Dietary Restriction in C. elegans

  • Yue Zhang
  • William B. MairEmail author
Part of the Healthy Ageing and Longevity book series (HAL)


Ageing increases risk for multiple chronic diseases. Dietary restriction (DR), reducing food intake without malnutrition, is a potent intervention that delays ageing and onset of age-related diseases from yeast to mammals. Research using model organisms such as C. elegans can therefore be used to elucidate mechanisms underpinning DR that might have therapeutic potential. In this chapter, we discuss the advantages and disadvantages of using C. elegans to study how DR modulates healthy ageing. We provide a comprehensive summary on the different methods of DR used to date, and the effects of DR on healthspan and models of age-related diseases. We focus on the molecular mechanisms and physiological processes used by DR to promote longevity, highlighting advantages of using C. elegans as a model to discover novel mechanisms that can be translated to anti-ageing interventions in humans.


Dietary restriction C. elegans Ageing Healthspan Insulin signalling SKN-1 PHA-4 AMPK TOR Autophagy 



We thank members of the Mair lab for helpful discussion and critical reading of the manuscript. We would like to apologize to those whose work could not be cited here due to space limitations. W.M. is funded by the Ellison Medical Foundation and the NIH/NIA R01AG044346.


  1. 1.
    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 CrossRefGoogle Scholar
  2. 2.
    Christensen K, Doblhammer G, Rau R, Vaupel JW (2009) Ageing populations: the challenges ahead. Lancet 374(9696):1196–1208. doi: 10.1016/S0140-6736(09)61460-4 PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Gillum LA, Gouveia C, Dorsey ER, Pletcher M, Mathers CD, McCulloch CE, Johnston SC (2011) NIH disease funding levels and burden of disease. PLoS ONE 6(2), e16837. doi: 10.1371/journal.pone.0016837 PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Weindruch R, Walford RL (1988) The retardation of aging and disease by dietary restriction. C.C. Thomas, SpringfieldGoogle Scholar
  5. 5.
    Mair W, Dillin A (2008) Aging and survival: the genetics of life span extension by dietary restriction. Annu Rev Biochem 77(1):727–754. doi: 10.1146/annurev.biochem.77.061206.171059 PubMedCrossRefGoogle Scholar
  6. 6.
    McCay C, Crowell MF, Maynard LA (1935) The effect of retarded growth upon the length of life span and upon the ultimate body size. J Nutr 10(1):63–79Google Scholar
  7. 7.
    Fontana L, Partridge L (2015) Promoting health and longevity through diet: from model organisms to humans. Cell 161(1):106–118. doi: 10.1016/j.cell.2015.02.020 PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Longo VD, Fontana L (2010) Calorie restriction and cancer prevention: metabolic and molecular mechanisms. Trends Pharmacol Sci 31(2):89–98. doi: 10.1016/ PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Martin B, Mattson MP, Maudsley S (2006) Caloric restriction and intermittent fasting: two potential diets for successful brain aging. Ageing Res Rev 5(3):332–353. doi: 10.1016/j.arr.2006.04.002 PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Speakman JR, Mitchell SE (2011) Caloric restriction. Mol Asp Med 32(3):159–221. doi: 10.1016/j.mam.2011.07.001 CrossRefGoogle Scholar
  11. 11.
    Dolinsky VW, Dyck JR (2011) Calorie restriction and resveratrol in cardiovascular health and disease. Biochim Biophys Acta 1812(11):1477–1489. doi: 10.1016/j.bbadis.2011.06.010 PubMedCrossRefGoogle Scholar
  12. 12.
    Dirks AJ, Leeuwenburgh C (2006) Caloric restriction in humans: potential pitfalls and health concerns. Mech Ageing Dev 127(1):1–7. doi: 10.1016/j.mad.2005.09.001 PubMedCrossRefGoogle Scholar
  13. 13.
    Klass MR (1977) Aging in the nematode C. elegans: major biological and environmental factors influencing life span. Mech Ageing Dev 6(6):413–429PubMedCrossRefGoogle Scholar
  14. 14.
    Kenyon CJ (2010) The genetics of ageing. Nature 464(7288):504–512. doi: 10.1038/nature08980 PubMedCrossRefGoogle Scholar
  15. 15.
    Houthoofd K (2003) Life extension via dietary restriction is independent of the Ins/IGF-1 signalling pathway in C. elegans. Exp Gerontol 38(9):947–954. doi: 10.1016/s0531-5565(03)00161-x PubMedCrossRefGoogle Scholar
  16. 16.
    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 PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Panowski SH, Wolff S, Aguilaniu H, Durieux J, Dillin A (2007) PHA-4/Foxa mediates diet-restriction-induced longevity of C. elegans. Nature 447(7144):550–555. doi: 10.1038/nature05837 PubMedCrossRefGoogle Scholar
  18. 18.
    Bishop NA, Guarente L (2007) Two neurons mediate diet-restriction-induced longevity in C. elegans. Nature 447(7144):545–549. doi: 10.1038/nature05904 PubMedCrossRefGoogle Scholar
  19. 19.
    Houthoofd K, Braeckman BP, Lenaerts I, Brys K, De Vreese A, Van Eygen S, Vanfleteren JR (2002) Axenic growth up-regulates mass-specific metabolic rate, stress resistance, and extends life span in C. elegans. Exp Gerontol 37(12):1371–1378. doi: 10.1016/S0531-5565(02)00173-0 PubMedCrossRefGoogle Scholar
  20. 20.
    Lenaerts I, Walker GA, Van Hoorebeke L, Gems D, Vanfleteren JR (2008) Dietary restriction of C. elegans by axenic culture reflects nutritional requirement for constituents provided by metabolically active microbes. J Gerontol A Biol Sci Med Sci 63(3):242–252PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Zhang M, Poplawski M, Yen K, Cheng H, Bloss E, Zhu X, Patel H, Mobbs CV (2009) Role of CBP and SATB-1 in aging, dietary restriction, and insulin-like signaling. PLoS Biol 7(11), e1000245. doi: 10.1371/journal.pbio.1000245 PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Castelein N, Cai H, Rasulova M, Braeckman BP (2014) Lifespan regulation under axenic dietary restriction: a close look at the usual suspects. Exp Gerontol 58:96–103. doi: 10.1016/j.exger.2014.07.015 PubMedCrossRefGoogle Scholar
  23. 23.
    Hosono R, Nishimoto S, Kuno S (1989) Alterations of life span in the nematode C. elegans under monoxenic culture conditions. Exp Gerontol 24(3):251–264. doi: 10.1016/0531-5565(89)90016-8 PubMedCrossRefGoogle Scholar
  24. 24.
    Avery L (1993) The genetics of feeding in C. elegans. Genetics 133(4):897–917PubMedPubMedCentralGoogle Scholar
  25. 25.
    Lakowski B, Hekimi S (1998) The genetics of caloric restriction in C. elegans. Proc Natl Acad Sci U S A 95(22):13091–13096. doi: 10.1073/pnas.95.22.13091 PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Kauffman AL, Ashraf JM, Corces-Zimmerman MR, Landis JN, Murphy CT (2010) Insulin signaling and dietary restriction differentially influence the decline of learning and memory with age. PLoS Biol 8(5), e1000372. doi: 10.1371/journal.pbio.1000372 PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Jia K, Levine B (2007) Autophagy is required for dietary restriction-mediated life span extension in C. elegans. Autophagy 3(6):597–599PubMedCrossRefGoogle Scholar
  28. 28.
    Hansen M, Chandra A, Mitic LL, Onken B, Driscoll M, Kenyon C (2008) A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet 4(2), e24. doi: 10.1371/journal.pgen.0040024 PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Heestand BN, Shen Y, Liu W, Magner DB, Storm N, Meharg C, Habermann B, Antebi A (2013) Dietary restriction induced longevity is mediated by nuclear receptor NHR-62 in C. elegans. PLoS Genet 9(7), e1003651. doi: 10.1371/journal.pgen.1003651 PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Hansen M, Hsu AL, Dillin A, Kenyon C (2005) New genes tied to endocrine, metabolic, and dietary regulation of lifespan from a C. elegans genomic RNAi screen. PLoS Genet 1(1):119–128. doi: 10.1371/journal.pgen.0010017 PubMedCrossRefGoogle Scholar
  31. 31.
    Longo VD, Mattson MP (2014) Fasting: molecular mechanisms and clinical applications. Cell Metab 19(2):181–192. doi: 10.1016/j.cmet.2013.12.008 PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Kaeberlein TL, Smith ED, Tsuchiya M, Welton KL, Thomas JH, Fields S, Kennedy BK, Kaeberlein M (2006) Lifespan extension in C. elegans by complete removal of food. Aging Cell 5(6):487–494. doi: 10.1111/j.1474-9726.2006.00238.x PubMedCrossRefGoogle Scholar
  33. 33.
    Lee GD, Wilson MA, Zhu M, Wolkow CA, de Cabo R, Ingram DK, Zou S (2006) Dietary deprivation extends lifespan in C. elegans. Aging Cell 5(6):515–524. doi: 10.1111/j.1474-9726.2006.00241.x PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Angelo G, Van Gilst MR (2009) Starvation protects germline stem cells and extends reproductive longevity in C. elegans. Science 326(5955):954–958. doi: 10.1126/science.1178343 PubMedCrossRefGoogle Scholar
  35. 35.
    Steinkraus KA, Smith ED, Davis C, Carr D, Pendergrass WR, Sutphin GL, Kennedy BK, Kaeberlein M (2008) Dietary restriction suppresses proteotoxicity and enhances longevity by an hsf-1-dependent mechanism in C. elegans. Aging Cell 7(3):394–404. doi: 10.1111/j.1474-9726.2008.00385.x PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Honjoh S, Yamamoto T, Uno M, Nishida E (2009) Signalling through RHEB-1 mediates intermittent fasting-induced longevity in C. elegans. Nature 457(7230):726–730. doi: 10.1038/nature07583 PubMedCrossRefGoogle Scholar
  37. 37.
    Uno M, Honjoh S, Matsuda M, Hoshikawa H, Kishimoto S, Yamamoto T, Ebisuya M, Yamamoto T, Matsumoto K, Nishida E (2013) A fasting-responsive signaling pathway that extends life span in C. elegans. Cell Rep 3(1):79–91. doi: 10.1016/j.celrep.2012.12.018 PubMedCrossRefGoogle Scholar
  38. 38.
    Greer EL, Dowlatshahi D, Banko MR, Villen J, Hoang K, Blanchard D, Gygi SP, Brunet A (2007) An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans. Curr Biol 17(19):1646–1656. doi: 10.1016/j.cub.2007.08.047 PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Greer EL, Brunet A (2009) Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans. Aging Cell 8(2):113–127. doi: 10.1111/j.1474-9726.2009.00459.x PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Ching TT, Paal AB, Mehta A, Zhong L, Hsu AL (2010) drr-2 encodes an eIF4H that acts downstream of TOR in diet-restriction-induced longevity of C. elegans. Aging Cell 9(4):545–557. doi: 10.1111/j.1474-9726.2010.00580.x PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    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):119–125. doi: 10.1111/j.1474-9726.2005.00152.x PubMedCrossRefGoogle Scholar
  42. 42.
    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 PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Mair W, Piper MD, Partridge L (2005) Calories do not explain extension of life span by dietary restriction in Drosophila. PLoS Biol 3(7), e223. doi: 10.1371/journal.pbio.0030223 PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Piper MD, Partridge L, Raubenheimer D, Simpson SJ (2011) Dietary restriction and aging: a unifying perspective. Cell Metab 14(2):154–160. doi: 10.1016/j.cmet.2011.06.013 PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    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 PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325(5937):201–204. doi: 10.1126/science.1173635 PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    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. doi: 10.1038/nature11432 PubMedCrossRefGoogle Scholar
  48. 48.
    Samuel TK, Sinclair JW, Pinter KL, Hamza I (2014) Culturing C. elegans in axenic liquid media and creation of transgenic worms by microparticle bombardment. J Vis Exp 90, e51796. doi: 10.3791/51796 Google Scholar
  49. 49.
    Lu NC, Goetsch KM (1993) Carbohydrate requirement of C. elegans and the final development of a chemically defined medium. Nematologica 39:303–311CrossRefGoogle Scholar
  50. 50.
    Szewczyk NJ, Mancinelli RL, McLamb W, Reed D, Blumberg BS, Conley CA (2005) C. elegans survives atmospheric breakup of STS-107, space shuttle Columbia. Astrobiology 5(6):690–705. doi: 10.1089/ast.2005.5.690 PubMedCrossRefGoogle Scholar
  51. 51.
    Heintz C, Mair W (2014) You are what you host: microbiome modulation of the aging process. Cell 156(3):408–411. doi: 10.1016/j.cell.2014.01.025 PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    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 PubMedCrossRefGoogle Scholar
  53. 53.
    Brandhorst S, Choi IY, Wei M, Cheng CW, Sedrakyan S, Navarrete G, Dubeau L, Yap LP, Park R, Vinciguerra M, Di Biase S, Mirzaei H, Mirisola MG, Childress P, Ji L, Groshen S, Penna F, Odetti P, Perin L, Conti PS, Ikeno Y, Kennedy BK, Cohen P, Morgan TE, Dorff TB, Longo VD (2015) A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan. Cell Metab 22(1):86–99. doi: 10.1016/j.cmet.2015.05.012 PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    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. doi: 10.1111/j.1474-9726.2009.00533.x PubMedCrossRefGoogle Scholar
  55. 55.
    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 PubMedCrossRefGoogle Scholar
  56. 56.
    Johnson TE (1990) Increased life-span of age-1 mutants in C. elegans and lower Gompertz rate of aging. Science 249(4971):908–912PubMedCrossRefGoogle Scholar
  57. 57.
    Henderson ST, Johnson TE (2001) daf-16 integrates developmental and environmental inputs to mediate aging in the nematode C. elegans. Curr Biol 11(24):1975–1980PubMedCrossRefGoogle Scholar
  58. 58.
    Murphy CT, McCarroll SA, Bargmann CI, Fraser A, Kamath RS, Ahringer J, Li H, Kenyon C (2003) Genes that act downstream of DAF-16 to influence the lifespan of C. elegans. Nature 424(6946):277–283. doi: 10.1038/nature01789 PubMedCrossRefGoogle Scholar
  59. 59.
    Padmanabhan S, Mukhopadhyay A, Narasimhan SD, Tesz G, Czech MP, Tissenbaum HA (2009) A PP2A regulatory subunit regulates C. elegans insulin/IGF-1 signaling by modulating AKT-1 phosphorylation. Cell 136(5):939–951. doi: 10.1016/j.cell.2009.01.025 PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Tao L, Xie Q, Ding YH, Li ST, Peng S, Zhang YP, Tan D, Yuan Z, Dong MQ (2013) CAMKII and calcineurin regulate the lifespan of C. elegans through the FOXO transcription factor DAF-16. Elife 2, e00518. doi: 10.7554/eLife.00518 PubMedPubMedCentralGoogle Scholar
  61. 61.
    Lee SJ, Murphy CT, Kenyon C (2009) Glucose shortens the life span of C. elegans by downregulating DAF-16/FOXO activity and aquaporin gene expression. Cell Metab 10(5):379–391. doi: 10.1016/j.cmet.2009.10.003 PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Wolff S, Ma H, Burch D, Maciel GA, Hunter T, Dillin A (2006) SMK-1, an essential regulator of DAF-16-mediated longevity. Cell 124(5):1039–1053. doi: 10.1016/j.cell.2005.12.042 PubMedCrossRefGoogle Scholar
  63. 63.
    Riedel CG, Dowen RH, Lourenco GF, Kirienko NV, Heimbucher T, West JA, Bowman SK, Kingston RE, Dillin A, Asara JM, Ruvkun G (2013) DAF-16 employs the chromatin remodeller SWI/SNF to promote stress resistance and longevity. Nat Cell Biol 15(5):491–501. doi: 10.1038/ncb2720 PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Seo M, Seo K, Hwang W, Koo HJ, Hahm JH, Yang JS, Han SK, Hwang D, Kim S, Jang SK, Lee Y, Nam HG, Lee SJ (2015) RNA helicase HEL-1 promotes longevity by specifically activating DAF-16/FOXO transcription factor signaling in C. elegans. Proc Natl Acad Sci U S A 112(31):E4246–E4255. doi: 10.1073/pnas.1505451112 PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Heimbucher T, Liu Z, Bossard C, McCloskey R, Carrano AC, Riedel CG, Tanasa B, Klammt C, Fonslow BR, Riera CE, Lillemeier BF, Kemphues K, Yates JR 3rd, O’Shea C, Hunter T, Dillin A (2015) The deubiquitylase MATH-33 controls DAF-16 stability and function in metabolism and longevity. Cell Metab 22(1):151–163. doi: 10.1016/j.cmet.2015.06.002 PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Berdichevsky A, Viswanathan M, Horvitz HR, Guarente L (2006) C. elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life span. Cell 125(6):1165–1177. doi: 10.1016/j.cell.2006.04.036 PubMedCrossRefGoogle Scholar
  67. 67.
    Tullet JM (2015) DAF-16 target identification in C. elegans: past, present and future. Biogerontology 16(2):221–234. doi: 10.1007/s10522-014-9527-y PubMedCrossRefGoogle Scholar
  68. 68.
    Chang HC, Guarente L (2014) SIRT1 and other sirtuins in metabolism. Trends Endocrinol Metab 25(3):138–145. doi: 10.1016/j.tem.2013.12.001 PubMedCrossRefGoogle Scholar
  69. 69.
    Wang Y, Tissenbaum HA (2006) Overlapping and distinct functions for a C. elegans SIR2 and DAF-16/FOXO. Mech Ageing Dev 127(1):48–56. doi: 10.1016/j.mad.2005.09.005 PubMedCrossRefGoogle Scholar
  70. 70.
    Hansen M, Taubert S, Crawford D, Libina N, Lee SJ, Kenyon C (2007) Lifespan extension by conditions that inhibit translation in C. elegans. Aging Cell 6(1):95–110. doi: 10.1111/j.1474-9726.2006.00267.x PubMedCrossRefGoogle Scholar
  71. 71.
    Moroz N, Carmona JJ, Anderson E, Hart AC, Sinclair DA, Blackwell TK (2014) Dietary restriction involves NAD(+) -dependent mechanisms and a shift toward oxidative metabolism. Aging Cell 13(6):1075–1085. doi: 10.1111/acel.12273 PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Tissenbaum HA, Guarente L (2001) Increased dosage of a sir-2 gene extends lifespan in C. elegans. Nature 410(6825):227–230. doi: 10.1038/35065638 PubMedCrossRefGoogle Scholar
  73. 73.
    Burnett C, Valentini S, Cabreiro F, Goss M, Somogyvari M, Piper MD, Hoddinott M, Sutphin GL, Leko V, McElwee JJ, Vazquez-Manrique RP, Orfila AM, Ackerman D, Au C, Vinti G, Riesen M, Howard K, Neri C, Bedalov A, Kaeberlein M, Soti C, Partridge L, Gems D (2011) Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature 477(7365):482–485. doi: 10.1038/nature10296 PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Viswanathan M, Guarente L (2011) Regulation of C. elegans lifespan by sir-2.1 transgenes. Nature 477(7365):E1–E2. doi: 10.1038/nature10440 PubMedCrossRefGoogle Scholar
  75. 75.
    Mouchiroud L, Houtkooper RH, Moullan N, Katsyuba E, Ryu D, Canto C, Mottis A, Jo YS, Viswanathan M, Schoonjans K, Guarente L, Auwerx J (2013) The NAD(+)/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154(2):430–441. doi: 10.1016/j.cell.2013.06.016 PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Hardie DG, Ross FA, Hawley SA (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13(4):251–262. doi: 10.1038/nrm3311 PubMedCrossRefGoogle Scholar
  77. 77.
    Burkewitz K, Zhang Y, Mair WB (2014) AMPK at the nexus of energetics and aging. Cell Metab 20(1):10–25PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Apfeld J, O’Connor G, McDonagh T, DiStefano PS, Curtis R (2004) The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev 18(24):3004–3009. doi: 10.1101/gad.1255404 PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Mair W, Morantte I, Rodrigues AP, Manning G, Montminy M, Shaw RJ, Dillin A (2011) Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB. Nature 470(7334):404–408. doi: 10.1038/nature09706 PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Tullet JM, Araiz C, Sanders MJ, Au C, Benedetto A, Papatheodorou I, Clark E, Schmeisser K, Jones D, Schuster EF, Thornton JM, Gems D (2014) DAF-16/FoxO directly regulates an atypical AMP-activated protein kinase gamma isoform to mediate the effects of insulin/IGF-1 signaling on aging in C. elegans. PLoS Genet 10(2), e1004109. doi: 10.1371/journal.pgen.1004109 PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Altarejos JY, Montminy M (2011) CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nat Rev Mol Cell Biol 12(3):141–151. doi: 10.1038/nrm3072 PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Burkewitz K, Morantte I, Weir HJ, Yeo R, Zhang Y, Huynh FK, Ilkayeva OR, Hirschey MD, Grant AR, Mair WB (2015) Neuronal CRTC-1 governs systemic mitochondrial metabolism and lifespan via a catecholamine signal. Cell 160(5):842–855. doi: 10.1016/j.cell.2015.02.004 PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    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):140–144. doi: 10.1126/science.1177221 PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Chen D, Li PW, Goldstein BA, Cai W, Thomas EL, Chen F, Hubbard AE, Melov S, Kapahi P (2013) Germline signaling mediates the synergistically prolonged longevity produced by double mutations in daf-2 and rsks-1 in C. elegans. Cell Rep 5(6):1600–1610. doi: 10.1016/j.celrep.2013.11.018 PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149(2):274–293. doi: 10.1016/j.cell.2012.03.017 PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Dibble CC, Manning BD (2013) Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nat Cell Biol 15(6):555–564. doi: 10.1038/ncb2763 PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Martin TD, Chen XW, Kaplan RE, Saltiel AR, Walker CL, Reiner DJ, Der CJ (2014) Ral and Rheb GTPase activating proteins integrate mTOR and GTPase signaling in aging, autophagy, and tumor cell invasion. Mol Cell 53(2):209–220. doi: 10.1016/j.molcel.2013.12.004 PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Robida-Stubbs S, Glover-Cutter K, Lamming DW, Mizunuma M, Narasimhan SD, Neumann-Haefelin E, Sabatini DM, Blackwell TK (2012) TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab 15(5):713–724. doi: 10.1016/j.cmet.2012.04.007 PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Soukas AA, Kane EA, Carr CE, Melo JA, Ruvkun G (2009) Rictor/TORC2 regulates fat metabolism, feeding, growth, and life span in C. elegans. Genes Dev 23(4):496–511. doi: 10.1101/gad.1775409 PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Mizunuma M, Neumann-Haefelin E, Moroz N, Li Y, Blackwell TK (2014) mTORC2-SGK-1 acts in two environmentally responsive pathways with opposing effects on longevity. Aging Cell 13(5):869–878. doi: 10.1111/acel.12248 PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Schreiber MA, Pierce-Shimomura JT, Chan S, Parry D, McIntire SL (2010) Manipulation of behavioral decline in C. elegans with the Rag GTPase raga-1. PLoS Genet 6(5), e1000972. doi: 10.1371/journal.pgen.1000972 PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Lamming DW, Ye L, Sabatini DM, Baur JA (2013) Rapalogs and mTOR inhibitors as anti-aging therapeutics. J Clin Invest 123(3):980–989. doi: 10.1172/JCI64099 PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Johnson SC, Rabinovitch PS, Kaeberlein M (2013) mTOR is a key modulator of ageing and age-related disease. Nature 493(7432):338–345. doi: 10.1038/nature11861 PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Sheaffer KL, Updike DL, Mango SE (2008) The target of Rapamycin pathway antagonizes pha-4/FoxA to control development and aging. Curr Biol 18(18):1355–1364. doi: 10.1016/j.cub.2008.07.097 PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Chen D, Thomas EL, Kapahi P (2009) HIF-1 modulates dietary restriction-mediated lifespan extension via IRE-1 in C. elegans. PLoS Genet 5(5), e1000486. doi: 10.1371/journal.pgen.1000486 PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Seo K, Choi E, Lee D, Jeong DE, Jang SK, Lee SJ (2013) Heat shock factor 1 mediates the longevity conferred by inhibition of TOR and insulin/IGF-1 signaling pathways in C. elegans. Aging Cell 12(6):1073–1081. doi: 10.1111/acel.12140 PubMedCrossRefGoogle Scholar
  97. 97.
    Lapierre LR, De Magalhaes Filho CD, McQuary PR, Chu CC, Visvikis O, Chang JT, Gelino S, Ong B, Davis AE, Irazoqui JE, Dillin A, Hansen M (2013) The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in C. elegans. Nat Commun 4:2267. doi: 10.1038/ncomms3267 PubMedGoogle Scholar
  98. 98.
    McQuary PR, Liao CY, Chang JT, Kumsta C, She X, Davis A, Chu CC, Gelino S, Gomez-Amaro RL, Petrascheck M, Brill LM, Ladiges WC, Kennedy BK, Hansen M (2016) C. elegans S6K mutants require a creatine-kinase-like effector for lifespan extension. Cell Rep 14(9):2059–2067. doi: 10.1016/j.celrep.2016.02.012 PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Mango SE (2009) The molecular basis of organ formation: insights from the C. elegans foregut. Annu Rev Cell Dev Biol 25:597–628. doi: 10.1146/annurev.cellbio.24.110707.175411 PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Rubinsztein DC, Marino G, Kroemer G (2011) Autophagy and aging. Cell 146(5):682–695. doi: 10.1016/j.cell.2011.07.030 PubMedCrossRefGoogle Scholar
  101. 101.
    Smith-Vikos T, de Lencastre A, Inukai S, Shlomchik M, Holtrup B, Slack FJ (2014) MicroRNAs mediate dietary-restriction-induced longevity through PHA-4/FOXA and SKN-1/Nrf transcription factors. Curr Biol 24(19):2238–2246. doi: 10.1016/j.cub.2014.08.013 PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Blackwell TK, Steinbaugh MJ, Hourihan JM, Ewald CY, Isik M (2015) SKN-1/Nrf, stress responses, and aging in C. elegans. Free Radic Biol Med 88(Pt B):290–301. doi: 10.1016/j.freeradbiomed.2015.06.008 PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Tullet JM, Hertweck M, An JH, Baker J, Hwang JY, Liu S, Oliveira RP, Baumeister R, Blackwell TK (2008) Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell 132(6):1025–1038. doi: 10.1016/j.cell.2008.01.030 PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Wang J, Robida-Stubbs S, Tullet JM, Rual JF, Vidal M, Blackwell TK (2010) RNAi screening implicates a SKN-1-dependent transcriptional response in stress resistance and longevity deriving from translation inhibition. PLoS Genet 6(8). doi: 10.1371/journal.pgen.1001048
  105. 105.
    Paek J, Lo JY, Narasimhan SD, Nguyen TN, Glover-Cutter K, Robida-Stubbs S, Suzuki T, Yamamoto M, Blackwell TK, Curran SP (2012) Mitochondrial SKN-1/Nrf mediates a conserved starvation response. Cell Metab 16(4):526–537. doi: 10.1016/j.cmet.2012.09.007 PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Pang S, Lynn DA, Lo JY, Paek J, Curran SP (2014) SKN-1 and Nrf2 couples proline catabolism with lipid metabolism during nutrient deprivation. Nat Commun 5:5048. doi: 10.1038/ncomms6048 PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Ewald CY, Landis JN, Porter Abate J, Murphy CT, Blackwell TK (2015) Dauer-independent insulin/IGF-1-signalling implicates collagen remodelling in longevity. Nature 519(7541):97–101. doi: 10.1038/nature14021 PubMedCrossRefGoogle Scholar
  108. 108.
    Anckar J, Sistonen L (2011) Regulation of HSF1 function in the heat stress response: implications in aging and disease. Annu Rev Biochem 80:1089–1115. doi: 10.1146/annurev-biochem-060809-095203 PubMedCrossRefGoogle Scholar
  109. 109.
    Hsu AL, Murphy CT, Kenyon C (2003) Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300(5622):1142–1145. doi: 10.1126/science.1083701 PubMedCrossRefGoogle Scholar
  110. 110.
    Chiang WC, Ching TT, Lee HC, Mousigian C, Hsu AL (2012) HSF-1 regulators DDL-1/2 link insulin-like signaling to heat-shock responses and modulation of longevity. Cell 148(1–2):322–334. doi: 10.1016/j.cell.2011.12.019 PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Morley JF, Morimoto RI (2004) Regulation of longevity in C. elegans by heat shock factor and molecular chaperones. Mol Biol Cell 15(2):657–664. doi: 10.1091/mbc.E03-07-0532 PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Douglas PM, Baird NA, Simic MS, Uhlein S, McCormick MA, Wolff SC, Kennedy BK, Dillin A (2015) Heterotypic signals from neural HSF-1 separate thermotolerance from longevity. Cell Rep 12(7):1196–1204. doi: 10.1016/j.celrep.2015.07.026 PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Baird NA, Douglas PM, Simic MS, Grant AR, Moresco JJ, Wolff SC, Yates JR 3rd, Manning G, Dillin A (2014) HSF-1-mediated cytoskeletal integrity determines thermotolerance and life span. Science 346(6207):360–363. doi: 10.1126/science.1253168 PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Semenza GL (2010) HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev 20(1):51–56. doi: 10.1016/j.gde.2009.10.009 PubMedCrossRefGoogle Scholar
  115. 115.
    Mehta R, Steinkraus KA, Sutphin GL, Ramos FJ, Shamieh LS, Huh A, Davis C, Chandler-Brown D, Kaeberlein M (2009) Proteasomal regulation of the hypoxic response modulates aging in C. elegans. Science 324(5931):1196–1198. doi: 10.1126/science.1173507 PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Leiser SF, Begun A, Kaeberlein M (2011) HIF-1 modulates longevity and healthspan in a temperature-dependent manner. Aging Cell 10(2):318–326. doi: 10.1111/j.1474-9726.2011.00672.x PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Lee SJ, Hwang AB, Kenyon C (2010) Inhibition of respiration extends C. elegans life span via reactive oxygen species that increase HIF-1 activity. Curr Biol 20(23):2131–2136. doi: 10.1016/j.cub.2010.10.057 PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Leiser SF, Miller H, Rossner R, Fletcher M, Leonard A, Primitivo M, Rintala N, Ramos FJ, Miller DL, Kaeberlein M (2015) Cell nonautonomous activation of flavin-containing monooxygenase promotes longevity and health span. Science 350(6266):1375–1378. doi: 10.1126/science.aac9257 PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Robinson-Rechavi M, Carpentier A-S, Duffraisse M, Laudet V (2001) How many nuclear hormone receptors are there in the human genome? Trends Genet 17(10):554–556. doi: 10.1016/s0168-9525(01)02417-9 PubMedCrossRefGoogle Scholar
  120. 120.
    Francis GA, Fayard E, Picard F, Auwerx J (2003) Nuclear receptors and the control of metabolism. Annu Rev Physiol 65(1):261–311. doi: 10.1146/annurev.physiol.65.092101.142528 PubMedCrossRefGoogle Scholar
  121. 121.
    Corton JC, Apte U, Anderson SP, Limaye P, Yoon L, Latendresse J, Dunn C, Everitt JI, Voss KA, Swanson C, Kimbrough C, Wong JS, Gill SS, Chandraratna RA, Kwak MK, Kensler TW, Stulnig TM, Steffensen KR, Gustafsson JA, Mehendale HM (2004) Mimetics of caloric restriction include agonists of lipid-activated nuclear receptors. J Biol Chem 279(44):46204–46212. doi: 10.1074/jbc.M406739200 PubMedCrossRefGoogle Scholar
  122. 122.
    Reilly SM, Bhargava P, Liu S, Gangl MR, Gorgun C, Nofsinger RR, Evans RM, Qi L, Hu FB, Lee CH (2010) Nuclear receptor corepressor SMRT regulates mitochondrial oxidative metabolism and mediates aging-related metabolic deterioration. Cell Metab 12(6):643–653. doi: 10.1016/j.cmet.2010.11.007 PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Fisher AL, Lithgow GJ (2006) The nuclear hormone receptor DAF-12 has opposing effects on C. elegans lifespan and regulates genes repressed in multiple long-lived worms. Aging Cell 5(2):127–138. doi: 10.1111/j.1474-9726.2006.00203.x PubMedCrossRefGoogle Scholar
  124. 124.
    Van Gilst MR, Hadjivassiliou H, Yamamoto KR (2005) A C. elegans nutrient response system partially dependent on nuclear receptor NHR-49. Proc Natl Acad Sci U S A 102(38):13496–13501. doi: 10.1073/pnas.0506234102 PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Vella MC, Slack FJ (2005) C. elegans microRNAs. WormBook, pp 1–9. doi: 10.1895/wormbook.1.26.1
  126. 126.
    Smith-Vikos T, Slack FJ (2012) MicroRNAs and their roles in aging. J Cell Sci 125(Pt 1):7–17. doi: 10.1242/jcs.099200 PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75(5):843–854PubMedCrossRefGoogle Scholar
  128. 128.
    Wightman B, Ha I, Ruvkun G (1993) Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 75(5):855–862PubMedCrossRefGoogle Scholar
  129. 129.
    Boehm M, Slack F (2005) A developmental timing microRNA and its target regulate life span in C. elegans. Science 310(5756):1954–1957. doi: 10.1126/science.1115596 PubMedCrossRefGoogle Scholar
  130. 130.
    Ibanez-Ventoso C, Yang M, Guo S, Robins H, Padgett RW, Driscoll M (2006) Modulated microRNA expression during adult lifespan in C. elegans. Aging Cell 5(3):235–246. doi: 10.1111/j.1474-9726.2006.00210.x PubMedCrossRefGoogle Scholar
  131. 131.
    Kato M, Chen X, Inukai S, Zhao H, Slack FJ (2011) Age-associated changes in expression of small, noncoding RNAs, including microRNAs, in C. elegans. RNA 17(10):1804–1820. doi: 10.1261/rna.2714411 PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    de Lencastre A, Pincus Z, Zhou K, Kato M, Lee SS, Slack FJ (2010) MicroRNAs both promote and antagonize longevity in C. elegans. Curr Biol 20(24):2159–2168. doi: 10.1016/j.cub.2010.11.015 PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Mori MA, Raghavan P, Thomou T, Boucher J, Robida-Stubbs S, Macotela Y, Russell SJ, Kirkland JL, Blackwell TK, Kahn CR (2012) Role of microRNA processing in adipose tissue in stress defense and longevity. Cell Metab 16(3):336–347. doi: 10.1016/j.cmet.2012.07.017 PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Vora M, Shah M, Ostafi S, Onken B, Xue J, Ni JZ, Gu S, Driscoll M (2013) Deletion of microRNA-80 activates dietary restriction to extend C. elegans healthspan and lifespan. PLoS Genet 9(8), e1003737. doi: 10.1371/journal.pgen.1003737 PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Bansal A, Zhu LJ, Yen K, Tissenbaum HA (2015) Uncoupling lifespan and healthspan in C. elegans longevity mutants. Proc Natl Acad Sci U S A 112(3):E277–E286. doi: 10.1073/pnas.1412192112 PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Pincus Z, Smith-Vikos T, Slack FJ (2011) MicroRNA predictors of longevity in C. elegans. PLoS Genet 7(9), e1002306. doi: 10.1371/journal.pgen.1002306 PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Kane AE, Hilmer SN, Boyer D, Gavin K, Nines D, Howlett SE, de Cabo R, Mitchell SJ (2016) Impact of longevity interventions on a validated mouse clinical frailty index. J Gerontol A Biol Sci Med Sci 71(3):333–339. doi: 10.1093/gerona/glu315 PubMedCrossRefGoogle Scholar
  138. 138.
    Pinkston JM, Garigan D, Hansen M, Kenyon C (2006) Mutations that increase the life span of C. elegans inhibit tumor growth. Science 313(5789):971–975. doi: 10.1126/science.1121908 PubMedCrossRefGoogle Scholar
  139. 139.
    Houthoofd K, Braeckman BP, Lenaerts I, Brys K, Vreese A, Eygen S, Vanfleteren JR (2002) No reduction of metabolic rate in food restricted C. elegans. Exp Gerontol 37(12):1359–1369PubMedCrossRefGoogle Scholar
  140. 140.
    Melendez A, Talloczy Z, Seaman M, Eskelinen EL, Hall DH, Levine B (2003) Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301(5638):1387–1391. doi: 10.1126/science.1087782 PubMedCrossRefGoogle Scholar
  141. 141.
    Kim J, Kundu M, Viollet B, Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13(2):132–141. doi: 10.1038/ncb2152 PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, Vasquez DS, Joshi A, Gwinn DM, Taylor R, Asara JM, Fitzpatrick J, Dillin A, Viollet B, Kundu M, Hansen M, Shaw RJ (2011) Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331(6016):456–461. doi: 10.1126/science.1196371 PubMedCrossRefGoogle Scholar
  143. 143.
    Lapierre LR, Gelino S, Melendez A, Hansen M (2011) Autophagy and lipid metabolism coordinately modulate life span in germline-less C. elegans. Curr Biol 21(18):1507–1514. doi: 10.1016/j.cub.2011.07.042 PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Pyo JO, Yoo SM, Ahn HH, Nah J, Hong SH, Kam TI, Jung S, Jung YK (2013) Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat Commun 4:2300. doi: 10.1038/ncomms3300 PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Green DR, Galluzzi L, Kroemer G (2011) Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 333(6046):1109–1112. doi: 10.1126/science.1201940 PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Syntichaki P, Troulinaki K, Tavernarakis N (2007) eIF4E function in somatic cells modulates ageing in C. elegans. Nature 445(7130):922–926. doi: 10.1038/nature05603 PubMedCrossRefGoogle Scholar
  147. 147.
    Pan KZ, Palter JE, Rogers AN, Olsen A, Chen D, Lithgow GJ, Kapahi P (2007) Inhibition of mRNA translation extends lifespan in C. elegans. Aging Cell 6(1):111–119. doi: 10.1111/j.1474-9726.2006.00266.x PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Rogers AN, Chen D, McColl G, Czerwieniec G, Felkey K, Gibson BW, Hubbard A, Melov S, Lithgow GJ, Kapahi P (2011) Life span extension via eIF4G inhibition is mediated by posttranscriptional remodeling of stress response gene expression in C. elegans. Cell Metab 14(1):55–66. doi: 10.1016/j.cmet.2011.05.010 PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Zid BM, Rogers AN, Katewa SD, Vargas MA, Kolipinski MC, Lu TA, Benzer S, Kapahi P (2009) 4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila. Cell 139(1):149–160. doi: 10.1016/j.cell.2009.07.034 PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Barzilai N, Huffman DM, Muzumdar RH, Bartke A (2012) The critical role of metabolic pathways in aging. Diabetes 61(6):1315–1322. doi: 10.2337/db11-1300 PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Walker AK, Yang F, Jiang K, Ji JY, Watts JL, Purushotham A, Boss O, Hirsch ML, Ribich S, Smith JJ, Israelian K, Westphal CH, Rodgers JT, Shioda T, Elson SL, Mulligan P, Najafi-Shoushtari H, Black JC, Thakur JK, Kadyk LC, Whetstine JR, Mostoslavsky R, Puigserver P, Li X, Dyson NJ, Hart AC, Naar AM (2010) Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP. Genes Dev 24(13):1403–1417. doi: 10.1101/gad.1901210 PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Van Gilst MR, Hadjivassiliou H, Jolly A, Yamamoto KR (2005) Nuclear hormone receptor NHR-49 controls fat consumption and fatty acid composition in C. elegans. PLoS Biol 3(2), e53. doi: 10.1371/journal.pbio.0030053 PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    O’Rourke EJ, Ruvkun G (2013) MXL-3 and HLH-30 transcriptionally link lipolysis and autophagy to nutrient availability. Nat Cell Biol 15(6):668–676. doi: 10.1038/ncb2741 PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Folick A, Oakley HD, Yu Y, Armstrong EH, Kumari M, Sanor L, Moore DD, Ortlund EA, Zechner R, Wang MC (2015) Aging. Lysosomal signaling molecules regulate longevity in C. elegans. Science 347(6217):83–86. doi: 10.1126/science.1258857 PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Bratic A, Larsson NG (2013) The role of mitochondria in aging. J Clin Invest 123(3):951–957. doi: 10.1172/JCI64125 PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Nisoli E, Tonello C, Cardile A, Cozzi V, Bracale R, Tedesco L, Falcone S, Valerio A, Cantoni O, Clementi E, Moncada S, Carruba MO (2005) Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 310(5746):314–317. doi: 10.1126/science.1117728 PubMedCrossRefGoogle Scholar
  157. 157.
    Civitarese AE, Carling S, Heilbronn LK, Hulver MH, Ukropcova B, Deutsch WA, Smith SR, Ravussin E, Team CP (2007) Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med 4(3), e76. doi: 10.1371/journal.pmed.0040076 PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Guarente L (2008) Mitochondria – a nexus for aging, calorie restriction, and sirtuins? Cell 132(2):171–176. doi: 10.1016/j.cell.2008.01.007 PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Dillin A, Hsu AL, Arantes-Oliveira N, Lehrer-Graiwer J, Hsin H, Fraser AG, Kamath RS, Ahringer J, Kenyon C (2002) Rates of behavior and aging specified by mitochondrial function during development. Science 298(5602):2398–2401. doi: 10.1126/science.1077780 PubMedCrossRefGoogle Scholar
  160. 160.
    Yang W, Hekimi S (2010) A mitochondrial superoxide signal triggers increased longevity in C. elegans. PLoS Biol 8(12), e1000556. doi: 10.1371/journal.pbio.1000556 PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M (2007) Glucose restriction extends C. elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab 6(4):280–293. doi: 10.1016/j.cmet.2007.08.011 PubMedCrossRefGoogle Scholar
  162. 162.
    Liesa M, Shirihai OS (2013) Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab 17(4):491–506. doi: 10.1016/j.cmet.2013.03.002 PubMedCrossRefGoogle Scholar
  163. 163.
    Gao AW, Canto C, Houtkooper RH (2014) Mitochondrial response to nutrient availability and its role in metabolic disease. EMBO Mol Med 6(5):580–589. doi: 10.1002/emmm.201303782 PubMedPubMedCentralGoogle Scholar
  164. 164.
    Scheckhuber CQ, Erjavec N, Tinazli A, Hamann A, Nystrom T, Osiewacz HD (2007) Reducing mitochondrial fission results in increased life span and fitness of two fungal ageing models. Nat Cell Biol 9(1):99–105. doi: 10.1038/ncb1524 PubMedCrossRefGoogle Scholar
  165. 165.
    Scheckhuber CQ, Wanger RA, Mignat CA, Osiewacz HD (2011) Unopposed mitochondrial fission leads to severe lifespan shortening. Cell Cycle 10(18):3105–3110. doi: 10.4161/cc.10.18.17196 PubMedCrossRefGoogle Scholar
  166. 166.
    Bernhardt D, Muller M, Reichert AS, Osiewacz HD (2015) Simultaneous impairment of mitochondrial fission and fusion reduces mitophagy and shortens replicative lifespan. Sci Rep 5:7885. doi: 10.1038/srep07885 PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    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 (Dordr) 30(4):187–199. doi: 10.1007/s11357-008-9048-1 CrossRefGoogle Scholar
  168. 168.
    Check Hayden E (2015) Anti-ageing pill pushed as bona fide drug. Nature 522(7556):265–266. doi: 10.1038/522265a PubMedCrossRefGoogle Scholar
  169. 169.
    Chin RM, Fu X, Pai MY, Vergnes L, Hwang H, Deng G, Diep S, Lomenick B, Meli VS, Monsalve GC, Hu E, Whelan SA, Wang JX, Jung G, Solis GM, Fazlollahi F, Kaweeteerawat C, Quach A, Nili M, Krall AS, Godwin HA, Chang HR, Faull KF, Guo F, Jiang M, Trauger SA, Saghatelian A, Braas D, Christofk HR, Clarke CF, Teitell MA, Petrascheck M, Reue K, Jung ME, Frand AR, Huang J (2014) The metabolite alpha-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature 510(7505):397–401. doi: 10.1038/nature13264 PubMedPubMedCentralGoogle Scholar
  170. 170.
    Petrascheck M, Ye X, Buck LB (2007) An antidepressant that extends lifespan in adult C. elegans. Nature 450(7169):553–556. doi: 10.1038/nature05991 PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  1. 1.Department of Genetics and Complex DiseasesHarvard T.H. Chan School of Public HealthBostonUSA

Personalised recommendations