Abstract
Aging is an elusive property of life, and many important questions about aging depend on its definition. This article proposes to draw a definition from the scientific literature on aging. First, a broad review reveals five features commonly used to define aging: structural damage, functional decline, depletion, typical phenotypic changes or their cause, and increasing probability of death. Anything that can be called ‘aging’ must present one of these features. Then, although many conditions are not consensual instances of aging, aging is consensually described as a process of loss characterized by a rate and resulting from the counteraction of protective mechanisms against mechanisms that limit lifespan. Beyond such an abstract definition, no one has yet succeeded in defining aging by a specific mechanism of aging because of an explanatory gap between such a mechanism and lifespan, a consensual explanandum of a theory of aging. By contrast, a sound theoretical definition can be obtained by revisiting the evolutionary theory of aging. Based on this theory, aging evolves thanks to the impossibility that natural selection eliminates late traits that are neutral mainly due to decreasing selective pressure. Yet, the results of physiological research suggest that this theory should be revised to also account for the small number of different aging pathways and for the existence of mechanisms counteracting these pathways, that must, on the contrary, have been selected. A synthetic, but temporary definition of aging can finally be proposed.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Notes
This paper will thus rely heavily on the scientific literature. It follows Carnap’s views on explication (or rational reconstruction) as a preliminary work useful for science (Wagner 2012). It is not only descriptive, but also constructive whenever useful, and reflects important uncertainties instead of trying to solve them.
Most of the references cited in this article are among the most cited in their field (according to Web of Science). This does not necessarily make them the most interesting, but they are arguably the most representative.
In humans and many mammals. Depending on how it is defined, sarcopenia is not necessarily a universal trait. An interesting discussion of the aging phenotype of C. elegans can be found in (Garigan et al. 2002).
The choice of a defining feature has empirical consequences. For example, sarcopenia can be interpreted in terms of structural decay and measured as a loss of muscular mass, but also in functional terms, as a loss of strength, or even in terms of the muscle mass/strength ratio (Doherty 2003). It can be used as a sign predictive of disability (Guralnik et al. 1995) or even death.
Thanks to an anonymous referee for suggesting the analogy.
Concepts, such as lifespan and longevity, should nevertheless be clarified as well.
Typically, Rose (1995) starts with a definition based on common sense then provides one based on his theory (see below).
An alternative is the reliability theory of aging (Gavrilov and Gavrilova 2001, 2003). Reliability is the probability that a physiological system (organism, organ, etc.) fulfils its role at a given point in its lifetime. This forms the basis of the definition of a mathematical function that represents the accumulation of causes of potential failures of the system. The shape of the resulting curve lies between two extremes: exponential increasing (Gompertz’s law of mortality) and exponentially decreasing/increasing (Weibull’s law) functions, respectively corresponding to systems with many redundant but less reliable components and to systems with few, non-redundant but extremely reliable components. A simple definition would be: aging is the progressive disappearance of the parts of a system that make it reliable, according to a pattern lying between Gompertz’s law and Weibull’s law. In this view, the diversity of the pathways of aging is lost, but the main feature is probably conserved.
I contrast an age-structured population with an age-structured model of a population. In the former, traits do differ importantly depending on age and not all populations are age-structured, while in the latter, any population can in principle be age-structured, although differing traits are not necessarily important. Hamilton (1966) has described and formalized these effects on a population, but he did not clearly stated that age structure is a condition of the evolution of aging. See also (Charlesworth 1994).
Different definitions of ‘extrinsic cause of death’ have been used. I consider this one to be the most consistent with the theory of the evolution of aging.
Thanks to an anonymous reviewer for pointing this to me. The reviewer also objected, rightly I think, that if fecundity increases with age, the force of natural selection should not decrease as much (or at all) with age. In this case, this should be added as a condition to the evolution of aging.
Slightly different formalized versions of the evolutionary theory of aging can be found in Rose (1995, Martin et al. (1996), Bengtson et al. (2008). I emphasize logical independence rather than chronological sequence. I also choose to present the main result of the disposable soma theory as an additional, independent condition for aging to evolve. Some think that it is just a case of antagonistic pleiotropy. Kirkwood himself sees them as complementary: while the antagonistic pleiotropy theory explains that variations limiting longevity are selected because they enhance early maintenance, the disposable soma theory explains that variations that limit early maintenance and longevity are selected because they enhance early reproduction (Kirkwood and Rose 1991). In this account, I consider the condition of limited maintenance to be Kirkwood’s truly original contribution. An additional question is whether the contribution of biodemography is original (Carey and Vaupel 2006).
References
Ahuja N, Li Q, Mohan AL et al (1998) Aging and DNA methylation in colorectal mucose and cancer. Can Res 58:5489–5494
Alcendor RR, Gao S, Zhai P et al (2007) Sirt1 regulates aging and resistance to oxidative stress in the heart. Circ Res 100:1512–1521. https://doi.org/10.1161/01.RES.0000267723.65696.4a
Alizon S, Méthot P-O (2018) Reconciling Pasteur and Darwin to control infectious diseases. PLoS Biol 16:e2003815. https://doi.org/10.1371/journal.pbio.2003815
Ames BN (1989) Endogenous oxidative DNA damage, aging, and cancer. Free Radic Res Commun 7:121–128. https://doi.org/10.3109/10715768909087933
Ames BN, Shigenaga MK, Hagen TM (1993) Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci USA 90:7915–7922
Aubert G, Lansdorp PM (2008) Telomeres and aging. Physiol Rev 88:557–579. https://doi.org/10.1152/physrev.00026.2007
Austad SN (2004) Is aging programed? Aging Cell 3:249–251. https://doi.org/10.1111/j.1474-9728.2004.00112.x
Balaban RS, Nemoto S, Finkel T (2005) Mitochondria, oxidants, and aging. Cell 120:483–495. https://doi.org/10.1016/j.cell.2005.02.001
Bandeen-Roche K, Xue QL, Ferrucci L et al (2006) Phenotype of frailty: characterization in the women’s health and aging studies. J Gerontol Ser Biol Sci Med Sci 61:262–266. https://doi.org/10.1093/gerona/61.3.262
Bengtson VL, Gans D, Putney N, Silverstein M (eds) (2008) Handbook of theories of aging, 2nd edn. Springer, New York
Berlett BS, Stadtman ER (1997) Protein oxidation in aging, disease, and oxidative stress. J Biol Chem 272:20313–20316. https://doi.org/10.1074/jbc.272.33.20313
Blasco MA (2005) Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet 6:611. https://doi.org/10.1038/nrg1656
Boorse C (1977) Health as a theoretical concept. Philos Sci 44:542–573
Brandes RP, Fleming I, Busse R (2005) Endothelial aging. Cardiovasc Res 66:286–294. https://doi.org/10.1016/j.cardiores.2004.12.027
Bratic A, Larsson N-G (2013) The role of mitochondria in aging. J Clin Invest 123:951–957. https://doi.org/10.1172/JCI64125
Broekmans FJ, Soules MR, Fauser BC (2009) Ovarian aging: mechanisms and clinical consequences. Endocr Rev 30:465–493. https://doi.org/10.1210/er.2009-0006
Brunk UT, Terman A (2002) The mitochondrial-lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosis. Eur J Biochem 269:1996–2002. https://doi.org/10.1046/j.1432-1033.2002.02869.x
Burke SN, Barnes CA (2006) Neural plasticity in the ageing brain. Nat Rev Neurosci 7:30–40. https://doi.org/10.1038/nrn1809
Cadenas E, Davies KJA (2000) Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med 29:222–230. https://doi.org/10.1016/S0891-5849(00)00317-8
Campisi J (2013) Aging, cellular senescence, and cancer. Annu Rev Physiol 75(75):685–705
Caplan AL (1981) The unnaturalness of aging: a sickness unto death? In: Caplan AL, Engelhardt HT Jr, McCartney JJ (eds) Concepts of health and disease: interdisciplinary perspectives. Addison-Wesley, Advanced Book Program/World Science Division, Boston, pp 725–737
Carey JR, Vaupel JW (2006) Biodemography. Handbook of population. Kluwer Academic Publishers, New York, pp 625–658
Castle SC (2000) Clinical relevance of age-related immune dysfunction. Clin Infect Dis 31:578–585. https://doi.org/10.1086/313947
Charlesworth B (1994) Evolution in age-structured populations. Cambridge University Press, Cambridge
Christensen K (2008) Human biodemography: some challenges and possibilities. Demogr Res 19:1575–1586. https://doi.org/10.4054/DemRes.2008.19.43
Collado M, Blasco MA, Serrano M (2007) Cellular senescence in cancer and aging. Cell 130:223–233. https://doi.org/10.1016/j.cell.2007.07.003
Corpas E, Harman D, Blackman M (1993) Human growth-hormone and human aging. Endocr Rev 14:20–39. https://doi.org/10.1210/er.14.1.20
Cuervo AM, Bergamini E, Brunk UT et al (2005) Autophagy and aging: the importance of maintaining “clean” cells. Autophagy 1:131–140. https://doi.org/10.4161/auto.1.3.2017
de Grey ADNJ, Ames BN, Andersen JK et al (2002) Time to talk SENS: critiquing the immutability of human aging. Ann N Y Acad Sci 959:452–462 (discussion 463–465)
De Winter G (2015) Aging as disease. Med Health Care Philos 18:237–243. https://doi.org/10.1007/s11019-014-9600-y
Dent E, Kowal P, Hoogendijk EO (2016) Frailty measurement in research and clinical practice: a review. Eur J Inter Med 31:3–10. https://doi.org/10.1016/j.ejim.2016.03.007
Doherty TJ (2003) Invited review: aging and sarcopenia. J Appl Physiol 95:1717–1727. https://doi.org/10.1152/japplphysiol.00347.2003
Engelhardt HT (1977) Treating aging: restructuring the human condition. In: Extending the human life span: social policy and social ethics. National Science Foundation, Washington, DC, pp 35–40
Ershler WB, Keller ET (2000) Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med 51:245–270. https://doi.org/10.1146/annurev.med.51.1.245
Ewald CY, Landis JN, Abate JP et al (2015) Dauer-independent insulin/IGF-1-signalling implicates collagen remodelling in longevity. Nature 519:97–101. https://doi.org/10.1038/nature14021
Ferrucci L, Corsi A, Lauretani F et al (2005) The origins of age-related proinflammatory state. Blood 105:2294–2299. https://doi.org/10.1182/blood-2004-07-2599
Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408:239–247. https://doi.org/10.1038/35041687
Franceschi C, Campisi J (2014) Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol Ser Biol Sci Med Sci 69:S4–S9. https://doi.org/10.1093/gerona/glu057
Franceschi C, Bonafe M, Valensin S, et al (2000) Inflamm-aging: an evolutionary perspective on immunosenescence. In: Toussaint O, Osiewacz HD, Lithgow GJ, Brack C (eds) Molecular and cellular gerontology, pp 244–254
Franceschi C, Garagnani P, Vitale G et al (2017) Inflammaging and “Garb-aging”. Trends Endocrinol Metab 28:199–212. https://doi.org/10.1016/j.tem.2016.09.005
Franceschi C, Garagnani P, Morsiani C et al (2018) The continuum of aging and age-related diseases: common mechanisms but different rates. Front Med (Lausanne) 5:61. https://doi.org/10.3389/fmed.2018.00061
Fried LP, Tangen CM, Walston J et al (2001) Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 56:M146–M156
Fried LP, Ferrucci L, Darer J et al (2004) Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care. J Gerontol A Biol Sci Med Sci 59:M255–M263. https://doi.org/10.1093/gerona/59.3.M255
Fries J (1980) Aging, natural death, and the compression of morbidity. N Engl J Med 303:130–135. https://doi.org/10.1056/NEJM198007173030304
Garigan D, Hsu AL, Fraser AG et al (2002) Genetic analysis of tissue aging in Caenorhabditis elegans: a role for heat-shock factor and bacterial proliferation. Genetics 161:1101–1112
Gavrilov LA, Gavrilova NS (2001) The reliability theory of aging and longevity. J Theor Biol 213:527–545. https://doi.org/10.1006/jtbi.2001.2430
Gavrilov LA, Gavrilova NS (2003) The quest for a general theory of aging and longevity. Sci Aging Knowl Environ 2003:RE5
Gillis S, Kozak R, Durante M, Weksler M (1981) Immunological studies of aging: decreased production of and response to t-cell growth-factor by lymphocytes from aged humans. J Clin Invest 67:937–942. https://doi.org/10.1172/JCI110143
Goldberger AL, Amaral LAN, Hausdorff JM et al (2002) Fractal dynamics in physiology: alterations with disease and aging. Proc Natl Acad Sci USA 99:2466–2472. https://doi.org/10.1073/pnas.012579499
Goldstein S (1990) Replicative senescence: the human fibroblast comes of age. Science 249:1129–1133. https://doi.org/10.1126/science.2204114
Gordon EH, Peel NM, Samanta M et al (2017) Sex differences in frailty: a systematic review and meta-analysis. Exp Gerontol 89:30–40. https://doi.org/10.1016/j.exger.2016.12.021
Gruver A, Hudson L, Sempowski G (2007) Immunosenescence of ageing. J Pathol 211:144–156. https://doi.org/10.1002/path.2104
Guarente L (2000) Sir2 links chromatin silencing, metabolism, and aging. Genes Dev 14:1021–1026
Guarente L, Kenyon C (2000) Genetic pathways that regulate ageing in model organisms. Nature 408:255. https://doi.org/10.1038/35041700
Guralnik JM, Ferrucci L, Simonsick E et al (1995) Lower-extremity function in persons over the age of 70 years as a predictor of subsequent disability. N Engl J Med 332:556–561. https://doi.org/10.1056/NEJM199503023320902
Hamilton WD (1966) The moulding of senescence by natural selection. J Theor Biol 12:12–45
Hannum G, Guinney J, Zhao L et al (2013) Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell 49:359–367. https://doi.org/10.1016/j.molcel.2012.10.016
Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11:298–300
Harman D (1972) The biologic clock: the mitochondria? J Am Geriatr Soc 20:145–147. https://doi.org/10.1111/j.1532-5415.1972.tb00787.x
Harman D (1981) The aging process. Proc Natl Acad Sci USA Biol Sci 78:7124–7128. https://doi.org/10.1073/pnas.78.11.7124
Harman D (1992) Free-radical theory of aging. Mutat Res 275:257–266. https://doi.org/10.1016/0921-8734(92)90030-S
Harman D (2006) Free radical theory of aging: an update increasing the functional life span. In: Rattan S, Kristensen P, Clark BFC (eds) Understanding and modulating aging, pp 10–21
Herker E, Jungwirth H, Lehmann KA et al (2004) Chronological aging leads to apoptosis in yeast. J Cell Biol 164:501–507. https://doi.org/10.1083/jcb.200310014
Hoeijmakers JHJ (2009) DNA damage, aging, and cancer. N Engl J Med 361:1475–1485. https://doi.org/10.1056/NEJMra0804615
Horvath S (2013) DNA methylation age of human tissues and cell types. Genome Biol 14:R115. https://doi.org/10.1186/gb-2013-14-10-r115
Hsu A-L, Murphy CT, Kenyon C (2003) Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300:1142–1145. https://doi.org/10.1126/science.1083701
Johnson FB, Sinclair DA, Guarente L (1999) Molecular biology of aging. Cell 96:291–302. https://doi.org/10.1016/S0092-8674(00)80567-X
Johnson SC, Rabinovitch PS, Kaeberlein M (2013) mTOR is a key modulator of ageing and age-related disease. Nature 493:338–345. https://doi.org/10.1038/nature11861
Keller L, Genoud M (1997) Extraordinary lifespans in ants: a test of evolutionary theories of ageing. Nature 389:958–960. https://doi.org/10.1038/40130
Kennedy BK, Berger SL, Brunet A et al (2014) Geroscience: linking aging to chronic disease. Cell 159:709–713. https://doi.org/10.1016/j.cell.2014.10.039
Kenyon C (2001) A conserved regulatory system for aging. Cell 105:165–168. https://doi.org/10.1016/S0092-8674(01)00306-3
Kenyon C (2005) The plasticity of aging: insights from long-lived mutants. Cell 120:449–460. https://doi.org/10.1016/j.cell.2005.02.002
Kenyon CJ (2010) The genetics of ageing. Nature 464:504–512. https://doi.org/10.1038/nature08980
Kirkwood TB (1977) Evolution of ageing. Nature 270:301–304
Kirkwood TBL (2005) Understanding the odd science of aging. Cell 120:437–447. https://doi.org/10.1016/j.cell.2005.01.027
Kirkwood TBL, Austad SN (2000) Why do we age? Nature 408:233–238. https://doi.org/10.1038/35041682
Kirkwood T, Rose M (1991) Evolution of senescence: late survival sacrificed for reproduction. Philos Trans R Soc B Biol Sci 332:15–24. https://doi.org/10.1098/rstb.1991.0028
Kirkwood TBL, Boys RJ, Gillespie CS et al (2003) Towards an e-biology of ageing: integrating theory and data. Nat Rev Mol Cell Biol 4:243–249. https://doi.org/10.1038/nrm1051
Kregel KC, Zhang HJ (2007) An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations. Am J Physiol Regul Integr Comp Physiol 292:R18–R36. https://doi.org/10.1152/ajpregu.00327.2006
Krishnamurthty J, Torrice C, Ramsey MR et al (2004) Ink4a/Arf expression is a biomarker of aging. J Clin Invest 114:1299–1307. https://doi.org/10.1172/JCI200422475
Krtolica A, Parrinello S, Lockett S et al (2001) Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci USA 98:12072–12077. https://doi.org/10.1073/pnas.211053698
Kujoth GC, Hiona A, Pugh TD et al (2005) Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309:481–484. https://doi.org/10.1126/science.1112125
Lamberts SWJ, van den Beld AW, van der Lely A-J (1997) The endocrinology of aging. Science 278:419–424. https://doi.org/10.1126/science.278.5337.419
Levy M, Allsopp R, Futcher A et al (1992) Telomere end-replication problem and cell aging. J Mol Biol 225:951–960. https://doi.org/10.1016/0022-2836(92)90096-3
Lombard DB, Chua KF, Mostoslavsky R et al (2005) DNA repair, genome stability, and aging. Cell 120:497–512. https://doi.org/10.1016/j.cell.2005.01.028
Lopez-Otin C, Blasco MA, Partridge L et al (2013) The hallmarks of aging. Cell 153:1194–1217. https://doi.org/10.1016/j.cell.2013.05.039
Marengoni A, Angleman S, Melis R et al (2011) Aging with multimorbidity: a systematic review of the literature. Age Res Rev 10:430–439. https://doi.org/10.1016/j.arr.2011.03.003
Martin GM, Austad SN, Johnson TE (1996) Genetic analysis of ageing: role of oxidative damage and environmental stresses. Nat Genet 13:25–34. https://doi.org/10.1038/ng0596-25
Martincorena I, Fowler JC, Wabik A et al (2018) Somatic mutant clones colonize the human esophagus with age. Science. https://doi.org/10.1126/science.aau3879
Matthewson J, Griffiths PE (2017) Biological criteria of disease: four ways of going wrong. J Med Philos A Forum Bioeth Philos Med 42:447–466. https://doi.org/10.1093/jmp/jhx004
Medawar P (1952) An unsolved problem of biology. University College, London
Miller RA (1996) The aging immune system: primer and prospectus. Science 273:70–74. https://doi.org/10.1126/science.273.5271.70
Miller RA (1999) Kleemeier award lecture: are there genes for aging? J Gerontol A Biol Sci Med Sci 54:B297–B307
Miquel J, Economos AC, Fleming J, Johnson JE (1980) Mitochondrial role in cell aging. Exp Gerontol 15:575–591. https://doi.org/10.1016/0531-5565(80)90010-8
Mitnitski AB, Mogilner AJ, Rockwood K (2001) Accumulation of deficits as a proxy measure of aging. Sci World J 1:323–336. https://doi.org/10.1100/tsw.2001.58
Morange M (2011) Development and aging. Biol Theory 6:59–64. https://doi.org/10.1007/s13752-011-0010-6
Morrison JH, Hof PR (1997) Life and death of neurons in the aging brain. Science 278:412–419. https://doi.org/10.1126/science.278.5337.412
Mostoslavsky R, Chua KF, Lombard DB et al (2006) Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124:315–329. https://doi.org/10.1016/j.cell.2005.11.044
Muller FL, Lustgarten MS, Jang Y et al (2007) Trends in oxidative aging theories. Free Radic Biol Med 43:477–503. https://doi.org/10.1016/j.freeradbiomed.2007.03.034
Olshansky SJ (2010) The law of mortality revisited: interspecies comparisons of mortality. J Comp Pathol 142(Suppl 1):S4–S9. https://doi.org/10.1016/j.jcpa.2009.10.016
Olshansky SJ, Carnes BA (1997) Ever since gompertz. Demography 34:1–15
Partridge L, Barton N (1993) Optimality, mutation and the evolution of aging. Nature 362:305–311. https://doi.org/10.1038/362305a0
Partridge L, Gems D (2002) Mechanisms of ageing: public or private? Nat Rev Genet 3:165–175. https://doi.org/10.1038/nrg753
Poeggeler B, Reiter RJ, Tan D-X et al (1993) Melatonin, hydroxyl radical-mediated oxidative damage, and aging: a hypothesis. J Pineal Res 14:151–168. https://doi.org/10.1111/j.1600-079X.1993.tb00498.x
Rando TA (2006) Stem cells, ageing and the quest for immortality. Nature 441:1080–1086. https://doi.org/10.1038/nature04958
Renshaw M, Rockwell J, Engleman C et al (2002) Cutting edge: impaired toll-like receptor expression and function in aging. J Immunol 169:4697–4701. https://doi.org/10.4049/jimmunol.169.9.4697
Robine J-M, Vaupel JW, Jeune B, Allard M (2012) Longevity: to the limits and beyond. Springer, Berlin
Rockwood K, Song X, MacKnight C et al (2005) A global clinical measure of fitness and frailty in elderly people. CMAJ 173:489–495. https://doi.org/10.1503/cmaj.050051
Rose MR (1995) Evolutionary biology of aging, New edn. OUP USA, New York
Rossi DJ, Jamieson CHM, Weissman IL (2008) Stems cells and the pathways to aging and cancer. Cell 132:681–696. https://doi.org/10.1016/j.cell.2008.01.036
Rowe JW, Kahn RL (1987) Human aging: usual and successful. Science 237:143–149. https://doi.org/10.1126/science.3299702
Rowe JW, Kahn RL (1997) Successful aging. Gerontologist 37:433–440. https://doi.org/10.1093/geront/37.4.433
Rubinsztein DC, Marino G, Kroemer G (2011) Autophagy and aging. Cell 146:682–695. https://doi.org/10.1016/j.cell.2011.07.030
Sacher GA (1956) On the statistical nature of mortality, with especial reference to chronic radiation mortality. Radiology 67:250–258. https://doi.org/10.1148/67.2.250
Shigenaga M, Hagen T, Ames B (1994) Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci USA 91:10771–10778. https://doi.org/10.1073/pnas.91.23.10771
Sinclair DA, Guarente L (1997) Extrachromosomal rDNA circles: a cause of aging in yeast. Cell 91:1033–1042. https://doi.org/10.1016/S0092-8674(00)80493-6
Sohal RS, Weindruch R (1996) Oxidative stress, caloric restriction, and aging. Science 273:59–63
Sohal R, Ku H, Agarwal S et al (1994) Oxidative damage, mitochondrial oxidant generation and antioxidant defenses during aging and in response to food restriction in the mouse. Mech Ageing Dev 74:121–133. https://doi.org/10.1016/0047-6374(94)90104-X
Stearns SC, Koella JC (2008) Evolution in health and disease, 2nd edn. Oxford University Press, New York
Stenderup K, Justesen J, Clausen C, Kassem M (2003) Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells. Bone 33:919–926. https://doi.org/10.1016/j.bone.2003.07.005
Stern Y (2012) Cognitive reserve in ageing and Alzheimer’s disease. Lancet Neurol 11:1006–1012. https://doi.org/10.1016/S1474-4422(12)70191-6
Timiras PS (ed) (2007) Physiological basis of aging and geriatrics, 4th edn. CRC Press, New York
Wagner P (ed) (2012) Carnap’s ideal of explication and naturalism. Palgrave Macmillan, London
Wallace DC (2005) A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39:359–407. https://doi.org/10.1146/annurev.genet.39.110304.095751
Weismann A (1892) Essays upon heredity and kindred biological problems. Clarendon Press, Oxford
Weksler M, Hutteroth T (1974) impaired lymphocyte function in aged humans. J Clin Invest 53:99–104. https://doi.org/10.1172/JCI107565
Wensink MJ, Caswell H, Baudisch A (2017) The rarity of survival to old age does not drive the evolution of senescence. Evol Biol 44:5–10. https://doi.org/10.1007/s11692-016-9385-4
Williams GC (1957) Pleiotropy, natural selection, and the evolution of senescence. Evolution 11:398–411. https://doi.org/10.2307/2406060
Williams G, Nesse R (1991) The dawn of darwinian medicine. Q Rev Biol 66:1–22. https://doi.org/10.1086/417048
Wolff S, Jiang Z, Hunt J (1991) Protein glycation and oxidative stress in diabetes-mellitus and aging. Free Radic Biol Med 10:339–352. https://doi.org/10.1016/0891-5849(91)90040-A
Yancik R (1997) Cancer burden in the aged: an epidemiologic and demographic overview. Cancer 80:1273–1283. https://doi.org/10.1002/(SICI)1097-0142(19971001)80:7%3c1273:AID-CNCR13%3e3.3.CO;2-5
Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12:21–35. https://doi.org/10.1038/nrm3025
Acknowledgements
Thanks to the Conceptual Biology and Medicine Group in Bordeaux, and most particularly to Jean-François Moreau, for reading and commenting on earlier versions of the paper. The final version has improved thanks to the objections of one anonymous referee.
Funding
No specific funding.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
