REVIEW: Aging as a Programmed Process or Result of Wear and Tear (Stochastics): The Dichotomy that Excludes Simple Non-Obligatory Dysregulation as a Root Cause of Aging

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Alexander V. Khalyavkin^1,a*

¹Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, 119334 Moscow, Russia

^* To whom correspondence should be addressed.

Received: November 14, 2025; Revised: November 14, 2025; Accepted: November 26, 2025

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In the 1990s, Vladimir P. Skulachev, a proponent of the genetic program of aging, proposed extending the concept of programmed cell death (apoptosis) to the level of an entire organism, a phenomenon he termed phenoptosis. According to his terminology, rapid phenoptosis, is characteristic of species with a single reproductive cycle, such as pink salmon and mayflies, whereas slow phenoptosis is typical of species with multiple reproductive cycles, including humans. Interestingly, rapid phenoptosis resembles obligate apoptosis observed during development, such as the disappearance of pharyngeal slits, tail, and interdigital webbing in human embryo. Slow phenoptosis is more akin to non-obligate apoptosis, which is triggered by irreversible damage or functional cell redundancy. Just as non-obligate apoptosis is not inevitable, a similar non-inevitability should not be excluded for slow phenoptosis – that is, natural aging. This interpretation is supported by the plasticity of aging, the reversibility of age-associated traits, and the absence of the replicative (Hayflick) limit in tissue stem cells, a feature they share with immortalized cells. Additionally, human (and animal) mortality patterns resemble those of non-aging hydras and immortalized cells subjected to suboptimal conditions. It has been said that a “correctly posed” question endures indefinitely. In our view, the question “Is aging programmed or stochastic?” falls into the category of “correct” questions. Its apparent dichotomy excludes the obvious third option: in many species with repeated reproductive cycles, aging is associated with neither genetic program nor purely stochastic damage, but rather results from cumulative consequences of living under conditions that are pessimal for stable, non-aging functioning.

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KEY WORDS: root cause of aging, program, wear and tear, dysregulation, non-obligate apoptosis and phenoptosis, aging of immortalized cells, aging of non-aging hydra, reversibility of aging traits

DOI: 10.1134/S0006297925604010

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