Advertisement

AGE

, Volume 38, Issue 5–6, pp 419–431 | Cite as

Age-associated vulval integrity is an important marker of nematode healthspan

  • Scott F. Leiser
  • Gholamali Jafari
  • Melissa Primitivo
  • George L. Sutphin
  • Jingyi Dong
  • Alison Leonard
  • Marissa Fletcher
  • Matt Kaeberlein
Original Article

Abstract

Improving healthspan, defined as the period where organisms live without frailty and/or disease, is a major goal of biomedical research. While healthspan measures in people are relatively easy to identify, developing robust markers of healthspan in model organisms has proven challenging. Studies using the nematode Caenorhabditis elegans have provided vital information on the basic mechanisms of aging; however, worm health is difficult to define, and the impact of interventions that increase lifespan on worm healthspan has been controversial. Here, we describe a marker of population healthspan in C. elegans that we term age-associated vulval integrity defects, or Avid, frequently described elsewhere as rupture or exploding. We connect the presence of this phenotype with temperature, reproduction, diet, and longevity. Our results show that Avid occurs in post-reproductive worms under common laboratory conditions at a frequency that correlates negatively with temperature; Avid is rare in worms kept at 25 °C and more frequent in worms kept at 15 °C. We describe the kinetics of Avid, link the phenotype to oocyte production, and describe how Avid involves the ejection of worm proteins and/or internal organ(s) from the vulva. Finally, we find that Avid is preventable by removing worms from food, suggesting that Avid results from the intake, digestion, and/or absorption of food. Our results show that Avid is a significant cause of death in worm populations maintained under laboratory conditions and that its prevention often correlates with worm longevity. We propose that Avid is a powerful marker of worm healthspan whose underlying molecular mechanisms may be conserved.

Keywords

C. elegans Healthspan Temperature Rupture Longevity Reproduction 

Notes

Acknowledgments

Strains were provided by the Caenorhabditis Genetics Center. This work was supported by NIH grant R01AG038518 to MK and NIH grant K99AG045200 to SFL. SFL was supported by NIH Training Grant T32AG000057. SFL was also supported by an AFAR post-doctoral fellowship. Additional support was provided by the UW Healthy Aging and Longevity Research Institute, the UW Nathan Shock Center of Excellence in the Basic Biology of Aging (NIH grant P30AG013280), and an award to MK from the M. J. Murdock Charitable Trust.

Compliance with Ethical Standards

Authors’ contributions

SFL, GJ, and MK designed the experiments. SFL, GJ, MP, GLS, JD, AL, and MF performed the experiments. SFL, GJ, and MK analyzed the experiments. SFL, GJ, and MK wrote the paper.

Supplementary material

11357_2016_9936_MOESM1_ESM.pdf (41 kb)
Table S1 (PDF 40 kb)
11357_2016_9936_MOESM2_ESM.pdf (110 kb)
Table S2 (PDF 110 kb)
11357_2016_9936_MOESM3_ESM.pdf (60 kb)
Table S3 (PDF 59 kb)
11357_2016_9936_MOESM4_ESM.pdf (52 kb)
Table S4 (PDF 52 kb)
11357_2016_9936_MOESM5_ESM.pdf (306 kb)
Fig. S1 (PDF 305 kb)
11357_2016_9936_MOESM6_ESM.pdf (49 kb)
Fig. S2 (PDF 49 kb)

References

  1. Bansal A, Zhu LJ, Yen K, Tissenbaum HA (2015) Uncoupling lifespan and healthspan in Caenorhabditis elegans longevity mutants. Proc Natl Acad Sci U S A 112:E277–286CrossRefPubMedPubMedCentralGoogle Scholar
  2. Barton MK, Schedl TB, Kimble J (1987) Gain-of-function mutations of fem-3, a sex-determination gene in Caenorhabditis elegans. Genetics 115:107–119PubMedPubMedCentralGoogle Scholar
  3. Beanan MJ, Strome S (1992) Characterization of a germ-line proliferation mutation in C. elegans. Development 116:755–766PubMedGoogle Scholar
  4. Berman JR, Kenyon C (2006) Germ-cell loss extends C. elegans life span through regulation of DAF-16 by kri-1 and lipophilic-hormone signaling. Cell 124:1055–1068CrossRefPubMedGoogle Scholar
  5. Bishop NA, Guarente L (2007) Two neurons mediate diet-restriction-induced longevity in C. elegans. Nature 447:545–549CrossRefPubMedGoogle Scholar
  6. Blagosklonny MV (2012) Answering the ultimate question “what is the proximal cause of aging?”. Aging (Albany NY) 4:861–877CrossRefGoogle Scholar
  7. Blagosklonny MV (2013) Aging is not programmed: genetic pseudo-program is a shadow of developmental growth. Cell Cycle 12:3736–3742CrossRefPubMedPubMedCentralGoogle Scholar
  8. Burch JB, Augustine AD, Frieden LA, Hadley E, Howcroft TK, Johnson R, Khalsa PS, Kohanski RA, Li XL, Macchiarini F, Niederehe G, Oh YS, Pawlyk AC, Rodriguez H, Rowland JH, Shen GL, Sierra F, Wise BC (2014) Advances in geroscience: impact on healthspan and chronic disease. J Gerontol A Biol Sci Med Sci 69(Suppl 1):S1–3CrossRefPubMedPubMedCentralGoogle Scholar
  9. Chen D, Thomas EL, Kapahi P (2009) HIF-1 modulates dietary restriction-mediated lifespan extension via IRE-1 in Caenorhabditis elegans. PLoS Genet 5:e1000486CrossRefPubMedPubMedCentralGoogle Scholar
  10. Chen J, Caswell-Chen EP (2004) Facultative Vivipary is a Life-History Trait in Caenorhabditis elegans. J Nematol 36:107–113PubMedPubMedCentralGoogle Scholar
  11. Coburn C, Allman E, Mahanti P, Benedetto A, Cabreiro F, Pincus Z, Matthijssens F, Araiz C, Mandel A, Vlachos M, Edwards SA, Fischer G, Davidson A, Pryor RE, Stevens A, Slack FJ, Tavernarakis N, Braeckman BP, Schroeder FC, Nehrke K, Gems D (2013) Anthranilate fluorescence marks a calcium-propagated necrotic wave that promotes organismal death in C. elegans. PLoS Biol 11:e1001613CrossRefPubMedPubMedCentralGoogle Scholar
  12. Corsi AK, Wightman B, Chalfie M (2015) A Transparent Window into Biology: A Primer on Caenorhabditis elegans. Genetics 200:387–407CrossRefPubMedPubMedCentralGoogle Scholar
  13. Depuydt G, Xie F, Petyuk VA, Shanmugam N, Smolders A, Dhondt I, Brewer HM, Camp DG, Smith RD, Braeckman BP (2013) Reduced insulin/insulin-like growth factor-1 signaling and dietary restriction inhibit translation but preserve muscle mass in Caenorhabditis elegans. Mol Cell Proteomics 12:3624–3639CrossRefPubMedPubMedCentralGoogle Scholar
  14. Friedman DB, Johnson TE (1988) A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics 118:75–86PubMedPubMedCentralGoogle Scholar
  15. Félix MA, Duveau F (2012) Population dynamics and habitat sharing of natural populations of Caenorhabditis elegans and C. briggsae. BMC Biol 10:59CrossRefPubMedPubMedCentralGoogle Scholar
  16. Garigan D, Hsu AL, Fraser AG, Kamath RS, Ahringer J, Kenyon C (2002) Genetic analysis of tissue aging in Caenorhabditis elegans: a role for heat-shock factor and bacterial proliferation. Genetics 161:1101–1112PubMedPubMedCentralGoogle Scholar
  17. Gems D, Partridge L (2013) Genetics of longevity in model organisms: debates and paradigm shifts. Annu Rev Physiol 75:621–644CrossRefPubMedGoogle Scholar
  18. 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 17:1646–1656CrossRefPubMedPubMedCentralGoogle Scholar
  19. Hamilton B, Dong Y, Shindo M, Liu W, Odell I, Ruvkun G, Lee SS (2005) A systematic RNAi screen for longevity genes in C. elegans. Genes Dev 19:1544–1555CrossRefPubMedPubMedCentralGoogle Scholar
  20. Hansen M, Taubert S, Crawford D, Libina N, Lee SJ, Kenyon C (2007) Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell 6:95–110CrossRefPubMedGoogle Scholar
  21. Herndon LA, Schmeissner PJ, Dudaronek JM, Brown PA, Listner KM, Sakano Y, Paupard MC, Hall DH, Driscoll M (2002) Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans. Nature 419:808–814CrossRefPubMedGoogle Scholar
  22. Hodgkin J (1986) Sex determination in the nematode C. elegans: analysis of tra-3 suppressors and characterization of fem genes. Genetics 114:15–52PubMedPubMedCentralGoogle Scholar
  23. Huang C, Xiong C, Kornfeld K (2004) Measurements of age-related changes of physiological processes that predict lifespan of Caenorhabditis elegans. Proc Natl Acad Sci U S A 101:8084–8089CrossRefPubMedPubMedCentralGoogle Scholar
  24. Johnson TE, Cypser J, de Castro E, de Castro S, Henderson S, Murakami S, Rikke B, Tedesco P, Link C (2000) Gerontogenes mediate health and longevity in nematodes through increasing resistance to environmental toxins and stressors. Exp Gerontol 35:687–694CrossRefPubMedGoogle Scholar
  25. Kaeberlein TL, Smith ED, Tsuchiya M, Welton KL, Thomas JH, Fields S, Kennedy BK, Kaeberlein M (2006) Lifespan extension in Caenorhabditis elegans by complete removal of food. Aging Cell 5:487–494CrossRefPubMedGoogle Scholar
  26. Kamath RS, Fraser AG, Dong Y, Poulin G, Durbin R, Gotta M, Kanapin A, Le Bot N, Moreno S, Sohrmann M, Welchman DP, Zipperlen P, Ahringer J (2003) Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 421:231–237CrossRefPubMedGoogle Scholar
  27. Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R (1993) A C. elegans mutant that lives twice as long as wild type. Nature 366:461–464CrossRefPubMedGoogle Scholar
  28. Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G (1997) daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277:942–946CrossRefPubMedGoogle Scholar
  29. Kirkland JL, Peterson C (2009) Healthspan, translation, and new outcomes for animal studies of aging. J Gerontol A Biol Sci Med Sci 64:209–212CrossRefPubMedGoogle Scholar
  30. Klass M (1983) A method for the isolation of longevity mutants in the nematode Caenorhabditis elegans and initial results. Mech Ageing Dev 22:279CrossRefPubMedGoogle Scholar
  31. Klass MR (1977) Aging in the nematode Caenorhabditis elegans: major biological and environmental factors influencing life span. Mech Ageing Dev 6:413–429CrossRefPubMedGoogle Scholar
  32. Lee SS, Lee RY, Fraser AG, Kamath RS, Ahringer J, Ruvkun G (2003) A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nat Genet 33:40–48CrossRefPubMedGoogle Scholar
  33. Leiser SF, Begun A, Kaeberlein M (2011) HIF-1 modulates longevity and healthspan in a temperature-dependent manner. Aging Cell 10:318–326CrossRefPubMedPubMedCentralGoogle Scholar
  34. 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):1375–1378Google Scholar
  35. Machin SE, Mukhopadhyay S (2011) Pelvic organ prolapse: review of the aetiology, presentation, diagnosis and management. Menopause Int 17:132–136PubMedGoogle Scholar
  36. Martin GM, Bergman A, Barzilai N (2007) Genetic determinants of human health span and life span: progress and new opportunities. PLoS Genet 3:e125CrossRefPubMedPubMedCentralGoogle Scholar
  37. McGee MD, Weber D, Day N, Vitelli C, Crippen D, Herndon LA, Hall DH, Melov S (2011) Loss of intestinal nuclei and intestinal integrity in aging C. elegans. Aging Cell 10:699–710CrossRefPubMedPubMedCentralGoogle Scholar
  38. 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 324:1196–1198CrossRefPubMedPubMedCentralGoogle Scholar
  39. Nadarajan S, Govindan JA, McGovern M, Hubbard EJ, Greenstein D (2009) MSP and GLP-1/Notch signaling coordinately regulate actomyosin-dependent cytoplasmic streaming and oocyte growth in C. elegans. Development 136:2223–2234CrossRefPubMedPubMedCentralGoogle Scholar
  40. Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA, Ruvkun G (1997) The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389:994–999CrossRefPubMedGoogle Scholar
  41. Petrascheck M, Ye X, Buck LB (2009) A high-throughput screen for chemicals that increase the lifespan of Caenorhabditis elegans. Ann N Y Acad Sci 1170:698–701CrossRefPubMedGoogle Scholar
  42. Rompay LV, Borghgraef C, Beets I, Caers J, Temmerman L (2015) New genetic regulators question relevance of abundant yolk protein production in C. elegans. Sci Rep 5:16381CrossRefPubMedPubMedCentralGoogle Scholar
  43. Schneider CA, Rasband WS, Eliceiri KW (2012) NIH Image to ImageJ: 25 years of image analysis. Nat Methods 9:671–675CrossRefPubMedGoogle Scholar
  44. Seidell JC, Björntorp P, Sjöström L, Kvist H, Sannerstedt R (1990) Visceral fat accumulation in men is positively associated with insulin, glucose, and C-peptide levels, but negatively with testosterone levels. Metabolism 39:897–901CrossRefPubMedGoogle Scholar
  45. Steinbaugh MJ, Narasimhan SD, Robida-Stubbs S, Moronetti Mazzeo LE, Dreyfuss JM, Hourihan JM, Raghavan P, Operaña TN, Esmaillie R, Blackwell TK (2015) Lipid-mediated regulation of SKN-1/Nrf in response to germ cell absence. Elife 4:e07836CrossRefPubMedCentralGoogle Scholar
  46. Sutphin GL, Kaeberlein M (2008) Dietary restriction by bacterial deprivation increases life span in wild-derived nematodes. Exp Gerontol 43:130–135CrossRefPubMedGoogle Scholar
  47. Sutphin GL, Kaeberlein M (2009) Measuring Caenorhabditis elegans life span on solid media. J Vis Exp 12(27):1152. doi: 10.3791/1152
  48. Sutphin GL, Bishop E, Yanos ME, Moller RM, Kaeberlein M (2012) Caffeine extends life span, improves healthspan, and delays age-associated pathology in Caenorhabditis elegans. Longev Healthspan 1:9CrossRefPubMedPubMedCentralGoogle Scholar
  49. TeKippe M, Aballay A (2010) C. elegans germline-deficient mutants respond to pathogen infection using shared and distinct mechanisms. PLoS One 5:e11777CrossRefPubMedPubMedCentralGoogle Scholar
  50. Zhang Y, Shao Z, Zhai Z, Shen C, Powell-Coffman JA (2009) The HIF-1 hypoxia-inducible factor modulates lifespan in C. elegans. PLoS One 4:e6348CrossRefPubMedPubMedCentralGoogle Scholar
  51. Zhang B, Xiao R, Ronan EA, He Y, Hsu AL, Liu J, Xu XZ (2015) Environmental Temperature Differentially Modulates C. elegans Longevity through a Thermosensitive TRP Channel. Cell Rep 11:1414–1424CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© American Aging Association 2016

Authors and Affiliations

  • Scott F. Leiser
    • 1
  • Gholamali Jafari
    • 1
  • Melissa Primitivo
    • 1
  • George L. Sutphin
    • 1
  • Jingyi Dong
    • 1
  • Alison Leonard
    • 1
  • Marissa Fletcher
    • 1
  • Matt Kaeberlein
    • 1
  1. 1.Department of PathologyUniversity of WashingtonSeattleUSA

Personalised recommendations