The Geroscience Hypothesis: Is It Possible to Change the Rate of Aging?

  • Steven N. AustadEmail author


Aging is not a disease. It is a generalized and progressive loss of function with the passage of time that makes us increasingly vulnerable to a broad suite of diseases. The Geroscience Hypothesis asserts that any intervention that retards the aging process will simultaneously delay the onset of multiple diseases. Retarding the aging process is not only a worthwhile medical enterprise; it is achievable as shown by the fact that nature has achieved it many times. Humans, for instance, age about half as fast as their close evolutionary relatives, chimpanzees. Experimentally, dietary restriction retards aging in a variety of laboratory organisms. Dietary restriction not only increases longevity, but it also slows the rate of functional decline in many systems, delays multiple chronic diseases, and has been repeated in multiple laboratories in multiple genotypes. In addition, direct manipulation of dozens to hundreds of individual genes also appears to slow aging, as indicated by a life-lengthening effect. The knowledge gained in genetic studies has now been employed to design pharmacological interventions. The National Institute on Aging’s Interventions Testing Program has been phenomenally successful at discovering compounds that extend life in genetically heterogeneous mice. Five compounds that extend life in at least one mouse sex have been reported to date, suggesting the real possibility that successful interventions in the aging process can be developed for humans.


Aging Geroscience Comparative biology Aging interventions Dietary restriction Models of aging 



The author is grateful for the advice and ideas shared by members of the Geroscience Network supported by NIH grant R24 AG044396.

Editor: Leslie Frieden, National Institute of Dental and Craniofacial Research (NIDCR), NIH.


  1. 1.
    Oeppen J, Vaupel JW (2002) Demography. Broken limits to life expectancy. Science 296(5570):1029–1031PubMedGoogle Scholar
  2. 2.
    Goldman DP, Cutler D, Rowe JW, Michaud PC, Sullivan J, Peneva D, Olshansky SJ (2013) Substantial health and economic returns from delayed aging may warrant a new focus for medical research. Health Aff (Millwood) 32(10):1698–1705. doi: 10.1377/hlthaff.2013.0052 Google Scholar
  3. 3.
    Murphy SL, Xu J, Kochanek KD (2013) Deaths: final data for 2010. Natl Vital Stat Rep 61(4):1–117PubMedGoogle Scholar
  4. 4.
    Raber J, Huang Y, Ashford JW (2004) ApoE genotype accounts for the vast majority of AD risk and AD pathology. Neurobiol Aging 25(5):641–650. doi: 10.1016/j.neurobiolaging.2003.12.023 PubMedGoogle Scholar
  5. 5.
    Miniño AM, Arias E, Kochanek KD, Murphy SL, Smith BL (2002) Deaths: final data for 2000. Natl Vital Stat Rep 50(15):1–120PubMedGoogle Scholar
  6. 6.
    Holloszy JO (1997) Mortality rate and longevity of food-restricted exercising male rats: a reevaluation. J Appl Physiol 82(2):399–403PubMedGoogle Scholar
  7. 7.
    Rajpathak SN, Liu Y, Ben-David O, Reddy S, Atzmon G, Crandall J, Barzilai N (2011) Lifestyle factors of people with exceptional longevity. J Am Geriatr Soc 59(8):1509–1512. doi: 10.1111/j.1532-5415.2011.03498.x PubMedGoogle Scholar
  8. 8.
    Friedman DB, Johnson TE (1988) A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics 118(1):75–86PubMedCentralPubMedGoogle Scholar
  9. 9.
    Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R (1993) A C. elegans mutant that lives twice as long as wild type. Nature 366(6454):461–464. doi: 10.1038/366461a0 PubMedGoogle Scholar
  10. 10.
    Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G (1997) daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277(5328):942–946PubMedGoogle Scholar
  11. 11.
    Henderson ST, Rea SL, Johnson TE (2006) Dissecting the processes of aging using the nematode Caenorhabditis elegans. In: Masoro EJ, Austad SN (eds) Handbook of the biology of aging, 6th edn. Academic, San Diego, pp 360–399Google Scholar
  12. 12.
    Chalfie M, Tu Y, Euskirchen G, Ward WW, Prasher DC (1994) Green fluorescent protein as a marker for gene expression. Science 263(5148):802–805PubMedGoogle Scholar
  13. 13.
    Klass M, Hirsh D (1976) Non-ageing developmental variant of Caenorhabditis elegans. Nature 260(5551):523–525PubMedGoogle Scholar
  14. 14.
    Felix MA, Braendle C (2010) The natural history of Caenorhabditis elegans. Curr Biol 20(22):R965–R969. doi: 10.1016/j.cub.2010.09.050 PubMedGoogle Scholar
  15. 15.
    Riddle DL, Albert PS (1997) Genetic and environmental regulation of dauer larva development. In: Riddle DL, Blumenthal T, Meyer BJ, Priess JR (eds) C. elegans II, 2nd edn. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New YorkGoogle Scholar
  16. 16.
    Ayyadevara S, Alla R, Thaden JJ, Shmookler Reis RJ (2008) Remarkable longevity and stress resistance of nematode PI3K-null mutants. Aging Cell 7(1):13–22PubMedGoogle Scholar
  17. 17.
    Chen J, Senturk D, Wang JL, Muller HG, Carey JR, Caswell H, Caswell-Chen EP (2007) A demographic analysis of the fitness cost of extended longevity in Caenorhabditis elegans. J Gerontol A Biol Sci Med Sci 62(2):126–135PubMedCentralPubMedGoogle Scholar
  18. 18.
    Garsin DA, Villanueva JM, Begun J, Kim DH, Sifri CD, Calderwood SB, Ruvkun G, Ausubel FM (2003) Long-lived C. elegans daf-2 mutants are resistant to bacterial pathogens. Science 300(5627):1921PubMedGoogle Scholar
  19. 19.
    Burger JM, Buechel SD, Kawecki TJ (2010) Dietary restriction affects lifespan but not cognitive aging in Drosophila melanogaster. Aging Cell 9(3):327–335. doi: 10.1111/j.1474-9726.2010.00560.x PubMedGoogle Scholar
  20. 20.
    Bass TM, Grandison RC, Wong R, Martinez P, Partridge L, Piper MD (2007) Optimization of dietary restriction protocols in Drosophila. J Gerontol A Biol Sci Med Sci 62(10):1071–1081PubMedCentralPubMedGoogle Scholar
  21. 21.
    Lee KP, Simpson SJ, Clissold FJ, Brooks R, Ballard JW, Taylor PW, Soran N, Raubenheimer D (2008) Lifespan and reproduction in Drosophila: new insights from nutritional geometry. Proc Natl Acad Sci U S A 105(7):2498–2503. doi: 10.1073/pnas.0710787105 PubMedCentralPubMedGoogle Scholar
  22. 22.
    Deshpande SA, Carvalho GB, Amador A, Phillips AM, Hoxha S, Lizotte KJ, Ja WW (2014) Quantifying Drosophila food intake: comparative analysis of current methodology. Nat Methods 11(5):535–540. doi: 10.1038/nmeth.2899 PubMedCentralPubMedGoogle Scholar
  23. 23.
    Wang L, Karpac J, Jasper H (2014) Promoting longevity by maintaining metabolic and proliferative homeostasis. J Exp Biol 217(Pt 1):109–118. doi: 10.1242/jeb.089920 PubMedCentralPubMedGoogle Scholar
  24. 24.
    Resende LP, Jones DL (2012) Local signaling within stem cell niches: insights from Drosophila. Curr Opin Cell Biol 24(2):225–231. doi: 10.1016/ PubMedGoogle Scholar
  25. 25.
    Losick VP, Morris LX, Fox DT, Spradling A (2011) Drosophila stem cell niches: a decade of discovery suggests a unified view of stem cell regulation. Dev Cell 21(1):159–171. doi: 10.1016/j.devcel.2011.06.018 PubMedGoogle Scholar
  26. 26.
    Hedrich HJ (ed) (2012) The laboratory mouse. Handbook of experimental animals, 2nd edn. Academic, New YorkGoogle Scholar
  27. 27.
    Yuan R, Tsaih S-W, Petkova SB, de Evsikova CM, Xing S, Marion MA, Bogue MA, Mills KD, Peters LL, Bult CJ, Rosen CJ, Sundberg JP, Harrison DE, Churchill GA, Paigen B (2009) Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels. Aging Cell 8:277–287PubMedCentralPubMedGoogle Scholar
  28. 28.
    Miller RA, Nadon NL (2000) Principles of animal use for gerontological research. J Gerontol A Biol Sci Med Sci 55(3):B117–B123PubMedGoogle Scholar
  29. 29.
    Liang H, Masoro EJ, Nelson JF, Strong R, McMahan CA, Richardson A (2003) Genetic mouse models of extended lifespan. Exp Gerontol 38(11–12):1353–1364PubMedGoogle Scholar
  30. 30.
    Kastenmayer RJ, Fain MA, Perdue KA (2006) A retrospective study of idiopathic ulcerative dermatitis in mice with a C57BL/6 background. J Am Assoc Lab Anim Sci 45(6):8–12PubMedGoogle Scholar
  31. 31.
    Turturro A, Duffy P, Hass B, Kodell R, Hart R (2002) Survival characteristics and age-adjusted disease incidences in C57BL/6 mice fed a commonly used cereal-based diet modulated by dietary restriction. J Gerontol A Biol Sci Med Sci 57(11):B379–B389PubMedGoogle Scholar
  32. 32.
    Kasahara T, Abe K, Mekada K, Yoshiki A, Kato T (2010) Genetic variation of melatonin productivity in laboratory mice under domestication. Proc Natl Acad Sci U S A 107(14):6412–6417. doi: 10.1073/pnas.0914399107 PubMedCentralPubMedGoogle Scholar
  33. 33.
    Ishimura R, Nagy G, Dotu I, Zhou H, Yang XL, Schimmel P, Senju S, Nishimura Y, Chuang JH, Ackerman SL (2014) RNA function. Ribosome stalling induced by mutation of a CNS-specific tRNA causes neurodegeneration. Science 345(6195):455–459. doi: 10.1126/science.1249749 PubMedCentralPubMedGoogle Scholar
  34. 34.
    Miller RA, Harrison DE, Astle CM, Floyd RA, Flurkey K, Hensley KL, Javors MA, Leeuwenburgh C, Nelson JF, Ongini E, Nadon NL, Warner HR, Strong R (2007) An aging interventions testing program: study design and interim report. Aging Cell 6(4):565–575PubMedGoogle Scholar
  35. 35.
    Nadon NL, Strong R, Miller RA, Nelson J, Javors M, Sharp ZD, Peralba JM, Harrison DE (2008) Design of aging intervention studies: the NIA interventions testing program. Age 30(4):187–199PubMedCentralPubMedGoogle Scholar
  36. 36.
    Spencer CC, Howell CE, Wright AR, Promislow DE (2003) Testing an ‘aging gene’ in long-lived drosophila strains: increased longevity depends on sex and genetic background. Aging Cell 2(2):123–130PubMedCentralPubMedGoogle Scholar
  37. 37.
    Kortschak RD, Samuel G, Saint R, Miller DJ (2003) EST analysis of the cnidarian Acropora millepora reveals extensive gene loss and rapid sequence divergence in the model invertebrates. Curr Biol 13(24):2190–2195PubMedGoogle Scholar
  38. 38.
    Austad SN (2009) Is there a role for new invertebrate models for aging research? J Gerontol A Biol Sci Med Sci 64(2):192–194PubMedGoogle Scholar
  39. 39.
    Harel I, Benayoun BA, Machado B, Singh PP, Hu CK, Pech MF, Valenzano DR, Zhang E, Sharp SC, Artandi SE, Brunet A (2015) A platform for rapid exploration of aging and diseases in a naturally short-lived vertebrate. Cell 160(5):1013–1026. doi: 10.1016/j.cell.2015.01.038 PubMedGoogle Scholar
  40. 40.
    Shineman DW, Basi GS, Bizon JL, Colton CA, Greenberg BD, Hollister BA, Lincecum J, Leblanc GG, Lee LB, Luo F, Morgan D, Morse I, Refolo LM, Riddell DR, Scearce-Levie K, Sweeney P, Yrjanheikki J, Fillit HM (2011) Accelerating drug discovery for Alzheimer’s disease: best practices for preclinical animal studies. Alzheimers Res Ther 3(5):28. doi: 10.1186/alzrt90 PubMedCentralPubMedGoogle Scholar
  41. 41.
    Hall AM, Roberson ED (2012) Mouse models of Alzheimer’s disease. Brain Res Bull 88(1):3–12. doi: 10.1016/j.brainresbull.2011.11.017 PubMedCentralPubMedGoogle Scholar
  42. 42.
    Janssen JC, Beck JA, Campbell TA, Dickinson A, Fox NC, Harvey RJ, Houlden H, Rossor MN, Collinge J (2003) Early onset familial Alzheimer’s disease: Mutation frequency in 31 families. Neurology 60(2):235–239PubMedGoogle Scholar
  43. 43.
    Costa DA, Cracchiolo JR, Bachstetter AD, Hughes TF, Bales KR, Paul SM, Mervis RF, Arendash GW, Potter H (2007) Enrichment improves cognition in AD mice by amyloid-related and unrelated mechanisms. Neurobiol Aging 28(6):831–844. doi: 10.1016/j.neurobiolaging.2006.04.009 PubMedGoogle Scholar
  44. 44.
    Berardi N, Braschi C, Capsoni S, Cattaneo A, Maffei L (2007) Environmental enrichment delays the onset of memory deficits and reduces neuropathological hallmarks in a mouse model of Alzheimer-like neurodegeneration. J Alzheimers Dis 11(3):359–370PubMedGoogle Scholar
  45. 45.
    Garcia-Mesa Y, Lopez-Ramos JC, Gimenez-Llort L, Revilla S, Guerra R, Gruart A, Laferla FM, Cristofol R, Delgado-Garcia JM, Sanfeliu C (2011) Physical exercise protects against Alzheimer’s disease in 3xTg-AD mice. J Alzheimers Dis 24(3):421–454. doi: 10.3233/JAD-2011-101635 PubMedGoogle Scholar
  46. 46.
    Leon WC, Canneva F, Partridge V, Allard S, Ferretti MT, DeWilde A, Vercauteren F, Atifeh R, Ducatenzeiler A, Klein W, Szyf M, Alhonen L, Cuello AC (2010) A novel transgenic rat model with a full Alzheimer’s-like amyloid pathology displays pre-plaque intracellular amyloid-beta-associated cognitive impairment. J Alzheimers Dis 20(1):113–126. doi: 10.3233/JAD-2010-1349 PubMedGoogle Scholar
  47. 47.
    Hsu PD, Lander ES, Zhang F (2014) Development and applications of CRISPR-Cas9 for genome engineering. Cell 157(6):1262–1278. doi: 10.1016/j.cell.2014.05.010 PubMedCentralPubMedGoogle Scholar
  48. 48.
    Finch CE, Austad SN (2015) Commentary: is Alzheimer’s disease uniquely human? Neurobiol Aging 36(2):553–555. doi: 10.1016/j.neurobiolaging.2014.10.025 PubMedCentralPubMedGoogle Scholar
  49. 49.
    Austad SN (2009) Comparative biology of aging. J Gerontol A Biol Sci Med Sci 64(2):199–201PubMedGoogle Scholar
  50. 50.
    Tian X, Azpurua J, Hine C, Vaidya A, Myakishev-Rempel M, Ablaeva J, Mao Z, Nevo E, Gorbunova V, Seluanov A (2013) High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature. nature12234 [pii]. doi: 10.1038/nature12234
  51. 51.
    Ungvari Z, Buffenstein R, Austad SN, Podlutsky A, Kaley G, Csiszar A (2008) Oxidative stress in vascular senescence: lessons from successfully aging species. Front Biosci 13:5056–5070PubMedGoogle Scholar
  52. 52.
    Austad SN (2010) Methusaleh’s Zoo: how nature provides us with clues for extending human health span. J Comp Pathol 142(Suppl 1):S10–S21PubMedCentralPubMedGoogle Scholar
  53. 53.
    McCay CM, Crowell MF, Maynard LA (1935) The effect of retarded growth upon the length of the life span and upon ultimate body size. J Nutr 13:669–679Google Scholar
  54. 54.
    Weindruch R, Walford RL (1988) The retardation of aging and disease by dietary restriction. Charles C. Thomas, SpringfieldGoogle Scholar
  55. 55.
    Mattison JA, Roth GS, Beasley TM, Tilmont EM, Handy AM, Herbert RL, Longo DL, Allison DB, Young JE, Bryant M, Barnard D, Ward WF, Qi W, Ingram DK, de Cabo R (2012) Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 489(7415):318–321. nature11432 [pii]. doi: 10.1038/nature11432
  56. 56.
    Colman RJ, Beasley TM, Kemnitz JW, Johnson SC, Weindruch R, Anderson RM (2014) Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Nat Commun 5:3557. doi: 10.1038/ncomms4557 PubMedCentralPubMedGoogle Scholar
  57. 57.
    Austad SN (2012) Ageing: mixed results for dieting monkeys. Nature 489(7415):210–211. nature11484 [pii]. doi: 10.1038/nature11484
  58. 58.
    Austad SN, Kristan DM (2003) Are mice calorically restricted in nature? Aging Cell 2(4):201–207PubMedGoogle Scholar
  59. 59.
    Piper MD, Partridge L (2007) Dietary restriction in Drosophila: delayed aging or experimental artefact? PLoS Genet 3(4):e57. doi: 10.1371/journal.pgen.0030057 PubMedCentralPubMedGoogle Scholar
  60. 60.
    Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11(3):298–300PubMedGoogle Scholar
  61. 61.
    Duffy PH, Feuers RJ, Hart RW (1990) Effect of chronic caloric restriction on the circadian regulation of physiological and behavioral variables in old male B6C3F1 mice. Chronobiol Int 7(4):291–303PubMedGoogle Scholar
  62. 62.
    McCarter RJ, Palmer J (1992) Energy metabolism and aging: a lifelong study of Fischer 344 rats. Am J Physiol 263(3 Pt 1):E448–E452PubMedGoogle Scholar
  63. 63.
    Sohal RS, Weindruch R (1996) Oxidative stress, caloric restriction, and aging. Science 273(5271):59–63PubMedCentralPubMedGoogle Scholar
  64. 64.
    Perez VI, Bokov A, Remmen HV, Mele J, Ran Q, Ikeno Y, Richardson A (2009) Is the oxidative stress theory of aging dead? Biochim Biophys Acta 1790(10):1005–1014PubMedCentralPubMedGoogle Scholar
  65. 65.
    Sapolsky RM, Krey LC, McEwen BS (1986) The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. Endocr Rev 7(3):284–301. doi: 10.1210/edrv-7-3-284 PubMedGoogle Scholar
  66. 66.
    Sabatino F, Masoro EJ, McMahan CA, Kuhn RW (1991) Assessment of the role of the glucocorticoid system in aging processes and in the action of food restriction. J Gerontol 46(B171):B179Google Scholar
  67. 67.
    Cerami A (1985) Hypothesis. Glucose as a mediator of aging. J Am Geriatr Soc 33(9):626–634PubMedGoogle Scholar
  68. 68.
    Masoro EJ (1996) Possible mechanisms underlying the antiaging actions of caloric restriction. Toxicol Pathol 24(6):738–741PubMedGoogle Scholar
  69. 69.
    Cabelof DC, Yanamadala S, Raffoul JJ, Guo Z, Soofi A, Heydari AR (2003) Caloric restriction promotes genomic stability by induction of base excision repair and reversal of its age-related decline. DNA Repair (Amst) 2(3):295–307Google Scholar
  70. 70.
    Heydari AR, You S, Takahashi R, Gutsmann A, Sarge KD, Richardson A (1996) Effect of caloric restriction on the expression of heat shock protein 70 and the activation of heat shock transcription factor 1. Dev Genet 18(2):114–124PubMedGoogle Scholar
  71. 71.
    Rao KS (2003) Dietary calorie restriction, DNA-repair and brain aging. Mol Cell Biochem 253(1–2):313–318PubMedGoogle Scholar
  72. 72.
    Frier B, Locke M (2005) Preservation of heat stress induced myocardial hsp 72 in aged animals following caloric restriction. Exp Gerontol 40(7):615–617PubMedGoogle Scholar
  73. 73.
    Hart RW, Leakey JE, Chou M, Duffy PH, Allaben WT, Feuers RJ (1992) Modulation of chemical toxicity by modification of caloric intake. Adv Exp Med Biol 322:73–81PubMedGoogle Scholar
  74. 74.
    Maglich JM, Watson J, McMillen PJ, Goodwin B, Willson TM, Moore JT (2004) The nuclear receptor CAR is a regulator of thyroid hormone metabolism during caloric restriction. J Biol Chem 279(19):19832–19838PubMedGoogle Scholar
  75. 75.
    Hart RW, Keenan K, Turturro A, Abdo KM, Leakey J, Lyn-Cook B (1995) Caloric restriction and toxicity. Fundam Appl Toxicol 25(2):184–195PubMedGoogle Scholar
  76. 76.
    Masoro EJ, Iwasaki K, Gleiser CA, McMahan CA, Seo EJ, Yu BP (1989) Dietary modulation of the progression of nephropathy in aging rats: an evaluation of the importance of protein. Am J Clin Nutr 49(6):1217–1227PubMedGoogle Scholar
  77. 77.
    Shimokawa I, Higami Y, Hubbard GB, McMahan CA, Masoro EJ, Yu BP (1993) Diet and the suitability of the male Fischer 344 rat as a model for aging research. J Gerontol 48(1):B27–B32PubMedGoogle Scholar
  78. 78.
    Zimmerman JA, Malloy V, Krajcik R, Orentreich N (2003) Nutritional control of aging. Exp Gerontol 38(1–2):47–52PubMedGoogle Scholar
  79. 79.
    Miller RA, Buehner G, Chang Y, Harper JM, Sigler R, Smith-Wheelock M (2005) Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance. Aging Cell 4(3):119–125PubMedGoogle Scholar
  80. 80.
    Solon-Biet SM, McMahon AC, Ballard JW, Ruohonen K, Wu LE, Cogger VC, Warren A, Huang X, Pichaud N, Melvin RG, Gokarn R, Khalil M, Turner N, Cooney GJ, Sinclair DA, Raubenheimer D, Le Couteur DG, Simpson SJ (2014) The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice. Cell Metab 19(3):418–430. doi: 10.1016/j.cmet.2014.02.009 PubMedGoogle Scholar
  81. 81.
    Bartke A, Wright JC, Mattison JA, Ingram DK, Miller RA, Roth GS (2001) Extending the lifespan of long-lived mice. Nature 414(6862):412PubMedGoogle Scholar
  82. 82.
    Liao CY, Rikke BA, Johnson TE, Diaz V, Nelson JF (2010) Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. Aging Cell 9(1):92–95. ACE533 [pii]. doi: 10.1111/j.1474-9726.2009.00533.x
  83. 83.
    Rikke BA, Liao CY, McQueen MB, Nelson JF, Johnson TE (2010) Genetic dissection of dietary restriction in mice supports the metabolic efficiency model of life extension. Exp Gerontol 45(9):691–701. doi: 10.1016/j.exger.2010.04.008 PubMedCentralPubMedGoogle Scholar
  84. 84.
    Schleit J, Johnson SC, Bennett CF, Simko M, Trongtham N, Castanza A, Hsieh EJ, Moller RM, Wasko BM, Delaney JR, Sutphin GL, Carr D, Murakami CJ, Tocchi A, Xian B, Chen W, Yu T, Goswami S, Higgins S, Holmberg M, Jeong KS, Kim JR, Klum S, Liao E, Lin MS, Lo W, Miller H, Olsen B, Peng ZJ, Pollard T, Pradeep P, Pruett D, Rai D, Ros V, Singh M, Spector BL, Vander Wende H, An EH, Fletcher M, Jelic M, Rabinovitch PS, MacCoss MJ, Han JD, Kennedy BK, Kaeberlein M (2013) Molecular mechanisms underlying genotype-dependent responses to dietary restriction. Aging Cell 12(6):1050–1061. doi: 10.1111/acel.12130 PubMedGoogle Scholar
  85. 85.
    Klass MR (1977) Aging in the nematode Caenorhabditis elegans: major biological and environmental factors influencing life span. Mech Ageing Dev 6(6):413–429PubMedGoogle Scholar
  86. 86.
    Kopec S (1928) On the influence of intermittent starvation on the longevity of the imaginal stage of Drosophila melanogaster. Brit J Exp Biol 5:8Google Scholar
  87. 87.
    Turturro A, Witt WW, Lewis S, Hass BS, Lipman RD, Hart RW (1999) Growth curves and survival characteristics of the animals used in the Biomarkers of Aging Program. J Gerontol A Biol Sci Med Sci 54(11):B492–B501PubMedGoogle Scholar
  88. 88.
    Tatar M, Post S, Yu K (2014) Nutrient control of Drosophila longevity. Trends Endocrinol Metab 25(10):509–517. doi: 10.1016/j.tem.2014.02.006 PubMedCentralPubMedGoogle Scholar
  89. 89.
    Carvalho GB, Kapahi P, Benzer S (2005) Compensatory ingestion upon dietary restriction in Drosophila melanogaster. Nat Methods 2(11):813–815PubMedCentralPubMedGoogle Scholar
  90. 90.
    Min KJ, Tatar M (2006) Restriction of amino acids extends lifespan in Drosophila melanogaster. Mech Ageing Dev 127(7):643–646PubMedGoogle Scholar
  91. 91.
    Grandison RC, Piper MD, Partridge L (2009) Amino-acid imbalance explains extension of lifespan by dietary restriction in Drosophila. Nature 462(7276):1061–1064. doi: 10.1038/nature08619 PubMedCentralPubMedGoogle Scholar
  92. 92.
    Piper MD, Mair W, Partridge L (2005) Counting the calories: the role of specific nutrients in extension of life span by food restriction. J Gerontol A Biol Sci Med Sci 60(5):549–555PubMedGoogle Scholar
  93. 93.
    Piper MD, Blanc E, Leitao-Goncalves R, Yang M, He X, Linford NJ, Hoddinott MP, Hopfen C, Soultoukis GA, Niemeyer C, Kerr F, Pletcher SD, Ribeiro C, Partridge L (2014) A holidic medium for Drosophila melanogaster. Nat Methods 11(1):100–105. doi: 10.1038/nmeth.2731 PubMedGoogle Scholar
  94. 94.
    Libert S, Zwiener J, Chu X, Vanvoorhies W, Roman G, Pletcher SD (2007) Regulation of Drosophila life span by olfaction and food-derived odors. Science 315(5815):1133–1137. doi: 10.1126/science.1136610 PubMedGoogle Scholar
  95. 95.
    Clancy DJ, Gems D, Harshman LG, Oldham S, Stocker H, Hafen E, Leevers SJ, Partridge L (2001) Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science 292(5514):104–106PubMedGoogle Scholar
  96. 96.
    Clancy DJ, Gems D, Hafen E, Leevers SJ, Partridge L (2002) Dietary restriction in long-lived dwarf flies. Science 296(5566):319. doi: 10.1126/science.1069366 PubMedGoogle Scholar
  97. 97.
    Gems D, Riddle DL (2000) Defining wild-type life span in Caenorhabditis elegans. J Gerontol A Biol Sci Med Sci 55(5):B215–B219PubMedGoogle Scholar
  98. 98.
    Garigan D, Hsu AL, Fraser AG, Kamath RS, Ahringer J, Kenyon C (2002) Genetic analysis of tissue aging in Caenorhabditis elegans: a role for heat-shock factor and bacterial proliferation. Genetics 161(3):1101–1112PubMedCentralPubMedGoogle Scholar
  99. 99.
    Houthoofd K, Gems D, Johnson TE, Vanfleteren JR (2007) Dietary restriction in the nematode Caenorhabditis elegans. Interdiscip Top Gerontol 35:98–114PubMedGoogle Scholar
  100. 100.
    Greer E, Brunet A (2011) The genetic network of life-span extension by dietary restriction. In: Masoro EJ, Austad SN (eds) Handbook of the biology of aging, 7th edn. Academic, San Diego, pp 3–24Google Scholar
  101. 101.
    Mair W, Panowski SH, Shaw RJ, Dillin A (2009) Optimizing dietary restriction for genetic epistasis analysis and gene discovery in C. elegans. PLoS One 4(2):e4535. doi: 10.1371/journal.pone.0004535 PubMedCentralPubMedGoogle Scholar
  102. 102.
    Tatar M, Kopelman A, Epstein D, Tu MP, Yin CM, Garofalo RS (2001) A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292(5514):107–110PubMedGoogle Scholar
  103. 103.
    Brown-Borg HM, Borg KE, Meliska CJ, Bartke A (1996) Dwarf mice and the ageing process. Nature 384(6604):33PubMedGoogle Scholar
  104. 104.
    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(12):6736–6741PubMedCentralPubMedGoogle Scholar
  105. 105.
    Coschigano KT, Clemmons D, Bellush LL, Kopchick JJ (2000) Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. Endocrinology 141(7):2608–2613PubMedGoogle Scholar
  106. 106.
    Suh Y, Atzmon G, Cho MO, Hwang D, Liu B, Leahy DJ, Barzilai N, Cohen P (2008) Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci USA 105(9):3438–3442PubMedCentralPubMedGoogle Scholar
  107. 107.
    Van Voorhies WA, Fuchs J, Thomas S (2005) The longevity of Caenorhabditis elegans in soil. Biol Lett 1(2):247–249PubMedCentralPubMedGoogle Scholar
  108. 108.
    Fabris N, Pierpaoli W, Sorkin E (1972) Lymphocytes, hormones and ageing. Nature 240(5383):557–559PubMedGoogle Scholar
  109. 109.
    Coschigano KT, Holland AN, Riders ME, List EO, Flyvbjerg A, Kopchick JJ (2003) Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor I levels and increased life span. Endocrinology 144(9):3799–3810PubMedGoogle Scholar
  110. 110.
    Bonkowski MS, Rocha JS, Masternak MM, Al Regaiey KA, Bartke A (2006) Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction. Proc Natl Acad Sci USA 103(20):7901–7905PubMedCentralPubMedGoogle Scholar
  111. 111.
    Sun LY, Spong A, Swindell WR, Fang Y, Hill C, Huber JA, Boehm JD, Westbrook R, Salvatori R, Bartke A (2013) Growth hormone-releasing hormone disruption extends lifespan and regulates response to caloric restriction in mice. Elife 2:e01098. doi: 10.7554/eLife.01098 PubMedCentralPubMedGoogle Scholar
  112. 112.
    Bokov AF, Garg N, Ikeno Y, Thakur S, Musi N, DeFronzo RA, Zhang N, Erickson RC, Gelfond J, Hubbard GB, Adamo ML, Richardson A (2011) Does reduced IGF-1R signaling in Igf1r+/− mice alter aging? PLoS One 6(11):e26891. PONE-D-11-07865 [pii]. doi: 10.1371/journal.pone.0026891
  113. 113.
    Xu J, Gontier G, Chaker Z, Lacube P, Dupont J, Holzenberger M (2014) Longevity effect of IGF-1R(+/−) mutation depends on genetic background-specific receptor activation. Aging Cell 13(1):19–28. doi: 10.1111/acel.12145 PubMedCentralPubMedGoogle Scholar
  114. 114.
    Selman C, Lingard S, Choudhury AI, Batterham RL, Claret M, Clements M, Ramadani F, Okkenhaug K, Schuster E, Blanc E, Piper MD, Al-Qassab H, Speakman JR, Carmignac D, Robinson IC, Thornton JM, Gems D, Partridge L, Withers DJ (2008) Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice. FASEB J 22(3):807–818PubMedGoogle Scholar
  115. 115.
    Taguchi A, Wartschow LM, White MF (2007) Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science 317(5836):369–372PubMedGoogle Scholar
  116. 116.
    Bluher M, Kahn BB, Kahn CR (2003) Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299(5606):572–574PubMedGoogle Scholar
  117. 117.
    Dazert E, Hall MN (2011) mTOR signaling in disease. Curr Opin Cell Biol 23(6):744–755. doi: 10.1016/ PubMedGoogle Scholar
  118. 118.
    Kapahi P, Chen D, Rogers AN, Katewa SD, Li PW, Thomas EL, Kockel L (2010) With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in aging. Cell Metab 11(6):453–465. S1550-4131(10)00153-1 [pii]. doi: 10.1016/j.cmet.2010.05.001
  119. 119.
    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(6967):620PubMedGoogle Scholar
  120. 120.
    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(10):885–890PubMedCentralPubMedGoogle Scholar
  121. 121.
    Selman C, Tullet JM, Wieser D, Irvine E, Lingard SJ, Choudhury AI, Claret M, Al-Qassab H, Carmignac D, Ramadani F, Woods A, Robinson IC, Schuster E, Batterham RL, Kozma SC, Thomas G, Carling D, Okkenhaug K, Thornton JM, Partridge L, Gems D, Withers DJ (2009) Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326(5949):140–144PubMedGoogle Scholar
  122. 122.
    Emran S, Yang M, He X, Zandveld J, Piper MD (2014) Target of rapamycin signalling mediates the lifespan-extending effects of dietary restriction by essential amino acid alteration. Aging 6(5):390–398PubMedCentralPubMedGoogle Scholar
  123. 123.
    Sun LY, Bartke A (2007) Adult neurogenesis in the hippocampus of long-lived mice during aging. J Gerontol A Biol Sci Med Sci 62(2):117–125PubMedGoogle Scholar
  124. 124.
    Martin GM, Austad SN, Johnson TE (1996) Genetic analysis of ageing: role of oxidative damage and environmental stresses. Nat Genet 13(1):25–34PubMedGoogle Scholar
  125. 125.
    Benedetti MG, Foster AL, Vantipalli MC, White MP, Sampayo JN, Gill MS, Olsen A, Lithgow GJ (2008) Compounds that confer thermal stress resistance and extended lifespan. Exp Gerontol 43(10):882–891. S0531-5565(08)00289-1 [pii]. doi: 10.1016/j.exger.2008.08.049
  126. 126.
    Burger JM, Promislow DE (2006) Are functional and demographic senescence genetically independent? Exp Gerontol 41(11):1108–1116PubMedGoogle Scholar
  127. 127.
    Bansal A, Zhu LJ, Yen K, Tissenbaum HA (2015) Uncoupling lifespan and healthspan in Caenorhabditis elegans longevity mutants. Proc Natl Acad Sci U S A 112(3):E277–E286. doi: 10.1073/pnas.1412192112 PubMedCentralPubMedGoogle Scholar
  128. 128.
    Harman D (1961) Prolongation of the normal lifespan and inhibition of spontaneous cancer by antioxidants. J Gerontol 16:247–254PubMedGoogle Scholar
  129. 129.
    Milgram NW, Racine RJ, Nellis P, Mendonca A, Ivy GO (1990) Maintenance on L-deprenyl prolongs life in aged male rats. Life Sci 47(5):415–420PubMedGoogle Scholar
  130. 130.
    Carney JM, Starke-Reed PE, Oliver CN, Landum RW, Cheng MS, Wu JF, Floyd RA (1991) Reversal of age-related increase in brain protein oxidation, decrease in enzyme activity, and loss in temporal and spatial memory by chronic administration of the spin-trapping compound N-tert-butyl-alpha-phenylnitrone. Proc Natl Acad Sci U S A 88(9):3633–3636PubMedCentralPubMedGoogle Scholar
  131. 131.
    Edamatsu R, Mori A, Packer L (1995) The spin-trap N-tert-alpha-phenyl-butylnitrone prolongs the life span of the senescence accelerated mouse. Biochem Biophys Res Commun 211(3):847–849. doi: 10.1006/bbrc.1995.1889 PubMedGoogle Scholar
  132. 132.
    Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le CD, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444(7117):337–342PubMedGoogle Scholar
  133. 133.
    Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP, Lanfrancone L, Pelicci PG (1999) The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402(6759):309–313. doi: 10.1038/46311 PubMedGoogle Scholar
  134. 134.
    Ramsey JJ, Tran D, Giorgio M, Griffey SM, Koehne A, Laing ST, Taylor SL, Kim K, Cortopassi GA, Lloyd KC, Hagopian K, Tomilov AA, Migliaccio E, Pelicci PG, McDonald RB (2014) The influence of Shc proteins on life span in mice. J Gerontol A Biol Sci Med Sci 69(10):1177–1185. doi: 10.1093/gerona/glt198 PubMedCentralPubMedGoogle Scholar
  135. 135.
    Strong R, Miller RA, Astle CM, Floyd RA, Flurkey K, Hensley KL, Javors MA, Leeuwenburgh C, Nelson JF, Ongini E (2008) Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice. Aging Cell 7(5):641–650PubMedCentralPubMedGoogle Scholar
  136. 136.
    Group AI (2013) Study design of ASPirin in Reducing Events in the Elderly (ASPREE): a randomized, controlled trial. Contemp Clin Trials 36(2):555–564. doi: 10.1016/j.cct.2013.09.014 Google Scholar
  137. 137.
    Strong R, Miller RA, Astle CM, Floyd RA, Flurkey K, Hensley KL, Javors MA, Leeuwenburgh C, Nelson JF, Ongini E, Nadon NL, Warner HR, Harrison DE (2008) Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice. Aging Cell 7(5):641–650. doi: 10.1111/j.1474-9726.2008.00414.x PubMedCentralPubMedGoogle Scholar
  138. 138.
    Harrison DE, Strong R, Allison DB, Ames BN, Astle CM, Atamna H, Fernandez E, Flurkey K, Javors MA, Nadon NL, Nelson JF, Pletcher S, Simpkins JW, Smith D, Wilkinson JE, Miller RA (2014) Acarbose, 17-alpha-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Aging Cell 13(2):273–282. doi: 10.1111/acel.12170 PubMedCentralPubMedGoogle Scholar
  139. 139.
    Moos W, Dykens JA, Nohynek D, Rubinchik E, Howell N (2009) Review of the effects of 17α − estrakiol in humans: a less feminizing estrogen with neuroprotective potential. Drug Dev Res 70:20Google Scholar
  140. 140.
    Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA (2009) Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460(7253):392–395PubMedCentralPubMedGoogle Scholar
  141. 141.
    Charbonnier LM, Le MA (2012) Rapamycin as immunosuppressant in murine transplantation model. Methods Mol Biol 821:435–445. doi: 10.1007/978-1-61779-430-8_28 PubMedGoogle Scholar
  142. 142.
    Liu JY, Song M, Guo M, Huang F, Ma BJ, Zhu L, Xu G, Li J, You RX (2015) Sirolimus versus tacrolimus as primary immunosuppressant after renal transplantation: a meta-analysis and economics evaluation. Am J Ther. doi: 10.1097/MJT.0000000000000186 Google Scholar
  143. 143.
    Hall MN (2008) mTOR-what does it do? Transplant Proc 40(10 Suppl):S5–S8. S0041-1345(08)01361-4 [pii]. doi: 10.1016/j.transproceed.2008.10.009
  144. 144.
    Adelman SJ (2010) Sirolimus and its analogs and its effects on vascular diseases. Curr Pharm Des 16(36):4002–4011, BSP/CPD/E-Pub/000283 [pii]PubMedGoogle Scholar
  145. 145.
    SoRelle R (2004) Everolimus stent proves effective. Circulation 109(18):e9041–e9042. doi: 10.1161/01.CIR.0000132284.04047.55 PubMedGoogle Scholar
  146. 146.
    Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124(3):471–484. S0092-8674(06)00108-5 [pii]. doi: 10.1016/j.cell.2006.01.016
  147. 147.
    Thoreen CC, Sabatini DM (2009) Rapamycin inhibits mTORC1, but not completely. Autophagy 5(5):725–726PubMedGoogle Scholar
  148. 148.
    Chen C, Liu Y, Liu Y, Zheng P (2009) mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal 2(98):ra75PubMedCentralPubMedGoogle Scholar
  149. 149.
    Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Rosenfeld SV, Blagosklonny MV (2011) Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle 10(24):4230–4236. 18486 [pii]. doi: 10.4161/cc.10.24.18486
  150. 150.
    Fok WC, Chen Y, Bokov A, Zhang Y, Salmon AB, Diaz V, Javors M, Wood WH 3rd, Zhang Y, Becker KG, Perez VI, Richardson A (2014) Mice fed rapamycin have an increase in lifespan associated with major changes in the liver transcriptome. PLoS One 9(1):e83988. doi: 10.1371/journal.pone.0083988 PubMedCentralPubMedGoogle Scholar
  151. 151.
    Neff F, Flores-Dominguez D, Ryan DP, Horsch M, Schroder S, Adler T, Afonso LC, Aguilar-Pimentel JA, Becker L, Garrett L, Hans W, Hettich MM, Holtmeier R, Holter SM, Moreth K, Prehn C, Puk O, Racz I, Rathkolb B, Rozman J, Naton B, Ordemann R, Adamski J, Beckers J, Bekeredjian R, Busch DH, Ehninger G, Graw J, Hofler H, Klingenspor M, Klopstock T, Ollert M, Stypmann J, Wolf E, Wurst W, Zimmer A, Fuchs H, Gailus-Durner V, Hrabe de Angelis M, Ehninger D (2013) Rapamycin extends murine lifespan but has limited effects on aging. J Clin Invest 123(8):3272–3291. doi: 10.1172/JCI67674 PubMedCentralPubMedGoogle Scholar
  152. 152.
    Miller RA, Harrison DE, Astle CM, Fernandez E, Flurkey K, Han M, Javors MA, Li X, Nadon NL, Nelson JF, Pletcher S, Salmon AB, Sharp ZD, Van Roekel S, Winkleman L, Strong R (2014) Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell 13(3):468–477. doi: 10.1111/acel.12194 PubMedCentralPubMedGoogle Scholar
  153. 153.
    Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, Richardson A, Strong R, Galvan V (2010) Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer’s disease. PLoS One 5(4):e9979PubMedCentralPubMedGoogle Scholar
  154. 154.
    Caccamo A, Majumder S, Richardson A, Strong R, Oddo S (2010) Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments. J Biol Chem 285(17):13107–13120. M110.100420 [pii]. doi: 10.1074/jbc.M110.100420
  155. 155.
    Halloran J, Hussong SA, Burbank R, Podlutskaya N, Fischer KE, Sloane LB, Austad SN, Strong R, Richardson A, Hart MJ, Galvan V (2012) Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice. Neuroscience 223C:102–113. S0306-4522(12)00672-0 [pii]. doi: 10.1016/j.neuroscience.2012.06.054
  156. 156.
    Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O’Kane CJ, Rubinsztein DC (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36(6):585–595. doi: 10.1038/ng1362 PubMedGoogle Scholar
  157. 157.
    Pakala R, Stabile E, Jang GJ, Clavijo L, Waksman R (2005) Rapamycin attenuates atherosclerotic plaque progression in apolipoprotein E knockout mice: inhibitory effect on monocyte chemotaxis. J Cardiovasc Pharmacol 46(4):481–486PubMedGoogle Scholar
  158. 158.
    Beutner F, Brendel D, Teupser D, Sass K, Baber R, Mueller M, Ceglarek U, Thiery J (2012) Effect of everolimus on pre-existing atherosclerosis in LDL-receptor deficient mice. Atherosclerosis 222(2):337–343. doi: 10.1016/j.atherosclerosis.2012.03.003 PubMedGoogle Scholar
  159. 159.
    Livi CB, Hardman RL, Christy BA, Dodds SG, Jones D, Williams C, Strong R, Bokov A, Javors MA, Ikeno Y, Hubbard G, Hasty P, Sharp ZD (2013) Rapamycin extends life span of Rb1+/− mice by inhibiting neuroendocrine tumors. Aging 5(2):100–110PubMedCentralPubMedGoogle Scholar
  160. 160.
    Hasty P, Livi CB, Dodds SG, Jones D, Strong R, Javors M, Fischer KE, Sloane L, Murthy K, Hubbard G, Sun L, Hurez V, Curiel TJ, Sharp ZD (2014) eRapa restores a normal life span in a FAP mouse model. Cancer Prev Res (Phila) 7(1):169–178. doi: 10.1158/1940-6207.CAPR-13-0299 Google Scholar
  161. 161.
    Ramos FJ, Chen SC, Garelick MG, Dai DF, Liao CY, Schreiber KH, MacKay VL, An EH, Strong R, Ladiges WC, Rabinovitch PS, Kaeberlein M, Kennedy BK (2012) Rapamycin reverses elevated mTORC1 signaling in lamin A/C-deficient mice, rescues cardiac and skeletal muscle function, and extends survival. Sci Transl Med 4(144):144ra103. 4/144/144ra103 [pii]. doi: 10.1126/scitranslmed.3003802
  162. 162.
    Keating R, Hertz T, Wehenkel M, Harris TL, Edwards BA, McClaren JL, Brown SA, Surman S, Wilson ZS, Bradley P, Hurwitz J, Chi H, Doherty PC, Thomas PG, McGargill MA (2013) The kinase mTOR modulates the antibody response to provide cross-protective immunity to lethal infection with influenza virus. Nat Immunol 14(12):1266–1276. doi: 10.1038/ni.2741 PubMedGoogle Scholar
  163. 163.
    Zhang Y, Bokov A, Gelfond J, Soto V, Ikeno Y, Hubbard G, Diaz V, Sloane L, Maslin K, Treaster S, Rendon S, van Remmen H, Ward W, Javors M, Richardson A, Austad SN, Fischer K (2014) Rapamycin extends life and health in C57BL/6 mice. J Gerontol A Biol Sci Med Sci 69(2):119–130. doi: 10.1093/gerona/glt056 PubMedGoogle Scholar
  164. 164.
    Flynn JM, O’Leary MN, Zambataro CA, Academia EC, Presley MP, Garrett BJ, Zykovich A, Mooney SD, Strong R, Rosen CJ, Kapahi P, Nelson MD, Kennedy BK, Melov S (2013) Late-life rapamycin treatment reverses age-related heart dysfunction. Aging Cell 12(5):851–862. doi: 10.1111/acel.12109 PubMedCentralPubMedGoogle Scholar
  165. 165.
    Fraenkel M, Ketzinel-Gilad M, Ariav Y, Pappo O, Karaca M, Castel J, Berthault MF, Magnan C, Cerasi E, Kaiser N, Leibowitz G (2008) mTOR inhibition by rapamycin prevents beta-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes. Diabetes 57(4):945–957. doi: 10.2337/db07-0922 PubMedGoogle Scholar
  166. 166.
    Houde VP, Brule S, Festuccia WT, Blanchard PG, Bellmann K, Deshaies Y, Marette A (2010) Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue. Diabetes 59(6):1338–1348. doi: 10.2337/db09-1324 PubMedCentralPubMedGoogle Scholar
  167. 167.
    Liu Y, Diaz V, Fernandez E, Strong R, Ye L, Baur JA, Lamming DW, Richardson A, Salmon AB (2014) Rapamycin-induced metabolic defects are reversible in both lean and obese mice. Aging 6(9):742–754PubMedCentralPubMedGoogle Scholar
  168. 168.
    Fang Y, Westbrook R, Hill C, Boparai RK, Arum O, Spong A, Wang F, Javors MA, Chen J, Sun LY, Bartke A (2013) Duration of rapamycin treatment has differential effects on metabolism in mice. Cell Metab 17(3):456–462. doi: 10.1016/j.cmet.2013.02.008 PubMedCentralPubMedGoogle Scholar
  169. 169.
    Bruno L, Merkenschlager M (2008) Directing T cell differentiation and function with small molecule inhibitors. Cell Cycle 7(15):2296–2298PubMedGoogle Scholar
  170. 170.
    Kim KW, Chung BH, Kim BM, Cho ML, Yang CW (2015) The effect of mammalian target of rapamycin inhibition on T helper type 17 and regulatory T cell differentiation in vitro and in vivo in kidney transplant recipients. Immunology 144(1):68–78. doi: 10.1111/imm.12351 PubMedGoogle Scholar
  171. 171.
    Goldberg EL, Smithey MJ, Lutes LK, Uhrlaub JL, Nikolich-Zugich J (2014) Immune memory-boosting dose of rapamycin impairs macrophage vesicle acidification and curtails glycolysis in effector CD8 cells, impairing defense against acute infections. J Immunol 193(2):757–763. doi: 10.4049/jimmunol.1400188 PubMedCentralPubMedGoogle Scholar
  172. 172.
    Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, Lonetto MA, Maecker HT, Kovarik J, Carson S, Glass DJ, Klickstein LB (2014) mTOR inhibition improves immune function in the elderly. Sci Transl Med 6(268):268ra179. doi: 10.1126/scitranslmed.3009892 PubMedGoogle Scholar
  173. 173.
    Hinojosa CA, Mgbemena V, Van RS, Austad SN, Miller RA, Bose S, Orihuela CJ (2012) Enteric-delivered rapamycin enhances resistance of aged mice to pneumococcal pneumonia through reduced cellular senescence. Exp Gerontol 47(12):958–965. S0531-5565(12)00250-1 [pii]. doi: 10.1016/j.exger.2012.08.013
  174. 174.
    Goldberg EL, Romero-Aleshire MJ, Renkema KR, Ventevogel MS, Chew WM, Uhrlaub JL, Smithey MJ, Limesand KH, Sempowski GD, Brooks HL, Nikolich-Zugich J (2015) Lifespan-extending caloric restriction or mTOR inhibition impair adaptive immunity of old mice by distinct mechanisms. Aging Cell 14(1):130–138. doi: 10.1111/acel.12280 PubMedCentralPubMedGoogle Scholar
  175. 175.
    Sonntag WE, Carter CS, Ikeno Y, Ekenstedt K, Carlson CS, Loeser RF, Chakrabarty S, Lee S, Bennett C, Ingram R, Moore T, Ramsey M (2005) Adult-onset growth hormone and insulin-like growth factor I deficiency reduces neoplastic disease, modifies age-related pathology, and increases life span. Endocrinology 146(7):2920–2932. doi: 10.1210/en.2005-0058 PubMedGoogle Scholar

Copyright information

© Springer International Publishing 2016

Authors and Affiliations

  1. 1.Department of BiologyUniversity of Alabama at BirminghamBirminghamUSA

Personalised recommendations