Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Programmed and altruistic ageing


Ageing is widely believed to be a non-adaptive process that results from a decline in the force of natural selection. However, recent studies in Saccharomyces cerevisiae are consistent with the existence of a programme of altruistic ageing and death. We suggest that the similarities between the molecular pathways that regulate ageing in yeast, worms, flies and mice, together with evidence that is consistent with programmed death in salmon and other organisms, raise the possibility that programmed ageing or death can also occur in higher eukaryotes.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Computational simulations of stochastic and programmed ageing in Saccharomyces cerevisiae.


  1. 1

    Finch, C. E. Longevity, Senescence, and the Genome (University Press, Chicago, 1990).

    Google Scholar 

  2. 2

    Martin, G. M., Austad, S. N. & Johnson, T. E. Genetic analysis of ageing: role of oxidative damage and environmental stresses. Nature Genet. 13, 25–34 (1996).

    CAS  Article  Google Scholar 

  3. 3

    Nemoto, S. & Finkel, T. Ageing and the mystery at Arles. Nature 429, 149–152 (2004).

    CAS  Article  Google Scholar 

  4. 4

    Austad, S. N. Is aging programmed? Aging Cell 3, 249–251 (2004).

    CAS  Article  Google Scholar 

  5. 5

    Longo, V. D. & Finch, C. E. Evolutionary medicine: from dwarf model systems to healthy centenarians. Science 299, 1342–1346 (2003).

    Article  Google Scholar 

  6. 6

    Kenyon, C. The plasticity of aging: insights from long-lived mutants. Cell 120, 449–460 (2005).

    CAS  Article  Google Scholar 

  7. 7

    Herker, E. et al. Chronological aging leads to apoptosis in yeast. J. Cell Biol. 164, 501–507 (2004).

    CAS  Article  Google Scholar 

  8. 8

    Fabrizio, P. et al. Superoxide is a mediator of an altruistic aging program in Saccharomyces cerevisiae. J. Cell Biol. 166, 1055–1067 (2004).

    CAS  Article  Google Scholar 

  9. 9

    Longo, V. D., Ellerby, L. M., Bredesen, D. E., Valentine, J. S. & Gralla, E. B. Human Bcl-2 reverses survival defects in yeast lacking superoxide dismutase and delays death of wild-type yeast. J. Cell Biol. 137, 1581–1588 (1997).

    CAS  Article  Google Scholar 

  10. 10

    Harman, D. A theory based on free radical and radiation chemistry. J. Gerontol. 11, 298–300 (1956).

    CAS  Article  Google Scholar 

  11. 11

    Balaban, R. S., Nemoto, S. & Finkel, T. Mitochondria, oxidants, and aging. Cell 120, 483–495 (2005).

    CAS  Article  Google Scholar 

  12. 12

    Weissmann, A. Essays upon Heredity and Kindred Biological Problems (Claderon, Oxford, 1889).

    Book  Google Scholar 

  13. 13

    Kirkwood, T. B. Understanding the odd science of aging. Cell 120, 437–447 (2005).

    CAS  Article  Google Scholar 

  14. 14

    Mitteldorf, J. Can experiments on caloric restriction be reconciled with the disposable soma theory for the evolution of senescence? Evolution Int. J. Org. Evolution 55, 1902–1905; discussion 1906 (2001).

    CAS  Article  Google Scholar 

  15. 15

    Shanley, D. P. & Kirkwood, T. B. Calorie restriction and aging: a life-history analysis. Evolution Int. J. Org. Evolution 54, 740–750 (2000).

    CAS  Article  Google Scholar 

  16. 16

    Walker, D. W., McColl, G., Jenkins, N. L., Harris, J. & Lithgow, G. J. Evolution of lifespan in C. elegans. Nature 405, 296–297 (2000).

    CAS  Article  Google Scholar 

  17. 17

    Jenkins, N. L., McColl, G. & Lithgow, G. J. Fitness cost of extended lifespan in Caenorhabditis elegans. Proc. Biol. Sci. 271, 2523–2526 (2004).

    Article  Google Scholar 

  18. 18

    Medawar, P. An Unsolved Problem in Biology (HK Lewis, London, 1952).

    Google Scholar 

  19. 19

    Shaw, F. H., Promislow, D. E., Tatar, M., Hughes, K. A. & Geyer, C. J. Toward reconciling inferences concerning genetic variation in senescence in Drosophila melanogaster. Genetics 152, 553–566 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Mair, W., Goymer, P., Pletcher, S. D. & Partridge, L. Demography of dietary restriction and death in Drosophila. Science 301, 1731–1733 (2003).

    CAS  Article  Google Scholar 

  21. 21

    Merry, B. J. Molecular mechanisms linking calorie restriction and longevity. Int. J. Biochem. Cell Biol. 34, 1340–1354 (2002).

    CAS  Article  Google Scholar 

  22. 22

    Partridge, L., Pletcher, S. D. & Mair, W. Dietary restriction, mortality trajectories, risk and damage. Mech. Ageing Dev. 126, 35–41 (2005).

    CAS  Article  Google Scholar 

  23. 23

    Sun, J. & Tower, J. FLP recombinase-mediated induction of Cu/Zn-superoxide dismutase transgene expression can extend the life span of adult Drosophila melanogaster flies. Mol. Cell. Biol. 19, 216–228 (1999).

    CAS  Article  Google Scholar 

  24. 24

    Sun, J., Folk, D., Bradley, T. J. & Tower, J. Induced overexpression of mitochondrial Mn-superoxide dismutase extends the life span of adult Drosophila melanogaster. Genetics 161, 661–72 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Fabrizio, P. et al. SOD2 functions downstream of Sch9 to extend longevity in yeast. Genetics 163, 35–46 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Fabrizio, P., Pozza, F., Pletcher, S. D., Gendron, C. M. & Longo, V. D. Regulation of longevity and stress resistance by Sch9 in yeast. Science 292, 288–290 (2001).

    CAS  Article  Google Scholar 

  27. 27

    Tatar, M. et al. A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292, 107–110 (2001).

    CAS  Article  Google Scholar 

  28. 28

    Gallagher, I. M., Jenner, P., Glover, V. & Clow, A. CuZn-superoxide dismutase transgenic mice: no effect on longevity, locomotor activity and 3H-mazindol and 3H-spiperone binding over 19 months. Neurosci. Lett. 289, 221–223 (2000).

    CAS  Article  Google Scholar 

  29. 29

    Schriner, S. E. et al. Extension of murine lifespan by overexpression of catalase targeted to mitochondria. Science 308, 1909–1911 (2005).

    CAS  Article  Google Scholar 

  30. 30

    Bredesen, D. E. The non-existent aging program: how does it work? Aging Cell 3, 255–259 (2004).

    CAS  Article  Google Scholar 

  31. 31

    Hamilton, W. D. The genetical evolution of social behaviour. J. Theor. Biol. 7, 1–16 (1964).

    CAS  Article  Google Scholar 

  32. 32

    Wilson, D. S. Human groups as units of selection. Science 276, 1816–1817 (1997).

    CAS  Article  Google Scholar 

  33. 33

    Wynne-Edwards, V. C. Animal Dispersion in Relation to Social Behaviour (Oliver & Boyd, Edinburgh, 1962).

    Google Scholar 

  34. 34

    Mitteldorf, J. in Proc. 9th Int. Conf. Simulation Synthesis Living Systems (MIT Press, Boston, 2004).

    Google Scholar 

  35. 35

    Skulachev, V. P. in Topics in Current Genetics Vol. 3 (eds Nystrom, T. & Osiewacz, H. D.) 191–238 (Springer, Heidelberg, 2003).

    Google Scholar 

  36. 36

    Jin, C. & Reed, J. C. Yeast and apoptosis. Nature Rev. Mol. Cell Biol. 3, 453–459 (2002).

    CAS  Article  Google Scholar 

  37. 37

    Ligr, M. et al. Mammalian Bax triggers apoptotic changes in yeast. FEBS Lett. 438, 61–65 (1998).

    CAS  Article  Google Scholar 

  38. 38

    Skulachev, V. P. Programmed death in yeast as adaptation? FEBS Lett. 528, 23–26 (2002).

    CAS  Article  Google Scholar 

  39. 39

    Frohlich, K. & Madeo, F. Apoptosis in yeast — a monocellular organism exhibits altruistic behaviour. FEBS Lett. 473, 6–9 (2000).

    CAS  Article  Google Scholar 

  40. 40

    Madeo, F. et al. Oxygen stress: a regulator of apoptosis in yeast. J. Cell Biol. 145, 757–767 (1999).

    CAS  Article  Google Scholar 

  41. 41

    Ludovico, P., Sousa, M. J., Silva, M. T., Leao, C. & Corte-Real, M. Saccharomyces cerevisiae commits to a programmed cell death process in response to acetic acid. Microbiology 147, 2409–2415 (2001).

    CAS  Article  Google Scholar 

  42. 42

    Madeo, F. et al. A caspase-related protease regulates apoptosis in yeast. Mol. Cell 9, 911–917 (2002).

    CAS  Article  Google Scholar 

  43. 43

    Narasimhan, M. L. et al. A plant defense response effector induces microbial apoptosis. Mol. Cell 8, 921–930 (2001).

    CAS  Article  Google Scholar 

  44. 44

    Severin, F. F. & Hyman, A. A. Pheromone induces programmed cell death in S. cerevisiae. Curr. Biol. 12, R233–R235 (2002).

    CAS  Article  Google Scholar 

  45. 45

    Pozniakovsky, A. I. et al. Role of mitochondria in the pheromone- and amiodarone-induced programmed death in yeast. J. Cell Biol. 168, 257–269 (2005).

    CAS  Article  Google Scholar 

  46. 46

    Longo, V. D. The Pro-Senescence Role of Ras2 in the Chronological Life Span of Yeast. Thesis, Univ. California (1997).

    Google Scholar 

  47. 47

    Lewis, K. Programmed death in bacteria. Microbiol. Mol. Biol. Rev. 64, 503–514 (2000).

    CAS  Article  Google Scholar 

  48. 48

    Fabrizio, P. & Longo, V. D. The chronological life span of Saccharomyces cerevisiae. Aging Cell 2, 73–81 (2003).

    CAS  Article  Google Scholar 

  49. 49

    Jazwinski, S. M. The genetics of aging in the yeast Saccharomyces cerevisiae. Genetica 91, 35–51 (1993).

    CAS  Article  Google Scholar 

  50. 50

    Zambrano, M. M., Siegele, D. A., Almiron, M., Tormo, A. & Kolter, R. Microbial competition: Escherichia coli mutants that take over stationary phase cultures. Science 259, 1757–1760 (1993).

    CAS  Article  Google Scholar 

  51. 51

    Mitteldorf, J. Aging selected for its own sake. Evol. Ecol. Res. 6, 1–17 (2004).

    Google Scholar 

  52. 52

    Kirkwood, T. B. & Cremer, T. Cytogerontology since 1881: a reappraisal of August Weismann and a review of modern progress. Hum. Genet. 60, 101–121 (1982).

    CAS  Article  Google Scholar 

  53. 53

    Wodinsky, J. Hormonal inhibition of feeding and death in octopus: control by optic gland secretion. Science 198, 948–951 (1977).

    CAS  Article  Google Scholar 

  54. 54

    Robertson, O. H. & Wexler, B. C. Histological changes in the organs and tissues of senile castrated kokanee salmon (Oncorhynchus nerka kennerlyi). Gen. Comp. Endocrinol. 2, 458–472 (1962).

    CAS  Article  Google Scholar 

  55. 55

    Zyuganov, V. V. Long-lived parasite prolonging life of his host. Dokl. Acad. Nauk (in the press).

  56. 56

    Loison, A., Festa-Bianchet, M., Gaillard, J. M., Jorgenson, J. T. & Jullien, J. M. Age-specific survival in five populations of ungulates: evidence of senescence. Ecology 80, 2539–2554 (1999).

    Article  Google Scholar 

  57. 57

    Darwin, C. The Descent of Man (John Murray, London, 1871).

    Google Scholar 

  58. 58

    Friedman, D. B. & Johnson, T. E. A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics 118, 75–86 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Kenyon, C., Chang, J., Gensch, E., Rudner, A. & Tabtiang, R. A C. elegans mutant that lives twice as long as wild type. Nature 366, 461–464 (1993).

    CAS  Article  Google Scholar 

  60. 60

    Morris, J. Z., Tissenbaum, H. A. & Ruvkun, G. A phospatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 382, 536–539 (1996).

    CAS  Article  Google Scholar 

  61. 61

    Longo, V. D., Gralla, E. B. & Valentine, J. S. Superoxide dismutase activity is essential for stationary phase survival in Saccharomyces cerevisiae. Mitochondrial production of toxic oxygen species in vivo. J. Biol. Chem. 271, 12275–12280 (1996).

    CAS  Article  Google Scholar 

  62. 62

    Lin, K., Dorman, J. B., Rodan, A. & Kenyon, C. daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science 278, 1319–1322 (1997).

    CAS  Article  Google Scholar 

  63. 63

    Longo, V. D. & Fabrizio, P. Regulation of longevity and stress resistance: a molecular strategy conserved from yeast to humans? Cell. Mol. Life Sci. 59, 903–908 (2002).

    CAS  Article  Google Scholar 

  64. 64

    Brown-Borg, H. M., Borg, K. E., Meliska, C. J. & Bartke, A. Dwarf mice and the ageing process. Nature 384, 33 (1996).

    CAS  Article  Google Scholar 

  65. 65

    Flurkey, K., Papaconstantinou, J. & Harrison, D. E. The Snell dwarf mutation Pit1dw can increase life span in mice. Mech. Ageing Dev. 123, 121–30. (2002).

    CAS  Article  Google Scholar 

  66. 66

    Holzenberger, M. et al. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182–187 (2003).

    CAS  Article  Google Scholar 

  67. 67

    Coschigano, K. T., Clemmons, D., Bellush, L. L. & Kopchick, J. J. Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. Endocrinology 141, 2608–2613 (2000).

    CAS  Article  Google Scholar 

  68. 68

    Brown-Borg, H. M. & Rakoczy, S. G. Catalase expression in delayed and premature aging mouse models. Exp. Gerontol. 35, 199–212 (2000).

    CAS  Article  Google Scholar 

  69. 69

    Brown-Borg, H. M., Rakoczy, S. G., Romanick, M. A. & Kennedy, M. A. Effects of growth hormone and insulin-like growth factor-1 on hepatocyte antioxidative enzymes. Exp. Biol. Med. 227, 94–104 (2002).

    CAS  Article  Google Scholar 

  70. 70

    Sharma, H. S., Nyberg, F., Gordh, T., Alm, P. & Westman, J. Neurotrophic factors influence upregulation of constitutive isoform of heme oxygenase and cellular stress response in the spinal cord following trauma. An experimental study using immunohistochemistry in the rat. Amino Acids 19, 351–361 (2000).

    CAS  Article  Google Scholar 

  71. 71

    Williams, G. C. Pleiotropy, natural selection, and the evolution of senescence. Evolution 11, 398–411 (1957).

    Article  Google Scholar 

  72. 72

    Maynard Smith, J. Group selection and kin selection. Nature 201, 1145–1147 (1964).

    Article  Google Scholar 

  73. 73

    Shanahan, T. The troubled past and uncertain future of group selectionism. Endeavour 22, 57–60 (1998).

    Article  Google Scholar 

Download references


We thank C. E. Finch for careful review of the manuscript and helpful suggestions.

Author information



Corresponding author

Correspondence to Valter D. Longo.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links


Entrez Gene





Rights and permissions

Reprints and Permissions

About this article

Cite this article

Longo, V., Mitteldorf, J. & Skulachev, V. Programmed and altruistic ageing. Nat Rev Genet 6, 866–872 (2005).

Download citation

Further reading


Quick links