Biologia 72/5: 475—485, 2017

Section Cellular and Molecular Biology

DOI: 10.1515/biolog-2017-0064
Hypothesis

Why we age – a new evolutionary view

Igor Peregrim*
Faculty of Medicine, Department of Medical Physiology, Pavol Jozef Šafárik University in Košice, Trieda SNP 1, SK-04011,
Košice, Slovakia; e-mail: igor.peregrim1@upjs.sk

Abstract: This article introduces a new evolutionary theory of aging, which suggests that aging is the result of imperfections
in cell turnover in organisms. Some of the simplest animals demonstrate the strongest ability of cell renewal and therefore,
according to this theory, their aging often seems to be negligible. Evolutionarily related organisms (e.g. mammals) share
similar abilities in tissue cell turnover but they differ in the rates at which the process is performed. These rate differences
are more or less forced by the speed of irreversible damage (e.g. lipofuscin) increase in their cells. This speed is the result of
an evolutionary trade-off of “function vs. resistance to irreversible damage” in their cell molecules. The article also offers an
explanation of the differences in basal metabolic rate between different species. Put simply, while a trade-off in irreversible
damage plays a role in aging, the trade-off in reversible damage plays a role in basal metabolic rate.
Key words: aging; evolution; cell turnover; basal metabolic rate.
Abbreviations: AD, Alzheimer’s disease; BM, body mass; BMR, basal metabolic rate; CR, calorie restriction; DMD,
Duchenne muscular dystrophy; GH, growth hormone; Gpx1, glutathione peroxidase 1; IGF-1, insulin-like growth factor-1;
MLS, maximum lifespan; MOSTA, mitochondrial oxidative stress theory of aging; PUFAs, polyunsaturated fatty acids;
ROS, reactive oxygen species; Sod1, superoxide dismutase 1; SSA, senile systemic amyloidosis; TTR, transthyretin.

Why we age – a new evolutionary view
A wide range of research over the last decade has cast
serious doubts over the veracity of the mitochondrial
oxidative stress theory of aging (MOSTA), the theory
which argues that the aging process is a result of reac-
tive oxygen species (ROS) accumulation, a consequence
of mitochondrial activity in particular (Andziak et al.
2005; Vermulst et al. 2007; Pérez et al. 2009; Cabreiro
et al. 2011; Brown & Borutaite 2012; Edrey & Salmon
2014). Moreover, this theory seems to be flawed from
the perspective of evolutionary theory. For example,
proponents of MOSTA have suggested an evolution-
ary trade-off between expending energy on reproduc-
tion and expending energy on the inhibition of ROS
(Speakman & Garratt 2014); in reality, no such trade-
off is necessary in times of food surpluses, and labora-
tory studies have shown that calorie restriction can, in
fact, lead to prolonged lifespans in some species (Ma-
soro 2005). Those, who wish to deny the occurrence
of occasional food surpluses in nature, should at least
explain why satiety is also the result of evolution.
This article proposes a new theory of aging, which
is based on the well-known phenomenon of continual
irreversible damage accumulation in cells (Nowotny et
al. 2014). In the following section, the novel aspects of
the theory are presented in relation to earlier theories of
aging. The discussion section then contrasts the theory
with the current state of research into the aging process.
The theory
The constant origin of irreversible damage (or irrepara-
ble changes) can be seen in every cell, both in DNA
structures and also in other cell masses (e.g. lipofuscin,
the irreversible lipid-protein changes stored as “cellular
waste”). Multicellular organisms attempt to overcome
the effects of this continual increase in damage through
the creation of cells, basically stem cells, with two main
tasks: (i) the maximum protection of DNA integrity;
and (ii) the production of new cells to replace old ones.
This would imply three to four aspects as follows:
1. Organisms with the potential to recover per-
fectly from their stem cells (if we disregard occasional
mutations in their DNA) would theoretically be im-
mortal. Higher vertebrates (or more generally “evo-
lutionarily higher organisms”) are more complex and
have had less time to improve their recovery ability
than lower vertebrates (or “evolutionarily lower or-
ganisms”); therefore, at the same rate of tissue cell
turnover, they typically demonstrate higher tissue dis-
organization rate, i.e. faster aging.
2. When we compare evolutionarily related organ-
isms (i.e. those placed close to each other in a phy-

* Corresponding author


c 2017 Institute of Molecular Biology, Slovak Academy of Sciences Brought to you by | New York University
Authenticated
Download Date | 6/26/17 2:25 PM
476
logenetic tree, e.g. mammals), we find similar levels
of stem-cell ability/inability to recover tissues. In this
case, animals with higher rates of tissue cell turnover
(i.e. shorter cell lifespans) show quicker tissue disorga-
nization, i.e. faster aging.
3. There is an evolutionarily trade-off in some cell
molecules (typically proteins and lipids; see below) be-
tween their function and their resistance to irreversible
damage. Organisms, which prefer molecules with better
functional properties, accumulate higher levels of irre-
versible damage, which lead in turn to a more urgent
need for cell turnover from stem cells. This third point is
the molecular foundation of the antagonistic pleiotropy
theory of aging.
Another possible trade-off is in the speed of tissue
cell turnover, i.e. present lower level of irreversible dam-
age in cells (positive effect of higher speed) vs. quicker
increase of tissue disorganization due to stem cell im-
perfection (negative effect of higher speed).
These first three points offer a clear summation of
how the theory understands the concept of aging: it is
an increase of irreversible damage in cells and also an
increase in tissue disorganization due to adult stem cell
imperfections.
Lipofuscin, which is composed mainly of proteins
and lipids, is probably the most important component
of irreversible damage in cells. On the other hand, the
functioning of cells is mainly contained in the reactions
of proteins, which very often take place in the lipid bi-
layers. Therefore, the trade-off in the cell molecules be-
tween their function and their resistance to irreversible
damage can be simplified into the following relation:
function of cellular proteins and lipids vs. resistance to
lipofuscin increase in cells. The choice of investment in
some particular animal species is determined by its spe-
cific population turnover in nature, and this is in turn
determined by its specific traits, such as ability to fly
or move in trees, etc. (for more details, see the section
“Specific species traits vs. lifespan”).
4. A further point, which is more concerned with
age-related diseases rather than aging per se, could
also be considered. Death in nature is a result of a
combination of aging and a wide range of external
factors. Organisms in protected environments can live
longer. However, two problems arise: (A) due to the
fact that the DNA, during its evolution in one species,
has rarely or possibly never occurred in such differ-
ent organism’s internal environment (i.e. excessive lev-
els of irreversible damage in cells plus excessive tis-
sue disorganization), it would suggest that the DNA
has not been able to adapt to these circumstances;
age-related diseases, such as amyloidosis, osteoporo-
sis, macular degeneration or cataract are indicative
of the absence of this type of evolutionary adapta-
tion; and (B) due to the fact that the DNA, dur-
ing its evolution in one species, has rarely or possi-
bly never occurred in such long-lived organism (longer
time means a higher probability of mutations), it would
again suggest that the DNA has been unable to adapt
to these circumstances; the process of cancer is indica-
I. Peregrim
tive of the absence of this type of evolutionary adapta-
tion.
Generally, age-related diseases are only due to a
lack of selection at high age, which means that, unlike
aging per se, they can be explained with Medawar’s
theory.
The novelty of the theory
The exhaustion of stem cells is not a cause of aging
There is a widespread view that the exhaustion of stem
cells is largerly responsible for the aging process (López-
Otín et al. 2013; Oh et al. 2014; Ahmed et al. 2017).
However, this appears to be contradicted by observa-
tions. Elderly individuals have not been known to die
due to the exhaustion of hematopoietic or intestinal
stem cells (i.e. anaemia or inability to digest food), and
these are classic examples of rapidly dividing cells. Also,
I know of no study, which would suggest that blood do-
nation speeds up the aging process. Taking this into ac-
count, the problem with the exhaustion of other adult
stem cells should be largely negligible. Furthermore, we
may ask why adult stem cells should be expected to fail
given that embryonic stem cells can divide indefinitely.
The previously proposed trade-off between cancer and
adult stem cell exhaustion (Beausejour & Campisi 2006;
Sharpless & DePinho 2007) is critically discussed in the
section “Special discussion to point 4B”.
There are also some other theories, which do not
consider stem cell exhaustion to be involved in the ag-
ing process. However, to the best of my knowledge, they
do not offer any explanation of why organisms would
thereby lack the ability to renew themselves perma-
nently. As an example of this, we can mention the the-
ory of Khokhlov et al. (2013), which simply states that
cell turnover is limited in higher organisms and aging
is a consequence of the gradual accumulation of genetic
mutations in these non-renewing cells, especially neu-
rons and cardiomyocytes. However, if this were the case,
then we would expect all mammal species, from mice
to whales, to have similar maximum lifespans (MLSs).
According to the presented theory, the difference
between the stem cells of young and old individuals is
negligible. As was mentioned in point “1” above, ag-
ing is a consequence of the deficiency of stem cells to
recover tissues. Muscle tissue can be offered as an ex-
ample of this. The presented theory states that satellite
cells are roughly the same in both young and old indi-
viduals; however, due to their inherent imperfection,
the amount of fibrous and fat tissue and overall disor-
ganization increases in muscles with gradually increas-
ing cell turnover (Evans & Lexell 1995; Gallagher et al.
2005; Boettcher et al. 2009). Consequently, it follows
that individuals of the same species with a faster cell
turnover in muscles, such as those with Duchenne mus-
cular dystrophy (DMD), display a faster aging process
in their muscles (see also below “Special discussion to
point 2”).
As mentioned in points “1” and “2”, individual
species differ in their ability to recover tissues from stem
Brought to you by | New York University
Authenticated
Download Date | 6/26/17 2:25 PM
Why we age
cells. The evolution of ontogenesis always precedes the
evolution of tissue recovery from stem cells. Therefore,
as an example, the evolution of brain recovery in hu-
mans takes a shorter time than the evolution of nerve
system recovery in hydras. In addition to this, hydras
are able to reproduce faster (which results in an ac-
celerated rate of evolution) and their nerve system is
also simpler. It is therefore not surprising that the re-
covery ability of the Hydra nerve system is better than
that of humans (David 2012). Similar differences, al-
beit to a lesser extent, seem to be between higher and
lower vertebrates. Many studies support superior tis-
sue recovery abilities in fish and amphibians compared
to birds or mammals (although these are mainly in-
direct data regarding the ability to regenerate tissues
and organs after injuries) (Kishi et al. 2003; Raya et al.
2004; Godwin & Rosenthal 2014; Shi et al. 2015). Yet
despite the general tendency for better recovery abili-
ties in lower organisms, many exceptions probably exist
in the cases of simple organisms, such as Caenorhabdi-
tis elegans, which do not contain any adult stem cells
and therefore do not show any tissue cell turnover (see
“Special discussion to point 1”).
Species, which have especially both higher stem cell
abilities to recover tissues and also lower stem cell stim-
ulus to tissue recovery (i.e. to tissue cell turnover), show
slower rates of increase in tissue disorganization, which
means slower aging. In simplified terms, we can com-
pare this to copying a paper document, then copying
the copy, then copying the copy again, etc. The qual-
ity of the copier symbolizes the ability of stem cells
to renew tissue, the number of copies reflects the cell
turnover in the tissue, and new sheets of paper mean tis-
sue without irreversible damage, especially tissue with-
out lipofuscin, the age pigment (similar to brown stains,
or foxing, on books).
Identification of the real molecular foundation of Wil-
liams’s antagonistic pleiotropy theory of aging: the
trade-off between function and resistance to irreversible
damage of cell molecules (typically proteins and lipids)
There are two major evolutionary theories of aging.
Medawar’s theory considers the absence of selection as
the cause of aging, namely in the sense that organisms
in nature do not live to an advanced age (due to the ex-
ternal environment, e.g. predators); therefore the genes
responsible for signs of aging cannot be selected out
(Gavrilov & Gavrilova 2002). Williams’s antagonistic
pleiotropy theory assumes the existence of some trade-
off mechanism. It proposes the existence of genes with
pleiotropic effects: one effect of their effects offers some
type of functional advantage at a young age, while, in
contrast, a second effect results in some kind of func-
tional disadvantage (i.e. aging) at a later age (Gavrilov
& Gavrilova 2002). Various individual examples of ben-
eficial genes, which are known to cause harm among
the elderly [for example Alzheimer’s disease (AD)] are
offered as examples in support of this theory (Wick
et al. 2003). However, to the best of my knowledge
there is only one general and widely accepted biochem-
477
ical mechanism explaining Williams’s theory. It is de-
scribed by Kirkwood’s theory (Gavrilov & Gavrilova
2002). This theory assumes the existence of a trade-off
between energy put into reproduction and to tissue re-
covery or generally anti-aging processes. Although this
mechanism can be used beneficially in simple organisms
(see below in the section “Special discussion to point
1”), in more complex organisms it appears to be useful
only very exceptionally, such as in the case of salmon.
In nature, situations may occur where food supplies ex-
ist in such profusion that organisms could theoretically
eat and digest even more, but they could no longer
use it in a reasonable way. In these specific situations,
Kirkwood’s trade-off would not apply and anti-aging
processes would be able to run fully. Under laboratory
conditions, surpluses of food can be maintained indefi-
nitely, however, no extension of life has been observed
in this way. On the contrary, life can easily be pro-
longed by calorie restriction in some animals (Masoro
2005). Kirkwood’s theory is thus inapplicable for higher
animals, such as mammals.
As mentioned in the point “3”, the presented the-
ory proposes a trade-off between the function of cell
molecules (typically proteins and lipids) and their re-
sistance to irreversible damage (especially lipofuscin)
as the real molecular foundation of Williams’s theory
of aging. Lipofuscin makes up a large portion of non-
dividing cells (e.g. in neurons) in elderly individuals,
even in short-lived species such as rats; for example,
in the cerebral cortex neurons of lamina Vb it occu-
pies 23% of the soma volume in rats with ages of 630–
700 days (Samorajski et al. 1968; Brizzee & Johnson
1970). If it grows at the same rate in humans, it would
soon fill the entire neuron soma volume. The presented
theory assumes that rapid lipofuscin increases in mice
are a consequence of the specific structure of proteins
and lipids, and that their negative aspects are compen-
sated for (i.e. the trade-off) by their improved func-
tion in the body. Mice, due to their species traits, have
a rapid population turnover (see more below in “Spe-
cific species traits vs. lifespan”), which means that they
are unlikely to reach a higher age (e.g. more than 3-4
years) in nature. Therefore, for example, in compari-
son with humans, they prefer the improved function of
their molecules more than resistance against irreversible
damage.
The section “Special discussion to point 3” offers a
more detailed description of the trade-off of both pro-
teins and lipids in short- and long-lived animals. Here, I
will just briefly mention that according to several stud-
ies, long-lived species differ in their body composition
from short-lived ones. For example, those short-lived
show higher levels of polyunsaturated fatty acids (PU-
FAs) in their lipid bilayers and also higher amounts of
some amino acids (e.g. cysteine and methionine) in their
mitochondrial proteins. Why is that so? According to
the presented theory, these mentioned substances have
some functional benefits but, on the other hand, they
increase the probability of irreversible damage in cells.
The greater the increase of irreversible damage in
Brought to you by | New York University
Authenticated
Download Date | 6/26/17 2:25 PM
478
cells, the stronger the adult stem cell stimulus for tis-
sue cell turnover. The measure of the real response of
adult stem cells may be regarded as another aspect of
Williams’s theory, i.e. a faster tissue cell turnover means
momentarily less lipofuscin within cells; on the other
hand, from a long-term perspective, tissue disorganiza-
tion gradually increases.
Medawar’s theory of aging offers an adequate explana-
tion of age-related diseases (point “4”)
In fact, it is possible to state that Medawar’s theory
“implicitly” assumes that some aging has already oc-
curred. Indeed, for what reason should the deleterious
gene effects be activated in advanced age if no biochem-
ical changes (i.e. a lack of aging) have ever occurred in
the life of the body to date? As age-related diseases typ-
ically begin at advanced ages when the effects of the ag-
ing process are already obvious (see “Special discussion
to point 4A and 4B”), Medawar’s theory is adequate for
their explanation. The same applies if we attempt to ex-
plain age-related diseases, such as AD, using Williams’s
theory. It is simply as follows: a gene with some nega-
tive effect at advanced age (Medawar’s theory) is addi-
tionally associated with some positive function in the
body (Williams’s theory). According to the presented
theory, if a gene manifests negatively at advanced ages,
e.g. after 80 in humans, it is always Medawar’s theory of
aging, which appears to be valid, regardless of whether
the gene has any positive function in youth, because
its negative effect at later ages is already exempt from
the influence of selective pressure and therefore, from
an evolutionary point of view, we cannot talk about
the presence of a trade-off mechanism. From a practi-
cal point of view this means, for example, that genes
of age-related diseases do not differ from other genes
in terms of the importance of their positive function in
the body (if there is, in fact, any), because there is no
trade-off and their negative effect at advanced age is
purely accidental from an evolutionary point of view,
e.g. their selection from human genomes would have no
special negatives compared to other genes.
Point 4B is a special case involving only cancer,
the cause of which, unlike other age-related diseases, is
predominantly independent of aging. Its appearance is a
consequence of the gradual accumulation of mutations,
which is a function of time.
The main contribution of the presented theory is
likely in its general connection of evolutionary and bio-
chemical views of aging. The theory does not see any
evolutionary reason for “adult stem cell exhaustion”
(see above) or “insufficiency of antioxidant system” (the
function of antioxidant enzymes is to suppress the ag-
ing process, which means there can be no trade-off in
the sense of faster aging process, but on the other hand
an improved enzyme function). A wider acceptance of
the presented theory would therefore seem to influence
the further direction of biological research. For exam-
ple, the persistence of ideas about stem cell exhaustion
allows the continued belief that it is sufficient merely
to administer young stem cells to the body or to renew
I. Peregrim
old ones within the body to mitigate the aging pro-
cess or diseases related to it (Oh et al. 2014; Turner
& Knoepfler 2016; Ahmed et al. 2017; Kuriyan et al.
2017). Similarly, the concept of antioxidant system de-
ficiency supports the research into various external an-
tioxidants. It is theoretically true that levels of ROS in
cells even lower than those found under physiological
circumstances could have some pronounced anti-aging
benefits. For example, it is possible to consider the ex-
istence of some trade-off for different levels of ROS; just
hypothetically, the higher the level of ROS, the higher
the body resistance to different pathogens (similar to
higher core body temperature, which also accelerates
the aging process). In this case, each animal species
would maintain its own (i.e. specifically preferred) level
of ROS in the body. Independently, however, it has no
positive effect to flood the organism with high amounts
of antioxidants, which is supported by several studies
(Selman et al. 2006; Bjelakovic et al. 2014).
Discussion
Special discussion to point 1
The phyla of Porifera and Cnidaria contain some of the
simplest animals on Earth, and some of these species are
known to have lifespans of thousands of years (Roark
et al. 2009; Jochum et al. 2012). Moreover, some Hydra
species seem to undergo no aging (Martínez & Bridge
2012). Surprisingly, some of them, e.g. Hydra oligactis,
show increased mortality and physiological deteriora-
tion resembling aging after the stimulation of sexual
reproduction (Martínez & Bridge 2012). Nonetheless,
it is possible to offer an explanation of this by using
Kirkwood’s theory. If the aging process applies gener-
ally to all Hydra oligactis individuals, two claims would
seem to be true: (i) all food, which can be consumed
and digested, can also be metabolized by the body (typ-
ically, other organisms including humans would be able
to eat and digest much more than they can actually
use); and (ii) gamete production is preferred to tissue
cell turnover. Interestingly, the model organism C. ele-
gans does not contain any adult stem cells (Coffman
et al. 2016). Hypothetically, a rapid species popula-
tion turnover (see “Specific species traits vs. lifespan”)
means that the investment into them would not provide
any return – they require a certain amount of energy,
they also represent a kind of cellular mass, which the
organism must carry for life, and on the other hand, fail
to offer any substantial advantages.
The lifespan of zebrafish is approximately as long
as that of rats, yet the cell turnover of zebrafish my-
ocytes is so rapid that it is impossible to observe lipo-
fuscin granules in them over the entire lifetime of a ze-
brafish (Kishi et al. 2003). In addition to higher recov-
ery abilities in lower vertebrates (point “1”), this also
supports a trade-off in the speed of tissue cell turnover
(point “3”).
Special discussion to point 2
Several studies have suggested that tissue cell turnover
Brought to you by | New York University
Authenticated
Download Date | 6/26/17 2:25 PM
Why we age
is faster in short-lived mammals than in long-lived ones.
According to Rigamonti et al. (2011), 0.7% of human
cells and 4.8% of mice cells in adipose tissue show pos-
itive results for both Ki67 (marker of cell proliferation)
and C/EBPα (marker of preadipocytes) at any time.
The turnover period for thyroid follicular cells is 8.5–
14.4 years in humans, 1.75–2.5 years in dogs and about
0.5 year in rats, according to 3 H thymidine labelling
(Coclet et al. 1989). Studies by Dayer et al. (2005) and
Gould et al. (2001) have shown that cells in the neocor-
tex (with the exception of neurons) are 70 times more
labelled by the proliferation marker bromodeoxyuridine
in rats than in macaques (Cameron & Dayer 2008).
Individuals with premature aging syndromes seem
to exhibit reduced cell lifespans in their tissues and/or
(compare with point “1”) a reduced ability to recover
their tissues from stem cells (De Boer et al. 2002; Tyner
et al. 2002; Espada et al. 2008; Hiona et al. 2010; Zhang
et al. 2011; Brunauer & Kennedy 2015; see also Bern-
erd & Asselineau 1998; Gregg et al. 2012; Weidemann
et al. 2013). In DMD, a genetic disorder characterized
by a reduced myocyte lifespan, the premature aging is
restricted solely to the muscles; increases in fibrous tis-
sue and fat infiltration also occur as in normally aging
muscles but this takes place at a faster rate (Mora 1989;
Jennekens et al. 1991; Evans & Lexell 1995; Gallagher
et al. 2005; Boettcher et al. 2009). According to Boldrin
et al. (2015), the ability of satellite cells (muscle stem
cells) to regenerate muscles is similar in both the DMD-
model and wild-type mice, but it remains insufficient in
the former because of the pathological muscle environ-
ment. This is in accordance with the theory presented
in this article, which does not involve stem cell impair-
ment. The imperfection of stem cells results only in the
progressive deterioration of the tissue environment; nat-
urally, this altered environment also backwardly influ-
ences stem cells and their tissue regeneration ability,
which forms a circulus vitiosus in the aging process.
Special discussion to point 3
Point “3” is in accordance with the membrane pace-
maker theory of aging, which proposes that the fatty
acid composition of cell membranes, via its influence
on peroxidation of lipids, is an important determinant
of lifespan (Hulbert et al. 2007, 2014); this is especially
the case if we take into account that lipid peroxidation
is thought to be one of the major contributors to lipo-
fuscin accumulation in cells (Chowdhury et al. 2004).
As PUFAs, the main contributors to lipid peroxida-
tion in cell membranes, are also known to enhance and
speed up many membrane processes (Pinot et al. 2014;
Vásquez et al. 2014; Randall et al. 2015), it is possible
to hypothesize a specific trade-off for these PUFAs, i.e.
“enhancing and speeding up of many membrane pro-
cesses resulting in some higher abilities (e.g. greater
agility) of organism vs. higher susceptibility of mem-
branes to peroxidation damage resulting in speeding
up of irreversible damage (e.g. lipofuscin) accumula-
tion”. One recent study also suggests that, irrespective
of unsaturation effects, having long-chain fatty acids
479
in cell membranes is an important strategy in Aves to
achieve high longevity (Galván et al. 2015). There also
appear to be differences in the ways, in which some
of the amino acids (e.g. methionine, cysteine, threo-
nine) are contained in mitochondrial proteins in short-
and long-lived animals (Aledo et al. 2011; Kitazoe et
al. 2011; Seim et al. 2013; Mariadassou & Pellay 2014).
These findings of different particle composition in short-
and long-lived animals support the existence of some
lipid/protein trade-off between function and resistance
to irreversible damage. In the study by Jobson et al.
(2010), genes involved in fatty acid biosynthesis and
collagen composition showed a higher level of variabil-
ity in group of short-lived species than long-living ones;
this finding is in accordance with the presented the-
ory because organisms with long lifespans are expected
to avoid molecule structures, which contribute to irre-
versible damage.
Basal metabolic rate (BMR) vs. lifespan
The introduction of the concept “reversible damage (i.e.
adverse changes in the cell, but reversible if energy is
used)” allows us to explain the relationship between
MLS and BMR. Put simply, while irreversible damage
contributes to aging, reversible damage contributes to
BMR; as an example of this relationship, Saimiri sci-
ureus (MLS = 30.2 years, BMR = 5.3 mW/g; all data
of MLS and BMR in this article are from the AnAge
database; http://genomics.senescence.info/species/)
consists of more unstable molecules than Elephas max-
imus (MLS = 65.5 years, BMR = 0.6 mW/g), but the fi-
nal damage is predominantly reversible. In contrast, Re-
ithrodon auritus (MLS = 5.5 years, BMR = 5.4 mW/g)
also consists of many unstable molecules, however, their
damage is often irreversible. It is worth mentioning that
the half-life of rat skin collagen is 74 days, while the
half-life of human skin collagen is 14.8 years (BMR of
rats = 6.8 mW/g, BMR of humans = 1.2 mW/g) (Ruck-
lidge et al. 1992; Verzijl et al. 2000). Reversible damage
could also explain different BMR values between en-
dothermic and ectothermic organisms.
Specific species traits vs. lifespan
It is known that species with higher body mass or which
possess some specific skills (for example the ability to
fly or to move in trees, eusociality or higher forms of
sociality typical especially for humans) exhibit longer
MLSs (Healy et al. 2014; Healy 2015; Williams & Shat-
tuck 2015). This is generally explained by their higher
resistance to predation or even to unfavourable condi-
tions, which they can endure, e.g. protection against
cold in eusocial animals (Buffenstein & Edrey 2009;
Healy et al. 2014; Williams & Shattuck 2015). How-
ever, it is also known that long-lived species produce
fewer progeny per year and also exhibit slower post-
natal growth rate (Wilkinson & South 2002; De Ma-
galhăes et al. 2007). This means that long-lived ani-
mals are also exposed to lower pressure from young in-
dividuals of the same species. Moreover, it seems that
the level of this intra-species “young-adult” competi-
Brought to you by | New York University
Authenticated
Download Date | 6/26/17 2:25 PM
480
tion is also influenced by the body mass and the above-
mentioned specific skills. The long-lived and eusocially
living naked mole rats (MLS = at least 31.0 years) rep-
resent an interesting example of this; although these
individuals can reproduce quickly, typically only one
female within the group of the average size of 75 mem-
bers is fertile at any one time (Buffenstein & Edrey
2009), and therefore new competition for adult indi-
viduals develops slowly. Smaller herbivores usually ex-
hibit increased litter sizes due to the fact that they
can hide their poorly-developed young deep within their
burrows. Small animals can also grow quickly, e.g. fe-
male mice and rats reach sexual maturity on 42nd and
90th day (Mus musculus and Rattus norvegicus), respec-
tively (http://genomics.senescence.info/species/). On
the other hand, maturity can be delayed by the need
to acquire specific skills. We can conclude that some
species traits influence adult resistance/exposure to
young individuals as well as to predators and various
ambient conditions, such as cold or dry, and that this
results in species specific population turnover rates. Ac-
cording to the theory presented here, this phenomenon
has a direct impact on trade-offs: “function vs. resis-
tance to irreversible damage” of molecules; organisms
whose lifespan is more limited by their species traits
tend to focus more into function of their molecules and
vice versa. Similarly, the trade-off of “function vs. re-
sistance to reversible damage” of molecules differs in
animals with high and low body mass because those
with high body mass must avoid high BMR due to the
accumulation of heat in their body.
Caloric restriction vs. lifespan
Caloric, protein or some amino acid (methionine, tryp-
tophan) restriction is known to extend lifespans in ro-
dent models (Mirzaei et al. 2014). The sub-nutrition
caused by these diets inhibits or even disables repro-
duction, which indicates that it may be evolutionar-
ily advantageous for organisms to activate some trade-
off in order to achieve a longer lifespan; this suggests
the influence of reproductive rate on the aging process
not only in different species (as mentioned above in
“Specific species traits vs. lifespan”) but also in one
individual species. As the variability of “food abun-
dance vs. deficiency” in the external environment is
greater between 2-year cycles than between 20-year
cycles, it even suggests that some trade-off involved
in longevity is more likely to have evolved in rodents
than in, for example, monkeys. In the study of Jové
et al. (2014), calorie restriction (CR) significantly de-
creased the total number of fatty acid double bonds
in mouse livers through decreasing PUFA levels and
increasing monounsaturated fatty acid levels. Reduc-
tions in body temperature have also been found in con-
nection to CR (Keil et al. 2015). As it is well known,
higher temperatures generally speed up chemical re-
actions, and this is, of course, also true for those in-
volved in increase of irreversible damage. Reductions
in body temperature are also known to inhibit lipo-
fuscin formation (Sheehy 2002; Valenzano et al. 2006)
I. Peregrim
and to prolong lifespan (Conti et al. 2006). Interest-
ingly, naked mole rats likely exhibit both the longest
lifespan and the lowest body temperature (32.1 ◦C;
http://genomics.senescence.info/species/) among ro-
dents (Keil et al. 2015). Since low body temperature has
also many negative effects (Kluger et al. 1998; Frazier
et al. 2006; James 2013), it is possible to assume that
some trade-off between longevity and body tempera-
ture exists. However, under conditions of methionine
restriction, in which the organism has enough energy to
maintain body temperature, no sign of decreased body
temperature was found (Hasek et al. 2010); therefore,
reductions in body temperature during CR is likely to
be a passive process. According to the presented theory,
changes in membrane fatty acids (probably a result of
trade-off) and body temperature decline (probably a re-
sult of a passive process) together suppress an increase
in irreversible damage during CR; this process inhibits
apoptosis in tissues and consequently also restricts cell
turnover from stem cells. Several studies have found
suppressed apoptosis in different tissues (neurons, kid-
neys, liver, somatic muscles) under caloric restriction
in rodents (Sinclair 2005; Marzetti et al. 2009), while
other research has reported enhanced apoptosis, which
is thought to be a mechanism for the suppression of
cancer (Dunn et al. 1997; Sinclair 2005).
Decreased PUFA levels vs. lifespan
Interestingly, life-long treatment with atenolol de-
creased membrane fatty acid unsaturation in mice,
but this was not matched by any change in longevity
(Gómez et al. 2014). Apoptosis inhibition was probably
also not achieved as the level of apoptosis-inducing fac-
tor had not changed (Gómez et al. 2014). It seems that
the mice had maintained their cell turnover at the level
of the assumed population turnover and that this had
occurred in spite of the low level of irreversible damage
in cells. As it also seems to be the case for zebrafish (see
“Special discussion to point 1” above), it is likely that
there was a preference for a lower present level of irre-
versible damage in cells over slower aging. It should be
mentioned here that under optimal husbandry condi-
tions, wild-type mice and some of those with an im-
paired antioxidant defence system (e.g. Sod2+/− or
Gpx1−/− mice) share the same lifespan (Pérez et al.
2009), a finding which suggests a similarity with the
relationship between recipients and non-recipients of
atenolol. This is especially true when we consider that
the combination of optimal husbandry conditions and
impaired antioxidant defence system may better reflect
the conditions, which occur in nature; life-long optimal
levels of vitamins and micronutrients or pathogen-free
conditions are, of course, non-typical in the natural en-
vironment.
Special discussion to point 4A
Amyloidoses such as AD and senile systemic amyloido-
sis (SSA) are a good example of age-related diseases.
Some controversy exists over the cause of AD (Herrup
2015; Kumar et al. 2016) but it is important to note
Brought to you by | New York University
Authenticated
Download Date | 6/26/17 2:25 PM
Why we age
here that although the incidence of AD increases with
age from about 1.5–2.0 per 1,000 persons at age 65–69
to about 50 per 1,000 persons at age 90 and over (Di
Carlo et al. 2002; Bermejo-Pareja et al. 2008), some
individuals do not develop Aβ pathology no matter
how long they live (Mizutani & Shimada 1992). There
is one case report of a 115-year-old woman, who was
not clinically demented during life and whose brain, on
autopsy, showed almost no Aβ plaques (den Dunnen
et al. 2008). Similarly, diseases such as osteoporosis or
cataract are very common (44% and 88%, respectively)
in supercentenarians, i.e. humans who are older than
110, but these illnesses are not found in all supercente-
narians (Schoenhofen et al. 2006). Limited data indi-
cates that SSA is the most typical cause of death in
supercentenarians; the disease is characterized by grad-
ual transthyretin (TTR) amyloid deposition in blood
vessels resulting in heart failure (Leslie 2008). Interest-
ingly, TTR null mice display no obvious phenotypic ab-
normalities postnatally and their longevity and fertility
do not differ from that of wild-type mice (Episkopou et
al. 1993). This suggests that the elimination of genes,
which predispose for SSA in humans would have no
negative (or only negligible) effects at young ages.
Special discussion to point 4B
If we take into account MLS and body mass (BM) of
both whales (Balaena mysticetus, MLS = 211 years,
BM = 100 tons) and mice (Mus musculus, MLS = 4
years, BM = 20.5 g; http://genomics.senescence.info/
species/), they suggests that whales are a quarter bil-
lion times more resistant to cancer than mice. Moreover,
some rodents have been found to exhibit two different
levels of cancer resistance; the first level is active with
sufficient food, whereas the second one is activated in
tandem with the above-mentioned aging inhibiting pro-
cesses under conditions of CR (Herranz et al. 2010; Lv
et al. 2014). This indicates that the cancer resistance
of a species is stabilized by selective pressure on the
level, which is just enough for a typical lifespan in na-
ture due to aging and external factors. Returning to
point “2” of the presented theory, this would also sug-
gest that there is no such thing as a “limit of stem
cell proliferation resulting in stem cell exhaustion and
subsequent tissue aging, all of which is due to cancer
suppression” (Beausejour & Campisi 2006; Sharpless &
DePinho 2007). If this was so, rodents, for example,
could theoretically increase the proliferation limit of
their stem cells by several 100 times and exchange it for
a different kind of resistance to cancer. As it has been
shown previously, this is an area, which shows great po-
tential for such a development. For example, one simple
possibility would be to multiply the p53 genes in DNA
(García-Cao et al. 2002).
The special discussion to point “4” (4A and 4B)
shows characteristic signs of Medawar’s theory (i.e. the
lack of selection at high age) in age-related diseases,
i.e. (i) their negligible occurrence at young ages and
a strong increase in old age; nonetheless 100% repre-
sentation in human population is not even reached at
481
the highest ages (in contrast to the general gradual in-
crease in aging such as lipofuscin in cells, fibrous tissue
in muscles or presbyopia); and (ii) the removal of these
diseases from the population would have no negative
(or only negligible) effects at young ages.
Interestingly, some species traits are able to bal-
ance the negative impact of aging on the mortality
rate in nature. The life-long growth of the organism
seems to have a particularly strong effect in this re-
spect. Some species with this trait, such as the turtle
Gopherus agassizii, even show an age-related deceler-
ation in mortality rate (Jones et al. 2014). Mammals
do not display lifelong body growth, but in eusocially
living naked mole rats, breeders can gradually increase
their colony of workers (i.e. induce the growth of the
colony), the turnover of which has, in addition, the same
effect as if they had not aged (the lifespan of workers
in nature is around 4 times shorter than that of breed-
ers). Under laboratory conditions, naked mole rats do
not show the typical age-related acceleration in mor-
tality risk that characterizes every other known mam-
malian species. They can therefore be seen as a species,
in which the mechanism described by Medawar’s the-
ory is strongly inhibited. The aging process is clear, e.g.
signs of heart fibrosis as well as increases of lipofuscin in
various organs are obvious, but it remains problematic
to determine the precise cause of death. In laboratory
rodents, such as mice or rats, the typical cause of death
is cancer or renal failure. In aged naked mole rats, very
little pathology has been observed in the kidneys and
spontaneous neoplasia seems to be extremely rare. Fur-
thermore, clinical manifestations of heart disease have
not yet been observed (Edrey et al. 2011; Grimes et al.
2012; Taylor et al. 2017).
Treatments for aging
As follows from the section “Caloric restriction vs. lifes-
pan”, it will be harder to prolong life in humans than in
short-lived species, such as rats or mice. In both of these
cases three factors seem to be required: (i) a change in
the lipid composition in cell membranes (e.g. through
the effect of atenolol; see Gómez et al. 2014) or the in-
hibition of irreversible damage accumulation in cells by
some other way (e.g. by lowering the core body tem-
perature; see Sheehy 2002; Conti et al. 2006; Valenzano
et al. 2006); (ii) an increase in resistance against can-
cer; and especially (iii) an inhibition of cell turnover in
tissues. However, in rodents special genes have already
been prepared for all of these effects – the genes, which
are activated in times of starvation.
Interestingly, there is some evidence that CR re-
duces the incidence of cancer in macaques (Mattison
et al. 2012; Colman et al. 2014), i.e. in long-lived an-
imals. This could be explained as a defence against
mutagenic substances, such as some mycotoxins (De
Ruyck et al. 2015), the intake of which is more likely,
i.e. more expected by animals, in times of shortage. It
is useful here to compare Laron mice with Laron syn-
drome in humans. In both cases, the growth hormone
(GH) / insulin-like growth factor-1 (IGF-1) pathway is
Brought to you by | New York University
Authenticated
Download Date | 6/26/17 2:25 PM
482
strongly inhibited, and this is a process, which is also
present during CR. Laron mice live about 40% longer
than wild-type mice (Coschigano et al. 2000). Patients
with Laron syndrome show a lower incidence of can-
cer, and possibly even slower cell turnover (IGF-1 is
a well-known proliferation promoter; Suh et al. 2008),
but they also suffer a range of adverse aspects, which
can ultimately limit the lifespans of sufferers; indeed,
no prolongation of lifespan has been observed to date
among sufferers of this genetic disorder (Laron 2008;
Laron et al. 2016).
Even if we were able to transfer the “positive ef-
fects of starvation in rodents” into humans, according
to the presented theory, this would result in some neg-
ative aspects at young ages. It is therefore questionable
whether people would prefer a longer MLS over, for ex-
ample, reduced overall agility or even intellect in their
youth. We can also try to increase the resistance to age-
related diseases as observed in naked mole rats, or even
to improve tissue recovery abilities, such as those exhib-
ited by zebrafish. Both approaches would have many
benefits but they would not lead to a deceleration in
irreversible damage accumulation in neurons.
In conclusion, I would like to suggest specific
research topics, which could support or refute this
new theory. It is of particular importance to compare
cell turnover of different tissues between evolutionar-
ily related animals differing substantially in MLS but
only minimally in BMR, e.g. (i) rats vs. naked mole
rats; (ii) rodents vs. bats; or (iii) quails vs. parrots. Sim-
ilarly, it would be of great value to discover whether dif-
ferent knockout, transgenic, mutant and drug-receiving
(e.g. atenolol or resveratrol) rodents with changed or
normal longevity differ from each other in terms of cell
turnover. Moreover, some other animal models could
be prepared, in which adult somatic cells exhibit en-
hanced apoptosis, but adult stem cells are certainly
unchanged as can be seen in, for example, DMD mice
muscles. It would also be useful to find out if there are
any general differences in the structure of proteins in
various cellular compartments (not only mitochondrial)
between long- and short-lived animals, and also be-
tween organisms with higher and lower levels of BMR.
The lifespan of rats or mice under caloric restriction
should also be studied in relation to different ambi-
ent temperatures (body-weight, metabolic rate, IGF-1,
level of lipofuscin in different tissues, core body tem-
perature and MLS should be measured and their re-
lationship determined). According to this theory, no
effect of caloric restriction on MLS should be found
in long-lived animals; alternatively, only a small dif-
ference should be recorded, e.g. as the result of lower
body temperature or the lower incidence of some dis-
eases (or also as the result of over-nutrition in control
group).
Conflict of interest
The author has no conflict of interest in this work.
I. Peregrim
References
Ahmed A.S.I., Sheng M.H., Wasnik S., Baylink D.J. & Lau
K.H.W. 2017. Effect of aging on stem cells. World J. Exp.
Med. 7: 1–10.
Aledo J.C., Li Y., De Magalhăes J.P., Ruíz-Camacho M. & Pérez-
Claros J.A. 2011. Mitochondrially encoded methionine is in-
versely related to longevity in mammals. Aging Cell 10: 198–
207.
Andziak B., O’Connor T.P. & Buffenstein R. 2005. Antioxidants
do not explain the disparate longevity between mice and the
longest-living rodent, the naked mole-rat. Mech. Ageing Dev.
126: 1206–1212.
Beausejour C.M. & Campisi J. 2006. Ageing: balancing regener-
ation and cancer. Nature 443: 404–405.
Bermejo-Pareja F., Benito-León J., Vega S., Medrano M.J.,
Román G.C. & Neurological Disorders in Central Spain
(NEDICES) Study Group. 2008. Incidence and subtypes of
dementia in three elderly populations of central Spain. J. Neu-
rol. Sci. 264: 63–72.
Bernerd F. & Asselineau D. 1998. UVA exposure of human skin
reconstructed in vitro induces apoptosis of dermal fibroblasts:
subsequent connective tissue repair and implications in pho-
toaging. Cell Death Differ. 5: 792–802.
Bjelakovic G., Nikolova D. & Gluud C. 2014. Antioxidant sup-
plements and mortality. Curr. Opin. Clin. Nutr. Metab. Care
17: 40–44.
Boettcher M., Machann J., Stefan N., Thamer C., Häring H.U.,
Claussen C.D., Fritsche A. & Schick F. 2009. Intermuscular
adipose tissue (IMAT): association with other adipose tissue
compartments and insulin sensitivity. J. Magn. Reson. Imag-
ing 29: 1340–1345.
Boldrin L., Zammit P.S. & Morgan J.E. 2015. Satellite cells
from dystrophic muscle retain regenerative capacity. Stem
Cell Res. 14: 20–29.
Brizzee K.R. & Johnson F.A. 1970. Depth distribution of lipo-
fuscin pigment in cerebral cortex of albino rat. Acta Neu-
ropathol. 16: 205–219.
Brown G.C. & Borutaite V. 2012. There is no evidence that mi-
tochondria are the main source of reactive oxygen species in
mammalian cells. Mitochondrion 12: 1–4.
Brunauer R. & Kennedy B.K. 2015. Progeria accelerates adult
stem cell aging. Science 348: 1093–1094.
Buffenstein R. & Edrey Y.H. 2009. Slow aging: insights from
an exceptionally long-lived rodent, the naked mole-rat, pp.
141–156. In: Sell C., Lorenzini A. & Brown-Borg H.M. (eds),
Life-Span Extension: Single-Cell Organisms to Man. Humana
Press, NY, USA.
Cabreiro F., Ackerman D., Doonan R., Araiz C., Back P., Papp
D., Braeckman B.P. & Gems D. 2011. Increased life span
from overexpression of superoxide dismutase in Caenorhab-
ditis elegans is not caused by decreased oxidative damage.
Free Radic. Biol. Med. 51: 1575–1582.
Cameron H.A. & Dayer A.G. 2008. New interneurons in the adult
neocortex: small, sparse, but significant? Biol. Psychiatry 63:
650–655.
Chowdhury P.K., Halder M., Choudhury P.K., Kraus G.A., De-
sai M.J., Armstrong D.W., Casey T.A., Rasmussen M.A. &
Petrich J.W. 2004. Generation of fluorescent adducts of mal-
ondialdehyde and amino acids: toward an understanding of
lipofuscin. Photochem. Photobiol. 79: 21–25.
Coclet J., Foureau F., Ketelbant P., Galand P. & Dumont J.E.
1989. Cell population kinetics in dog and human adult thy-
roid. Clin. Endocrinol. 31: 655–666.
Coffman J.A., Rieger S., Rogers A.N., Updike D.L. & Yin V.P.
2016. Comparative biology of tissue repair, regeneration and
aging. npj Regener. Med. 1: 16003.
Colman R.J., Beasley T.M., Kemnitz J.W., Johnson S.C., Wein-
druch R. & Anderson R.M. 2014. Caloric restriction reduces
age-related and all-cause mortality in rhesus monkeys. Nat.
Commun. 5: 3557.
Conti B., Sanchez-Alavez M., Winsky-Sommerer R., Morale
M.C., Lucero J., Brownell S., Fabre V., Huitron-Resendiz S.,
Henriksen S., Zorrilla E.P., de Lecea L. & Bartfai T. 2006.
Brought to you by | New York University
Authenticated
Download Date | 6/26/17 2:25 PM
Why we age
Transgenic mice with a reduced core body temperature have
an increased life span. Science 314: 825–828.
Coschigano K.T., Clemmons D., Bellush L.L. & Kopchick J.J.
2000. Assessment of growth parameters and life span of
GHR/BP gene-disrupted mice. Endocrinology 141: 2608–
2613.
David C.N. 2012. Interstitial stem cells in Hydra: multipotency
and decision-making. Int. J. Dev. Biol. 56: 489–497.
Dayer A.G., Cleaver K.M., Abouantoun T. & Cameron H.A.
2005. New GABAergic interneurons in the adult neocortex
and striatum are generated from different precursors. J. Cell
Biol. 168: 415–427.
De Boer J., Andressoo J.O., de Wit J., Huijmans J., Beems R.B.,
van Steeg H., Weeda G., van der Horst G.T., van Leeuwen
W., Themmen A.P., Meradji M. & Hoeijmakers J.H. 2002.
Premature aging in mice deficient in DNA repair and tran-
scription. Science 296: 1276–1279.
De Magalhăes J.P., Costa J. & Church G.M. 2007. An analysis
of the relationship between metabolism, developmental sched-
ules, and longevity using phylogenetic independent contrasts.
J. Gerontol. A Biol. Sci. Med. Sci. 62: 149–160.
De Ruyck K., De Boevre M., Huybrechts I. & De Saeger S. 2015.
Dietary mycotoxins, co-exposure, and carcinogenesis in hu-
mans: short review. Mutat. Res. Rev. Mutat. Res. 766: 32–
41.
den Dunnen W.F., Brouwer W.H., Bijlard E., Kamphuis J., van
Linschoten K., Eggens-Meijer E. & Holstege G. 2008. No dis-
ease in the brain of a 115-year-old woman. Neurobiol. Aging
29: 1127–1132.
Di Carlo A., Baldereschi M., Amaducci L., Lepore V., Bracco L.,
Maggi S., Bonaiuto S., Perissinotto E., Scarlato G., Farchi
G. & Inzitari D. 2002. Incidence of dementia, Alzheimer’s
disease, and vascular dementia in Italy. The ILSA Study. J.
Am. Geriatr. Soc. 50: 41–48.
Dunn S.E., Kari F.W., French J., Leininger J.R., Travlos G.,
Wilson R. & Barrett J.C. 1997. Dietary restriction reduces
insulin-like growth factor I levels, which modulates apopto-
sis, cell proliferation, and tumor progression in p53-deficient
mice. Cancer Res. 57: 4667–4672.
Edrey Y.H. & Salmon A.B. 2014. Revisiting an age-old question
regarding oxidative stress. Free Radic. Biol. Med. 71: 368–
378.
Edrey Y.H., Hanes M., Pinto M., Mele J. & Buffenstein R. 2011.
Successful aging and sustained good health in the naked mole
rat: a long-lived mammalian model for biogerontology and
biomedical research. ILAR J. 52: 41–53.
Episkopou V., Maeda S., Nishiguchi S., Shimada K., Gaitanaris
G.A., Gottesman M.E. & Robertson E.J. 1993. Disruption of
the transthyretin gene results in mice with depressed levels of
plasma retinol and thyroid hormone. Proc. Natl. Acad. Sci.
USA 90: 2375–2379.
Espada J., Varela I., Flores I., Ugalde A.P., Cadińanos J., Pendás
A.M., Stewart C.L, Tryggvason K., Blasco M.A., Freije J.M.P
& López-Otín C. 2008. Nuclear envelope defects cause stem
cell dysfunction in premature-aging mice. J. Cell Biol. 181:
27–35.
Evans W.J. & Lexell J. 1995. Human aging, muscle mass, and
fiber type composition. J. Gerontol. A Biol. Sci. Med. Sci.
50: 11–16.
Frazier M.R., Huey R.B. & Berrigan D. 2006. Thermodynamics
constrains the evolution of insect population growth rates:
“warmer is better”. Am. Nat. 168: 512–520.
Gallagher D., Kuznia P., Heshka S., Albu J., Heymsfield S.B.,
Goodpaster B., Visser M. & Harris T.B. 2005. Adipose tissue
in muscle: a novel depot similar in size to visceral adipose
tissue. Am. J. Clin. Nutr. 81: 903–910.
Galván I., Naudí A., Erritzøe J., Møller A.P., Barja G. & Pam-
plona R. 2015. Long lifespans have evolved with long and
monounsaturated fatty acids in birds. Evolution 69: 2776–
2784.
García-Cao I., García-Cao M., Martín-Caballero J., Criado L.M.,
Klatt P., Flores J.M., Weill J.C., Blasco M.A. & Serrano M.
2002. ‘Super p53’ mice exhibit enhanced DNA damage re-
sponse, are tumor resistant and age normally. EMBO J. 21:
6225–6235.
483
Gavrilov L.A. & Gavrilova N.S. 2002. Evolutionary theories of
aging and longevity. Sci. World J. 2: 339–356.
Godwin J.W. & Rosenthal N. 2014. Scar-free wound healing and
regeneration in amphibians: immunological influences on re-
generative success. Differentiation 87: 66–75.
Gómez A., Sánchez-Roman I., Gomez J., Cruces J., Mate I.,
Lopez-Torres M., Naudi A., Portero-Otin M., Pamplona R.,
De la Fuente M. & Barja G. 2014. Lifelong treatment with
atenolol decreases membrane fatty acid unsaturation and
oxidative stress in heart and skeletal muscle mitochondria
and improves immunity and behavior, without changing mice
longevity. Aging Cell 13: 551–560.
Gould E., Vail N., Wagers M. & Gross C.G. 2001. Adult-
generated hippocampal and neocortical neurons in macaques
have a transient existence. Proc. Natl. Acad. Sci. USA 98:
10910–10917.
Gregg S.Q., Gutiérrez V., Rasile Robinson A., Woodell T., Nakao
A., Ross M.A., Michalopoulos G.K., Rigatti L., Rothermel
C.E., Kamileri I., Garinis G., Stolz D.B. & Niedernhofer L.J.
2012. A mouse model of accelerated liver aging caused by a
defect in DNA repair. Hepatology 55: 609–621.
Grimes K.M., Lindsey M.L., Gelfond J.A. & Buffenstein R. 2012.
Getting to the heart of the matter: age-related changes in
diastolic heart function in the longest-lived rodent, the naked
mole rat. J. Gerontol. A Biol. Sci. Med. Sci. 67: 384–394.
Hasek B.E., Stewart L.K., Henagan T.M., Boudreau A., Lenard
N.R., Black C., Shin J., Huypens P., Malloy V.L., Plaisance
E.P., Krajcik R.A., Orentreich N. & Gettys T.W. 2010. Di-
etary methionine restriction enhances metabolic flexibility
and increases uncoupled respiration in both fed and fasted
states. Am. J. Physiol. Regul. Integr. Comp. Physiol. 299:
R728–R739.
Healy K. 2015. Eusociality but not fossoriality drives longevity
in small mammals. Proc. Biol. Sci. 282: 20142917.
Healy K., Guillerme T., Finlay S., Kane A., Kelly S.B., McClean
D., Kelly D.J., Donohue I., Jackson A.L. & Cooper N. 2014.
Ecology and mode-of-life explain lifespan variation in birds
and mammals. Proc. R. Soc. B 281: 20140298.
Herranz D., Muńoz-Martin M., Cańamero M., Mulero F.,
Martinez-Pastor B., Fernandez-Capetillo O. & Serrano M.
2010. Sirt1 improves healthy ageing and protects from
metabolic syndrome-associated cancer. Nat. Commun. 1: 3.
Herrup K. 2015. The case for rejecting the amyloid cascade hy-
pothesis. Nat. Neurosci. 18: 794–799.
Hiona A., Sanz A., Kujoth G.C., Pamplona R., Seo A.Y., Hofer
T., Someya S., Miyakawa T., Nakayama C., Samhan-Arias
A.K., Servais S., Barger J.L., Portero-Otín M., Tanokura M.,
Prolla T.A. & Leeuwenburgh C. 2010. Mitochondrial DNA
mutations induce mitochondrial dysfunction, apoptosis and
sarcopenia in skeletal muscle of mitochondrial DNA mutator
mice. PloS One 5: e11468.
Hulbert A.J., Kelly M.A. & Abbott S.K. 2014. Polyunsaturated
fats, membrane lipids and animal longevity. J. Comp. Physiol.
B 184: 149–166.
Hulbert A.J., Pamplona R., Buffenstein R. & Buttemer W.A.
2007. Life and death: metabolic rate, membrane composition,
and life span of animals. Physiol. Rev. 87: 1175–1213.
James R.S. 2013. A review of the thermal sensitivity of the me-
chanics of vertebrate skeletal muscle. J. Comp. Physiol. B
183: 723–733.
Jennekens F.G.I, Ten Kate L.P., De Visser M. & Wintzen A.R.
1991. Diagnostic criteria for Duchenne and Becker muscular
dystrophy and myotonic dystrophy. Neuromuscul. Disord. 1:
389–391.
Jobson R.W., Nabholz B. & Galtier N. 2010. An evolutionary
genome scan for longevity-related natural selection in mam-
mals. Mol. Biol. Evol. 27: 840–847.
Jochum K.P., Wang X., Vennemann T.W., Sinha B. & Müller
W.E. 2012. Siliceous deep-sea sponge Monorhaphis chuni:
a potential paleoclimate archive in ancient animals. Chem.
Geol. 300: 143–151.
Jones O.R., Scheuerlein A., Salguero-Gómez R., Camarda C.G.,
Schaible R., Casper B.B., Dahlgren J.P., Ehrlén J., Gar-
cía M.B., Menges E.S., Quintana-Ascencio P.F., Caswell H.,
Brought to you by | New York University
Authenticated
Download Date | 6/26/17 2:25 PM
484
Baudisch A. & Quintana-Ascencio P.F. 2014. Diversity of age-
ing across the tree of life. Nature 505: 169–173.
Jové M., Naudí A., Ramírez-Núńez O., Portero-Otín M., Selman
C., Withers D.J. & Pamplona R. 2014. Caloric restriction
reveals a metabolomic and lipidomic signature in liver of male
mice. Aging Cell 13: 828–837.
Keil G., Cummings E. & de Magalhaes J.P. 2015. Being cool: how
body temperature influences ageing and longevity. Biogeron-
tology 16: 383–397.
Khokhlov A.N. 2013. Impairment of regeneration in aging: ap-
propriateness or stochastics? Biogerontology 14: 703–708.
Kishi S., Uchiyama J., Baughman A.M., Goto T., Lin M.C. &
Tsai S.B. 2003. The zebrafish as a vertebrate model of func-
tional aging and very gradual senescence. Exp. Gerontol. 38:
777-786.
Kitazoe Y., Kishino H., Hasegawa M., Matsui A., Lane N. &
Tanaka M. 2011. Stability of mitochondrial membrane pro-
teins in terrestrial vertebrates predicts aerobic capacity and
longevity. Genome Biol. Evol. 3: 1233-1244.
Kluger M.J., Kozak W., Conn C.A., Leon L.R. & Soszynski D.
1998. Role of fever in disease. Ann. N. Y. Acad. Sci. 856:
224–233.
Kumar D.K.V., Choi S.H., Washicosky K.J., Eimer W.A., Tucker
S., Ghofrani J., Lefkowitz A., McColl G., Goldstein L.E.,
Tanzi R.E. & Moir, R.D. 2016. Amyloid-β peptide protects
against microbial infection in mouse and worm models of
Alzheimer’s disease. Sci. Transl. Med. 8: 340ra72.
Kuriyan A.E., Albini T.A., Townsend J.H., Rodriguez M.,
Pandya H.K., Leonard R.E., Parrott M.B., Rosenfeld P.J.,
Flynn H.W. Jr & Goldberg J.L. 2017. Vision loss after in-
travitreal injection of autologous “stem cells” for AMD. New
England J. Med. 376: 1047–1053.
Laron Z. 2008. The GH-IGF1 axis and longevity. The paradigm
of IGF1 deficiency. Hormones (Athens) 7: 24–27.
Laron Z., Kauli R., Lapkina L. & Werner H. 2016. IGF-I defi-
ciency, longevity and cancer protection of patients with Laron
syndrome. Mutat. Res. 772: 123–133.
Leslie M. 2008. Aging. Searching for the secrets of the super old.
Science 321: 1764–1765.
López-Otín C., Blasco M.A., Partridge L., Serrano M. & Kroemer
G. 2013. The hallmarks of aging. Cell 153: 1194–1217.
Lv M., Zhu X., Wang H., Wang F. & Guan W. 2014. Roles
of caloric restriction, ketogenic diet and intermittent fasting
during initiation, progression and metastasis of cancer in ani-
mal models: a systematic review and meta-analysis. PloS One
9: e115147.
Mariadassou M. & Pellay F.X. 2014. Identification of amino acids
in mitochondrially encoded proteins that correlate with lifes-
pan. Exp. Gerontol. 56: 53–58.
Martínez D.E. & Bridge D. 2012. Hydra, the everlasting embryo,
confronts aging. Int. J. Dev. Biol. 56: 479–487.
Marzetti E., Carter C.S., Wohlgemuth S.E., Lees H.A., Giovan-
nini S., Anderson B., Quinn L.S. & Leeuwenburgh C. 2009.
Changes in IL-15 expression and death-receptor apoptotic
signaling in rat gastrocnemius muscle with aging and life-long
calorie restriction. Mech. Ageing Dev. 130: 272–280.
Masoro E.J. 2005. Overview of caloric restriction and ageing.
Mech. Ageing Dev. 126: 913–922.
Mattison J.A., Roth G.S., Beasley T.M., Tilmont E.M., Handy
A.H., Herbert R.L., Longo D.L., Allison D.B., Young J.E.,
Bryant M., Barnard D., Ward W.F., Qi W., Ingram D.K. &
de Cabo R. 2012. Impact of caloric restriction on health and
survival in rhesus monkeys from the NIA study. Nature 489:
318–321.
Mirzaei H., Suarez J.A. & Longo V.D. 2014. Protein and amino
acid restriction, aging and disease: from yeast to humans.
Trends Endocrinol. Metab. 25: 558–566.
Mizutani T. & Shimada H. 1992. Neuropathological background
of twenty-seven centenarian brains. J. Neurol. Sci. 108: 168–
177.
Mora M. 1989. Fibrous-adipose replacement in skeletal muscle
biopsy. Eur. Heart J. 10: 103–104.
Nowotny K., Jung T., Grune T. & Höhn A. 2014. Accumulation
of modified proteins and aggregate formation in aging. Exp.
Gerontol. 57: 122–131.
I. Peregrim
Oh J., Lee Y.D. & Wagers A.J. 2014. Stem cell aging: mecha-
nisms, regulators and therapeutic opportunities. Nat. Med.
20: 870–880.
Pérez V.I., Bokov A., Van Remmen H., Mele J., Ran Q., Ikeno Y.
& Richardson A. 2009. Is the oxidative stress theory of aging
dead? Biochim. Biophys. Acta 1790: 1005–1014.
Pinot M., Vanni S., Pagnotta S., Lacas-Gervais S., Payet L.A.,
Ferreira T., Gautier R., Goud B., Antonny B. & Barelli H.
2014. Polyunsaturated phospholipids facilitate membrane de-
formation and fission by endocytic proteins. Science 345:
693–697.
Randall A.S., Liu C.H., Chu B., Zhang Q., Dongre S.A., Juusola
M., Franze K., Wakelam M.J.O. & Hardie R.C. 2015. Speed
and sensitivity of phototransduction in Drosophila depend on
degree of saturation of membrane phospholipids. J. Neurosci.
35: 2731–2746.
Raya Á., Consiglio A., Kawakami Y., Rodriguez-Esteban C. &
Izpisúa-Belmonte J.C. 2004. The zebrafish as a model of heart
regeneration. Cloning Stem Cells 6: 345–351.
Rigamonti A., Brennand K., Lau F. & Cowan C.A. 2011. Rapid
cellular turnover in adipose tissue. PLoS One 6: e17637.
Roark E.B., Guilderson T.P., Dunbar R.B., Fallon S.J. & Muccia-
rone D.A. 2009. Extreme longevity in proteinaceous deep-sea
corals. Proc. Natl. Acad. Sci. USA 106: 5204–5208.
Rucklidge G.J., Milne G., McGaw B.A., Milne E. & Robins S.P.
1992. Turnover rates of different collagen types measured
by isotope ratio mass spectrometry. Biochim. Biophys. Acta
1156: 57–61.
Samorajski T., Ordy J.M. & Rady-Reimer P. 1968. Lipofuscin
pigment accumulationin the nervous system of aging mice.
Anat. Rec. 160: 555–573.
Schoenhofen E.A., Wyszynski D.F., Andersen S., Pennington J.,
Young R., Terry D.F., Perls T.T. 2006. Characteristics of 32
supercentenarians. J. Am. Geriatr. Soc. 54: 1237–1240.
Seim I., Fang X., Xiong Z., Lobanov A.V., Huang Z., Ma S.,
Feng Y., Turanov A.A., Zhu Y., Lenz T.L., Gerashchenko
M.V., Fan D., Yim S.H., Yao X., Jordan D., Xiong Y., Ma
Y., Lyapunov A.N., Chen G., Kulakova O.I., Sun Y., Lee
S., Bronson R.T., Moskalev A.A., Sunyaev S.R., Zhang G.,
Krogh A., Wang J. & Gladyshev V.N. 2013. Genome analysis
reveals insights into physiology and longevity of the Brandt’s
bat Myotis brandtii. Nat. Commun. 4: 2212.
Selman C., McLaren J.S., Meyer C., Duncan J.S., Redman P.,
Collins A.R., Duthie G.G. & Speakman J.R. 2006. Life-long
vitamin C supplementation in combination with cold expo-
sure does not affect oxidative damage or lifespan in mice, but
decreases expression of antioxidant protection genes. Mech.
Ageing Dev. 127: 897–904.
Sharpless N.E. & DePinho R.A. 2007. How stem cells age and
why this makes us grow old. Nat. Rev. Mol. Cell Biol. 8:
703–713.
Sheehy M.R.J. 2002. Role of environmental temperature in aging
and longevity: insights from neurolipofuscin. Arch. Gerontol.
Geriatr. 34: 287–310.
Shi W., Fang Z., Li L. & Luo L. 2015. Using zebrafish as the model
organism to understand organ regeneration. Sci. China Life
Sci. 58: 343–351.
Sinclair D.A. 2005. Toward a unified theory of caloric restriction
and longevity regulation. Mech. Ageing Dev. 126: 987–1002.
Speakman J.R. & Garratt M. 2014. Oxidative stress as a cost of
reproduction: beyond the simplistic trade-off model. Bioes-
says 36: 93–106.
Suh Y., Atzmon G., Cho M.O., Hwang D., Liu B., Leahy D.J.,
Barzilai N. & Cohen P. 2008. Functionally significant insulin-
like growth factor I receptor mutations in centenarians. Proc.
Natl. Acad. Sci. USA 105: 3438–3442.
Taylor K.R., Milone N.A. & Rodriguez C.E. 2017. Four cases of
spontaneous neoplasia in the naked mole-rat (Heterocephalus
glaber), a putative cancer-resistant species. J. Gerontol. A
Biol. Sci. Med. Sci. 72: 38-43.
Turner L. & Knoepfler P. 2016. Selling stem cells in the USA:
assessing the direct-to-consumer industry. Cell Stem Cell 19:
154–157.
Tyner S.D., Venkatachalam S., Choi J., Jones S., Ghebranious
N., Igelmann H., Lu X., Soron G., Cooper B., Brayton C.,
Brought to you by | New York University
Authenticated
Download Date | 6/26/17 2:25 PM
Why we age
Park S.H., Thompson T., Karsenty G., Bradley A. & Done-
hower L.A. 2002. p53 mutant mice that display early ageing-
associated phenotypes. Nature 415: 45–53.
Valenzano D.R., Terzibasi E., Cattaneo A., Domenici L. & Cel-
lerino A. 2006. Temperature affects longevity and age-related
locomotor and cognitive decay in the short-lived fish Notho-
branchius furzeri. Aging Cell. 5: 275-278.
Vásquez V., Krieg M., Lockhead D. & Goodman M.B. 2014. Phos-
pholipids that contain polyunsaturated fatty acids enhance
neuronal cell mechanics and touch sensation. Cell Rep. 6:
70–80.
Vermulst M., Bielas J.H., Kujoth G.C., Ladiges W.C., Rabi-
novitch P.S., Prolla T.A. & Loeb L.A. 2007. Mitochondrial
point mutations do not limit the natural lifespan of mice. Nat.
Genet. 39: 540–543.
Verzijl N., DeGroot J., Thorpe S.R., Bank R.A., Shaw J.N., Lyons
T.J., Bijlsma J.W., Lafeber F.P., Baynes J.W. & TeKoppele
J.M. 2000. Effect of collagen turnover on the accumulation of
advanced glycation end products. J. Biol. Chem. 275: 39027–
39031.
485
Weidemann F., Sanchez-Nińo M.D., Politei J., Oliveira J.P., Wan-
ner C., Warnock D.G. & Ortiz A. 2013. Fibrosis: a key feature
of Fabry disease with potential therapeutic implications. Or-
phanet J. Rare Dis. 8: 116.
Wick G., Berger P., Jansen-Dürr P. & Grubeck-Loebenstein B.
2003. A Darwinian-evolutionary concept of age-related dis-
eases. Exp. Gerontol. 38: 13–25.
Wilkinson G.S. & South J.M. 2002. Life history, ecology and
longevity in bats. Aging Cell. 1: 124-131.
Williams S.A. & Shattuck M.R. 2015. Ecology, longevity and
naked mole-rats: confounding effects of sociality? Proc. Biol.
Sci. 282: 20141664.
Zhang J., Lian Q., Zhu G., Zhou F., Sui L., Tan C., Mutalif R.A.,
Navasankari R., Zhang Y., Tse H.F., Stewart C.L. & Colman
A. 2011. A human iPSC model of Hutchinson Gilford Progeria
reveals vascular smooth muscle and mesenchymal stem cell
defects. Cell Stem Cell 8: 31–45.
Received September 1, 2016
Accepted May 23, 2017
Brought to you by | New York University
Authenticated
Download Date | 6/26/17 2:25 PM