Geriatrics and Healthcare · Jul 31, 2026
Perspectives for the Control of Aging in the Framework of the Subtelomere-Telomere Theory of Aging with TERRA Sequences
By Libertini G, Corbi G, Conti V et al.
If aging is conceptualized as the cumulative consequence of stochastic damage, the identification of a unified and effective intervention strategy becomes inherently problematic. In contrast to this paradigm, a theory has been developed in recent years, the subtelomere-telomere theory of aging with TERRA sequences, based on ample evidence, and which conceptualizes aging as a genetically determined and modulated phenomenon. According to this model, aging results from progressive, site-specific epigenetic modifications occurring at precisely defined genomic loci. Specific subtelomeric sequences, called TERRA sequences (T-sequences), which have been extensively studied in recent molecular works, regulate this process. In turn, the progressive inhibition of the T-sequences is driven by telomere shortening, which causes an increasing repression by the telomere cap, whose size remains constant across cell divisions. This mechanistic cascade gives rise to three principal and interrelated outcomes: (1) gradual cell senescence in cells with shortened telomeres; (2) an increasing probability of activations of cell senescence, characterized by irreversible proliferative arrest and stereotypical functional alterations; and (3) a decline in the numbers of stem cells, leading to reduced and incomplete tissue renewal. Collectively, these processes give rise to an atrophic syndrome affecting all tissues and organs, and so a progressive decline in organismal fitness. Recognizing aging as a distinct biological function governed by a specific mechanism is essential for the development of suitable general strategies to modify and counteract this mechanism, moving beyond the idea of aging as an inevitable and unstoppable phenomenon. Potential complementary approaches include: (1) controlled activation of the telomerase enzyme; (2) selective elimination of senescent cells, provided that stem cell depletion is avoided; and (3) rejuvenation or renewal of stem cell populations. The development of these strategies, as a very important collateral benefit, is expected not only to enable the control of aging but also to provide therapeutic options for diseases characterized by tissue atrophy or cellular exhaustion.