REVIEW: Is Human Aging a Form of Phenoptosis?

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Giacinto Libertini^1,2,a*, Graziamaria Corbi^3,4,b, Olga Shubernetskaya^5,c, and Nicola Ferrara^2,6,d

¹Italian Society for Evolutionary Biology (SIBE), 14100 Asti, Italy

²Department of Translational Medical Sciences, Federico II University of Naples, 80131 Naples, Italy

³Department of Medicine and Health Sciences, University of Molise, 86100 Campobasso, Italy

⁴Italian Society of Gerontology and Geriatrics (SIGG), 50129 Firenze, Italy

⁵Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia

⁶Istituti Clinici Scientifici Maugeri SPA – Società Benefit, IRCCS, 82037 Telese Terme (BN), Italy

^* To whom correspondence should be addressed.

Received August 2, 2022; Revised August 28, 2022; Accepted August 29, 2022

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A much debated question is whether aging is the cumulative consequence of degenerative factors insufficiently opposed by natural selection, or, on the contrary, an ordered process, genetically determined and regulated, modeled by natural selection, and for which the definition of phenoptotic phenomenon would be entirely appropriate. In this review, theoretical arguments and empirical data about the two hypotheses are exposed, with more evidence in support of the thesis of aging as a form of phenoptosis. However, as the thesis of aging as an adaptive and programmed phenomenon necessarily requires the existence of specific mechanisms that determine to age, such as the subtelomere–telomere theory proposed for this purpose, the evidence supporting the mechanisms described by this theory is reported. In particular, it is highlighted that the recent interpretation of the role of TERRA sequences in the context of subtelomere–telomere theory is a fundamental point in supporting the hypothesized mechanisms. Furthermore, some characteristics of the mechanisms proposed by the theory, such as epigenetic modifications in aging, gradual cell senescence, cell senescence, limits in cell duplications, and fixed size of the telomeric heterochromatin hood, are exposed in their compatibility with both the thesis of aging as phenoptotic phenomenon and the opposite thesis. In short, aging as a form of phenoptosis appears a scientifically sound hypothesis while the opposite thesis should clarify the meaning of various phenomena that appear to invalidate it.

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KEY WORDS: phenoptosis, aging, subtelomere, telomere, subtelomere–telomere theory, gradual cell senescence, cell senescence, epigenetic changes

DOI: 10.1134/S0006297922120033

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