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REVIEW: Is Evidence Supporting the Subtelomere–Telomere Theory of Aging?

Giacinto Libertini1,2,a*, Olga Shubernetskaya3,b, Graziamaria Corbi4,5,c, and Nicola Ferrara2,6,d

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

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

3Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia

4Department of Medicine and Health Sciences, University of Molise, 86100 Campobasso, Italy

5Italian Society of Gerontology and Geriatrics (SIGG), 50129 Firenze, Italy

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

* To whom correspondence should be addressed.

Received June 16, 2021; Revised July 30, 2021; Accepted September 2, 2021
The telomere theory tries to explain cellular mechanisms of aging as mainly caused by telomere shortening at each duplication. The subtelomere–telomere theory overcomes various shortcomings of telomere theory by highlighting the essential role of subtelomeric DNA in aging mechanisms. The present work illustrates and deepens the correspondence between assumptions and implications of subtelomere–telomere theory and experimental results. In particular, it is investigated the evidence regarding the relationships between aging and (i) epigenetic modifications; (ii) oxidation and inflammation; (iii) telomere protection; (iv) telomeric heterochromatin hood; (v) gradual cell senescence; (vi) cell senescence; and (vii) organism decline with telomere shortening. The evidence appears broadly in accordance or at least compatible with the description and implications of the subtelomere–telomere theory. In short, phenomena of cellular aging, by which the senescence of the whole organism is determined in various ways, appear substantially dependent on epigenetic modifications regulated by the subtelomere–telomere–telomeric hood–telomerase system. These phenomena appear to be not random, inevitable, and irreversible but rather induced and regulated by genetically determined mechanisms, and modifiable and reversible by appropriate methods. All this supports the thesis that aging is a genetically programmed and regulated phenoptotic phenomenon and is against the opposite thesis of aging as caused by random and inevitable degenerative factors.
KEY WORDS: aging, phenoptosis, telomere, subtelomere, epigenetic changes, gradual cell senescence, cell senescence, telomeric heterochromatin hood

DOI: 10.1134/S0006297921120026