ISSN 0006-2979, Biochemistry (Moscow), 2026, Vol. 91, No. 1, pp. 76-80 © Pleiades Publishing, Ltd., 2026.
76
MINI-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
Alexander V. Khalyavkin
Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, 119334 Moscow, Russia
e-mail: antisenesc@mail.ru
Received November 14, 2025
Revised November 14, 2025
Accepted November 26, 2025
Abstract— In the 1990s, Vladimir P. Skulachev, a proponent of the genetic program of aging, proposed ex-
tending 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.
DOI: 10.1134/S0006297925604010
Keywords: 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
INTRODUCTION
In 2024, participants of the Gordon Research
Conference on the Biology of Aging discussed contem-
porary views on causes and mechanisms of aging, as
well as their individual interpretations of the essence
of this process. The results were discouraging. As pre-
sented in a joint article analyzing the various opin-
ions, the divergence of perspectives on aging proved
to be remarkably high [1].
Indeed, while the pioneering works by D.Harman
and N. M. Emanuel on the role of free radicals in the
1950s and by Leonard Hayflick and his followers on
the primary role of cellular aging in organismal aging
in the 1960s had laid the basis for a logical concept
on causes and mechanisms of aging, it has later be-
come evident that these steps were not in the entirely
right direction.
For example, suppression of free radical process-
es has been shown to extend lifespan only slightly
and only in individs with impaired physiology [2, 3].
In individs with a normal lifespan, such suppression
either had no effect [3] or even shortened the lifes-
pan [2], because reactive oxygen species, at appropri-
AGING: PROGRAM, WEAR AND TEAR, OR DYSREGULATION? 77
BIOCHEMISTRY (Moscow) Vol. 91 No. 1 2026
ate concentrations, act as essential second messengers
necessary for harmonious organism functioning.
As for Hayflick’s phenomenon of cellular aging,
the observed slowdown and eventual cessation in
population doublings during serial passaging of cul-
tured cells have not been confirmed at the organis-
mal level. Instead, these effects appear to be artifacts
of in vitro culturing or are associated with terminal
differentiation. In many differentiated cell types (e.g.,
neurons, corneocytes), cell division is determinis-
tically blocked as part of the normal development.
This phenomenon led A. M. Olovnikov, who in the
1970s explained the Hayflick limit by telomere short-
ening, to abandon his hypothesis that telomere short-
ening causes organismal aging in 2003 [4] and turn
tothe development of alternative hypotheses of aging.
Using immunosenescence and cellular zones tra-
ditionally considered non-renewable as examples,
here we present evidence suggesting that aging
can be regulated within broad limits and may be a
non-obligatory process.
ON THE DIFFERENCES
BETWEEN THE TERMS IMMUNOAGING,
IMMUNOSENESCENCE, AND INFLAMMAGING
For a Russian speaker, the terms immunoaging
and immunosenescence appear identical and inter-
changeable, as both aging and senescence translate
to Russian as “aging” (“старение”). However, their
meaning is different: aging refers to changes in age,
the process of becoming older. In its early stages,
age-related changes are primarily associated with
development, so aging as age-associated deviation of
structural and functional capacities from the norm is
generally not associated with this stage. Senescence,
however, is true aging. Its initial stages are typical-
ly manifested after completion of development and
attainment of maturity. Only then does a gradual in-
crease in all traits characteristic of this aging process
take place.
The thymus, as the central organ of the immune
system, begins its involution long before maturity,
which is often interpreted as an early manifestation
of genetic program of aging. However, thymus involu-
tion (immunoaging) appears to be related to its role
in the organism growth and development rather to
aging itself [5]. The true immunosenescence emerges
only after maturity, leading to inflammatory aging
(inflammaging) by the age of 50-60 [6, 7].
We should mention that before its recognition
as the primary immune organ, the thymus had been
known as the “growth gland,” or “childhood gland,”
for several decades. From puberty to full maturity, the
regulatory reduction in thymic mass and functional
activity serves to slow the rate of somatic growth and
occurs at the highest rate across the entire life cycle.
This early involution of the thymus (immunoaging)
is not a part of the organism’s aging program, but
rather a normal stage of organismal development [5].
Such immunosenescence (immunoaging) is physiolog-
ical and should be distinguished from true dysregu-
latory immunosenescence (immunosenescence), which
develops after maturity.
True immunosenescence (immunosenescence) is
associated with the fact that the thymus is a target
organ of the somatotropic hormone produced by the
anterior pituitary, the secretion of which declines
with age. This unnecessary and dysregulatory de-
crease occurs because under conditions of human
civilization (for humans) or captivity (for laboratory
animals), vital functions of the organism are regulat-
ed by control systems operating in an unstable mode,
with main indicators drifting toward weakening of
most functions.
After passing through non-obligatory yet, under
these conditions, inevitable stages of immune decline,
true immunosenescence progresses to inflammatory
aging (inflammaging). This phenomenon has attract-
ed considerable attention as one of the negative man-
ifestations of aging [6, 7]. However, inflammaging is
not the cause of aging but merely one of its conse-
quences [5, 8-11]. It typically becomes noticeable only
during the second half of life and predominantly
among residents of economically developed countries
as a lifestyle side effect [7]. Consequently, inflammag-
ing should not be regarded as an obligatory charac-
teristic of the second half of human life.
There are grounds to believe that immunosenes-
cence, which is observed after maturity (immunose-
nescence), may also be a non-obligatory feature of
an organism, similar to what has been proposed for
inflammatory aging (inflammaging) [5, 8-11].
PHYSIOLOGICAL REGENERATION
OF “NON-RENEWABLE” CELLULAR ZONES
It is commonly believed that some organs and
tissues contain regions where cellular renewal does
not occur. Cells in these zones include, for example,
neurons in the brain and cells in ovarian follicles.
Therefore, it is assumed that the natural loss of
neurons and their age-related changes increase the
organism’s vulnerability and contribute to aging or
even represents its primary cause. Age-related chang-
es in “dormant” oocytes in follicles and the depletion
of their pool, which is established in early ontogeny,
are considered the main factors underlying age-relat-
ed decline in fertility and the onset of the postmeno-
pausal period.
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BIOCHEMISTRY (Moscow) Vol. 91 No. 1 2026
However, stem cell precursors have been found
for both brain neurons and ovarian follicles [12, 13].
Like all stem cells, they are not subjects of proliferative
(Hayflick) limit and can effectively renew cellular com-
partments previously considered non-renewable. The
age-related decline in their cellularity is not related to
their “non-renewability,” because a similar reduction
in cell numbers (cytopenia) is also observed in tissues
with continuous turnover, such as the epidermis and
bone marrow. Importantly, these changes can be re-
versed at both tissue [14] and organ [15] levels. There
is also evidence of cardiomyopathy reversibility under
conditions reducing the load on the heart muscle, such
as after sessions of artificial circulation [16, 17].
These results, along with other evidence, suggest
that the root cause of systemic age-related cytopenia
is not an inherent inability of the organism’s cellular
compartments to self-maintain and self-repair. Most
likely, it arises from dysregulation of processes occur-
ring when the aging body operates outside the zone
of stability of its vital functions [8-11].
This explains the age-related decline in the poten-
tial for physiological and reparative regeneration; how-
ever, there is evidence that this decline is non-obligato-
ry, is regulated, and amenable to correction [8-11, 14].
CONCLUSION
Ideas akin to the concept of slow (non-obligato-
ry) phenoptosis have helped to answer the question
posed by Academician V. V. Frolkis: why do organisms
consisting of potentially non-aging cell lines actually
age? After all, their origins lie in tissue stem cells,
and like cancer cells, these cells have no limit on the
number of divisions. The renowned gerontologist Ber-
nard Strehler (USA) also believed that there is noth-
ing inherent in cells or multicellular organisms, that
would prevent them from functioning without aging.
But if the conditions necessary for such functioning
are not met, cells inevitably begin to age.
For example, it was demonstrated [18, 19] that
immortalized cells do not age under standard cultur-
ing conditions. Yet, under suboptimal conditions, even
these normally non-aging cells can undergo rapid ag-
ing [20], as evidenced by the exponential increase in
their mortality rate over time, consistent with the clas-
sic Gompertz law observed in humans and animals.
In 2025, this law of mathematical thanatology celebrat-
ed its 200th anniversary and remains a fundamental
tool for gerontologists and demographers alike.
Interestingly, it was also possible to create con-
ditions under which normally non-aging hydras [21]
begin to age, following the same classic Gompertz
law with an exponential increase in mortality rate
[22]. The mortality statistics across different coun-
tries, where populations live in diverse socio-eco-
nomic, climatic, and other conditions, reveal patterns
reminiscent of aging of hypothetically non-aging in-
dividuals [8]. Variations in conditions affect coordi-
nated changes of both parameters of the Gompertz
law, precisely following the trajectory away from the
boundaries of stable life activity (non-aging zone) in
the multidimensional space of the organismal states
in response to demands imposed by the external en-
vironment [23].
In fact, the kinetic patterns of human aging [8,
24] closely mirror those observed in non-aging hy-
dras under aging-inducing conditions. As civilization
progresses, humans are increasingly removed from
the pressure of natural environment and corre-
sponding behaviors, moving further away from the
non-aging zone. However, this shift occurs along with
civilizational reduction in baseline mortality, which
leads to the increase in the average life expectancy.
At the same time, the likelihood of extreme longevity
for individuals decreases due to the increase in the
kinetic parameter of the Gompertz law, i.e., faster in-
crease in the mortality rate with age. Nevertheless,
both the average and maximum lifespans of labora-
tory nematodes have been increased several times
by artificially minimizing both parameters (through
hypomorphic mutation of the regulatory genes daf-2
or age-1) [25, 26].
Acknowledgments
The author is grateful to Vladimir Petrovich Skulachev
and Anatoly Ivanovich Yashin for their long-standing
interest in this problem.
Funding
This work was supported by ongoing institutional
funding. No additional grants to carry out or direct
this particular research were obtained.
Ethics approval and consent to participate
This work does not contain any studies involving hu-
man or animal subjects.
Conflict of interest
The author of this work declares that he has no con-
flicts of interest.
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