Phenoptosis and the Evolution of Ageing


Phenoptosis describes ageing as the evolved product of a genome‐based program to limit lifespan and thereby favour evolution. Previously, programmed ageing was deemed incompatible with Darwinian dogma that population evolution depends upon genetic diversity resulting from selection of traits that provide individual benefit. To avoid this conflict, phenoptosis employs evolvability, an alternative theory of evolution through which biological systems can acquire novel functions that enhance population evolution without individual benefit. This article analyses the claim that ‘programmed’ ageing evolved de novo, specifically to limit lifespan exclusively under the cloak of evolvability, and if certain assumptions in phenoptosis theory are valid. A brief historic perspective of its origins will be followed by considerations of ‘when’, ‘why’ and ‘how’ it evolved. An alternative ‘programmatic’ theory that presents a mechanism for the coincidental evolution of ageing with the developmental program will be compared and contrasted with phenoptosis.

Key Concepts

  • Individual benefit is incompatible with phenoptosis (programmed ageing) theory, but compatible with development/ageing continuum (programmatic ageing) theory.
  • Immortal/nonageing animals preceded the evolution of phenoptosis.
  • Phenoptosis relies exclusively upon ‘evolvability’ to explain the evolution of ageing, yet ageing promotes ‘evolvability’ thereafter.
  • In nonsenescing populations (presumably existing before phenoptosis), evolution would be stifled by low adult death rate.
  • Natural selection in immortal populations causes unchecked birth rates, overpopulation and subsequent extinctions. Phenoptosis then emerges as an adaptation.
  • Phenoptosis evolved by the process of ‘supra‐individual’ selection.
  • Selection for ecological homeostasis counterbalances selection for expanding individual reproductive fitness and keeps growth rates in check.
  • Scheduled death increases individual turnover, provides more chances for evolution of diverse genotypes and thereby, increases evolvability.
  • Programmatic ageing is a product of coincidental evolution resulting from post‐maturational decay of the developmental program and of second‐order selection for population benefit.
  • Ageing is initiated and accelerated by progressive loss of temporal organisation within the whole organism, not by any individual or few factors affecting single metabolic or physiologic functions.

Keywords: phenoptosis; programmed ageing; evolvability; development‐ageing continuum; programmatic ageing; coincidental evolution; second‐order selection; circadian rhythms; temporal order; homeodynamics

Figure 1. Structure of the circadian system. The retina captures photic information and transmits signals to the hypothalamic suprachiasmatic nucleus (SCN) which serves as the circadian coordinating center. It integrates light/dark cycles and nutrient cues from the environment, then relays appropriate signals to peripheral clocks. Cross talk between extrinsic signals and the clock network leads to oscillation of metabolites, ROS, hormones, etc. which taken together constitute individual “body time” and establish overall physiological homeodynamics of throughout life. Desynchronization and decay of the clock network initiates and exacerbates aging over time, ultimately causing intrinsic disease and death. Source:‐mechanisms‐of‐the‐aging‐process‐and‐rejuvenation/circadian‐clock‐gene‐regulation‐in‐aging‐and‐drug‐discovery. Licensed under CC by 3.0.
Figure 2. Examples of circadian rhythms in older adults relative to rhythms in younger adults. In the 24‐h cycle, documented changes include rhythms of waking activity; core body temperature; SCN firing; release of hormones; and fasting plasma glucose levels. In older adults, amplitude of many rhythms dampen and in some cases, the peak of the rhythm also advances. Reproduced with permission from Hood and Amir . © American Society for Clinical Investigation.
Figure 3. Hallmark processes of aging. This diagram summarizes the hallmark processes that are typically affected by dysregulation of integrated circadian rhythms during aging. Source: Licensed under CC by 4.0.
Figure 4. Decay of the circadian system begins and accelerates at the end of development as part of the aging process. Upon completion of development when stringent regulation of homeodynamics ends, there is a progressive loss of temporal order that is expressed initially as loss of vitality then accelerates through progressively waning physical performance to intrinsic diseases and ultimately to death. Reproduced with permission from Tevy et al. . © Elsevier.


Adiba S, Nizak C, et al. (2010) From grazing resistance to pathogenesis: the coincidental evolution of virulence factors. PLoS ONE 5 (8).

Barton N and Partridge L (2000) Limits to natural selection. BioEssays 22: 1075–1084.

Blagosklonny MV (2006) Aging and immortality: quasi‐programmed senescence and its pharmacologic inhibition. Cell Cycle 5: 2087–2102.

Bourke AFG (2007) Kin selection and the evolutionary theory of aging. Annual Review of Ecology, Evolution, and Systematics 38: 103–128.

Budovskaya YV, Wu K, Southworth LK, et al. (2008) An elt‐3/elt‐5/elt‐6 transcription circuit guides aging in C. elegans. Cell 134: 291–303.

Carnes BA, Olshansky SJ and Grahn D (2003) Biological evidence for limits to the duration of life. Biogerontology 4: 31–45.

De Magalhaes JP and Church GM (2005) Genomes optimize reproduction: aging as a consequence of the developmental program. Physiology 20: 252–259.

De Magalhaes JP, Costa J, et al. (2007) An analysis of the relationship between metabolism, developmental schedules, and longevity using phylogenetic independent contrasts. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 62A: 149–160.

De Magalhaes JP (2012) Programmatic features of aging originating in development: aging mechanisms beyond molecular damage? The FASEB Journal 26: 4821–4826.

Goldsmith TC (2004) Aging as an evolved characteristic –Weismann's theory reconsidered. Medical Hypotheses 62: 304–308.

Goldsmith TC (2008) Aging, evolvability, and the individual benefit requirement; medical implications of aging theory controversies. Journal of Theoretical Biology 252: 764–768.

Goldsmith T (2014) The Evolution of Aging, 3rd edn. Chapt 7, Crownsville, MD: Azinet Press ISBN: 0978879856.

Goldsmith TC (2016) Evolution of aging theories: why modern programmed aging concepts are transforming medical research. Biochemistry (Moscow) 81 (12): 1406–1412.

Goldsmith T (2017) Evolvability, population benefit, and the evolution of programmed aging in mammals. Biochemistry (Moscow) 82 (12): 1423–1429.

Gould S and Lewontin R (1979) The spandrels of San Marco and the Panglossian paradigm: a critique of the adaptationist programme. Proceedings of the Royal Society of London, Series B: Biological Sciences 205: 581–598.

Halberg F (1963) Circadian (about twenty‐four‐hour) rhythms in experimental medicine. Journal of the Royal Society of Medicine 56 (4): 253–257.

Hofman MA (2000) The human circadian clock and aging. Chronobiology International 17 (3): 245–259.

Holliday R (2006) Aging is no longer an unsolved problem in biology. Annals of the New York Academy of Sciences 1067: 1–9.

Holliday R and Rattan SIS (2010) Longevity mutants do not establish any ‘new science’ of ageing. Biogerontology 11: 507–511.

Hood S and Amir S (2017) The aging clock: circadian rhythms and later life. The Journal of Clinical Investigation 127 (2): 437–446.

Kaloulis K, Chera S, Hassel M, et al. (2004) Reactivation of developmental programs: the cAMP‐response element‐binding protein pathway is involved in hydra head regeneration. PNAS 101 (8): 2363–2368.

Kim S (2008) What is the developmental drift theory? In: Sage Crossroads.53: Evolution of Aging.

Kirkwood TB and Melov S (2011) On the programmed/non‐programmed nature of ageing within the life history. Current Biology 21: R701–R707.

Lansing AI (1947) A transmissible cumulative, and reversible factor in aging. Journal of Gerontology 2: 228–239.

Levin B and Svanborg Edén C (1990) Selection and evolution of virulence in bacteria: an ecumenical excursion and modest suggestion. Parasitology (London Print) 100: 103–115.

Lloyd D, Aon MA and Cortassa S (2001) Why homeodynamics, not homeostasis? ScientificWorldJournal 4 (1): 133–145.

Libertini G (1988) An adaptive theory of increasing mortality with increasing chronological age in populations in the wild. Journal of Theoretical Biology 132 (2): 145–162.

Libertini G (2008) Empirical evidence for various evolutionary hypotheses on species demonstrating increasing mortality with increasing chronological age in the wild. Scientific World Journal 8: 182–93.

Libertini G (2012) Classification of phenoptotic phenomena. Biochemistry (Moscow) 77: 707–715.

Libertini G (2013) Evidence for aging theories from the study of a hunter–gatherer people (Ache of Paraguay). Biochemistry (Moscow) 78: 1023–1032.

Libertini G (2014) The concept of phenoptosis and its usefulness for controlling aging. Current Aging Science 7: 1–6.

Libertini G (2015) Non‐programmed versus programmed aging paradigm. Current Aging Science 8: 56–68.

Libertini G, Rengo G, Ferrara N (2017) Aging and aging theories. Journal of Genetics and Genomics 65: 59–77.

Materna SC and Davidson EH (2007) Logic of gene regulatory networks. Current Opinion in Biotechnology 18: 351–354.

Mitteldorf J (2006) Chaotic population dynamics and the evolution of aging. Evolutionary Ecology Research 8: 561–574.

Mitteldorf J and Pepper J (2007) How can evolutionary theory accommodate recent empirical results on organismal senescence? Theory in Biosciences 126: 3–8.

Mitteldorf JJ (2012) Adaptive aging in the context of evolutionary theory. Biochemistry (Moscow) 77 (7): 716–725.

Mitteldorf JJ and Goodnight C (2013) Post‐reproductive life span and demographic stability. Biochemistry (Moscow) 78 (9): 1013–1022.

Mitteldorf J and Martins ACR (2014) Programmed life span in the context of evolvability. The American Naturalist 184 (3): 289–302.

Mitteldorf J (2016) An epigenetic clock controls aging. Biogerontology 17 (1): 257–65.

Olshansky SJ, Hayflick L and Carnes BA (2002) Position statement on human aging. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 57: B292–B297.

Pincus A and Slack FJ (2008) Transcriptional (dys)regulation and aging in Caenorhabditis elegans. Genome Biology 9: 233–235.

Rattan SIS (2007) Homeostasis, homeodynamics, and aging. In: Birren J (ed.) Encyclopedia of Gerontology, 2nd edn, pp. 696–699. UK: Elsevier Inc.

Rattan SIS (2008) Increased molecular damage and heterogeneity as the basis of aging. Biological Chemistry 389: 267–272.

Rattan SIS (2014) Molecular gerontology: from homeodynamics to hormesis. Current Pharmaceutical Design 20: 3036–3039.

Samis HV (1968) Aging: the loss of temporal organization. Perspectives in Biology and Medicine 12: 95–102.

Schaiblea R, Scheuerleina A, Dańko MJ, et al. (2015) Constant mortality and fertility over age in Hydra. PNAS 112 (51): 15701–15706.

Singer MA (2015) Is aging an evolved developmental program? Healthy Aging Research 4: 6.

Skulachev VP (1997) Aging is a specific biological function rather than the result of a disorder in complex living systems: biochemical evidence in support of Weismann's hypothesis. Biochemistry (Moscow) 62 (11): 1191–1195.

Skulachev VP (1999) Phenoptosis: programmed death of an organism. Biochemistry (Moscow) 64: 1418–1426.

Skulachev VP (2002) The programmed death phenomena, aging, and the Samurai law of biology. Annals of the New York Academy of Sciences 959: 214–37.

Skulachev MV and Skulachev VP (2014) New data on programmed aging: slow phenoptosis. Biochemistry (Moscow) 79: 977–993.

Skulachev MV and Skulachev PV (2017) Programmed aging of mammals: proof of concept and prospects of biochemical approaches for anti‐aging therapy. Biochemistry (Moscow) 82 (12): 1403–1422.

Somel M, Guo S, Fu N, et al. (2010) MicroRNA, mRNA and protein expression link development and aging in human and macaque brain. Genome Research 20: 1207–1218.

Tevy MF, Giebultowicz J, Pincus Z, Mazzoccoli G and Vinciguerra M (2013) Trends in Endocrinology and Metabolism 24 (5): 229–237.

Travis JM (2004) The evolution of programmed death in a spatially structured population. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 59: 301–305.

Wagner GP and Altenberg L (1996) Perspective: complex adaptations and the evolution of evolvability. Evolution 50: 967–976.

Walker RF (2011) Developmental theory of aging revisited. focus on causal and mechanistic links between development and aging. Rejuvenation Research 14: 429–436.

Walker RF (2013) Why We Age: Insight into the cause of growing old. Dove Medical Press E‐book‐Kindle, ISBN 978-0-473-25035-5

Walker RF (2017) On the cause and mechanism of phenoptosis. Biochemistry (Moscow) 82 (12): 1462–1479.

Weismann A (1889) Duration of Life. In: Essays Upon Heredity and Kindred Biological Problems, 1st edn, vol. 1, pp. 1–65. Oxford: Clarendon Press.

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

Woods RJ, Barrick JE, Cooper TF, et al. (2011) Second‐order selection for evolvability in a large Escherichia coli population. Science 331: 1433–1436.

Yang JN (2013) Viscous populations evolve altruistic programmed ageing in ability conflict in a changing environment. Evolutionary Ecology Research 15: 527–543.

Further Reading

Albrecht U (2012) Timing to perfection: the biology of central and peripheral circadian clocks. Neuron 74 (2): 246–260.

Baron KG and Reid KJ (2014) Circadian misalignment and health. International Review of Psychiatry 26 (2): 139–154.

Davis S and Mirick DK (2006) Circadian disruption, shift work and the risk of cancer: a summary of the evidence and studies in Seattle. Cancer Causes & Control 17 (4): 539–45.

Foster RG and Kreitzman L (2014) The rhythms of life: what your body clock means to you! Experimental Physiology 99 (4): 599–606.

Issa J‐P (2014) Aging and epigenetic drift: a vicious cycle. The Journal of Clinical Investigation 124 (1): 24–29. DOI: 10.1172/JCI69735.

Khan S, Nabi G, Yao L, et al (2018) Health risks associated with genetic alterations in internal clock system by external factors. International Journal of Biological Sciences 14 (7): 791–798.

Lezzerini M, Smith RL and Budovskaya Y (2013) Developmental drift as a mechanism for aging: lessons from nematodes. Biogerontology 14: 693–701. DOI: 10.1007/s10522-013-9462-3.

Mitteldorf J (2010) Evolutionary origins of aging. In: Fahy GM, West MD, Coles LS, and Harris SB (eds) The Future of Aging, Chap. 5, pp. 88–119. Springer Science+Business Media B.V. DOI: 10.1007/978-90-481-3999-6_5,87.

Skulachev VP (2011) Aging as a particular case of phenoptosis, the programmed death of an organism (A response to Kirkwood and Melov “On the programmed/nonprogrammed nature of ageing within the life history”). Aging 3 (11): 1120–1123.

Skulachev MV, Severin FF and Skulachev VP (2015) Aging as an evolvability‐increasing program which can be switched off by organism to mobilize additional resources for survival. Current Aging Science 8: 95–109.

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Walker, Richard F(Dec 2018) Phenoptosis and the Evolution of Ageing. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0028293]