Skip to main content

Dietary Restriction in C. elegans

  • 2074 Accesses

Part of the Healthy Ageing and Longevity book series (HAL)

Abstract

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.

Keywords

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

This is a preview of subscription content, access via your institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-3-319-44703-2_16
  • Chapter length: 37 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   109.00
Price excludes VAT (USA)
  • ISBN: 978-3-319-44703-2
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Softcover Book
USD   149.99
Price excludes VAT (USA)
Hardcover Book
USD   219.99
Price excludes VAT (USA)
Fig. 16.1
Fig. 16.2

References

  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

    CrossRef  Google Scholar 

  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

    PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  4. Weindruch R, Walford RL (1988) The retardation of aging and disease by dietary restriction. C.C. Thomas, Springfield

    Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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):63–79

    CAS  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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/j.tips.2009.11.004

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  10. Speakman JR, Mitchell SE (2011) Caloric restriction. Mol Asp Med 32(3):159–221. doi:10.1016/j.mam.2011.07.001

    CAS  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    PubMed  CrossRef  Google Scholar 

  13. Klass MR (1977) Aging in the nematode C. elegans: major biological and environmental factors influencing life span. Mech Ageing Dev 6(6):413–429

    CAS  PubMed  CrossRef  Google Scholar 

  14. Kenyon CJ (2010) The genetics of ageing. Nature 464(7288):504–512. doi:10.1038/nature08980

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    PubMed  CrossRef  Google Scholar 

  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):242–252

    PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  24. Avery L (1993) The genetics of feeding in C. elegans. Genetics 133(4):897–917

    CAS  PubMed  PubMed Central  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  27. Jia K, Levine B (2007) Autophagy is required for dietary restriction-mediated life span extension in C. elegans. Autophagy 3(6):597–599

    PubMed  CrossRef  Google Scholar 

  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

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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. Lu NC, Goetsch KM (1993) Carbohydrate requirement of C. elegans and the final development of a chemically defined medium. Nematologica 39:303–311

    CrossRef  Google Scholar 

  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

    PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  56. Johnson TE (1990) Increased life-span of age-1 mutants in C. elegans and lower Gompertz rate of aging. Science 249(4971):908–912

    CAS  PubMed  CrossRef  Google Scholar 

  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):1975–1980

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    PubMed  PubMed Central  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  77. Burkewitz K, Zhang Y, Mair WB (2014) AMPK at the nexus of energetics and aging. Cell Metab 20(1):10–25

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    PubMed  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  100. Rubinsztein DC, Marino G, Kroemer G (2011) Autophagy and aging. Cell 146(5):682–695. doi:10.1016/j.cell.2011.07.030

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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. 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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  125. Vella MC, Slack FJ (2005) C. elegans microRNAs. WormBook, pp 1–9. doi:10.1895/wormbook.1.26.1

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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):843–854

    CAS  PubMed  CrossRef  Google Scholar 

  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):855–862

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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):1359–1369

    PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  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

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  155. Bratic A, Larsson NG (2013) The role of mitochondria in aging. J Clin Invest 123(3):951–957. doi:10.1172/JCI64125

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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

    CAS  CrossRef  Google Scholar 

  168. Check Hayden E (2015) Anti-ageing pill pushed as bona fide drug. Nature 522(7556):265–266. doi:10.1038/522265a

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  PubMed Central  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to William B. Mair .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and Permissions

Copyright information

© 2017 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Zhang, Y., Mair, W.B. (2017). Dietary Restriction in C. elegans . In: Olsen, A., Gill, M. (eds) Ageing: Lessons from C. elegans. Healthy Ageing and Longevity. Springer, Cham. https://doi.org/10.1007/978-3-319-44703-2_16

Download citation