TY  - JOUR
AU  - Libertini, Giacinto
PY  - 2025
DA  - 2025/09/10
TI  - The Cellular Mechanism of Aging as Programmed Epigenetic Phenomenon: From Hypothesis to Scientific Evidence
JO  - OBM Geriatrics
SP  - 325
VL  - 09
IS  - 03
AB  - There is a main difference between theories explaining aging as an adaptive phenomenon that is determined and modulated by genes (i.e., the result of a specific “program”) and theories explaining aging as a non-adaptive phenomenon caused by the accumulation of random degenerative events. In fact, for adaptive theories, a genetically determined and modulated program determining aging is indispensable, while for non-adaptive theories, such a program cannot exist. However, there appears to be strong evidence to support the existence of this program as proposed by the subtelomere-telomere (STT) theory with the action of TERRA sequences. The STT theory with TERRA sequences was developed in four successive phases: 1) Aging caused by limitations in cell duplication; 2) Aging caused by progressive telomere shortening; 3) Aging caused by progressive inhibition of particular hypothetical subtelomeric regulatory sequences (r-sequences) determined by progressive telomere shortening; 4) Identification of the r-sequences in the TERRA sequences whose effects are well known and documented. The theory, as proposed in phases 1 and 2, was untenable because the evidence contradicted the predictions. The theory, as proposed in phase 3, was based mainly on the hypothetical existence of regulatory sequences that required empirical confirmation. The further development of the theory in phase 4 overcame this difficulty. In particular, the identification of hypothetical r-sequences in widely documented sequences such as the TERRA sequences has transformed a hypothesis into a theory confirmed by empirical evidence. The mechanism proposed describes a genetically determined and regulated mechanism of aging as a program causing specific epigenetic modifications. This confirms the thesis that aging is an adaptive phenomenon and invalidates the opposing hypothesis. Among other things, for the validity of the opposite hypothesis of aging as a non-adaptive phenomenon, it would be essential to justify in evolutionary terms: (i) the position of regulatory sequences of great importance for cellular functions in a position where they are inhibited by telomere shortening; (ii) cell senescence which appears to be an oncogenic factor and so cannot be justified as a defense against cancer; and (iii) gradual cell senescence which cannot be hypothesized as an anti-cancer defense. Furthermore, the phenomena referred to in points (ii) and (iii) and TERRA sequences inhibition are entirely reversible with appropriate manipulations, and this is unlikely with their possible interpretation as a consequence of random degenerative phenomena.
SN  - 2638-1311
UR  - https://doi.org/10.21926/obm.geriatr.2503325
DO  - 10.21926/obm.geriatr.2503325
ID  - Libertini2025
ER  -