ISSN 0006-2979, Biochemistry (Moscow), 2023, Vol. 88, No. 11, pp. 1692-1703 © The Author(s) 2023. This article is an open access publication.
Published in Russian in Biokhimiya, 2023, Vol. 88, No. 11, pp. 2051-2065.
1692
REVIEW
Relationships among Development, Growth,
Body Size, Reproduction, Aging, and Longevity–
Trade-Offs and Pace-Of-Life
R o n g Y u a n
1,a
*, Erin Hascup
2,b
, Kevin Hascup
2,3,c
, and Andrzej Bartke
1,d
1
Southern Illinois University School of Medicine, Department of Internal Medicine,
19628 Springfield, Illinois, USA
2
Southern Illinois University School of Medicine, Department of Medical, Microbial,
Cellular Immunology and Biology, 19628 Springfield, Illinois, USA
3
Department of Neurology, Dale and Deborah Smith Center for Alzheimer’s Research and Treatment,
Neuroscience Institute, Southern Illinois University School of Medicine, Springfield, Illinois, USA
a
e-mail: ryuan@siumed.edu
b
e-mail: ehascup@siumed.edu
c
e-mail: khascup49@siumed.edu
d
e-mail: abartke@siumed.edu
Received July 26, 2023
Revised October 18, 2023
Accepted October 19, 2023
Abstract— Relationships of growth, metabolism, reproduction, and body size to the biological process of aging and
longevity have been studied for decades and various unifying “theories of aging” have been proposed to account for the
observed associations. In general, fast development, early sexual maturation leading to early reproductive effort, as well
as production of many offspring, have been linked to shorter lifespans. The relationship of adult body size to longevity
includes a remarkable contrast between the positive correlation in comparisons between different species and the negative
correlation seen in comparisons of individuals within the same species. We now propose that longevity and presumably also
the rate of aging are related to the “pace-of-life.” A slow pace-of-life including slow growth, late sexual maturation, and
a small number of offspring, predicts slow aging and long life. The fast pace of life (rapid growth, early sexual maturation,
and major reproductive effort) is associated with faster aging and shorter life, presumably due to underlying trade-offs.
The proposed relationships between the pace-of-life and longevity apply to both inter- and intra-species comparisons as
well as to dietary, genetic, and pharmacological interventions that extend life and to evidence for early life programming
of the trajectory of aging. Although available evidence suggests the causality of at least some of these associations, much
further work will be needed to verify this interpretation and to identify mechanisms that are responsible.
DOI: 10.1134/S0006297923110020
Keywords: aging, longevity, pace-of-life, trade-offs, developmental programming, growth, reproduction, body size
Abbreviations: DOHaD,Developmental Origins of Health and Disease; GH,growth hormone; GHR,growth hormone receptor;
GHRH,growth hormone releasing hormone; IGF-1, insulin-like growth factor-1; IGHD,isolated growth hormone deficiency.
* To whom correspondence should be addressed.
INTRODUCTION
Aging is a part of the life course of nearly all living
organisms, including all human beings. This is certain-
ly common knowledge, and it often leads to a common
belief that there is nothing we can do about aging. Sci-
entific evidence that the biological process of aging can
be modified and that these modifications can promote
health and extend life has been available for decades, but
it is only recently that this evidence is slowly starting to
be incorporated into the theoretical framework and daily
practice of medicine and into the public health policies.
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In this context, we believe that it is timely to consider
the trade-offs between development and aging, which
are associated with anti-aging interventions, and to
identify the underpinning mechanisms. Groundbreaking
studies of the effects of calorie restriction (CR, reduced
intake of nutrients without malnutrition) in laboratory
rodents demonstrated that extension of longevity was as-
sociated with reduced body size and suppression of fer-
tility. When juvenile animals were exposed to CR, their
growth rate was reduced and sexual maturation was de-
layed. Severe CR can completely suppress reproductive
function while still producing marked benefits in terms
of health and longevity. These and other findings lead
to the question of whether differences in longevity be-
tween different species, as well as between individuals of
the same species, are associated with (and perhaps due
to) similar trade-offs. In this article, we will briefly re-
view the relationships between sexual maturation and
reproduction, as well as somatic growth and adult body
size, and longevity. Additionally, we will discuss the role
of growth hormone (GH) and insulin-like growth fac-
tor-1 (IGF-1), key regulators of growth, maturation,
and adult body size, in the control of mammalian ag-
ing and the relationships between the “pace-of-life”,
the biological process of aging, and its developmental
programming. Finally, we will also discuss some of the
cellular and molecular mechanisms that may explain the
observed associations and trade-offs.
BODY SIZE AND LONGEVITY:
BIG MICE DIE YOUNG,
BUT LARGER MAMMALS
LIVE MUCH LONGER THAN MICE
The relationship between adult body size and lon-
gevity in mammals is very complex. In general, larger
species live longer, with the huge bowhead whale being
the longest-living mammal. The positive correlation be-
tween adult body size and maximal lifespan across all
mammalian species is well documented and striking [1].
However, there are important exceptions. Many species
of bats live much longer than similarly sized rodents
or shrews [2]. Another intriguing example of extended
longevity is the naked mole rat (Heterocephalus glaber).
Despite having a similar body size to laboratory mice, na-
ked mole rats live about ten times longer in controlled lab-
oratory environments [3]. Among mammals, primates live
longer than their body size would predict, with our own
species being the most extreme example. The average life
expectancy of humans far exceeds that of much larger ru-
minants or equids and the documented maximal human
lifespan, 122 years [4], exceeds the longevity of elephants.
The long life of large animals has been linked to
reduced risk of extrinsic mortality, particularly mortal-
ity due to predation. Longer life expectancy is coupled
with the evolutionary emergence of physiological char-
acteristics and reproductive strategies that favor (or are
compatible with) long survival. We will discuss these as-
sociations later in this article. Mechanistically, extremes
of longevity have been linked to molecular and cellular
mechanisms of protection from cancer (elephants) [5]
and to the capacity to repair DNA damage (bowhead
whales) [6]. Extended longevity of bats, naked mole rats,
and primates has been related to reduced risk of preda-
tion in animals capable of flying or living underground,
and protection from multiple causes of extrinsic mortality
by social organization combined with intelligence [2, 7].
In addition, the exceptionally long lifespan of naked
mole rats has been attributed not only to their special-
ized underground lifestyle but also to the accompanied
remarkable ability to tolerate hypoxic conditions and
thrive in environments with limited oxygen availability
which may result in reduced oxidative damage [8].
In sharp contrast to the positive correlation of body
size and longevity across mammalian species, there are
numerous examples of smaller, rather than larger indi-
viduals, within the same species having longevity advan-
tage [9, 10]. This is particularly striking and well-docu-
mented in laboratory populations of house mice and in
domestic dogs [11, 12]. Comparisons of the longevity of
mice from different inbred strains or lines selected for
differences in growth rate and/or adult body size [13-15]
and comparisons of individual mice from a genetical-
ly heterogeneous population [11] consistently show the
negative correlation between adult body size and longev-
ity. Moreover, mutations producing dwarfism also cause
a major extension of longevity. Mice with homozygous
alleles of these mutations can survive as much as 50%
longer than genetically normal (“wild type”) animals
born in the same litter and maintained under identical
nutritional and environmental conditions [16,17].
Comparisons of different breeds of domestic dogs
or individual dogs differing in size consistently show a
negative correlation between adult body weight and lon-
gevity [12]. Very small dogs typically live over 15 years,
while dogs from the largest breeds are not likely to reach
the age of 10 years [10, 18]. Similar negative associa-
tions of body size and lifespan have been described in
laboratory rats [19] and in domesticated horses [20], as
well as in various human populations [21]. Additionally,
studies have reported that interventions extending lon-
gevity, such as rapamycin treatment implemented at an
early age, are accompanied by reductions in body size
[22, 23]. However, the interpretation of the data con-
cerning the relationship of human stature to longevity is
complicated by the role of socio-economic status, early
life nutrition, access to medical care, progress in med-
icine, and a plethora of public health policies. Conse-
quently, the existence of a negative correlation between
human stature and life expectancy is not universal-
ly accepted and is often viewed as controversial [24].
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We have discussed this issue in more detail in previous
publications [25,26].
It deserves emphasis that the relationship of the
rate of growth and development (a key element of the
pace-of-life) to aging and longevity differs in import-
ant ways from the association of adult body size with
the same life history traits. Thus, slower growth is relat-
ed to slower aging and longer life in comparisons both
between and within species, but smaller adult size pre-
dicts longer life only in comparisons between individuals
from the same species. The paradox of the opposite re-
lationships is not easily explained. One study suggested
that the circulating levels of IGF-1, the key mediator of
stimulatory action of pituitary GH on somatic growth,
are unexpectedly lower in larger than in smaller spe-
cies [27]. This contrasts with the positive correlation be-
tween IGF-1 levels and body size within a species [28].
As will be discussed later in this article, we favor a dif-
ferent explanation, namely the role of the rate of growth,
development, and maturation (combined with the dura-
tion of growth and with other phenotypic characteristics)
in the programming of aging and longevity. Naturally,
these explanations are not mutually exclusive and other
mechanisms may also be involved. For example, dispar-
ities in longevity both within and between species could
be attributed to factors such as cell division dynamics
and growth [29], the composition of cell membranes [30],
DNA damage and repair [31], and the erosion of telo-
meres and telomerase activity [32]. These mechanisms
likely interact with one another. Additionally, it is plau-
sible that the correlations between body size and lon-
gevity do not imply a cause-and-effect relationship.
Instead, both factors could be influenced by a shared
factor, potentially one of the “pillars” or “hallmarks” of
aging, as discussed in the antagonistic pleiotropic theo-
ry[33] or the hyperfunction theory [34].
A slow pace of growth may also shape aging and
lifespan via its impacts on brain development [35].
A previous study analyzed 493 mammal species, span-
ning rodents to cetaceans, revealing a compelling link:
mammals with larger brains relative to their body size
tend to have longer lifespans and extended reproductive
periods [36]. This observation is intriguing, given that
larger brains come with metabolic expenses and pro-
tracted developmental phases. Natural selection, there-
fore, should favor the evolution of larger brains only if
they offer compensatory advantages. One such advantage
is the facilitation of adaptive responses to novel or com-
plex socioecological challenges, a concept encapsulated
by the Cognitive Buffer Hypothesis (CBH) [37]. CBH
posits that a larger brain enhances behavioral adaptabil-
ity in response to changing environmental conditions,
simplifies the learning process, and equips species to
surmount ecological hurdles effectively. Additionally,
this adaptability promotes the formation of stable social
groups, aligning with the Social Intelligence Hypothesis
(SIH), which suggests that species living in such groups
face increased cognitive demands, thus necessitating
larger brains to cope with the intricacies of group liv-
ing [38]. Indeed, stable social groups offer several ad-
vantages, including cooperative defense, resource shar-
ing, shared parental care, and improved reproductive
success, enhancing survival for individuals and offspring.
Interestingly, social structure can play a decisive role in
shaping the relationships between body size, reproduc-
tion, and lifespan. This is evident in eusocial insects
like ants and bees, as well as mammals like the mole rat.
In these species, reproducing females often exhibit sig-
nificantly larger body sizes yet live considerably longer
than other members of their societies. Thus, in these
animals, increased reproductive effort is associated with
extended rather than reduced longevity.
HORMONAL CONTROL
OF GROWTH AND LONGEVITY:
ROLE OF PITUITARY GROWTH HORMONE
IN THE CONTROL OF MAMMALIAN AGING
It is now more than 25 years since we suggested that
GH is importantly involved in the control of mamma-
lian aging. This was based on studies in GH transgenic
mice and in mice with hereditary dwarfism. We reported
that giant transgenic mice have numerous phenotypic
characteristics that resemble aging [39] and confirmed
that these animals live much shorter than their nor-
mal siblings [40]. We also reported that the longevity of
Prop1
df
(Ames dwarf) mice, which are deficient in sever-
al adenohypophyseal hormones including GH, is greatly
extended [17]. These findings implied that normal lev-
els of GH signaling incur “costs” in terms of longevity
and that pathological access to GH leads to accelerated
aging. The evidence for the role of GH in the control
of aging was greatly strengthened by subsequent demon-
stration that isolated GH deficiency caused by deletion
of the key hypothalamic regulator of GH biosynthesis
and secretion, GH releasing hormone (GHRH) [41],
or by a mutation of the GHRH receptor (GHRHR)
gene[42], as well as deletion of the GH receptor (GHR)
gene [43], also produce an impressive extension of mouse
longevity. In other words, the blockade of GH produc-
tion or its actions is sufficient to increase life expectancy.
These studies also indicated that extension of life in the
absence of GH signals is a highly reproducible finding
and that it is not limited to a particular mutation, the
genetic background of the animals, or husbandry con-
ditions in one laboratory. This point merits emphasis,
since a reduction rather than an extension of the lon-
gevity of hereditary dwarf mice was seen in one older
study [44], an observation now believed to be due to
husbandry conditions and animal health issues in this
laboratory [45-47].
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Importantly, additional studies in Ames dwarf mice
provided evidence that the link between GH deficien-
cy and the long life of these animals represents a cause:
effect relationship. Six weeks of GH replacement ther-
apy, started at one or two weeks of age, significantly
reduced the longevity of these animals [48]. Moreover,
most of the phenotypic characteristics that distinguish
Ames dwarf from normal (wild type) mice and are be-
lieved to represent mechanisms and/or markers of their
slower aging and extended longevity were completely or
near-completely normalized (“rescued”) by this reg-
imen of GH replacement [48-50]. The mechanisms by
which early-life GH treatment alters adult phenotype
and longevity are almost certainly epigenetic and involve
histone modifications [51].
The dramatic impact of GH deficiency, GH re-
sistance, and GH excess on the longevity of laboratory
mice prompted many questions about the applicability
of these findings to other species, particularly to hu-
mans [52]. Pathological GH excess in the syndromes
of acromegaly and gigantism reduces life expectancy in
humans [53, 54], thus echoing the findings in giant GH
transgenic mice [55, 56]. Moreover, many symptoms of
these conditions, including increased risk of diabetes,
cardiovascular disease, and some types of cancer, re-
semble symptoms of normal aging. However, in contrast
to the findings in various types of dwarf mice, humans
with isolated GH deficiency (IGHD) or GH resistance
(Laron syndrome) do not live longer [57, 58] and re-
duced life expectancy was reported in one population
of individuals with hereditary IGHD [59]. Interestingly,
even though life expectancy is not extended by genetic
syndromes that block GH signaling, GH-resistant, and
GH-deficient individuals are significantly protected
from chronic aging-associated diseases including can-
cer, diabetes, and atherosclerosis, show improvements
in the maintenance of various physiological functions
into advanced age [60], and in at least one population
of IGHD individuals appear to be more likely to achieve
exceptional longevity [61]. In terms of average longevity,
these protective features of GH-deficient and GH-resis-
tant individuals appear to be counterbalanced by an in-
creased risk of early deaths, particularly deaths related to
accidents and alcohol abuse [25, 60]. Increased chances
of living to very old age were reported also in the “lit-
tle people of Krk,” a population of individuals with a
GH deficiency caused by a mutation of the Prop1 gene,
the same gene which is mutated in the long-lived Ames
dwarf mice [57].
Several recent and ongoing studies addressed the
possible role of variations in GH and IGF-1 signaling
within the normal range in the control of human aging.
Offspring of long-lived families identified in the Leiden
Longevity Study [62] have been consistently shown to
exhibit several favorable health outcomes compared to
their partners. This includes a reduced incidence of di-
abetes, hypertension, and hypercholesterolemia, as well
as a decreased risk of other prevalent age-related diseas-
es, such as cardiovascular diseases (e.g., coronary ar-
tery disease, heart failure, and stroke), neurodegenera-
tive diseases (e.g., Alzheimer’s disease and Parkinson’s
disease), osteoporosis, chronic obstructive pulmonary
disease (COPD), arthritis, age-related macular degener-
ation, renal diseases, age-related hearing loss, and oth-
er conditions commonly associated with aging [63-68].
Importantly, the offspring of long-lived individuals also
demonstrate a lower mortality rate compared to their
partners [69]. It was also reported that these individu-
als have reduced rates and “tighter” control of GH se-
cretion [62, 70]. These data suggest that a normal level
of GH signaling acts to accelerate aging in humans as it
does in laboratory stocks of house mice and that lower
levels of GH are beneficial for healthspan and lifespan.
Of course, it is difficult to exclude alternative interpre-
tations, such as the existence of co-regulators that influ-
ence both GH secretion and the aging process.
Many studies addressed the possible involvement
of IGF-1 as a part of the IGF/insulin signaling(IIS) in
human aging, and both positive and negative associa-
tions with longevity have been reported. While a detailed
analysis of this complex set of observations is outside the
scope of this brief article, we would like to point out that
a likely reason for the discrepancies in findings from
different studies was recently proposed by Zhang and
colleagues in a study that analyzed the levels of IGF-1,
mortality, and aging-related diseases, including demen-
tia, diabetes, cancer, vascular disease, and osteoporosis,
among more than 400,000 people aged from the 30s to
the 70s [71]. The results suggest that IGF-1 is a nonlin-
ear predictor of risk, and interacts with age to modify
risk for a variety of clinical events. Specifically, younger
individuals with high IGF-1 levels exhibited a protective
effect against the disease, whereas older individuals with
elevated IGF-1 levels were at an increased risk of devel-
oping an incident disease or experiencing mortality [71].
Furthermore, the association between IGF-1 levels and
disease risk displayed a U-shaped relationship, indicat-
ing that excessively high and low levels of IGF1 may be
detrimental to disease susceptibility [71].
The intricate effects of IGF1 on aging, including
genetic variations, sex disparities, and the interaction be-
tween IGF1 and age, were examined in a comprehensive
meta-analysis, using 32 mouse inbred strains [72-74].
These strains represent the major diversity in the ge-
nome of Musmusculus, providing a rich source of ge-
netic variation, which is one to two orders of magnitude
higher than the level of sequence diversity observed in
human populations [75]. The results revealed an asso-
ciation between lower IGF-1 levels and extended me-
dian lifespan across the inbred strains [72]. However,
a sex-specific correlation was observed between IGF1
levels and the lifespan variation [74]. In females, lower
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IGF-1 levels were associated with an increased risk
of death at a young age (<180 days), but an extended
maximum lifespan, leading to greater variation in lifes-
pan. In males, although no significant alteration in the
risk of early death was observed, higher IGF-1 levels
were associated with an extended maximum lifespan.
Therefore, in males, the higher IGF-1 level is associ-
ated with elevated variation in the lifespan [74]. Nota-
bly, an intervention study was conducted on female and
male mice at old age (18 months) using the IGF-1 re-
ceptor (IGF1R) antibody. This treatment improved fe-
male healthspan and resulted in a 9% increase in median
lifespan, along with reductions in neoplasms and inflam-
mation. However, no significant changes were observed
in male mice [76]. These findings further highlight the
sex-specific effects of IGF-1 on aging and underscore
the importance of considering the time window for tar-
geting IGF-1 signaling to extend lifespan. Particularly,
it raises intriguing questions about whether increasing
IGF-1 levels during old age could potentially extend the
maximum lifespan of males.
REPRODUCTIVE DEVELOPMENT,
AGE OF SEXUAL MATURATION, AND AGING.
TRADE-OFFS AND DIFFERENT LIFE HISTORIES
Comparisons of the reproductive effort in short-
and long-lived species of mammals reveal major differ-
ences and suggest the existence of trade-offs. Short-lived
mammals typically have an early age of puberty, short
gestation, large litters, and early age of weaning asso-
ciated with short intervals between the litters. For ex-
ample, mice and other small rodents can reach sexual
maturity in less than two months and produce litters as
large as 10-12 pups at intervals of one to two months.
In contrast, large, longer-living species generally exhibit
opposite reproductive characteristics: late puberty, sin-
gle offspring or very small litters, and a long period of
nursing. For example, ruminants or equids (including
domestic cows, sheep, and horses) may not reach sex-
ual maturation in the year they are born, have gestation
lengths ranging from several to 11 months, produce one,
or, less commonly, two offspring once a year, and nurse
them for several months. Domestic dogs exhibit very
large differences in longevity between small and large
breeds and between mixed breed animals differing in
body size (details and references earlier in this article).
Bargas-Gallaraga and colleagues recently reported that
reproductive investment negatively impacts longevity in
this species and that this relationship could not be ex-
plained by the correlation of both reproductive effort
and longevity to body size [77]. A remarkable study of
life history trajectories in over seven thousand female
southern elephant seals in their natural habitat revealed
a correlation between the age at first reproduction and
the onset of actuarial senescence (defined as age-related
increase in mortality) [78]. However, early breeders in
this population outperformed delayed breeders in terms
of survival and net reproductive output [78]. Apparent-
ly, differences in the individual ability to cope with early
life challenges can override the effects of trade-offs be-
tween reproductive performance and longevity.
Evidence for trade-offs between reproduction and
longevity was derived from studies of calorie restriction
(CR) [79] and from studies in which the macronutrient
composition of the diet (primarily the relative content of
protein and carbohydrate) was varied by the investiga-
tors [80, 81] or determined by the choices of experimen-
tal animals themselves [82,83]. Generally, a higher in-
take of calories and protein favored reproduction but not
survival [83]. In laboratory rodents, CR can significant-
ly extend longevity in most of the examined populations
and can block or delay puberty and lead to infertility or
to reduced litter size and increased intervals between the
litters [84]. However, these trade-offs were nuanced and
depended on the specific features of the study. Specif-
ic outcomes depend on the species (for example rats vs.
mice), age of onset of CR, and the percentage of reduc-
tion in food intake [84]. In addition to the various sup-
pressive effects on reproduction, CR was also report-
ed to delay reproductive aging and to increase the age
atwhich reproduction can be “re-awakened” by refeed-
ing [85]. Delayed puberty, reduced litter size and in-
creased intervals between litters as well as various indi-
cations of delayed reproductive aging were reported also
in genetically dwarf mice in association with a remark-
able extension of longevity [86].
The relationship of the age of sexual maturation
to aging and longevity deserves particular emphasis.
The association of earlier puberty with shorter lifespan
is seen in comparisons both between and within species.
Importantly, the age of sexual maturation in short-liv-
ing animals is early not only in terms of chronological
age but also in proportion to the average life expectan-
cy. For example, laboratory mice reach puberty at the
age of three to six weeks which represents roughly 3-5%
of their average longevity, while humans typically reach
puberty at 12-15 years of age, corresponding to 15-19%
of the average lifespan. Correlation between the age of
puberty and longevity also was detected in comparisons
of individuals or cohorts (such as different strains or
breeds) within the same species [73].
Given the robust correlation observed between the
age of sexual maturation and lifespan, and the intricate
connection between body size with aging and longevi-
ty, an intriguing question emerges: Can retarding re-
productive development while leaving somatic growth
unaffected lead to delayed aging and extended lifespan?
Addressing this question is challenging due to the tight-
ly coordinated control between somatic growth and re-
productive development. Interestingly, our recent study
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involving heterogeneous UM-HET3 mice, where met-
formin was administered during early life (15-56 days),
found that while metformin increased circulating IGF1
levels and body size, it significantly delayed the age of
female sexual maturation [87]. This implies that met-
formin treatment could potentially decouple the regu-
latory pathways controlling somatic and reproductive
development. The underlying mechanism of this effect
may be linked to the molecular function of metformin
in upregulating AMPK activity [88]. Mammalian re-
production is an energy-consuming process that occurs
when there is adequate nutrition [89]. AMPK is a sen-
sor of nutrient status, and it is activated by the decrease
of ATP/AMP ratio or starvation. Activated AMPK acts
to switch off ATP-consuming pathways, such as protein
synthesis, lipogenesis, and gluconeogenesis, and turn
on ATP-generating pathways such as fatty acid oxida-
tion, glycolysis, and autophagy [90]. On the molecular
level, activated AMPK inhibits the mammalian target
of rapamycin (mTOR) by directly phosphorylating the
tumor suppressor tuberous sclerosis complex2 (TSC2)
and regulatory-associated protein of mTOR (RAPTOR)
[91]. Elevating mTOR signaling can significantly ac-
celerate female sexual maturation and enhance female
reproduction [92]. Importantly, in recent studies, sup-
pression of mTOR by rapamycin was shown to sup-
press reproduction but extend healthspan and lifespan
[22, 23]. The complex relationships among reproduc-
tion, body size, and aging are far from being resolved,
and understanding the roles of AMPK and mTOR sig-
naling in the co-regulation of development and aging is
of great interest. For a discussion of the underlying evo-
lutionary processes and a recent overview of this field of
study please see [93-95].
EARLY LIFE PROGRAMMING
OF ADULT CHARACTERISTICS.
CAN SLOWING THE PACE-OF-LIFE
PRODUCE LONGEVITY BENEFITS?
Interest in the role of early life events in program-
ming development started at least 64 years ago with the
pioneering work of Waddington on the “canalization” of
developmental events [96]. These studies provided the
groundwork for the present understanding of epigenetic
phenomena and mechanisms of induction of phenocop-
ies by environmental factors. Studies of the effects of
starvation during pregnancy on the risk of cardiovascu-
lar and metabolic disease in adult offspring lead to the
now solidly grounded concept of the Developmental Or-
igins of Health and Disease (DOHaD) [97]. While most
studies related to DOHaD addressed detrimental effects
of starvation, malnutrition, toxicants, and stress during
pregnancy, there is also considerable evidence that en-
vironmental insults during childhood and adolescence
can have lasting effects on health and the risk of chronic
disease [98,99]. Based on these findings, it would seem
reasonable to suggest that early life events can shape the
pace-of-life and associated trade-offs such as the parti-
tioning of available resources between reproduction and
processes promoting longevity.
Our studies of the effects of GH replacement ther-
apy in GH-deficient long-lived Ames dwarf mice pro-
vided additional support for early life programming of
aging and longevity [48]. In this work, dwarf animals
were injected with GH for only six weeks starting at one
or two weeks of age. This produced the expected accel-
eration of growth during the period of treatment and an
increase of adult body weight to values approximate-
ly intermediate between the weight of control (vehicle
injected) dwarfs and their normal (wild type) siblings.
As mentioned earlier in this article, various phenotypic
characteristics related to the “hallmarks” (“pillars”) of
aging, including markers of brain gliosis, plasma insu-
lin, adiponectin, ketone bodies, and lipid profiles, mea-
sured approximately one year or even later after the end
of GH therapy, were completely (or near completely)
normalized so that they no longer differed from values
measured in saline-treated wild-type controls [48-50].
Moreover, the remarkable longevity of these mice was
significantly reduced by six weeks of GH treatment in
early life [48]. Apparently, this early-life endocrine in-
tervention produced long-lasting, likely permanent
physiological changes reflecting (and/or contribut-
ing to) profound alterations in the trajectory of aging.
The underpinning mechanisms were almost certainly
epigenetic and evidence available to date suggests that
they involved histone modifications [51].
PACE-OF-LIFE AND AGING.
RELATIONSHIPS OF EARLY GROWTH
AND EARLY REPRODUCTIVE EFFORT
TO LONGEVITY
In previous sections of this article, we have dis-
cussed the evidence for the role of trade-offs with
growth, maturation, and reproduction in the control of
aging and the involvement of GH and IGF-1 in medi-
ating these trade-offs. Also mentioned were paradoxi-
cal differences between relationships of adult body size
to longevity in comparisons among vs. within species.
The picture that emerges from the available evidence is
consistent with the concept of developmental program-
ming of aging which is supported by much experimen-
tal evidence as well as theoretical considerations [96,
100-104]. In particular, faster early growth and great-
er body weight of juveniles have been related to higher
morbidity and mortality in studies of mice [105], dogs
[106], and humans [107, 108]. In laboratory mice, in-
terventions that affect early somatic growth were shown
YUAN et. al1698
BIOCHEMISTRY (Moscow) Vol. 88 No. 11 2023
to have a major impact on longevity. Shindyapina and
her colleagues have shown that treatment of genetically
diverse UMHET3 mice with rapamycin during the first
45 days of postnatal life resulted in reduced growth rate
and extended longevity (median life span) and impor-
tantly, also healthspan [22]. As was mentioned earlier, a
relatively brief period of GH treatment in early life ac-
celerated growth and reduced longevity in Ames dwarf
mice[48]. Extension of longevity by early life treatment
with rapamycin was achieved also in a small (plankton-
ic) crustacean, Daphnia, and in a fruit fly, Drosophila
[22,23]. Similar to early growth rate, early sexual mat-
uration was negatively related to longevity in various
studies [73].
What we believe deserves particular emphasis is that
the reciprocal relationship between longevity and key el-
ements of the pace-of-life, namely growth, maturation,
and reproductive effort, apply to comparisons between
different species of mammals as well as between differ-
ent strains, breeds, or individuals with a species. This
is in marked contrast to the relationship of longevity to
adult body size, which is opposite rather than consistent
in these comparisons. It is interesting that differences in
the pace of life also correlate with the differences in life
expectancy among humans with extremely short stature.
Thus, short stature due to isolated GH deficiency in
the Itabaianinha cohort or to GH resistance is associ-
ated with a slow pace-of-life (slow growth, delayed pu-
berty, and reduced fecundity), protection from various
age-related diseases and conditions leading to “healthy
aging” as well as with normal life expectancy [25, 109],
while short stature in various populations of pygmies is
associated with fast pace-of-life (fast development and
early age of first pregnancy) and very short life [110].
A particularly striking example of a reciprocal relation-
ship between the pace of life and longevity is provided
by an African fish, Nothobranchius furzeri which lives in
ephemeral ponds. The eggs of these remarkable animals
survive in the soil after the ponds dry up and hatch when
the pond is re-established by the next rainy season.
The young fish develop at the rate that has been de-
scribed as “explosive”, reproduce and age rapidly result-
ing in the average longevity of four to six months, the
shortest lifespan of any vertebrate [111]. Importantly,
rapid aging and early death are seen also in captive fish
of this species which are maintained in aquaria that (of
course) do not seasonally dry up and are provided with
a reliable supply of food [112], indicating the genetic ac-
commodation of the species to its natural environment.
The definition of the pace-of-life generally includes
basal metabolic rate and slow metabolism was frequent-
ly implicated in delayed aging, however, longevity is not
simply determined by the rate of metabolism. The most
striking example of this is provided by comparisons be-
tween mammals and birds. Birds have higher metabolic
rate than mammals of the same size and yet live longer
rather than shorter. This may be due to reduced extrin-
sic mortality of organisms that can avoid predators and
other environmental risks by flying [113,114]. Interest-
ingly, the average daily metabolic rate measured by oxy-
gen consumption per unit body mass is increased rather
than reduced in long-lived genetically growth hormone
deficient or growth hormone resistant mice [115]. Anal-
ysis and interpretation of data on energy metabolism
is complicated by differences between basal metabolic
rate, resting metabolic rate, and energy expenditure or
field metabolic rate, and by different ways of reporting
bioenergetic data. We have dealt with these complex is-
sues in earlier publications [116-118].
Unraveling the trade-offs among body size, repro-
duction, aging, and longevity requires further research
to understand the underlying mechanisms and their im-
plications for human health and aging. Incorporating
this knowledge into medical practice and public health
policies has the potential to promote health and extend
lifespan in the future.
Contributions. Rong Yuan and Andrzej Bartke con-
ceived the manuscript; Rong Yuan and Andrzej Bartke
wrote the manuscript with input from all authors; Erin
Hascup and Kevin Hascup edited the manuscript and
provided feedback.
Acknowledgments. We apologize to those whose
work pertinent to the issues discussed was not cited
due to limitations of the format or to inadvertent omis-
sions. We are grateful for editorial assistance provided
by Lisa Hensley.
Funding. This work was supported by the Geri-
atrics Research Initiative at SIU School of Medicine
(AB) and National Institutes of Health (R01 AG057767,
R01 AG061937), the Dale and Deborah Smith Center
for Alzheimer’s Research and Treatment, and the Ken-
neth Stark Endowment (ERH and KH).
Ethics declarations. The authors declare no con-
flicts of interest. This article does not contain any stud-
ies involving human participants or animals performed
by any of the authors.
Open access. This article is licensed under a Creative
Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution, and repro-
duction in any medium or format, as long as you give ap-
propriate credit to the original author(s) and the source,
provide a link to the Creative Commons license, and in-
dicate if changes were made. The images or other third
party material in this article are included in the article’s
Creative Commons license, unless indicated otherwise in
a credit line to the material. If material is not included in
the article’s Creative Commons license and your intended
use is not permitted by statutory regulation or exceeds the
permitted use, you will need to obtain permission directly
from the copyright holder. To view a copy of this license,
visit http://creativecommons.org/licenses/by/4.0/.
AGING AND LONGEVITY – TRADE-OFFS AND PACE-OF-LIFE 1699
BIOCHEMISTRY (Moscow) Vol. 88 No. 11 2023
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