REJUVENATION RESEARCH

Volume 24, Number 2, 2021

Mary Ann Liebert, Inc.
DOI: 10.1089/rej.2021.0018

Response to the Thought-Provoking Critique

of Hyperfunction Theory by Aubrey de Grey

Mikhail V. Blagosklonny

A rticulated in 2006, a new theory of aging initially had

no name.1 In brief, it is suggested that aging is not caused
by molecular damage but instead is a continuation of growth,
driven, in part, by hyperfunctional signaling pathways such as
mTOR (target of rapamycin).1 In 2013, David Gems, Yila de la
Guardia, and Linda Partridge named it ‘‘hyperfunction theo-
ry’’ for brevity,2,3 given its central term ‘‘hyperfunction.’’1
Aubrey de Grey noticed that my ‘‘first mistake was to
introduce a second name for the theory—the ‘‘quasi-
programmed’’ theory. I coined the term ‘‘quasi-programmed
aging’’ in 2006, as an alternative to both programmed and
stochastic aging. I emphasized that this quasi-program is the
unintended harmful purposeless continuation of the growth
program. A program of aging cannot exist from an evolu-
tionary perspective. I could not imagine at that time that the
term quasi-program would be conflated with the idea of a
‘‘program’’ of aging. But it is not only proponents of pro-
grammed aging, who exploited the term. Opponents of the
hyperfunction theory misinterpreted it as a programmed ag-
ing too. My articles were trashed by reviewers. Twelve years
ago, one reviewer, called the theory foolish, commenting that
not one serious scientist thinks that aging is programmed.
And it is not. I published the article entitled ‘‘Aging is not
programmed: genetic pseudo-program is a shadow of devel-
opmental growth.’’4 This did not help much.
The second criticism by de Grey is that I dismiss mo-
lecular damage (or ‘‘damage,’’ for brevity) theories without
defining the word ‘‘damage.’’ The reason is that, with a few
exceptions, damage theories do not define damage either.
According to Kirkwood, ‘‘the aging process is caused by
the gradual buildup of a huge number of individually tiny
faults—some damage to a DNA strand here, a deranged
protein molecule there, and so on.’’5 But what is ‘‘so on’’?
According to de Grey ‘‘Damage: any change in molecular
or cellular structure or composition that can occur to an
adult individual and that contributes to a reduction in
physiological performance.’’6
Some authors, in contrast, describe mild damage as an-
tiaging mechanisms (The paradox of hormesis could be
reconciled in the frame of hyperfunction theory7).
But lack of a universally accepted definition of damage is
not a significant issue, because most of us agree, when we
see it, on what is considered damage. We probably agree
that sunburns, DNA-strand breaks, telomere shortening,
protein misfolding, and crosslinking are damage, whereas
development and normal mitosis are not. Molecular damage
is typically unintended, random, harmful, irreversible, and,
importantly, possessing the ability to accumulate.
I do not want to impose my definition of damage on non-
hyperfunction theories. My only specific concern in defin-
ing this term is that normal signal transduction, which,
of course, involves a transient modification of molecules,
would not be called damage. Otherwise, everything will
be considered damage, any molecular interactions. Unlike
molecular damage, signal transduction does not accumulate,
is purposeful and intended, not random, and reversible.
Some opponents of hyperfunction theory define damage
so broadly that we may become confused about hyper-
function theory.8 For example, to dismiss hyperfunction
theory, Zimniak argued that intended protein phosphoryla-
tion during signal transduction is ‘‘damage.’’8 For example,
transient phosphorylation of S6 kinase by mTORC1 is
damage. If we will call normal signal transduction ‘‘dam-
age,’’ then, yes, hyperfunction theory is damage theory.9
In his critique, de Grey defines damage as ‘‘all progres-
sive changes.’’ This definition is too broad. Fortunately,
hyperfunction of signaling pathways can occur without
progressive changes of their activity. For example, when the
same activity of growth-promoting pathways remains un-
changed in postdevelopment, it is a hyperfunction. By
analogy, a car driving 65 mph on highway is not speeding
(hyperfunction) but driving 65 mph on the driveway is. In
the latter case, the car certainly will be damaged, but not by
rusting (molecular damage), but by damage of its macro-
parts. Similarly, hyperfunction does not cause molecular
damage, but causes organ damage. Thus, the brain is dam-
aged by stroke, which can be a result of hypertension,
which, in turn, is developed by hyperfunctional cells of
multiple tissues. There is no place for molecular damage in
this sequence of events: from the activity of signaling

Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Elm and Carlton Str, Buffalo, New York, USA.
ª Mikhail V. Blagosklonny 2021; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the
Creative Commons License [CC-BY] (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and re-
production in any medium, provided the original work is properly cited.

Correction added on June 10, 2021 after first online publication of April 19, 2021: The article reflects Open Access, with copyright
transferring to the author(s), and a Creative Commons License (CC-BY) added (http://creativecommons.org/licenses/by/4.0).

170
RESPONSE TO CRITIQUE OF HYPERFUNCTION
pathways that were not deactivated enough in post-
development to brain damage and death.
Except for hyperfunction theory, all theories, whether
programmed or stochastic, agree that ‘‘aging is functional
decline caused by accumulation of molecular damage.’’
Most articles on the subject start with this phrase. According
to hyperfunction theory, this would be the definition of
postaging. We know what postaging looks like in models of
accelerated aging: with mice dying from growth retardation,
bone marrow failure, and intestinal atrophy, accelerated
aging does not look like normal age-related diseases. Ac-
cording to hyperfunction theory, accumulation of damages
is slow and does not limit lifespan of normal animals.
De Grey argues ‘‘Thus, if there were indeed a type of
damage that accumulates so slowly that we’re already dead
from other causes (such as hyperfunction-driven mecha-
nisms) before it matters, then the genes whose action causes
it to accumulate so slowly will not experience significant
selection against mild mutations, so such mutations will
accumulate over evolutionary time, so the damage in
question will accumulate faster, until it indeed impacts
health at the same sort of age that everything else does.’’
As I understood this sentence as: damage-induced and
hyperfunctional aging should terminate life simultaneously.
This is a logical conclusion. One argument against this is
that damage-induced accelerated aging has distinct mani-
festations, such as bone marrow failure and intestinal atro-
phy, which are not major manifestations of normal aging.
But this argument is not sufficient and I think de Grey would
offer counterargument. There must be an explanation as to
why hyperfunctional aging occurs first and is life limiting.
I suggest that evolution selects both for slow damage-
induced aging and for fast hyperfunctional aging.
First, it is assumed that selection for good repair is needed to
delay aging. If so, selection would be relaxed, as de Grey men-
tioned. But nature does not care about aging. Rather, it selects for
good repair to avoid damages during embryogenesis, gameto-
genesis, and development early in life. Harmful damages may
interfere with fitness. [Note: de Grey himself proposed a similar
mechanism to prevent cancer early in life.10] Repair is needed for
something very early in life to avoid malformations and cancer
(or for something we have not thought about yet).
Second, in contrast, hyperfunctional mTOR is needed for
fitness early in life.11–13 Fitness early in life is so important that it
allows hyperfunctional aging to be manifested even in the wild.
The pressure to select for fitness early in life is so strong that
nature is powerless to eliminate it, despite the visible by-product
of accelerated hyperfunctional aging. This is why hyperfunc-
tional aging is life limiting in a protected environment, whereas
damage-induced aging is not. But the latter may become life
limiting, if humans will live 140 years, for instance. So, to
achieve the age of 1000 years, as de Grey envisions, it will indeed
be needed to treat damage-induced postaging.
The difference between average death from these two
‘‘agings’’ may be small, let say 30% (an arbitrary number).
And furthermore, some manifestations of nonlife-limiting
aging (postaging) may occur during over a lifetime, espe-
cially in supercentenarians.
De Grey disagrees with my claim that ‘‘mTOR expression
in adulthood is a prime example of hyperfunction..’’ De
Grey ‘‘can’t see how mTOR’s being a case of hyperfunction
can be reconciled with the finding that reducing its function
171
throughout life (via mutation), rather than only by adult-
onset pharmacological inhibition, also extends life.13’’
To reconcile, we should not forget the second name of the
theory ‘‘quasi-programmed.’’
The speed of aging is ‘‘quasi-programmed’’ in develop-
ment. By downregulating mTOR early in life, we can slow
down aging later is life. In normal mice, mTOR activity is
optimal for fitness (in a Darwinian sense), but hyperfunction
is not optimal for longevity (in a protected environment).
Nature does not care about longevity, only about fitness. So,
mTOR is too active for longevity, but perfect for fitness.
Life-long partial inactivation of mTOR by different
means11,13 (including and GH resistance11,12) renders mice
unfit and small. Reduced mTOR activity is suboptimal for
fitness, for reproduction, temperature, and anything. Such
animals are eliminated in the wild. But in a protected en-
vironment they manage to survive and live longer than
normal mice. Development is hardwired with aging (quasi-
programmed). Poor fitness is translated in slow aging and
longevity. In the wild, everything is about fitness. In a
protected environment (civilization), we are mostly con-
cerned about longevity.
I disagree with the belief that during famine, animals ac-
tivate damage repair to live longer and reproduce later. This
belief is the cornerstone of damage theories, because, in a
paradoxical way, it explains why limited resources during
famine are wasted on unneeded antiaging mechanisms.
However, I argue that animals could not care less about aging
during famine. First, aging does not limit life in nature, so
animals will not live longer anyway. During famine, it is a
useless waste of resources to fight aging. Animals do not die
from accumulation of molecular damage during starvation.
A straightforward explanation is that calorie restriction does
not fight damage-induced aging but instead inhibits the
nutrient-sensing mTOR pathway, not for the purpose of fu-
ture longevity, but for necessity, to save resources for im-
mediate survival. According to hyperfunction theory, there
are no longevity genes/mechanisms that require nutrients.
Repair enzymes are robust for a different purpose: activation
of certain pathways that drive aging (or, rather, this activation
is the aging process itself). And deactivation of nutrient-
sensing signaling decelerates hyperfunctional aging.
The most important criticism is overinterpretation of data
published in Ref.14 in my recent article that concluded ‘‘Failure
of rapamycin to extend lifespan in DNA repair mutant and
telomerase-knockout mice, while extending lifespan in normal
mice, indicates that neither DNA damage nor telomere short-
ening limits normal lifespan or causes normal aging.’’15 I sug-
gested that if normal aging is caused by molecular damage, then
rapamycin could not work in normal mice, because it does not
work in models where damage is certainly a cause of death.
De Grey offered an alternative explanation. This clever
explanation does not dismiss hyperfunction theory but re-
quires me to rule out the proposed mechanism before
jumping to conclusions. I rephrase de Grey’s long expla-
nation in a simple phrase: The Ercc repair enzyme is re-
quired for rapamycin to extend lifespan. This is a valid
hypothesis. But to make this hypothesis testable, we need an
exact mechanism. The simplest mechanism that could be
proposed is that rapamycin induces Ercc, and, obviously,
rapamycin cannot induce it when it is absent in mutant mice.
A brief PubMed search shows that inhibitors of mTOR
172
including rapamycin decrease, not increase, its level.16–18 Of
course, more complex mechanisms can be suggested, such
as Errc is required, but even its low activity is sufficient. So,
I cannot disprove this argument. In the same study, however,
inhibition of mTOR did not extend lifespan in another
mutant Xpg-/- mouse model, ‘‘carrying deficiencies in dif-
ferent DNA repair genes, ruling out that inability of rapa-
mycin to extend life span is somehow Ercc1-specific.’’14
In an additional study, with mice dying young from
telomere shortening, rapamycin even slightly shortened
lifespan while dramatically extending it in normal mice.19
Whereas de Grey’s (mechanistic) explanation would re-
quire three versions of mechanisms, my explanation re-
mains the same for all three cases: when mice die
unequivocally from damage, rapamycin cannot help.
Jokingly, I can define damage as ‘‘something not affected
by rapamycin.’’ Finally, there is evidence, unrelated to
rapamycin, showing that damage is not life limiting, as
discussed in the conclusion of Ref.15
I acknowledge that both hyperfunctional and damage-
induced aging occur in parallel, but the former is life lim-
iting for the reasons discussed here. Damage-induced aging
can be life limiting, when artificially accelerated or hyper-
functional aging is decelerated. Furthermore, I accept that
damage-induced aging may be life limiting in certain ani-
mals in special conditions, although I cannot name examples
right now. So, I am making steps to acknowledge damage as
potential cause of aging in some conditions. It seems that de
Grey too is halfway to accepting hyperfunction theory in
half. At least he accepts that hyperfunction and damage-
induced aging may terminate life at the same time. Also, he
accepts that one of the key assertions of hyperfunction
theory is that aging is not a risk factor of age-related dis-
eases,20 but that they are inseparable, almost the same. All
that is left for proponents of damage theories to accept is
that, in most cases, accumulation of damage is not life
limiting, and then everything will acquire perfect sense.
Most importantly, prevention and repair of damages will
extend life further when hyperfunction aging will be suffi-
ciently slowed down. Antidamage interventions will work,
extending life even further.
Author Disclosure Statement
No competing financial interests exist.
Funding Information
No funding was received for this article.
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Address correspondence to:
Mikhail V. Blagosklonny
Roswell Park Cancer Institute
Elm and Carlton Str.
Buffalo, NY 14263
USA
E-mail: blagosklonny@oncotarget.com
Received: March 30, 2021
Accepted: March 30, 2021