REVIEW

published: 26 August 2021

doi: 10.3389/fgene.2021.693071

The Evolution of the Hallmarks of

Aging
Maël Lemoine*
CNRS, ImmunoConcEpT, UMR 5164, Univ. Bordeaux, Bordeaux, France

The evolutionary theory of aging has set the foundations for a comprehensive
understanding of aging. The biology of aging has listed and described the “hallmarks
of aging,” i.e., cellular and molecular mechanisms involved in human aging. The present
paper is the first to infer the order of appearance of the hallmarks of bilaterian and
thereby human aging throughout evolution from their presence in progressively narrower
clades. Its first result is that all organisms, even non-senescent, have to deal with
at least one mechanism of aging – the progressive accumulation of misfolded or
unstable proteins. Due to their cumulation, these mechanisms are called “layers of
aging.” A difference should be made between the first four layers of unicellular aging,
present in some unicellular organisms and in all multicellular opisthokonts, that stem
and strike “from the inside” of individual cells and span from increasingly abnormal
Edited by: protein folding to deregulated nutrient sensing, and the last four layers of metacellular
Michael Rera, aging, progressively appearing in metazoans, that strike the cells of a multicellular
Délégation Paris B (CNRS), France
organism “from the outside,” i.e., because of other cells, and span from transcriptional
Reviewed by:
Joseph L. Graves Jr., alterations to the disruption of intercellular communication. The evolution of metazoans
North Carolina Agricultural and eumetazoans probably solved the problem of aging along with the problem of
and Technical State University,
United States
unicellular aging. However, metacellular aging originates in the mechanisms by which
David Lombard, the effects of unicellular aging are kept under control – e.g., the exhaustion of stem cells
University of Michigan, United States that contribute to replace damaged somatic cells. In bilaterians, additional functions
Philippe Huneman,
UMR 8590 Institut d’Histoire et have taken a toll on generally useless potentially limited lifespan to increase the fitness
de Philosophie des Sciences et des of organisms at the price of a progressively less efficient containment of the damage
Techniques (IHPST), France
of unicellular aging. In the end, this picture suggests that geroscience should be more
*Correspondence:
Maël Lemoine
efficient in targeting conditions of metacellular aging rather than unicellular aging itself.
mael.lemoine@u-bordeaux.fr
Keywords: aging, geroscience, evolution, unicellular aging, metacellular aging, bilaterians

Specialty section:
This article was submitted to
Genetics of Aging,
INTRODUCTION
a section of the journal
Frontiers in Genetics
The hallmarks of aging (López-Otín et al., 2013) are mechanisms jointly involved in human
aging that are likely to have evolved progressively on top of one another in a multilayered
Received: 09 April 2021
mechanism. To determine how they have evolved is key to understanding how mechanisms of
Accepted: 28 July 2021
Published: 26 August 2021 aging interact in humans.
Yet surprisingly, this question has never been investigated. Certainly, the biology of aging
Citation:
Lemoine M (2021) The Evolution
(BA) has investigated a variety of pathways with a focus on aging in humans. The Evolutionary
of the Hallmarks of Aging. Theory of Aging (ETA) has proposed two mechanisms: accumulation of mutations with late
Front. Genet. 12:693071. onset deleterious effects that decreasing selection pressure cannot eliminate (Medawar, 1952),
doi: 10.3389/fgene.2021.693071 antagonistic pleiotropy, that is, traits with an early favorable effect and a late deleterious effect

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Lemoine The Hallmarks of Aging Across the Tree of Life

(Williams, 1957). These mechanisms have been properly Fourth, this review considers that non-senescent species are
formalized (Hamilton, 1966). Later on, the disposable soma characterized not by the absence of mechanisms of aging, but
theory, which posits a general mechanism of trade-off between the absence of aging mechanisms. What explains this, is the
reproduction and repair (Kirkwood, 1977), has laid the presence of efficient mechanisms of anti-aging that strictly
foundations for the life history theory of aging. At last, the compensate the action of mechanisms of aging. In other terms,
biodemography of aging (BDA) has investigated the patterns of the hypothesis is that certain interventions in non-senescent
senescence across the tree of life (Jones et al., 2014; Shefferson species could in principle make them age. However, a shortened
et al., 2017). Yet few reviews have sketched which mechanisms of lifespan that follows a gene knock-out in a given species is
aging are involved in which species (Petralia et al., 2014; Cohen, no evidence that the corresponding protein is involved in a
2018), and none in an evolutionary perspective. mechanism of anti-aging. An active compensation of the effects
To propose a hypothesis of how human aging has evolved of a mechanism of aging must also be established. Typically, the
since the Last Universal Common Ancestor (LUCA), the present knock-out of genes that code for telomerase leads to a shorter
review relies on 4 working hypotheses: lifespan for yeasts, but this does not mean that yeasts have
First, it is based on the list of mechanisms of aging proposed evolved telomerase to increase their lifespan, although telomerase
by López-Otín et al. (2013), as the best available, for all its catalytic subunits are conserved across many branches of the tree
shortcomings (Cohen, 2018). However, instead of keeping the of life (Nakamura, 1997).
9 “synthetic” hallmarks, it develops them into the 20 “analytic” To establish a hypothesis on the order of appearance of
hallmarks reviewed in the original paper (Figure 1). the various layers of bilaterian/human aging in evolution, the
Second, it relies on a phylogenetic tree based on (Philippe present paper investigates the presence and activity of the
et al., 2009) and developed for similar purposes in a genealogy various mechanisms of aging in each clade from the broadest
of cancer genes (Domazet-Lošo and Tautz, 2010), as illustrated (cellular organisms), where only one is present, to the narrowest
in Figure 2. The limit is that not all major clades are relevant (bilaterians), where all are present. Note that a given mechanism
for the investigation of the evolution of aging, and that major of aging is not necessarily present in all species in the taxon,
transitions in aging may have occurred one after another inside as it may be lost in some. It must be present both in humans
of one such clade (typically, there are several new mechanisms of (bilaterians) and in another current species in the same taxon,
aging, not just one, from prokaryotes to archaea, from archaea to but not in any other species in the broader clade, to substantiate
eukaryotes, and from eumetazoa to bilateria). Additionally, the the hypothesis that the mechanism appeared at that stage in
investigation relies on the investigation of the highest number evolution. A final, important note is that the absence of evidence
of species in the clade, or of the most distant species possible in of a mechanism of aging in a species, is no evidence that it
each clade, but it heavily depends on the choice of models in the is absent in this species, except when the mechanism of aging
literature. Typically, the paradigmatic model of eukaryotic aging supposes parts that do not exist in the organism in question
is Saccharomyces cerevisiae, an opisthokont, while less is known (e.g., there cannot be degradation of nuclear architecture or
on aging in Chlamydomonas reinhardtii, a bikont. proteolytic systems in prokaryotes). However, the present article
Third, this review sets as an ideal experimental evidence being a review, it relies on as few and as strong hypotheses
that a mechanism is involved in the senescence of a species, as possible regarding species where a mechanism of aging has
but it is often bound to admit it on the basis of likelihood. not been documented. The burden of evidence relies on those
Indeed, the mere presence in some other species of the who are tempted to claim that a given mechanism of aging
components of a mechanism of aging in humans, does not is likely to have appeared earlier than documented in the
prove that these components are involved in the senescence of corresponding clade.
this species [as remarked by Cohen (2018)]. Moreover, essential The results are summarized in Figure 3.
components of a mechanism of aging must have evolved before
they participate in a mechanism of aging. Additionally, non-
senescent species are less devoid of mechanisms of aging than
RESULTS
efficient in countering their actions thanks to mechanisms of
anti-aging. In the end, a distinction must be made between a
mechanism of aging that causes the degradation of a function
Aging in Cellular Organisms (What Is
and is amplifying with time, and an aging mechanism, which Common to Bilaterians and
is less and less functional with time. An example is histones Prokaryotes?)
(component), histone modifications (mechanism of aging), If in any unicellular species, cell division produces two identical
and limitation and degradation of the replicative capacity in cells, and if the species can in principle reproduce indefinitely,
most eukaryotes and probably neomura (aging mechanism) – then this species cannot be senescent, for daughter cells
against which ciliates have evolved a separation of functions would be “older at birth” than their mother was so that
between two nuclei and conjugation. The criterion in such the species would eventually disappear. Since the end of the
an inquiry is that the action of a mechanism of aging on 19th century, it has been largely accepted that unicellular
an aging mechanism is established, e.g., the action of the organisms divided into identical individuals, and must therefore
accumulation of senescent cells in an organ on the progressively be non-senescent (Weismann, 1892). However, a distinction
degraded function. is made between chronological lifespan (CLS), i.e., the time

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Lemoine The Hallmarks of Aging Across the Tree of Life

FIGURE 1 | The 9 “synthetic” and the 20 “analytic” hallmarks of aging as originally proposed in López-Otín et al. (2013). The wheel in the original figure proposes only
9 hallmarks of aging, but the text distinguishes more. The present article is based on the detailed hallmarks, which are represented here as an extension of the wheel.

individual cells can live before they divide again, and replicative When it was established that daughter cells would systematically
lifespan (RLS), i.e., the number of times individual cells not have the same lifespan in Escherichia coli, a distinction was
can divide (Ackermann et al., 2007). Individual cells can proposed between ‘morphological asymmetry’ that characterizes
have a limited CLS and be senescent in that sense, but the division by budding, and ‘functional asymmetry,’ that equally
difficulty is whether there can be a limit to RLS as well. The characterized binary fission, at least in E. coli, and budding
discovery that in S. cerevisiae, cells divide into unidentical (Stewart et al., 2005). An important consequence is that the
individuals, an aging mother cell and a “rejuvenated” daughter evolution of aging does not start with the distinction of
cell, implied that at least some unicellular species display germline and soma in multicellular life, as originally speculated
replicative senescence (Mortimer and Johnston, 1959). A further (Weismann, 1892; Kirkwood and Cremer, 1982), nor even with
distinction was made between symmetric and asymmetric eukaryotic life, but as early as in cellular organisms (Ackermann
division (Partridge and Barton, 1993), the former implying non- et al., 2007). The most general mechanisms of aging should
senescence and characterizing prokaryotes, the latter implying therefore be investigated in prokaryotes, not eukaryotes. The
senescence and characterizing eukaryotes (Jazwinski, 1993). oldest of the hallmarks of aging cannot therefore be typically

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Lemoine The Hallmarks of Aging Across the Tree of Life

FIGURE 2 | Phylogeny used for the investigation of mechanisms of aging. Circles are clades. Their names are in white. Current species represented in each clade
are as remote as possible from humans phylogenetically and hypothetically as close as possible to the early species where the clade originated. The tree of life is
also represented on the figure.

eukaryotic, like the degradation of the nuclear architecture or proteins increase in quantity with the probability of death in
mitochondrial dysfunction. a bacterial culture (Maisonneuve et al., 2008a,b). In 9 bacterial
cells out of 10, there is only one inclusion body formed by
Appearance of the Degradation of damaged proteins in the dividing cell, which explains how
Chaperone-Mediated Protein Folding and Stability the asymmetric repartition of damage may occur passively,
It has long been suspected that functional asymmetry, if it without any dedicated mechanism (Lindner et al., 2008). This
existed, should be explained by “the polar localization of cell discovery weakens the case of a trade-off between repair and
components” (Stewart et al., 2005) – what has also been reproduction, as repair passively occurs at no energetic cost
called the “senescence factor” in the case of S. cerevisiae – during cell division, in contrast with the attempt to make
a “cytoplasmic factor” (Egilmez and Jazwinski, 1989). Current functionally asymmetric division a case of the disposable soma
evidence strongly substantiates the hypothesis that at least part of theory (Kirkwood, 2005), although there have been attempts to
this senescence factor is aggregated proteins. Indeed, aggregated save the theory (Teulière et al., 2020).

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Lemoine The Hallmarks of Aging Across the Tree of Life

FIGURE 3 | The evolution of the hallmarks of aging. The 20 layers of aging are represented in the order of appearance in evolution from cellular organisms to
bilaterians (from the earliest at the bottom to the latest at the top). The colors of the layers correspond to the original 9 “synthetic” hallmarks of aging. Clades are
represented in the gray zones along with corresponding model organisms. The sets of layers of unicellular aging and metacellular aging are represented.

Recently, it has also been shown that in situation of of chaperones pathways are known to be involved in proteostasis,
antibiotic stress, E. coli forms non-viable minicells of up to in bacteria, mostly Hsp70 and GroEL-GroES (Hartl et al., 2011).
20% of the mother cell size, containing damaged proteins The various mechanisms molecular chaperones are involved in
(Rang et al., 2018). However, the focus has rather been on the include holding, unfolding, targeting, pulling and disaggregating
ubiquitous machinery of molecular chaperones. Various classes misshaped proteins, which are likely to be triggered both in cycles

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Lemoine The Hallmarks of Aging Across the Tree of Life

and selectively according to environmental conditions (Mattoo Aging in Neomura (What Is Common to
and Goloubinoff, 2014). It has been suggested that increase in the Bilaterians and Archaea?)
production of aberrant polypeptides in the ribosome, not increase
A dominant view is that archaea and eukaryotes share a common
of oxidative damage to proteins nor decline of antioxidation
ancestor and constitute a clade, “neomura,” that branched out
defense, might be responsible for a progressive loss of proteostasis
of prokaryotes (Cavalier-Smith, 2002; Williams et al., 2013;
(Nyström, 2003).
Cavalier-Smith and Chao, 2020), although alternative hypotheses
In summary, the current picture is that aging in prokaryotes
have been proposed (Forterre, 2013; Mariscal and Doolittle,
is mainly about the management of abnormal proteins. In most
2015). Cavalier-Smith proposed that neomura are prokaryotes
cases, asymmetric division would insure that the lineage does
that have evolved in adaptation to thermophily. Current archaea
not wear out just because dysfunctional proteins would just
have further evolved in adaptation to hyperthermophily and
aggregate into one inclusion body, and various proteostatic
hyperacidity. For instance, the evolution of the archaeal cell
mechanisms involving chaperone molecules play a more minor
membrane to less permeability may have contributed to its
role in reducing the level of damaged proteins in a lineage
resistance to chronic energy stress (Valentine, 2007). Archaea and
(Moger-Reischer and Lennon, 2019).
eukaryotes share 19 common traits that sketch what neomura
would have looked like (Cavalier-Smith, 2002). None of these
Possibly No Other Hallmarks of Aging in Prokaryotes
traits is characterized in relation to an aging phenotype, and there
To date, loss of proteostasis through “chaperone-mediated
is currently no study of the involvement of various mechanisms
protein folding and stability” (López-Otín et al., 2013) is the
in the senescence of archaea.
only mechanism of aging that has been associated with aging
A speculation is that moderately challenging conditions
in prokaryotes. Other components of mechanisms of aging in
(mesophily or thermophily) have put pressure on the evolution
narrower taxa are already present. This includes mechanisms
of prokaryotic anti-damage mechanisms, making the anti-aging
of nutrient sensing which is active in starved bacteria under
‘reproductive strategy’ of bacteria insufficient. These anti-damage
the form of the ss factor and the alarmone ppGpp. It has been
mechanisms might have then become anti-aging mechanisms in
suggested that it might be a factor of aging similar to the
certain conditions.
RAS/cAMP/PKA (in yeast) and the daf-16 (in Caenorhabditis
elegans) regulatory pathways (Nyström, 2003, 2004). However, Conservation of the Mechanism of Degradation of
it seems to be involved in CLS only, not in RLS, and in Chaperone-Mediated Protein Folding and Stability in
the particular case of “conditional senescence,” that is in Neomura
circumstances of starvation. Besides, it does not seem to be Archaeal and eukaryotic chaperonins probably synchronize the
a case of “deregulated nutrient sensing,” but rather, a case of activity of their rings more efficiently than bacterial chaperonins
a buffering process with a time limit. Similarly, some repair thanks to a built-in cap (Reissmann et al., 2007). Indeed,
mechanisms of genetic damage are present, like non-homologous eubacterial chaperonins have 7 subunits and a distinct ‘GroES’
end-joining for double-strand break (Shuman and Glickman, Hsp10 cap to close the cylinder while neomura chaperonins
2007; Lieber, 2010), but they have never been investigated in would have evolved to 8 or 9 subunits and a built-in cap or
association with CLS or RLS in bacteria. A possible explanation lid, which may be preferable for a thermophile (Cavalier-Smith,
is that lateral gene transfer (Ochman et al., 2000) may act as a 2002). Note that hyperthermophiles have lost Hsp70 and Hsp90
potent replacement strategy in bacteria and discard any form of that eukaryotes have conserved.
aging by genomic instability. Epigenetic regulation in prokaryotes
does not seem to have been investigated in relation to aging either Appearance of the Components of ‘Histone
(Casadesús and Low, 2013). Modifications’ and ‘Chromatin Remodeling’
Mechanisms of Aging
Conclusive Remarks on Aging in Prokaryotes The most important, or investigated, evolutions from
Our current knowledge seems to suggest that protein aggregation prokaryotes to archaea regard genomic stability. Based on
is the oldest and more primitive form of aging – more comparison of eukaryotes, prokaryotes and archaea, it is
primitive than DNA damage, and that other mechanisms that likely that, from their prokaryote ancestors, neomura have
will have an anti-aging function later on are already present conserved MutL-MutS mismatch repair, transcription coupled
in bacteria, but do not play that role yet. An important repair mechanisms as well as non-homologous end-joining
conclusion is also that prokaryotes achieve a form of non- and homologous recombination for double-strand break, and
senescence through reproduction by functionally asymmetric have evolved more sophisticated forms of base excision repair
division (instead of functionally symmetric division showing that and nucleotide excision repair mechanisms than prokaryotes
they are not senescent). It has been speculated that in metazoans, (White and Allers, 2018). According to Cavalier-Smith, DNA-
in humans in particular, replicative lifespan characterizes stem handling proteins (replicative/repair polymerases and repair and
cells while chronological lifespan characterizes postmitotic cells recombination enzymes) have evolved to follow the changes in
(Longo et al., 2012). Some human age-related diseases, typically, histones, which may themselves have evolved from H1 linker
Alzheimer’s and Parkinson’s, are characterized by progressive histones (present in the eubacterial ancestor of neomura) to
decline in proteostasis and abnormal proteins aggregation core histones, both having been later conserved by eukaryotes
(Hartl et al., 2011). while archaea lost them (Cavalier-Smith, 2002). An ancestral

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Lemoine The Hallmarks of Aging Across the Tree of Life

form of chromatin structure based on tetramer histones may 2, mammals have 4 and higher plants may have more than 20
have evolved initially to regulate gene expression and, through (Schmollinger et al., 2013). Dictyostelium discoideum presents a
the appearance of histones with 8 subunits, have evolved very specific regulation of prion-like proteome (Malinovska et al.,
functions of DNA damage prevention in early eukaryotes 2015). In spite of these differences, there is also much in common.
(Ammar et al., 2012). The earliest function of sirtuins as well For instance, many proteins involved in proteostasis in plastids in
may have been chromatin structure regulation, but it may also plants (e.g., chloroplasts) are conserved from prokaryotes and are
have been metabolic regulation, as some sirtuins play this role involved in senescence (Sakamoto, 2006).
in prokaryotes already (Vaquero, 2009). However, the diversity The most important change in the mechanism of loss of
of proteins involved in the architecture of DNA is puzzling. To proteostasis is the appearance of autophagy. Evidence is now
reduce the enormous length of unfolded DNA, all kingdoms of strong that autophagy appeared early with eukaryotic life, as
life resort to similar strategies of supercoiling, macromolecular protists that do not present autophagy are likely to simply
crowding, and folding or organization, although structural have lost it (Duszenko et al., 2011). Indeed, in eukaryotes, the
proteins involved are diverse (Luijsterburg et al., 2008). Even turnover of proteins that can also be seen in prokaryotes must
if this remains controversial, there are hints that epigenetics be complemented by a turnover of organelles, which would have
could have emerged at the level of neomura (Blum and Payne, been the main role of autophagy. Autophagy is triggered in
2019). If this is the case, there is no reason to presuppose that if different situations like starvation or infection and modulates cell
histone modifications and chromatin remodeling are involved lifespan (Galluzzi et al., 2008). A possible hypothesis is that it has
in opisthokontic aging (Yi and Kim, 2020), as there is ample evolved as a temporary response to nutrient limitation, which also
evidence of, it should not be involved in archaeal aging as well to generates ROS and damaged proteins (Pérez-Pérez et al., 2012),
some degree. Indeed, histones and chromatin are highly potent, and that this mechanism had to adapt later on to a high level of
but vulnerable structures. However, there is no formal evidence ROS production in mitochondria and/or chloroplasts. Only then,
of their involvement in archaeal aging at this stage. it would have switched from a mechanism of stress resistance to
In humans, heterochromatin is known to decrease with age a mechanism of anti-aging.
and is probably associated to abnormal gene regulation and The recycling of protein aggregates and organelles by
expression (Greer and Shi, 2012). autophagy is functionally conserved in eukaryotes, including
unicellular alga C. reinhardtii, where crATG8, a biomarker of
Aging in Eukaryotes (What Is Common to autophagy, is upregulated in the stationary phase of cell culture
Bilaterians, Bikonts and Amoebozoans?) with a prominent role of the TOR pathway, and is thereby
There is a huge gap in the evolution of aging from prokaryotes associated with unicellular aging (Pérez-Pérez et al., 2010). In
and archaea to eukaryotes, as measured by the important plants too, autophagy is conserved, potentially selective (Li
differences between prokaryotes and eukaryotes in general: and Vierstra, 2012) and controlled by TOR pathways (Liu and
volume (1,000-fold on average), presence of a nucleus, Bassham, 2012), a regulator of growth in changing conditions
compartmentalization by endomembrane system and of nutrient availability (Díaz-Troya et al., 2008). Mutants show
cytoskeleton, presence of mitochondria, regulation of protein accelerated senescence (Doelling et al., 2002). Note, however,
function and turnover, and regulation of transcription (Koonin, that in unicellular algae and plants, there is no documented age-
2010). While everyone agrees on the endosymbiotic origin related deregulation of the TOR pathway. The involvement of
of mitochondria, there is disagreement over the origin is a the degradation of autophagic function in human aging is the
protoeukaryotic cell with an already formed nucleus which subject of intense investigation (Rubinsztein et al., 2011; Cuervo
later on phagocytized a protobacterion, or a symbiotic relation and Wong, 2014).
between an archaeon and a bacterion, the former engulfing the
latter and later on evolving a nucleus (O’Malley, 2010). Resolving The Conservation of Chromatin Remodeling and
this dispute will reveal crucial to a finer-grain description of Histone Modifications
the order of steps in the evolution of aging from archaea to In ciliates, transcriptionally active macronucleus, strongly
eukaryotes. Plausible preliminary steps of the evolution to involved in clonal aging, contrast with transcriptionally inactive
eukaryotes that are seemingly not directly related to aging, like micronucleus, which are not, mainly by histone modifications
the emergence of a cytoskeleton in some archaea (Zaremba- and chromatin remodeling (Chalker et al., 2013), a contrast that is
Niedzwiedzka et al., 2017), should provide a basis for speculation widely conserved across eukaryotes (Jahn and Klobutcher, 2002;
about the early evolution of aging. van Wolfswinkel and Ketting, 2010). This constitutes indirect,
but strong evidence of their role in aging in the whole clade.
The Appearance of Proteolytic Systems and the
Completion of the Mechanism of Loss of Proteostasis Components of the Mechanisms of DNA Methylation
Chaperon-mediated regulation of proteostasis has increased in and Transcriptional Alterations Appear but Are Not
complexity between prokaryotes and eukaryotes (for a review, Involved in Aging
see Hartl et al., 2011). Additionally, there is a wide diversity of DNA methylases, histone-modifying enzymes and RNAi systems
mechanisms across the domain of eukaryotes: for instance, while seem to have evolved together in eukaryotes (Iyer et al., 2011).
S. cerevisiae, Drosophila melanogaster and C. elegans only have Involved in human aging, the machinery of RNA interference
one heat shock factor, C. reinhardtii (a unicellular green alga) has [small interfering RNA (siRNA) and micro-RNA (miRNA)] is

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Lemoine The Hallmarks of Aging Across the Tree of Life

an original, early evolution of eukaryotes, although it has a Endosymbiosis has come with many advantages and as many
functional analog in prokaryotes and is probably not essential to drawbacks due to poor coordination of cell and mitochondrial
unicellular eukaryotic life, as it has been lost in several branches, genome expression, 1,000:1 ratio of mitochondrial to cell genome
e.g., S. cerevisiae (Shabalina and Koonin, 2008). RNA interference in the cell, oxidative damage, potential immune reaction to
in prokaryotes seems to essentially consist in an antiviral defense, PAMP and DAMP common to mitochondria and bacteria, and
while it has evolved in a broader regulatory mechanism of the risk of mutational meltdown that follows from exclusively
transcription in eukaryotes, involving histone modification and clonal reproduction of these organelles and is likely not to be
DNA methylation (van Wolfswinkel and Ketting, 2010), and not balanced by autophagy, chaperone proteins, and regulation of
limited to eukaryotes with a multicellular life, as shown by the the transcription of the mitochondrial genome (Youle, 2019).
presence of miRNA and siRNA in C. reinhardtii (Molnár et al., Many of these drawbacks are likely to converge in contributing
2007). More specific to eukaryotes, the Polycomb Repressive to aging in eukaryotes.
Complex 2 and its analogs in some species, which is involved in Of note, the role of the accumulation of ROS in aging in
transcriptional silencing and remains under the control of RNAi, general, human aging in particular, has been largely questioned
has probably been selected as a defense against transposons lately (Muller et al., 2007), including in López-Otín et al. (2013),
before evolving later on into developmental functions (Shaver which nevertheless lists ROS as one of the hallmarks of aging.
et al., 2010). In plants, less than a dozen miRNA genes It is widely acknowledged that they are mainly produced by
are widely conserved across species and deeply involved in mitochondria, and mainly damage mitochondria. It makes sense
crucial regulatory networks (development, stress response, and to hypothesize their role in aging as early as in eukaryotes.
nutritional response), while most others are specific to plants Importantly, there might be strong variation and an increase of
families and have probably no fixed function, suggestive of ROS damage in narrower clades, in many metazoans in particular,
neutral evolution (Cuperus et al., 2011). but not in most plants, as shown by the adaptation of the level of
A large part of the regulation of reproduction cycles in many production of methionine (Bender et al., 2008).
eukaryotes is under the control of such epigenetic mechanisms.
There is great variety in these cycles, some showing clear The Appearance of the Degradation of mtDNA and of
signs of limited RLS. For instance, some ciliates reproduce by Nuclear Architecture
endogenous budding, the mother showing signs of functional Because of the protective properties of histones and of chromatin
decline, and late-born daughter cells having more variable remodeling, it is likely to take more for DNA damage to become
lifespan and less progeny; others show alternate phases of DNA mutations. Moreover, DNA mutations are still much more
differentiation and dedifferentiation and regeneration of adult likely to be a cause of evolution than a cause of aging in
structures, which was suggested to have evolved to the same unicellular organisms. However, it is to be expected that mtDNA
abilities in early metazoans (Petralia et al., 2014), although ciliates accumulates damage and become a hallmark of aging at this stage,
are bikonts, not opisthokonts. However, a limitation in RLS and that the nuclear architecture that protects nuclear DNA will
does not necessarily stems from the epigenetic regulation of take some of the damage and thus become a hallmark of aging.
the mechanism, which it is not possible to consider an active In some bacterial species, non-homologous end-joining exists
mechanism of aging at this stage. in two forms, canonical and atypical, the former seemingly more
frequent in eukaryotes (Bétermier et al., 2014). For instance,
The Appearance of Mitochondria, Mitochondrial being particularly exposed to the genotoxic effects of light, plants
Defects in Biogenesis and ROS Damage and algae have evolved highly efficient repair mechanisms, the
The origin, evolution and multiplicity of functions of imperfection of which is a major cause of their senescence
mitochondria across eukaryotes is progressively unraveled (Bray and West, 2005). Mitochondria and chloroplasts too have
(Roger et al., 2017). Some eukaryotes (breviates and some ciliates) basic repair mechanisms that seems to be shared with bacteria,
have no mitochondria, and in others, there are chloroplasts too. while plants have evolved specific mechanisms in both their
It has long been known that a degradation of mitochondria and mitochondria and chloroplasts (Maréchal and Brisson, 2010).
chloroplasts occurs in stationary phases of culture of unicellular Although evidence is scarce, the degradation of mtDNA is likely
eukaryotes. For instance, in Tetrahymena pyriformis, changes in to be involved in the aging of all eukaryotic cells. In mammalians
the morphology, number and localization of mitochondria in in general and in humans in particular, the evidence is more
the stationary phase of cell culture was noted very early (Elliott substantial, although the main cause of this degradation has
and Bak, 1964). The unicellular alga Euglena gracilis shows recently been suggested to be less due to ROS production than
the same progression toward stationary phase of the culture to faulty replication of mitochondria (Kauppila et al., 2017).
and post-mitotic, quiescent state of cells as prokaryotes in the Ciliates illustrate a crucial aspect of the degradation of
same conditions of limited space and/or resources (Gomez nuclear architecture. They present nuclear dimorphism – while
et al., 1974a), which seems to correlate with signs of a loss of a micronucleus is inactive during vegetative life and phases of
proteostasis, and of a progressive degradation of mitochondria asexual reproduction, one macronucleus (at least) is active in this
(Gomez et al., 1974b). Chloroplasts progressively accumulate period. After a certain number of asexual divisions, paramecia age
photooxidative damage that they partially compensate for and die if they do not sexually reproduce. A necessary condition
by mechanisms of photoprotection, with the effect of photo- of such clonal aging is the progressive degradation of the
inhibition, a progressive diminution of the rate of photosynthesis macronucleus, as a sufficient experimental cause of rejuvenation
(Niyogi, 1999). is macronucleus transplantation (Aufderheide, 1986). The

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Lemoine The Hallmarks of Aging Across the Tree of Life

accumulation of damage in the architecture of DNA and of accumulates and the size and shape of the nucleolus changes with
the nucleus, not of individual mutations, is responsible for this, age (Pathak et al., 2021).
and sexual reproduction by conjugation makes one individual
paramecium potentially immortal. Indeed, macronuclei also The Conservation of the Mechanisms of Aging
undergo intense remodeling through fragmentation and de novo Through Mitochondrial Dysfunction
telomere addition (Jahn and Klobutcher, 2002). Hypotrichous It is unclear how much of the involvement of mitochondrial
ciliates also age through genomic instability based on a random dysfunction is already present in eukaryotes and not specific
segregations of genes in their macronuclei, a process not shared to opisthokonts. Longo, Shadel, Kaeberlein, and Kennedy have
among all ciliates (Duerr et al., 2004). In humans, the degradation proposed a network hypothesis of the control of CLS that
of nuclear architecture has long been known as the main cause includes mitochondria, nutrient sensing and stress response in
of progeria, traditionally seen as a disease of accelerated aging S. cerevisiae (Pan et al., 2011; Longo et al., 2012). In addition to
(Eriksson et al., 2003). the effects of the production of ROS in mitochondria in general,
there is a mother-daughter cell gradient of ROS production
Aging in Opisthokonts (What Is Common by mitochondria (Laun et al., 2004). During division, the
to Bilaterians and Fungi?) asymmetric repartition of damaged mitochondria depends on
Opisthokonts group animals and fungi. Their ancestor had a quality control machinery that involves Mmr1p, a protein
a unique, posterior flagella (lost later in most organisms, localized at the tip of the bud (McFaline-Figueroa et al., 2011).
but still present in sperm), and flat mitochondrial cristae Progressive mitochondrial dysfunction through loss of mtDNA
(Steenkamp et al., 2006). could contribute to age-associated loss of heterozygosity through
a dysfunction of iron-sulfur cluster biogenesis (Veatch et al.,
The Mechanisms of Aging by Loss of Proteostasis 2009). In turn, the decline in mitochondrial functioning seems to
Are Conserved be caused, at least in part, by a decline in the acidity of vacuoles,
Although major evolutions of proteostasis since prokaryotes which in turn reduces the uptake of neutral amino-acids –
are visible in all eukaryotes, they have been mainly studied in but it remains unknown why this would lead to mitochondrial
opisthokonts. The same form of passive mechanism of anti- dysfunction (Hughes and Gottschling, 2012).
aging as in prokaryotes, namely asymmetric repartition of the
“senescence factor” during asexual reproduction, can still be seen No Mechanism of Aging in Unicellular Eukaryotes
in S. cerevisiae, which reproduces by budding (Zhou et al., 2011), Involves Accumulation of Mutations in Nuclear DNA
and in Saccharomyces pombe, which reproduces by binary fission Although loss of heterozygosity (McMurray, 2003) has been
(Barker and Walmsley, 1999). One part of this senescence factor observed in diploid yeast, recent experiments have shown that
is oxidatively damaged proteins (Aguilaniu, 2003) and protein mutation accumulation is too slow to cause aging in wild type
aggregates (Liu et al., 2010; Zhou et al., 2011). With increasing S. cerevisiae, either in nuclear DNA or in mitochondrial DNA,
RLS, an increased level of Hsp104, the main chaperone in the and no genome structural arrangement observed at the individual
dissolution of these aggregates, is observed (Xie et al., 2012). level (Kaya et al., 2015). Only when it is greatly increased beyond
However, manipulation (deletion or upregulation) of Hsp104 a certain threshold in mutant strains, does it have a noticeable
does not affect lifespan (Kaeberlein et al., 2005; Andersson effect on lifespan (Lee et al., 2019). That said, extrachromosomal
et al., 2013). Simultaneously, there is a decrease in the level of rDNA circles (ERCs) do accumulate in the nucleus of mother cell
transcription of genes involved in protein folding and a loss due to closed mitosis, and are associated to an effect on lifespan
of stoichiometry (Janssens et al., 2015). Although autophagy countered by Sir2 (Sinclair and Guarente, 1997). However, it has
(reviewed in Reggiori and Klionsky, 2013) is involved in most been recently proposed that this just the effect of instability in
all classical interventions that successfully extended lifespan in ribosomal DNA (Kobayashi, 2008; Ganley and Kobayashi, 2014;
S. cerevisiae, it is unclear whether the activation of autophagy in Hu et al., 2014).
its various forms is sufficient (Tyler and Johnson, 2018).
The Appearance of Aging Through Deregulated
The Mechanisms of Aging Through Histone Nutrient Sensing
Modifications, Chromatin Remodeling and Opisthokonts have specific biosynthesis and metabolism (Adl
Degradation of the Nuclear Architecture Are et al., 2019), including glycogenesis (Ball et al., 2012). With
Conserved age, gluconeogenesis and energy storage increase while glycolysis
In S. cerevisiae, H3 and H2A histone protein levels decrease with decreases in S. cerevisiae (Lin et al., 2001). Autophagy is under
increasing replicative aging, and ectopic expression increases it the control of nutrient sensing pathways: TOR/Sch9, Ras/cAMP
significantly with an effect on longevity (Feser et al., 2010). This and PKA, AMPK/Snf1 and sirtuins (Sampaio-Marques et al.,
is partially under the influence of histone deacetylase Sir2, a 2014). First, insulin is a conserved part of a complex hormonal
member of the sirtuin family of proteins that also participates system that regulates growth, phagocytosis, ciliary regeneration,
in several mechanisms of anti-aging (Finkel et al., 2009). H4K16 chemotaxis in ciliates (Csaba, 2012). Second, the TOR pathway
acetylation also increases with age (Dang et al., 2009). Chromatin inhibits autophagy when amino-acid intracellular concentration
remodeling has also been confirmed to be involved in aging is high. This pathway becomes hyperactive with age. TOR also
(Pegoraro et al., 2009). Misshaped nuclear pore complexes seems to increase mitochondrial activity (Pan et al., 2011). Third,

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Lemoine The Hallmarks of Aging Across the Tree of Life

the Ras – cAMP – PKA pathway inhibits metabolism and display a complex pattern of up- and down-regulation, which is
autophagy when glucose in particular is high (Lin et al., 2001). also specific to cell types (Smith-Vikos and Slack, 2012).
Dietary restriction (DR) has an important effect on lifespan Cell senescence might also have appeared in multicellular
(Fontana et al., 2010), but it remains controversial that it is holozoans. It is attested in eumetazoans but has not been
mediated by sirtuins (Kaeberlein, 2010). investigated in metazoans nor in choanoflagellates. Indeed,
Of note, aging yeast increases in size. Some have proposed the programmed cell death (PCD) appeared early in evolution,
idea that the cell may interpret the consequences of its increasing probably before multicellular life and potentially involving more
size as a state of starvation (Yiu et al., 2008) and compensate in a than 30 different genes (Nedelcu, 2009). It obviously became a
detrimental feed forward loop. vital program for survival in multicellular organisms, although
There is overwhelming evidence that the deregulation of it may have initially evolved as a form of antagonistic pleiotropy
nutrient sensing plays a role in human aging, but it is still (Nedelcu et al., 2011). In particular, sequences coding for p53 are
unclear whether this is a cause or a consequence of other already present in choanoflagellates and could have evolved for
hallmarks of aging. purposes of proliferation control (Pearson and Alvarado, 2008),
although there is no experimental evidence of such functional
pathway yet (Nedelcu and Tan, 2007). Some processes close to
what is observed in apoptosis have been observed in unicellular
Aging in Holozoans (What Is Common to organisms (Nedelcu, 2009). The hypothesis is therefore that
Bilaterians and Choanoflagellates?) active cell death has evolved first either as an altruistic behavior
Holozoans evolved toward multicellularity probably to avoid or as an effect of antagonistic pleiotropy in unicellular organisms
predation and optimize food consumption, and through (Ameisen, 2002; Nedelcu et al., 2011), and that it became adaptive
the evolution of a gene toolkit involving cell adhesion, in multicellular organisms. In the case of an altruistic behavior, it
communication and differentiation (Rokas, 2008). Some would be consistent to hypothesize that PCD has evolved as an
choanoflagellates present the interesting case of unicellular adaptive reaction to some the detrimental effects of some form
organisms capable of a multicellular life (Dayel et al., 2011). In of cell “senescence,” be it simply the state of aged individual
the “colony hypothesis,” the intermediate between unicellular cells. In the case of antagonistic pleiotropy, senescence could
and multicellular organisms was a spheroidal colony with a have evolved as some sort of resistance to PCD. However, this
rudimentary division of labor between external flagellated cells is too speculative to hypothesize that cell senescence is involved
in charge of predation, including perception and locomotion, in aging in holozoans.
and internal cells in charge of reproduction, including digestion DNA methylation is not far from becoming the standard
(Richter and King, 2013). Salpingoeca rosetta, a colonial form of biological measurement of chronological aging in humans
choanoflagellates, present 5 different cell types. (Horvath, 2013), although it is still unknown whether the various
There is no well-developed literature on the aging of signatures that have recently been proposed are direct causes
choanoflagellates specifically. On the one hand, most earlier of aging, or markers of the activity of maintenance systems, or
mechanisms of aging have not been investigated. The TOR anything else. Transcriptional alterations associated with shifts
pathway is specifically present in choanoflagellates (Shertz et al., in miRNA expressions have been studied mainly in cancer (Iorio
2010), and there is no a priori reason why the other mechanisms et al., 2005), but also in other age-related diseases (Cogswell et al.,
should not be present. 2008; Rayner et al., 2010) and, to a lesser extent, in aging more
On the other hand, three hallmarks are both absent from generally (Smith-Vikos and Slack, 2012; Smith-Vikos et al., 2016;
the previous clade of opisthokonts and the next clade of Olivieri et al., 2017).
metazoans: DNA methylation, transcriptional alterations, and
decline in the regenerative potential of tissues. It can reasonably
be hypothesized that the former two appeared in holozoans, Aging in Metazoa (What Is Common to
while the latter appeared only in metazoans. If this hypothesis Bilaterians and Porifera?)
is true, holozoans should present ‘conditional senescence’, that The extremely long lifespan of sponges (Porifera), up to
is, age through these mechanisms at least in some specific 11,000 years in documented cases (Jochum et al., 2012),
environmental conditions. associated with no evidence of decline, has led to the claim
First, DNA methylation may have evolved from a mechanism that they belong to non-senescent species. Sponges have also
of cell defense in prokaryotes to a mechanism of adaptation been proposed as an illustration of the 6 “hallmarks of animal
in eukaryotes, to a mechanism of intercellular coordination multicellularity,” namely regulated cell cycle, programmed cell
in holozoans and beyond. Any uncoordinated pattern of death, cell-cell and cell-matrix adhesion, developmental signaling
methylation in holozoans may cause the degradation of the and gene regulation, allorecognition and innate immunity and
multicellular entity. However, there is no evidence if its specialization of cell types (Srivastava et al., 2010). They present
involvement in aging. Second, the same is true of the epigenetic the same structure as colonial choanoflagellates with a genetic
machinery of miRNA, which has been lost by S. cerevisiae, but development program. Most of their cells are called choanocytes,
is present in other unicellular opisthokonts (Bråte et al., 2018): a short-lived cell type organized in epithelia that form channels
a plausible hypothesis, which is not verified at this stage, is that through which they create a flow by the movement of their
it may be involved in aging in multicellular holozoans. Indeed, flagella (Leys and Hill, 2012). In total, porifera present 5–10
miRNAs control the expression of genes in time and consequently different cell types.

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Lemoine The Hallmarks of Aging Across the Tree of Life

To clarify this stage of the evolution of aging, I propose reproduction, competition, immunity – so that regeneration in
a distinction between unicellular aging and metacellular aging. ecological conditions depends on both intrinsic and extrinsic
Indeed, the engine of the process of aging in bilaterians may conditions, the availability of a sufficient number of totipotent
be the aging of the cells themselves. But it is important not to stem cells playing a crucial role in the process (Henry and Hart,
simplistically scale up cellular aging to whole organisms (Cohen, 2005). In Porifera, aging in the wild is likely to be involved when
2018). Non-senescent metazoans seem to be able to keep aging trade-offs are not favorable to regeneration. For that reason, it can
at bay thanks to a high proportion of stem cells with a high rate be hypothesized that if Porifera undergo conditional senescence,
of activity. In other terms, they themselves do not age while their it may be through the exhaustion of stem cells in a protracted
cells do age individually and intrinsically. Senescent metazoans state of demand on regeneration that they cannot meet.
age both because their cells do individually (unicellular aging) It is also likely that the rate of activity of stem cells is regulated
and because of an organization of multicellular life that leads through intercellular communication in early metazoans.
to an insufficient rate of renewal, something that may be called Intercellular signaling pathways have been particularly studied
metacellular aging. The default mode of multicellular life seems in Porifera development and involve Wnt, TGF-b, Hedgehog,
to have been non-senescence. tyrosine kinase, nuclear receptor, Notch, Jak/STAT (Barolo
and Posakoni, 2002). Probably because Porifera are considered
The Likely Conservation of Unicellular Mechanisms of non-senescent, the few studies of abnormal signaling in this
Aging Through Loss of Proteostasis, Epigenetic species do not evoke aging, but rather cancer – for instance,
Alterations, Genomic Instability, Deregulated Nutrient exposition to ectopic Wnt produces abnormal growth (just as
Sensing, Mitochondrial Dysfunction they do in cnidarians) and dysfunctional canals (reviewed in
The hallmarks of unicellular aging are not well known in Porifera. Leys and Hill, 2012). Tyrosine kinases in particular are signaling
Protein folding and repair by HSP70 has been studied in Porifera, proteins involved in many processes, evolved differently in many
but mostly in stress and not in unicellular aging (Vallmann forms in different branches (Richter and King, 2013). There are
et al., 2016). Regarding autophagy, there are only studies of claims that tyrosine kinases are involved in aging in general, but
the conservation of proteins involved, like Atg8 (Shpilka et al., they remain vague (e.g., Hunter, 2009). There is no sign of cell
2011). There is no study of the deregulation of nutrient sensing senescence either, although p53-driven apoptosis is still present
in porifera. Importantly, the genome of metazoan mitochondria just as it is in choanoflagellates (Rutkowski et al., 2010).
is 4 times smaller and contains 1.5 times less genes than the In humans, the exhaustion of stem cells is actively studied as a
genome of holozoan mitochondria (Lavrov et al., 2005). This mechanism both of aging and of cancer (Sharpless and DePinho,
compaction is accompanied in particular by codon reassignment 2007; Liu et al., 2019).
of AUA from isoleucine to methionine. There seems to be
a correlation between high aerobic metabolic rate and higher Aging in Eumetazoa (What Is Common to
levels of methionine (an antioxidant) in mitochondria than in
the rest of the cell, which is the case in most animals, and, Bilaterians and Cnidarians?)
inversely between lower aerobic metabolic rate and lower levels Many, but not all cnidarians, are non-senescent or at least
of methionine, which is the case in Porifera, cnidarians and long-lived species (Petralia et al., 2014). In particular, Hydra is
platyhelminthes (Bender et al., 2008). characterized by a body almost entirely composed of stem cells of
There are no studies on the role of histones, chromatin and three sorts and a rapid turn-over of cells: all the cells of the body
nuclear architecture in the mechanisms of aging in Porifera, of Hydra are replaced within 30 days, this form of maintenance
but some molecules they produce have been studied for their by full renewal probably being the main reason why some of them
pharmacological potential in modulating chromatin remodeling are non-senescent (Schaible et al., 2015), while others are not, due
(Luparello et al., 2020). miRNAs have not been studied in relation to imperfect turnover (Schaible et al., 2014).
to aging, but their regulatory role in Porifera has been established
(Wheeler et al., 2009). The Conservation of Unicellular Mechanisms of Aging
in Early Eumetazoans: Degradation of Proteolytic
Appearance of the Decline in the Regenerative Systems, ROS Damage, Degradation of the Nuclear
Potential of Tissues Architecture
In Porifera, a system of stem cells is composed of two How cnidarian cells manage protein aggregates does not seem
kinds of cells, archaeocytes, which act both as oocytes and as to have been investigated, while autophagy has raised interest.
totipotent stem cells, and choanocytes, which can produce sperm, When starved, Hydra can survive up to 40 days through
have physiological functions and act as pluripotent stem cells autophagy. Starvation periods have a sort of rejuvenation
(Funayama, 2010, 2018; Leys and Hill, 2012). Even dissociated effect on Hydra (Schaible et al., 2011), which might be an
from the organism, they can regrow functional tissue (Custodio effect of increased autophagy (Schaible et al., 2014). Starvation
et al., 1998). It has long been assumed that stem cells in Porifera does not affect the rate of production of new cells, but the
have a limitless capacity to regenerate the whole body of the total number of cells decreases. Two parallel processes are
animal (Schröder et al., 2003), notably under the influence of a observed: in ectodermal cells, autophagy leads to cell survival
high basal, normal rate of telomerase production (Koziol et al., and rapidly propagates insuring the survival of the animal, while
1998). However, it is not limitless, but it takes time and resources in endodermal cells, (Kazal1 mediated) autophagy insures the
that may be better allocated in other functions like growth, sexual elimination of excess cells by cell death, the rate remaining

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Lemoine The Hallmarks of Aging Across the Tree of Life

constant (Chera et al., 2009). In the senescent, cold sensitive Hydra, FoxO is expressed mainly in interstitial cells of the
strain Hydra oligactis, autophagy is deficient in epithelial cells as ectoderm, that is, the cells that give rise to nematocytes, neurons,
compared to cold resistant strain of the same species, and might secretory cells and gametes, and in reaction to heat shock but
emphasize deficiencies in autophagy in epithelial cells as the main not to starvation, which suggests that it might play a protective
cause of senescence in this strain, while autophagy would be role for gametes (Bridge et al., 2010). Piwi and Piwi-like genes are
one of the main condition to maintain a continuous rate of cell expressed mostly in germ line and somatic stem cells, typically
renewal (Tomczyk et al., 2020). in cnidarians, and may constitute an essential part of their
The role in aging of mitochondrial dysfunction, methylation, regeneration potential (Seipel et al., 2004).
transcriptional alteration, modification of histones, chromatin The various species of cnidarians and ctenophores are ideal
remodeling and the deregulation of nutrient sensing has not test cases for the inverse correlation that has often been
been investigated in cnidarians, although all those components hypothesized between longevity and level of differentiation
are present. Regarding ROS, Hydra regulate the expression of or complexity in animals (Petralia et al., 2014). A simple
mRNAs of superoxide dismutase, glutathione peroxidase and organization without much coordination is easy to maintain,
catalases, which are known defenses against ROS (Schaible but a more complex one is less easy or impossible to maintain
et al., 2014). Notably, the extreme simplicity of the nuclear perpetually (Schaible et al., 2017). Intercellular communication
envelope architecture in Hydra allows for extreme disturbances is a necessary condition for regeneration in Hydra and involves
in the nuclear lamina – HyLMN, the only gene coding for various specific or largely conserved proteins like Wnt and
lamin in Hydra, being expressed in proliferating stem cells only Notch, tyrosine kinases, but not cytokines and growth factors,
(Klimovich et al., 2018). except for an isomorph of TGF-b, and fibroblast growth factors,
all involved in a probably tight balance between renewal and
The Conservation of Decline in the Regenerative differentiation (Bosch, 2007). Components of the innate immune
Potential of Tissues and Altered Intercellular response (homologs of TLRs and TGF-b) seem to appear as
Communication and the Possible Appearance of Cell early as in choanoflagellates, possibly with a nutrient sensing
Senescence and Inflammation function (Richter et al., 2018). Communication between cells
Stem cells are present in most branches of Eumetazoan, which and extracellular matrix is essential to regeneration in Hydra
constitute an important step in their evolution (Bosch, 2009). (Shimizu et al., 2002). Laminin, a membrane protein that also
However, it is a fact without an explanation, why stem cells do influences the behavior of attached cells by ligand binding may
not accumulate damage in Hydra (Schaible et al., 2017). The have appeared in eumetazoans and finds its simplest known
three different types of stem cells in Hydra illustrate that stem expression in cnidarians, where its defects leads to loss of
cells must be multifunctional, have different sets of transcription regenerative ability for undetermined reasons (Domogatskaya
factors, signal transducers and effector genes involved in specific et al., 2012). Programmed cell death induced by caspase
activities related to cell cycle, cell adhesion and cytoskeleton, and bcl-2 protein families is found in Hydra and play a
extracellular matrix, and also have to maintain homeostasis by role in tissue homeostasis (Böttger and Alexandrova, 2007).
coordinating one another through ligands-receptors activations Bosch has suggested that so-called ‘senescence’ in Hydra is the
mainly via epithelial cells (Hemmrich et al., 2012). The case is result of an excessive redirection of signaling pathways from
different in so-called senescent Hydra. Senescent at 10◦ C (but differentiation to germline (Bosch, 2009). This may be a very
not at 18◦ C), H. oligactis shows signs of exhaustion of stem early form of conditional aging through inflammation in some
cells and disorganization of nervous apical cells and fibers of specific circumstances.
myoepithelial cells (Yoshida et al., 2006; Tomczyk et al., 2015). In The role of the accumulation of senescent cells (Dimri
senescent H. oligactis, functional, differentiated somatic cells like et al., 1995; Liu et al., 2009) and of the increase of systemic
nematocytes, nerve cells, and actin fibers (which serve as muscle) inflammation (Franceschi et al., 2000, 2018) during human aging
decline in number and efficiency, which can be interpreted has long been documented.
as a form of cell senescence, while the number of stem cells
remains constant and the number of germ cells increases during
starvation (Yoshida et al., 2006). Aging in Bilaterians (What Is Common to
A lot of research has focused on the function of FoxO genes Bilaterians?)
in stem cells. Neither choanoflagellates nor plants or fungi, Bilaterians are characterized by symmetric organization under
express FoxO (Bridge et al., 2010). FoxO is a family of proteins the control of Homeobox development genes, which regulate cell
involved both in the regulation of the insulin pathway and in division, cell death, cell adhesion and cell migration (Pearson
cell proliferation (Link, 2019). FoxO has been suggested to be et al., 2005). Importantly, some are non-senescent (flatworms
involved in longevity through the activation of autophagy, the like Schmidtea polychroa) while other are senescent (C. elegans,
resistance to oxidative stress and the maintenance of stemness flatworms like Macrostomum lignano), although sometimes
(Martins et al., 2016). FoxO expression is high in all three stem with alternative senescent and non-senescent trajectories. Most
cells lineages in Hydra, but low in differentiated cells; FoxO flatworms that are non-senescent avoid aging through asexual
silencing increases terminal differentiation and limits growth, reproduction by fission thanks to germline stem cells expressing
while overexpression of FoxO induces expression of stemness nanos, controlled shrinkage when starving, and regeneration
genes in differentiated nematocytes (Boehm et al., 2012). In from body fragments containing neoblasts, that is, pluripotent

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Lemoine The Hallmarks of Aging Across the Tree of Life

stem cells expressing Piwi, even when neoblasts are injected in an with age in some bilaterians, not in others, but instead of
irradiated animal (Petralia et al., 2014). M. lignano is a senescent being an explanation to the process of aging, it is generally
but long-lived flatworm (204 days) with high and non-declining considered an effect of the hallmarks of aging (Yun, 2015).
regeneration potential from the head thanks to blastocytes, no It depends on a balance between renewal of stem cells,
rejuvenation and obligatory sexual reproduction: it also shows apoptosis and cell senescence, likely to be regulated by the rate
exceptional resistance to radiation and no cancer (Mouton et al., of telomere attrition and important pathways of intercellular
2018). Signs of aging are body deformities, grooves in the head, communication. Senescent bilaterians seem to have traded
liquid-filled cysts, disintegration of gonads, but also metabolic off a high proportion of highly active stem cells for more
deregulation (Petralia et al., 2014). differentiation and organismic complexity.
The absence of stem cells in C. elegans may explain that the
Conserved Unicellular Aging in Bilaterians neutralization of apoptosis has no effect on the lifespan (Garigan
(Degradation of Chaperone-Mediated Protein Folding et al., 2002). Rotifers have no stem cells either (Snell, 2014). On
and Stability, Epigenetic Alterations) the contrary, in planarians in general, neoblasts represent 20%
The same kind of protein aggregates as observed in of total cells in the organism, with a major and highly effective
Saccharomyces cerevisiae is observed in the normally aging repair/regeneration function, tightly controlled by proliferation,
C. elegans (David et al., 2010), that does not have stem cells, and cell death and autophagy (Aboobaker, 2011). In planarians,
which rate of aging depends on heat shock proteins, while aged the existence of a regulator gene Smed-p53 that controls
individuals also display a high quantity of lipofuscin (Garigan proliferation, differentiation and which hyperactivity can even
et al., 2002). In this species, the proportion of proteins present induce exhaustion of stem cells, suggests that a single molecule
in cells of aging animals presented important shifts in balance, in the ancestor of bilaterians might have had the functions of
reduced in long-lived mutants and enhanced in short-lived antitumoral p53 family, and self-renewal p63 and p73 families
ones, a phenomenon that accompanies the long observed (Pearson and Alvarado, 2010). In planarians, Piwi genes may be
accumulation of aggregated proteins (Walther et al., 2015). primarily involved in the proper differentiation of neoblasts, and
The so-called free radical theory of aging, which has only secondarily in their renewal (Bely and Sikes, 2010).
emphasized the production of ROS and the accumulation of Defined as the state of arrest of a cell that normally could,
damage in mitochondria as a major cause of aging in animals but will not divide anymore in a multicellular organism, cell
(Shigenaga et al., 1994; Balaban et al., 2005), has now become less senescence is intimately associated with the other hallmarks
central in biogerontology, as noted above. of aging, exhaustion of stem cells in particular, in many ways
Regarding epigenetic alterations, alterations of chromatin (Dolivo et al., 2016). An important function of cell senescence
structure through histone modifications have proven to be a is to stop cell proliferation, notably, during ontogenesis (Muñoz-
major modulator of expression of key genes like p16, whose Espín et al., 2013; Storer et al., 2013), wound repair, or cancer
expression increases in senescent cells, and can be curbed notably development. When irradiated, the planarian Dugesia tigrina
under the influence of the inactivation of the H3K4 methylase shows a depletion of stem cells and a progressive accumulation
or demethylase, a transmissible factor of longevity in C. elegans of senescent cells over a period of 10 days as measured by
(O’Sullivan and Karlseder, 2012). Sir2 overexpression is not a decreased level of H3K27me3 (characteristic of stem cells)
associated with extended lifespan in all eukaryotes, typically not and an increased level of traditional markers of cell senescence,
in C. elegans or D. melanogaster (Burnett et al., 2011). The such as senescence-associated beta-galactosidase, maybe due
expression of sirtuins does not seem to change significantly to the accumulation of senescent cells in healing wounds
in association with aging in Brachionus manjavacas, a rotifer (Perrigue et al., 2015).
(Gribble and Mark Welch, 2017). An inverse correlation between the complexity of the immune
miRNAs are involved in the control of crucial pathways of system and the capacity to regenerate tissues has been proposed
aging, like the IGF1-insulin and AMPK pathways, mitochondrial (Peiris et al., 2014). The inflammatory response is considered to
degradation and cell senescence (Smith-Vikos and Slack, 2012). originate early in bilaterians, maybe as early as in eumetazoans,
In C. elegans, the inactivation of germline cells increases depending on how it is defined and what the mediators are
longevity by 60% through the mediation of miRNA mir-71 in supposed to be (Rowley, 1996). Some have suggested that
intestinal cells (Boulias and Horvitz, 2012). In D. melanogaster, immunity change with age starts with bilaterians, some showing
mir-34 downregulates the expression of the protein E74A, no sign of alteration (planarians) while others do (nematodes)
essential in development, during adult life, and the deletion (Ding et al., 2021). However, the picture is no so clear. In
of miR-34 produces an early-onset catastrophic phenotype of C. elegans, old individuals tend to accumulate bacteria in the
neurodegeneration (Liu et al., 2012). pharynx and intestine, which suggests that they cannot fight
infection anymore (Garigan et al., 2002), although it remains
The Underpinnings of Metacellular Aging: Decline in unclear what is causing what. The same pathways are chiefly
the Regenerative Potential of Tissues, Cell involved in the regulation of innate immunity and in the rate
Senescence, Telomere Attrition and Altered of aging, for example, the DBL-1 pathway, homolog to the
Intercellular Communication mammalian TGF-b pathway (Kurz and Tan, 2004). Several
Regeneration, extended to the whole body of some planarian downstream targets of the AMPK pathway are involved in the
or limited to some tissues in narrower clades, declines regulation of inflammation (Salminen et al., 2011), but there is

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no direct evidence that it is increasing in the nematode. On age and stands in opposition to the general law that metabolism
the other hand, Cathepsin C levels of expression increase in the is inversely proportional to body mass (Mouton et al., 2011).
aging B. manjavacas, a typical sign of inflammation in mammals Lifespan extension in C. elegans by manipulation of the IGF-1 –
(Gribble and Mark Welch, 2017). IIS pathway also depends on functional autophagy (Melendez,
Telomerase activity is high in Hydra as it is in Porifera or 2003), but autophagy alone does not seem to have this lifespan
in planarians that use this mechanism to preserve telomere extension effect (Hansen et al., 2008). A feedback loop between
integrity through a high level of proliferation (Schaible et al., mitochondrial biogenesis and mitophagy under the control of the
2014), but this does not seem to be involved in aging in SKN-1 transcription factor has been proposed in C. elegans, the
senescent Hydra. An important study has cast light on the uncoupling of which accompanies aging, leading to an increased
evolution of telomere attrition in planarians (Tan et al., 2012). number of dysfunctional mitochondria (Palikaras et al., 2015).
The comparison of a sexually and an asexually reproducing The complexification of the lamina (through the increase in
strain of the planarian Schmidtea mediterranea established that the number of lamin-binding proteins) may be a major cause of
both had insufficient telomerase activity to maintain the length the fragility of the nucleus and of cell senescence in bilaterians
of telomeres in the long run. However, the asexual strain (Klimovich et al., 2018). Mutations resulting from unrepaired
restores its telomere length with each fission whereas the DNA damage become permanent and are primarily driving
sexual strain restores it during sexual reproduction or during evolution by natural selection in unicellular organisms, where
embryogenesis. Interestingly, both strains also have the same their accumulation can hardly be considered a cause of aging;
regenerative capacity, although its repeated execution leads in multicellular organisms, the accumulation of mutations in
to severe reduction of telomere length in the sexual strain, somatic and stem cells only, not in germline cells, is generally
where telomerase activity during regeneration is lower, while the considered a cause of aging, including in humans (Vijg, 2021).
increased telomerase activity during regeneration in the asexual The conditions for accumulation of mutations to have an effect
strain suffices to renew telomere length. Telomerase seems to on aging is that the renewal of somatic or stem cells is not
already be present in early branching metazoans and even as early sufficient to prevent mutated somatic cells from having any
as in holozoans (Lai et al., 2017). Recently, it has been suggested lasting effect, which occurs in bilaterians.
that the rate of telomere shortening, not the absolute length of
telomeres, is predictive of lifespan in a wide variety of vertebrates
(Whittemore et al., 2019). Specificities of Aging in Narrower Clades
In humans, the shortening of telomeres with age has first of Bilaterians
been considered possibly as the main cause of aging, a view that All the “hallmarks of aging” have appeared as early as within
now seems exaggerated. More nuanced views have since been bilaterians (Table 1). All are therefore likely to be shared across
developed, as it was clear that telomere attrition would happen this clade. It would be interesting to establish the disappearance
during human aging (Blasco, 2007). of some of the mechanisms of aging in some narrower clades,
as the present review tends to claim that mechanisms of aging
Repercussions of Metacellular Aging on Unicellular can be controlled but are too entrenched in vital mechanisms to
Aging in Bilaterians: Aggravation of the Loss of disappear altogether. In contrast, evolved mechanisms of anti-
Proteostasis and of the Alteration of Nutrient aging may disappear. An example is the repression of telomerase
Sensing, Evolution of the Degradation of Nuclear production in adult mammals of more than 10kg (Gorbunova
Architecture, and Appearance of Aging Through et al., 2014). In various species, the respective importance of
Accumulation of Mutations these mechanisms of aging and mechanisms of anti-aging may
The rate of the degradation of proteostasis has been suggested lead to more or less pronounced slopes of aging (Jones et al.,
to depend mainly on the IGF-1 – IIS pathway (Cohen 2014). Such modulation is likely to explain the exceptional
et al., 2006). Other specific proteins are involved in the longevity of naked mole-rats (Takasugi et al., 2020), or elephants
process, like SKN1, an ortholog of the mammalian Nrf/CNC (Tian et al., 2017).
proteins, which also regulate response to oxidative stress A further characterization of human aging relies on yet
and metabolism (Blackwell et al., 2015). Proteostasis is also more specific hallmarks of aging, specific to humans or shared
degrading in the aging B. manjavacas, as several metabolic with other species. An example is the progressive reduction
pathways are also downregulated, including TOR and insulin of the repertoire of T cells, one of the components of human
(Gribble and Mark Welch, 2017). immunosenescence (Weiskopf et al., 2009) that may strike all
Importantly, the pathways of nutrient sensing in unicellular living organisms with an adaptive immune system, namely,
organisms has evolved to be sensitive to hormonal cues and gnathostomes (Cooper and Alder, 2006).
build a tissue-specific response in multicellular organisms It is also important to take into account the specificities of
(Chantranupong et al., 2015). In C. elegans, the rate of aging the aging of some organs or systems. The vascular system is
depends on the IGF-1 pathway, and dietary restriction has common ancestor to protostomes and deuterostomes, with the
been shown to have an important effect on lifespan (Garigan endothelium appearing later on in vertebrates (Monahan-Earley
et al., 2002). S. polychroa is a non-senescent flatworm with et al., 2013); but it is unclear when the aging of the endothelium
periodic and spectacular changes in body size, regeneration and has appeared in evolution. More generally, the specificities of
rejuvenation. It does not show any sign of reduced activity with aging in some species is likely to explain some striking variations

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Lemoine The Hallmarks of Aging Across the Tree of Life

TABLE 1 | A recapitulation the various mechanisms of aging that have been shown (or hypothesized) to be involved in aging in the different model organisms
mentioned in this review.

Common clade Investigated species Measurement of aging Mechanisms of aging involved References
with bilaterians/ or taxa
humans

Unicellular Cellular organism Escherichia coli Increasing time of Chaperone-mediated protein Stewart et al., 2005;
aging reproduction until death folding and stability Ackermann et al., 2007
Neomura Archaea Not investigated Chaperone-mediated protein Cavalier-Smith, 2002;
folding and stability? Reissmann et al., 2007
Histone modifications? Cavalier-Smith, 2002
Chromatin remodeling? Ammar et al., 2012
Eukaryotes Chlamydomonas Chronological lifespan. Chaperone-mediated protein Galluzzi et al., 2008
reinhardtii ciliates Replicative lifespan. folding and stability
Tetrahymena Pyriformis Clonal aging. Progressive
Euglena gracilis plants loss of function.
Histone modifications Chalker et al., 2013
Chromatin remodeling Chalker et al., 2013
Degradation of proteolytic systems Pérez-Pérez et al., 2010
Instable nuclear architecture Aufderheide, 1986
Mutations in mitochondrial DNA Maréchal and Brisson,
2010
Mitochondrial integrity and Elliott and Bak, 1964;
biogenesis Niyogi, 1999
ROS Bender et al., 2008
Opisthokonts Saccharomyces Chronological lifespan. Chaperone-mediated protein Zhou et al., 2011
cerevisiae Replicative lifespan folding and stability
Histone modifications Feser et al., 2010
Chromatin remodeling Pegoraro et al., 2009
Degradation of proteolytic systems Tyler and Johnson, 2018
Instable nuclear architecture Pathak et al., 2021
Mutations in mitochondrial DNA Longo et al., 2012
Mitochondrial integrity and Longo et al., 2012
biogenesis
ROS
Deregulated TOR nutrient sensing Sampaio-Marques et al.,
2014
Deregulated AMPK nutrient sensing
Deregulated sirtuin nutrient sensing
Deregulated insulin and IGF-1
nutrient sensing
Metacellular Holozoans Choanoflagellates Not investigated All previous mechanisms likely to be Richter and King, 2013
aging present but not investigated
DNA methylation? Transcriptional
alterations?
Metazoans Porifera Chronological lifespan All previous mechanisms likely to be Srivastava et al., 2010;
present but not investigated Jochum et al., 2012
Exhaustion of stem cells Henry and Hart, 2005
Eumetazoans Hydra Chronological lifespan. Chaperone-mediated protein Not investigated
Replicative lifespan. folding and stability, histone
modifications, chromatin
remodeling, mutations in
mitochondrial DNA, mitochondrial
integrity and biogenesis,
transcriptional alterations,
deregulation of nutrient sensing?
Degradation of proteolytic systems Schaible et al., 2014;
Tomczyk et al., 2020
ROS Schaible et al., 2014
Instable nuclear architecture Klimovich et al., 2018

(Continued)

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Lemoine The Hallmarks of Aging Across the Tree of Life

TABLE 1 | Continued

Common clade Investigated Measurement of aging Mechanisms of aging involved References

with bilaterians/ species or taxa
humans

Exhaustion of stem cells Yoshida et al., 2006;

Bridge et al., 2010
Accumulation of senescent cells Böttger and Alexandrova,
2007; Bosch, 2009
Alteration of intercellular Bosch, 2007
communication
Bilaterians Caenorhabditis Chronological lifespan Chaperone-mediated protein Garigan et al., 2002;
elegans Schmidtea folding and stability and David et al., 2010
polychroa degradation of proteolytic systems
Schmidtea
mediterranea
Brachionus
manjavacas
Drosophila
melanogaster
Histone modifications O’Sullivan and Karlseder,
2012
Chromatin remodeling
Instable nuclear architecture Klimovich et al., 2018
Mutations in mitochondrial DNA Palikaras et al., 2015
Mitochondrial integrity and
biogenesis
ROS Balaban et al., 2005
TOR nutrient sensing Smith-Vikos and Slack,
2012; Chantranupong
et al., 2015
AMPK nutrient sensing
Sirtuin nutrient sensing
Insulin and IGF-1 nutrient sensing
DNA methylation Transcriptional Smith-Vikos and Slack,
alterations 2012; Greer et al., 2015
Exhaustion of stem cells Aboobaker, 2011
Accumulation of senescent cells Smith-Vikos and Slack,
2012; Dolivo et al., 2016
Alteration of intercellular Kurz and Tan, 2004; Ding
communication et al., 2021
Telomere shortening Tan et al., 2012
Accumulation of nuclear DNA Vijg, 2021
mutations

in the risk of certain age-related diseases, as is the case with cancer organisms, it is universal. In other terms, no species is devoid
(Schiffman and Breen, 2015). of at least one mechanism of aging, although in some, its effects
are efficiently countered by mechanisms of anti-aging. The first
mechanism of anti-aging is disposal by cell division.
DISCUSSION The second layer of aging is epigenetic alterations
under the form of chromatin remodeling and histone
Bilaterian, and thereby human aging consists in an evolved, modifications. It has appeared with the evolution of a
multilayered mechanism (represented in Figure 3). A new more sophisticated support for DNA and does not seem
layer appears when a mechanism A is responsible for a to be causally related to the first layer. It concerns all
progressively degrading function, i.e., an aging mechanism archaea and eukaryotes.
B. Mechanism A then becomes a mechanism of aging. The third layer of aging contains mitochondrial dysfunction,
All the known layers of aging are present as widely more specifically, ROS damage and the progressive degradation
as in bilaterians. of mitochondrial integrity and biogenesis, damage to mtDNA and
The first layer of aging is the accumulation of unfolded damage to the nuclear architecture, and finally the progressive
or unstable proteins. As it appears as early as in unicellular degradation of proteolytic systems. The appearance of these

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Lemoine The Hallmarks of Aging Across the Tree of Life

mechanisms of aging is apparently unrelated to the existence of the regenerative potential of tissues together form the engine of
the previous ones. Yet, interactions are likely: the generation of aging in most senescent multicellular organisms.
ROS may increase the number of misshaped proteins, the loss The eighth and last layer of aging contains the accumulation
of mitochondrial integrity may increase the generation of ROS. of mutations in nuclear DNA, telomere attrition and alterations
The mechanisms of the third layer result from the appearance of of other forms of intercellular communications as those involved
the characteristics of eukaryotic life, the existence of a nucleus, in inflammation. These mechanisms of aging do not depend
of mitochondria (and chloroplasts), and the appearance of on the appearance of new entities with bilaterians, but on the
autophagy. All eukaryotes share the mechanisms of this third considerable complexification of intercellular communication
layer – except those who have possibly lost one of its components and mutual dependency that appears at this stage, under the
(Karnkowska et al., 2016). constraint of the existence of a complex organization.
The fourth layer of aging contains all the mechanisms grouped The last four layers of aging together constitute the hallmarks
under the label of ‘nutrient sensing’: sirtuins and the TOR, of metacellular aging, that is, the aging of the cells of the
AMPK and Insulin – IGF-1 pathways. These mechanisms also organism that happens in multicellular life only. Metacellular
appeared independently from mechanisms of the first three aging is the problem of aging left unsolved by evolution in
layers. However, the level of interactions increases dramatically many metazoans. It basically consists in the failure to control
with this layer, which may be interpreted as a mechanism the effects of unicellular aging, so that they progressively
focused on the management of the available energy sources affect the whole multicellular organism, which eventually dies.
that happens to control many of the mechanisms of aging Importantly, multicellular organisms may also control unicellular
of the first three layers (directly with the regulation of aging by other mechanisms than the renewal of cells, possibly,
autophagy or mitochondrial activity, indirectly through the the regulation of unicellular aging. For instance, aging mammals
double role of sirtuins in the regulation of this mechanism show significantly less protein aggregates than C. elegans,
and in genomic maintenance), and thereby modulate the pointing toward more a more efficient protein turn-over
rate of aging. These mechanisms characterize opisthokonts, (Walther et al., 2015).
but not all eukaryotes, as their components do not seem In the end, although the multilayer view of aging casts
to be involved in aging in bikonts, although most of considerable light on the general process of aging, there are three
them are present. important limitations, that all stem from the essentially ‘basic cell
These first four layers of aging together constitute the biology’ approach to aging taken in López-Otín et al. (2013). The
hallmarks of unicellular aging. Unicellular organisms contain first is that it ignores potentially important non-cellular factors
some or all of them and most multicellular opisthokonts still of multicellular aging, like the continuous remodeling, and
contain all of them. In unicellular organisms, the problem of progressive structural degradation, of the extracellular matrix.
unicellular aging is mainly solved through reproduction, sexual The second is that it does not describe how variations of the
or clonal, which resets the aging clock for at least one of the two general mechanism of aging explain the huge variety of the rate
cells that result from division. of aging among bilaterians. The third is that the importance, and
The fifth layer of aging contains DNA methylation maybe even the implication of some mechanisms of aging may
and transcriptional alterations. In general, these epigenetic depend on environmental factors, as shown in the example of
mechanisms, appeared early during the evolution of unicellular Furcifer labordi (Cohen et al., 2020).
organism, have the effect of modulating the expression of genes The present review has not taken a comparative view of
in a cell, which is necessary to the coordination of individual cells aging in different branches. An important question is whether
in multicellular life. There is evidence that they are involved as metazoans and plants justify different definitions of aging because
mechanisms of aging in metazoans but it is plausible that they of their different patterns of metacellular aging. Basically, plants
are involved in the aging of a colony in holozoans. have a much more modular structure than metazoans, close
The sixth layer of aging is the decline in the regenerative to that of colonial organisms. Aging seems to be a more local
potential of tissues. It appears with the distinction between stem phenomenon touching the phytomere (basic functional unit of
cells and somatic cells in metazoans. Importantly, this duality the plant) rather than the plant itself, and while aging refers
of cells is an elegant multicellular solution to the problems to the whole lifecycle of the plant, senescence (of the leaf)
of unicellular aging, as long as damaged somatic cells can is a necessary phase of nutrient remobilization (Avila-Ospina
be renewed, and as the renewal of stem cells can outpace et al., 2014) that may or may not lead to death. Moreover,
the accumulation of damage as efficiently as prokaryotes get senescence and death are related to competition between the
rid of accumulated protein aggregates by sequestrating them sink (net importer of nutrients) and the source (providing
into one lineage. When the renewal of cells is insufficient, precursors for sink metabolism). Several molecular mechanisms
multicellular organisms age. of aging may be involved in both metazoans and plants –
The seventh layer of aging contains both inflammation and epigenetic changes, loss of proteostasis (autophagy), nutrient
the accumulation of senescent cells. The mechanisms of aging in sensing (TOR), intercellular communication (e.g., hormones and
this layer are likely to be strongly dependent on the existence of cytokinins in plants), telomere shortening – but they do not
a lower rate of renewal of the cells in a multicellular organism, seem to have the same importance in both kingdoms, and
although they probably originate in some of the specificities of some mechanisms, like accumulation of mutations, are unlikely
eumetazoans. Inflammation, cell senescence and the decline in to play a role in aging in plants (Thomas, 2013), but may

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Lemoine The Hallmarks of Aging Across the Tree of Life

BOX 1 | Is Caenorhabditis elegans a good model of bilaterian aging?

Caenorhabditis elegans is one of the standard models in aging research. Many mechanisms of aging have been investigated, and aging-retarding drugs tested, on
this model organism. Mechanisms include: chaperone-mediated protein folding and stability (Walther et al., 2015), histone modifications (Yi and Kim, 2020),
chromatin remodeling (Greer et al., 2010), degradation of proteolytic systems (Hansen et al., 2008), nuclear architecture (Romero-Bueno et al., 2019), of mtDNA
(Trifunovic and Larsson, 2008), of mitochondrial integrity and biogenesis (Palikaras et al., 2015), ROS-inflicted damage (Finkel and Holbrook, 2000), alteration of
IIS-IGF1 nutrient sensing (Lin et al., 1997), Sirtuins nutrient sensing (Baur and Sinclair, 2006), AMPK nutrient sensing (Greer et al., 2007), TOR nutrient sensing
(Hansen et al., 2008), transcriptional alterations (Smith-Vikos and Slack, 2012), DNA methylation (Greer et al., 2015), inflammation (Salminen et al., 2008), alterations
in intercellular communication (Kurz and Tan, 2004; Ermolaeva and Schumacher, 2014).
However, Caenorhabditis elegans contains postmitotic cells only. For this reason, most characteristics of metacellular aging are, in this organism, different from
most bilaterian organisms, including decline in the regenerative potential of tissues, accumulation of senescent cells, telomere attrition, and accumulation of
mutations in nuclear DNA. This explains the main limit of extrapolation from aging in this worm to aging in most bilaterians, including mammals. If metacellular aging
is indeed the core of aging in senescent multicellular species, then the nematode is ill-suited to investigate its mechanisms. On the other hand, it is a paradoxically
good model to study unicellular aging in a multicellular organism without most of the layers of metacellular aging.

instead play a role in the evolution and adaptation of the to be the case, it is a clear sign of its superiority. Moreover,
species to pest (Plomion et al., 2018). Both in animals and slowing down the accumulation of damage to somatic cells
plants, the role of the production of ROS in mitochondria and does not imply that their replacement will be easy. On the
in chloroplasts (in plants) has recently been reevaluated from other hand, it is both necessary that stem cells are to some
a simple toxic byproduct to a possible regulator of various extent protected from unicellular aging, and unclear how
processes (Singh et al., 2016). they can avoid the accumulation of damage apart from a
This multilayered view of aging is subject to potential very high rate of proliferation, in a way that is very much
revisions. First, it relies on a lacunary literature on aging in reminiscent of how prokaryotes avoid limited RLS. To flesh
many clades and depends on the choice of model organisms out a more specific hypothesis, it would probably be of interest
(Box 1). In particular, the investigation of replicative lifespan in to systematically review the effects of the various anti-aging
archaea should cast some light on the transition to eukaryotic compounds that have been tested on various models, not only on
aging, while the investigation of the various mechanisms the lifespan or on senescence, but on the various mechanisms of
that limit the lifespan of the colony in holozoan and the aging and anti-aging.
investigation of conditional senescence in cnidarians and It is also indispensable to systematically review the
ctenophores should explain more on the onset of metacellular various modulations of these mechanisms that can be
aging. Second, I have made some explicit hypotheses on the observed in various bilaterian species, not necessarily to
appearance of aging though DNA methylation, transcriptional imitate them for interventions on human aging, but also
alterations and decline in the regenerative potential of tissues to understand what can and what cannot work to achieve
for lack of more specific studies in the literature. I have this practical goal.
also proposed surprising hypotheses that many will find In the end, genetic variations relevant for human aging
questionable – such as the late appearance of aging through combined with the diversity of environments will also cast light
nuclear DNA mutations. on how these mechanisms interact.

AUTHOR CONTRIBUTIONS
CONCLUSION
The author confirms being the sole contributor of this work and
This paper has proposed a multilayered evolutionary view on
has approved it for publication.
aging (MEVA). This view shows more concretely than the
ETA how aging may have evolved until bilaterians. It also
constitutes the first necessary step to build a comprehensive FUNDING
view of how aging works. In particular, it suggests a
dichotomy between layers of unicellular aging and layers of This work has been made possible by the support of the
metacellular aging. PHIBIOMED program (Région Nouvelle-Aquitaine), grant
This dichotomy in turn sketches the potential impact and #AAPR2020-2019-8209910.
limits of various anti-aging interventions. To put it in a nutshell,
some interventions target layers of unicellular aging, like the
TOR pathway, mitochondria or DNA damage, while other ACKNOWLEDGMENTS
target layers of multicellular aging, like senolytics. Targeting
unicellular aging may slow down the rate of accumulation I am grateful to Thomas Bosch and Nicole King
of dysfunctional cells with time while targeting multicellular for their help on cnidarians and choanoflagellates,
aging may stimulate the replacement of these accumulating respectively. Thanks to Bertrand Daignan-Fornier and
dysfunctional cells. If non-senescent animal species massively Jean-François Moreau for feedback on the first version
illustrate the latter strategy rather than the former, as it seems of this article.

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Lemoine The Hallmarks of Aging Across the Tree of Life

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