Theories of aging
Why we age remains a fundamental mystery of biology.[1] Over the past decade, there have been substantial advances in our understanding of the mechanistic process underlying aging. However, researchers across the field still fail to find consensus regarding what is aging and why it happens.[2] Many believe that understanding why we age, will ultimately lead to a better understanding of the aging proces and to more straightforward development of strategies to fight aging.
Several theories of aging exist, each of which provides a different perspective on why and how we age. These theories are not necessarily mutually exclusive, and it is possible that the aging process is a complex interplay of multiple factors.
Some of the most popular aging theories are:
Programmed theories
The ideas behind the programmed aging theory are originally based on 19th century August Weismman's "Essays upon heredity", which argues that aging evolved by natural selection to remove older individuals of the population and to favour the evolution of the species, by not competing with younger individuals for resources.[3] According to Weismman, reproduction is necessary to dissolve the damage that the environment causes to the individual over time.[4]
The modern programmed theory of aging proposed by Valter Longo argues that aging is a genetically programmed process that has evolved to cause senescence and death, in order to benefit future generations, referred to as "altruistic aging".[5]
Overall, the programmed theory of aging proposes that each species has an inherent genetic lifespan that is determined by a variety of factors, including the presence or absence of certain genes, the rate of DNA repair, and the activity of various metabolic processes. These factors combine to create an internal "clock" that determines the rate at which an organism ages.
Proponents of the programmed theory of aging point to the fact that different species have wildly different lifespans, which suggests that aging is not simply a matter of "wear and tear" on the body over time. They also note that certain species, such as lobsters or types of tortoises, appear to be able to live for centuries with negligible senescence, suggesting that their internal genetic clock has been set to allow for this. However, recent studies show that animals with negligible senescence such as the naked mole rat do indeed age, and show signs of skin or epigenetic aging, despite the fact of not showing demographic aging (no increase in the risk of death over time).[6]
Arguments against programmed aging theories
It is argued that if aging was genetically programmed, animals kept in captivity would have the same lifespan as animals of the same species living in the wild. However, there is extensive evidence that animals kept in captivity, such as mice, cats, dogs or chimpanzees have significantly longer lifespans than those living in the wild. It is also now largely discredited that animals in the wild do not survive to old age. Steven Austad and colleagues showed there is widespread evidence for natural populations of animals living to the age of senescence, and for old animals having an increased risk of dying than their younger counterparts.[7]
Other arguments against this theory point to the fact that no genes have been identified yet that have evolved to cause aging or death in old individuals.[8] Additionally, despite existing genome-wide knockdown screens in animals such as C. elegans, no single gene mutations have been identified that lead to the disruption of the aging process or to biological immortality.
Evolutionary theories
Aging remains an evolutionary paradox. Genes are selected for to ensure their propagation across organisms.[9] Therefore, dying appears a counterproductive phenomenon for this mission. Evolutionary theories propose that aging is a result of evolutionary trade-offs between longevity and reproductive success. According to this theory, organisms have evolved to allocate resources to reproduction rather than maintaining their bodies indefinitely.
Evolutionary theories are based on the concept of mutation accumulation proposed by Medawar in the 50s[10]
Damage-based theories
Damage accumulation is arguably one of the most intuitive theories. Damage-based theories propose that aging occurs as a result of the accumulation of damage to cells and tissues over time. This damage can be caused by a variety of factors, including free radicals, radiation, toxins, AGEs and other environmental stressors, which eventually result in organismal dysfunction and death.
Many have argued that an increase of entropy, following the second law of thermodynamics, is responsible for damage accumulation in any type of matter over time. However, scientist argue that living organisms are open systems with the capability of receiving external energy supply and therefore are not necessarily subject to a fixed increase in entropy, and repair systems could exist to counteract entropy forces, in theory indefinitely.
An argument against damage-based theories is that they largely fail to explain the evolutionary origin of aging.
Free radical theory
The free radical theory is a type of DNA damage theory that proposes aging is caused by the accumulation of free-radicals over time generated by reactive oxygen species (ROS). Free radicals are produced during normal metabolism and are highly reactive, unstable molecules containing oxygen, which have the capability of oxidising other molecules. The free radical theory of aging was first presented in the 50s by Harman[11] and it remains, as of 2022, the third most cited publication in the history of aging research.[12]
However, this theory has been now largely discredited: an increasing number of publications seem to contradict that aging can be solely explained by the accumulation of free radicals.[13] Instead, free radicals appear to be one of the many hallmarks associated to the aging process. For instance, if free radicals were sufficient to cause aging, experiments in which antioxidants (which can neutralise free radicals) are overexpressed, such be able to extend lifespan. However, this is not seen in some animal models such as flies[14] or mice[15], and might some times even lead to lifespan shortening.[16] Another argument against the free radical theory of aging points towards the fact that aging still occurs under anaerobic conditions, such as in yeast cells, where ROS are generated to a very small degree.[17]
Of note, recently mitochondria
Telomere shortening
Telomeres are the protective caps at the end of our chromosomes. Over time, telomeres gradually shorten, and this shortening is associated with the aging process.
Hormonal theories
These theories propose that changes in the levels of certain hormones, such as estrogen and testosterone, play a role in the aging process.
Immunological theories
These theories propose that the decline in immune system function with age leads to an increased susceptibility to disease and a decreased ability to fight off infections.
- ↑ Kirkwood TB, Austad SN (2000) Why do we age? Nature 408, 233–238.
- ↑ Cohen, A. A., Kennedy, B. K., Anglas, U., Bronikowski, A. M., Deelen, J., Dufour, F., ... & Fülöp, T. (2020). Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree, and the need for an interdisciplinary framework. Mechanisms of ageing and development, 191, 111316.
- ↑ Weismann A: Essays Upon Heredity. Ox- ford, Clarendon Press, 1891.
- ↑ Weismann A: Über die Dauer des Lebens. Fisher, Jena, 1882.
- ↑ Longo VD, Mitteldorf J, Skulachev VP (2005) Programmed and altruistic ageing. Nat. Rev. Genet. 6, 866–872.
- ↑ Kerepesi, C., Meer, M.V., Ablaeva, J. et al. Epigenetic aging of the demographically non-aging naked mole-rat. Nat Commun 13, 355 (2022). https://doi.org/10.1038/s41467-022-27959-9
- ↑ Nussey DH, Froy H, Lemaitre JF, Gaillard JM, Austad SN. Senescence in natural populations of animals: widespread evidence and its implications for bio-gerontology. Ageing Res Rev. 2013 Jan;12(1):214-25. doi: 10.1016/j.arr.2012.07.004. Epub 2012 Aug 4. PMID: 22884974; PMCID: PMC4246505.
- ↑ Gladyshev, V. N. (2016). Aging: progressive decline in fitness due to the rising deleteriome adjusted by genetic, environmental, and stochastic processes. Aging cell, 15(4), 594-602.
- ↑ Dawkins, R. (2016). The Selfish Gene: (Oxford Landmark Science).
- ↑ Medawar PB (1952) An Unsolved Problem of Biology. London: HK Lewis.
- ↑ Harman D.Aging: a theory based on free radical and radiation chemistry. J Gerontol 11: 298–300, 1956
- ↑ Haroon, Li Y-X, Ye C-X, Ahmad T, Khan M, Shah I, Su X-H, Xing L-X. The 100 Most Cited Publications in Aging Research: A Bibliometric Analysis. Electron J Gen Med. 2022;19(1):em342. https://doi.org/10.29333/ejgm/11413
- ↑ Gladyshev VN. The free radical theory of aging is dead. Long live the damage theory! Antioxid Redox Signal. 2014 Feb 1;20(4):727-31. doi: 10.1089/ars.2013.5228.
- ↑ Mockett RJ, Sohal BH, and Sohal RS.Expression of multiple copies of mitochondrially targeted catalase or genomic Mn superoxide dismutase transgenes does not extend the life span of Drosophila melanogaster. Free Radic Biol Med 49: 2028–2031, 2010
- ↑ Pérez VI, Van Remmen H, Bokov A, Epstein CJ, Vijg J, and Richardson A.The overexpression of major antioxidant enzymes does not extend the lifespan of mice. Aging Cell 8: 73–75, 2009
- ↑ Van Rammsdonk JM. and Hekimi S.Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in Caenorhabditis elegans. PLoS Genet 5: e1000361, 2009
- ↑ Koc A, Gasch AP, Rutherford JC, Kim HY, and Gladyshev VN.Methionine sulfoxide reductase regulation of yeast lifespan reveals reactive oxygen species-dependent and -independent components of aging. Proc Natl Acad Sci USA 101: 7999–8004, 2004
