IGF-I generation in response to GH would have the advantage of reducing plasma IGF-I levels without decreasing GH levels. sciencemag. Ramsey. Unlike most patients with GH deficiencies. Valentine. even after shortterm treatment (74). V. Flurkey. Gensch. activation. S. PKA.mutations suggests that a prosenescence pathway is also present in mammalian cells (79). C. whereas yeast that have reduced Ras activity survive 100% longer but grow at normal rates (7.. Silberberg. C. several surpassed the average life-span and one survived to age 91 (69 ). Nature 183. McCay. Rudner.org SCIENCE VOL 299 28 FEBRUARY 2003 1345 . 435 (2001). Rev. 3. C. Lin. Guarente. Growth hormone receptor knockout (Laron) mice. S. 26. Life Sci. T. Clancy et al. Phillip. Ames dwarf mice. 30. H. 6736 (2001). Genet. Cancer.g. E. 38. Coschigano. Annu. C. Longo. It is clear that a major and chronic increase in plasma GH/IGF-I levels increases morbidity and mortality. H. by reducing IGF-I but not GH levels. 11. Sonntag. 22. M.Tissenbaum. Drug Targets The data summarized here suggest that three categories of drugs may have the potential to prevent or postpone multiple age-related diseas- es: drugs that (i) simulate dwarf mutations and therefore decrease GH production by pituitary cells. Pletcher. Z. Akt-1/Akt2 and many other proteins that regulate longevity in worms are also shared with the mammalian IGF-I signaling pathway (Fig. 16. Ruvkun. Papaconstantinou. J. Science’s SAGE KE 2001. S. E. the pharmacological simulation of dwarf mutations should also increase obesity and extend longevity in mice. 129 (1998). 15.org/cgi/genedata/ sagekeGdbGene. 2374 (1999). Lin. the “antiaging” effects of GH therapy are typically observed after short-term treatment of patients with low plasma GH. L. E. Genetics 163. B. The well-characterized yeast and worm “longevity” pathways should provide templates for the identification of genes and drugs that regulate longevity and diseases in mammals. S. C. Nephrol. 5). Neuroscience 87. Weindruch. tg13 (17 October 2001). and intellectual deficiency but do not appear to shorten life-span (69 ). Science’s SAGE KE 2002.

a Paul Glenn Chair fund ( V. and both these genes and their endocrine systems are conserved among eukaryotes. L. Cancer Res. Related Resources: E. R. McMaster. 71. Evans. 59. Clin. 954 (1996). 898 (1982).S.AGING SPECIAL SECTION 43. Horm. 928. 81. the fly Drosophila melanogaster. Z. Dozens of genes extend adult longevity. 80. 197 (2001). and gonad (5. many of these genes are involved with hormonal signals. Yakar et al.. J. 47.. Bartke. R. 84. Prolla. Hematol. 64. P. Genes/Interventions Database. 72.D. Krishnan. W. D. Thus. C. A. Uchimura. Acad. 69. 319 (2002). Clin. Clin. Crawford. Shalet. R. K. In the nematode and the fly. Front. The products of these genes and others revealed insulin/IGF-like signal transduction as a central regulator of dauer and aging (5). S. R. A. muscle. R.A. Weaver. B. Physiol. fertility. C. and thyroid hormones are interdependent. Metab. K. K. D. G. Numano. Aging 22. New York. The insulin/IGF system and its associated downstream hormones are likely to prove particularly instructive. Gems. 1187 (2002). 75. 21. Weindruch.1 Andrzej Bartke. Laron.). Hughes. 2730 (1998). 3Max-Planck-Institut fu ¨r molekulare Genetik. M. Miller. S. R. Med. Clin. 1258 (2002). K. S. Dauer diapause is a nonfeeding. Nature Genet. Sampson. J. R. Akber. N. J.Y.2003/8/re2. Brown University. 305 (2001). K. 342.org . Sci. J. D. J.2 Adam Antebi3 Reduced signaling of insulin-like peptides increases the life-span of nematodes. Morohoshi. Res. In mammals. 48. 53. Free Radic. A. K. 7. Box G-W. N. Johannsson. E. Endocrinol. L. X. Weindruch. 209 (2001). J. Miller. Neurobiol. Klopp. 58. 4 ) (Fig. Ingram. Trimble. Pedersen.F. 70. 51. Metab. 4. 3. Del Aguila. G. E. C. R.. A. T. Nature 402. R. Environ. but with inevitable increases in stress resistance. Pathol. 50 (1996). K. R. they can illuminate the cellular and molecular causes of senescence. M. ns4 (26 February 2003). Bengtsson. J. Engl. C. G. A. but are also found in intestine. 45.). chap. D. Mock. 2596 (1999). N. Anti-aging Med. which is thus sequestered in the cytoplasm.sciencemag. 830 (2002). Prolla.org/cgi/content/full/ sageke. S. Diabetes 45. I. Endocrinol. Krzisnik et al. We thank R. in Microglia in the Regenerating and Degenerating Central Nervous System (SpringerVerlag. Springfield. Pahlavani. 181 (1997). 57. D-14195 Berlin. H.sciencemag. J. Takala et al. Saito et al. 79. Verdery. epidermis. J. Neurol.E. J. USA. Miller. at least among invertebrates. personal communication. and sterols are all candidate effectors of aging in organisms as diverse as the nematode Caenorhabditis elegans. lipophilic signaling molecules. 46. B211 (2002). C. Sci. Ann. Natl. E. K. 55. 50 (1988). adults directly reach reproductive maturity and age rapidly. elegans genome contains 37 insulin-like ligands that are mainly expressed in neurons. Arterioscler. Endocrinol. R. 22. K. F. Physiol.2003/8/ns4. J. 1110 (2001). Gottesman. 49. Arch. Engl. DAF-16 also is a key regulator of heat and oxidative stress resistance. Blackman et al. Dietary drawbacks. 4397 (1999). E. McNally. developmental arrest. M. *To whom correspondence should be addressed at Department of Ecology and Evolutionary Biology. D. Weindruch. Leevers. 9 (1999). T. A. Lane. Animals with weak alleles of Dafconstitutive mutants in the genes age-1 and daf-2 (2) can bypass dauer and become prodigiously long-lived adults in a manner dependent on the gene daf-16 (1. 55. R. Mech. Ivory.org/cgi/content/full/ sageke. M. Thromb. R. Science’s SAGE KE. Tang. M. JAMA 288.edu dependent functional decline. Effros. 50. Kirwan. Shea. J. 309 (1999). A. Bartke et al. H. 25. Metab. Bruunsgaard. B142 (1991). elegans with mutations in the dauer formation (Daf ) pathway were found to have unusually long lives (1). Catherwood. 31. M. J.. Science’s SAGE KE 2003. Ritchie. A. 13. A. S. M. J. C. T. Bartke and D.. G. N. 294 (2000). A. 4667 (1997). In this state. 78. 275–305. 84. Migliaccio et al. growth hormone. J. Science 296. J. Biol. M. 1A). RI 02912. J. Flurkey. Ihnestrasse 73. 8.org/cgi/ genesdb. 52. S. Neary. the John Douglas French Alzheimer’s Foundation. 76. McGeer. J. insulin-like growth factor–1. endocrine manipulations can slow aging without concurrent costs in reproduction. Science 285. U. Despite the similarities among mammals and invertebrates in insulin-like peptides and their signal cascade. Proc. Mayeux. insulin-like peptides. Am. J. 56. A. 1210 (2000). M. elegans Dauer and Aging The genetic dissection of aging rapidly advanced when strains of C. T. Ligand bound to DAF-2 insulin-like receptor signals through a kinase cascade to phosphorylate forkhead transcription factor DAF-16. 1390 (1999). W. R. Mutations that increase life-span through hormones are thought to initiate elements of this survival program independent of the appropriate environmental cues. M. slowing aging. A.. http://sageke. Oncol. DAF-16 promotes transcription and induces diapause and exceptional longevity (Fig. M. J. 83. Abdu. Metab. Kenyon. Genetics of C. the order in which the hormones act is unresolved because insulin. 1A). 85. secondary hormones downstream of insulin-like signaling appear to regulate aging. In all species examined to date. Hopkin. R. Walford. E. flies. Endocrinol. Ageing Dev. 57. K. N. Clayton. Metab. B. J. 933 (2000). B. Brown. D. Turyn. Belchetz. Biosci. F. Suppression of these hormones or their receptors can increase life-span and delay age1 Department of Ecology and Evolutionary Biology. pp. 45. Because mechanisms for survival often oppose the progress of aging. J. R. Utiger. Providence. 6 )... Finch et al. Fujisawa.. http://sageke. J. this response is attenuated by insulin/IGF signaling (9). Orme. Endocrine Genet. Endocrinol. 65. and extending life. Supported by NIH Grant AG 01028. J. H. L. Opin. 68. J. Clin. DAF-16 becomes localized to the nucleus in response to various stresses. Cartwright. 79. S. E57 (1990). Simpson. 67. 323. Providence.. Pedersen. 96. J. E-mail: marc_tatar@brown. Toxicol. more research is needed to determine whether these signals control aging in the same way in all the species by the same mechanism. P. Endocrinol. Walford. 799 (2001). M. D. 74. Am. 785 (1999). Without activation of the pathway. and the mouse Mus musculus. 8). L. Germany. Mitcheltree. E. F. Roth. T. 77. E1137 (2001). L. Gerontol. USA. Nally. 54. E. A. The C. 1 (1990). P. Moran. S. these hormones regulate the organism’s capacity to survive during states of reduced metabolism coupled with high stress resistance and arrested development. Dunn et al. 62. 61. L. Ward. Powell. P. J. Med. 82. Elhadd. 281.L. USA. REVIEW The Endocrine Regulation of Aging by Insulin-like Signals Marc Tatar. and rodents. Clancy. fat storage. 59. Curr. This regulation is likely to be adaptive because. R. 60. G. Diabetes 50. R. D. insulin-like growth factor (IGF). 1149 (2001). Weindruch. Nature 414. http://sageke. M. Davies. A. McGeer. E. 2282 (2002). 66. R. Brown University. R. Walford. MacCallum. A 57. 131 (2001). A. A. D. Subfield history. Luchsinger. B43. 412 (2001). Southern Illinois University. H. 44. Remarkably. Lee. I. stress-resistant larval state evolved for endurance and dispersal under adverse conditions. 258. Hafen. Gerontol. Dillin. A. IL 62794. D. Vasc. and the Alzheimer’s Association (C.sciencemag. Gibney et al. Med. 46. 193 (2002). D. Sonken. Fabrizio for reading the manuscript and for helpful comments and A. S. 341. caloric restriction. K. 5. Gems for providing images of dwarf mice and flies. 2Department of Medicine. Med. R. Science’s SAGE KE 2003. Partridge. Masoro.. Gerontol. Engl. R. D580 (2000). 73. and metabolism (5. Science 298. 2002). re2 (26 February 2003). R. Rudman et al. Biol. Elevated stress resistance combined with down-regulated central metabolism and reproduction may be coordinated physiological 1346 28 FEBRUARY 2003 VOL 299 SCIENCE www. Acad. 1. and P. 63. Lee. L.sciencemag. RI 02912.