Growth Hormone and Aging: Updated Review

Abstract

Role of growth hormone (GH) in mammalian aging is actively explored in clinical, epidemiological, and experimental studies. The age-related decline in GH levels is variously interpreted as a symptom of neuroendocrine aging, as one of causes of altered body composition and other unwelcome symptoms of aging, or as a mechanism of natural protection from cancer and other chronic diseases. Absence of GH signals due to mutations affecting anterior pituitary development, GH secretion, or GH receptors produces an impressive extension of longevity in laboratory mice. Extension of healthspan in these animals and analysis of survival curves suggest that in the absence of GH, aging is slowed down or delayed. The corresponding endocrine syndromes in the human have no consistent impact on longevity, but are associated with remarkable protection from age-related disease. Moreover, survival to extremely old age has been associated with reduced somatotropic (GH and insulin-like growth factor-1) signaling in women and men. In both humans and mice, elevation of GH levels into the supranormal (pathological) range is associated with increased disease risks and reduced life expectancy likely representing acceleration of aging. The widely advertised potential of GH as an anti-aging agent attracted much interest. However, results obtained thus far have been disappointing with few documented benefits and many troublesome side effects. Possible utility of GH in the treatment of sarcopenia and frailty remains to be explored.

Full text

INTRODUCTION
Aging is accompanied by numerous changes in
the f unction of the endocrine system. Many of these
changes are very pronounced, readily detectable, and
thoroughly documented. However, interpretation of
the biological meaning of these changes is far from
simple. Thus, age-related decline in circulating levels of
a particular hormone, dehydroepiandrosterone, estra-
diol 17 beta, testosterone, or growth hormone (GH) can
be viewed as yet another symptom of aging, as one of
its potential mechanisms, or as a protective adaptation
to alterations in physiological functioning and disease
risk in the aging organism. In this article, we will pro-
vide an overview of the intricate relationships between
GH and aging with emphasis on recent findings.
ACTIVITY OF THE SOMATOTROPIC
AXIS DECLINES DURING AGING
It is well documented that circulating levels of GH
decline with age in various mammalian species, in-
cluding humans [1-3], domestic dogs [4], and laboratory
rodents [5,6]. In the human, age-related decrease in
Received: Feb 28, 2018 Revised: Mar 5, 2018 Accepted: Mar 5, 2018 Published online May 11, 2018
Correspondence to: Andrzej Bartke https://orcid.org/0000-0002-2569-557X
Department of Internal Medicine, Southern Illinois University School of Medicine, 801 N, Rutledge St., P.O. Box 19628, Springfield, IL 62794-
9628, USA.
Tel: +1-217-545-7655, Fax: +1-217-545-8006, E-mail: abartke@siumed.edu
Copyright © 2019 Korean Society for Sexual Medicine and Andrology
Review Article
pISSN: 2287-4208 / eISSN: 2287-4690
World J Mens Health 2019 January 37(1): 19-30
https://doi.org/10.5534/wjmh.180018
Growth Hormone and Aging: Updated Review
Andrzej Bartke
Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL, USA
Role of growth hormone (GH) in mammalian aging is actively explored in clinical, epidemiological, and experimental stud-
ies. The age-related decline in GH levels is variously interpreted as a symptom of neuroendocrine aging, as one of causes of
altered body composition and other unwelcome symptoms of aging, or as a mechanism of natural protection from cancer
and other chronic diseases. Absence of GH signals due to mutations affecting anterior pituitary development, GH secretion,
or GH receptors produces an impressive extension of longevity in laboratory mice. Extension of healthspan in these animals
and analysis of survival curves suggest that in the absence of GH, aging is slowed down or delayed. The corresponding endo-
crine syndromes in the human have no consistent impact on longevity, but are associated with remarkable protection from
age-related disease. Moreover, survival to extremely old age has been associated with reduced somatotropic (GH and insu-
lin-like growth factor-1) signaling in women and men. In both humans and mice, elevation of GH levels into the supranormal
(pathological) range is associated with increased disease risks and reduced life expectancy likely representing acceleration of
aging. The widely advertised potential of GH as an anti-aging agent attracted much interest. However, results obtained thus
far have been disappointing with few documented benefits and many troublesome side effects. Possible utility of GH in the
treatment of sarcopenia and frailty remains to be explored.
Keywords: Aging; Growth hormone; Healthy aging; Life expectancy; Somatotropin
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0)
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

https://doi.org/10.5534/wjmh.180018
20 www.wjmh.org
plasma GH levels begins soon after attainment of final
height and full physical maturation, and continues
during the ensuing decades of life [1-3]. Circulating lev-
els of insulin-like growth factor-1 (IGF-1) also decline
during human aging, but the decrease is less step than
the changes in GH levels, with considerable overlap of
values measured in young adults and in elderly sub-
jects [7]. In relating the age-related changes in IGF-1 to
the levels of GH, it is necessary to consider that not all
of the circulating IGF-1 is derived f rom GH-dependent
hepatic secretion and that peripheral and tissue levels
of IGF-1 are differently regulated and thus might ex-
hibit different pattern of changes with age. Moreover,
bioavailability of IGF-1 present in the circulation, as
well as in the individual organs or tissues, is impor-
tantly influenced by complexing with IGF binding
proteins (IGFBPs). In mammals, there are at least six
IGFBPs. Regulation of biosynthesis of these proteins
and their IGF-1 related, as well as IGF-1-independent
effects, are outside the scope of this article. The inter-
ested reader is referred to recent reviews [8,9]. We will
return to the topic of biological actions of IGFBPs in
the discussion of the impact of somatotropic axis on
longevity of laboratory mice.
EFFECTS OF GROWTH HORMONE
THERAPY IN THE ELDERLY
Consistent with its lipolytic and anabolic activities,
administration of GH reduces adiposity and increases
lean body mass, including mass of skeletal muscula-
ture. A report of such changes in body composition in
elderly men with low plasma IGF-1 levels in response
to in jections of GH published in 1990 [10], attracted
enormous attention and wide interest in recombinant
human GH as an ‘anti-aging’ agent. Aging is normally
associated with increased adiposity and progressive
loss of muscle mass and, thus, ef fects of GH on body
composition were interpreted as reversal of important
symptoms of aging. Increases in bone mineral density
at some of the examined sites of the skeleton and in-
creased skin thickness in the elderly GH-treated men
[10], combined with the evidence for numerous benefits
of GH replacement therapy in younger individuals
with GH deficiency (GHD) [11-13], helped to increase
and sustain interest in GH treatment as an anti-aging
intervention.
However, further studies identif ied various side ef-
fects of GH treatment, including joint pain, edema,
carpal tunnel syndrome [14,15], and indicated that GH-
inducted increase in muscle mass is not accompanied
by increased strength [16,17]. Concerns were also raised
that the well documented anti-insulinemic eff ects of
GH and the impact of GH and IGF-1 on the progression
and, likely also the incidence, of neoplasms would lead
to increased risk of metabolic syndrome, diabetes, and
cancer in GH-treated individuals [18,19]. Remarkable
reduction in the incidence of cancer and diabetes in
individuals with genetic resistance to GH (details later
in this article) supports the validity of these concerns.
However, commercial promotion of GH and various
GH-related products as anti-aging agents continues and
abounds with great and, in some cases, ludicrous prom-
ises of ‘rejuvenation’. One major complication in critical
evaluation of the potential utility of GH as ‘anti-aging’
therapy is that its proponents usually compare (and
often equate) the benef its of injecting GH in healthy
elderly individuals, in which GH levels exhibit a nor-
mal age-related decline, to the results obtained in pa-
tients diagnosed with adult GHD, that is a pathological
and of ten abrupt decline of GH secretion resulting in
levels inappropriately low for age. The benefits of GH
therapy in healthy elderly people are controversial and,
according to many authors, questionable, unproven,
and likely non-existent, with a number of troublesome
side effects [14,15]. In contrast, GH therapy can be very
beneficial in younger individuals with GHD resulting
from traumatic brain injury, treatment of pituitary tu-
mors, or other causes [11-13,20-22]. The benefits include
reduced adiposity, increased muscle mass and improve-
ment in glucose homeostasis, general well-being, and
some aspects of cognitive f unction.
Current consensus of medical professional organiza-
tions and governmental regulatory agencies is that,
while adult GHD is a valid indication for GH replace-
ment therapy, old age without diagnosable somato-
tropic axis pathology is not [23]. Thus, until further
large, well-designed studies are conducted, prescribing
GH to endocrinologically-normal middle aged or elderly
individuals f or the purpose of delaying or reversing
aging is generally considered futile, unethical, and,
in the United States, also illegal [24]. In this author’s
opinion, an area which somewhat surprisingly re-
mains understudied, is the potential utility of GH in
the treatment of sarcopenia, one of key components of
age-related frailty. Another relatively unexplored area

Andrzej Bartke: Growth Hormone and Aging: Updated Review
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is the potential benefits of interventions aimed at in-
creasing the release of endogenous GH. Of particular
interest in this regard are agonists of the ghrelin re-
ceptor [25,26]. However, a major concern in any plans to
treat healthy middle-aged or elderly people with GH or
agents stimulating GH release in an attempt to slow or
reverse aging or some of its symptoms is the evidence
that GH may have opposite effects. The evidence that
physiological actions of GH may promote, rather than
prevent, aging will be summarized in the next section
of this article. We will also discuss recent studies aimed
at identifying mechanisms that appear to be involved.
DOES GROWTH HORMONE
ACCELERATE AGING? FINDINGS IN
GROWTH HORMONE-DEFICIENT
AND GROWTH HORMONE-
RESISTANT MICE
In laboratory mice, disruption of GH signaling leads
to a remarkable extension of longevity. This was origi-
nally demonstrated in animals homozygous for muta-
tions which disrupt development of selected lineages of
secretory cells in the anterior pituitary leading to defi-
ciency of several adenohypophyseal hormones includ-
ing GH [27,28]. These observations were soon extended
to animals with isolated GHD due to genetic defects in
hypothalamic control of GH release [28,29] and to ani-
mals with GH resistance due to targeted disruption of
the GH receptor gene [30]. These findings were hard to
interpret and were originally received with some skep-
ticism because they implied that normal actions of a
hormone have significant ‘costs’ in terms of longevity,
and that a gross defect in the f unctioning of the en-
docrine system can have striking benefits for healthy
survival. However, the evidence that absence of GH
signaling extends longevity of mice is strong, reproduc-
ible, and now generally accepted.
Several aspects of the findings in GH-deficient and
GH-resistant mice deserve particular emphasis. First,
the significant extension of longevity in these animals
is reproducible and not limited to a particular labora-
tory, diet, or genetic background [31-33]. Second, lifespan
is extended in both females and males [27-30]. Third, ex-
tension of longevity is associated with a similarly strik-
ing extension of healthspan [31,33]. Fourth, the magni-
tude of the increase in longevity exceeds the effects of
most genetic, pharmacological, or dietary interventions
that have anti-aging eff ects in mice. Recent analysis of
survival curves of GH-related mouse mutants indicates
that their mortality rate is lower than their normal
(‘wild type’) siblings, and increases only late in life, after
most of the normal siblings have died [34].
Evidence for extension of the healthspan and for
‘healthy aging’ of GH-deficient and GH-resistant mice
included demonstration that these animals maintain
youthful levels of cognitive function into advanced age
[35,36]. At the same chronological age, cognitive function
of their normal siblings is significantly impaired. Re-
cently, spatial learning and memory were shown to be
improved in 12-month-old GH receptor antagonist (GHA)
transgenic mice in comparison to their wild type litter-
mates [37]. Since GHA transgenic mice were previously
shown to have a normal lifespan [30], these findings
indicate that beneficial effects of reduced GH signaling
on cognitive f unction cam be dissociated from extension
of longevity and might involve different mechanisms.
In support of the negative association of cognitive f unc-
tion and GH signals, pathological excess of GH has been
associated with impairments of learning and memory
in different lines of transgenic mice [37,38].
A recent study examined longevity of mice lacking
both GH and functional GH receptors [39]. While these
tiny ‘double mutants’ were remarkably long-lived com-
pared to their normal siblings, they did not live signifi-
cantly longer than mice lacking only GH or only GH
receptors. In females, survival curves of GH-deficient
Ames dwarf, GH-resistant GHRKO, and ‘double mu-
tant’ (df/KO) animals were nearly identical, while lon-
gevity of double mutant males was numerically longer
than longevity of males from either of the parental
strains. Phenotypic characterization of the diminutive
df/KO mice and real-time PCR analysis of gene expres-
sion in different tissues revealed multiple differences
from wild type animals and from one of the single
mutants, but very f ew characteristics differed f rom
both Ames dwarf and GHRKO mice. These included
more extreme increases in relative brain weight and in
plasma adiponectin levels [39]. These findings indicate
that some of the characteristics of GH-related mutants
can be dissociated from longevity. However, it is equal-
ly possible that quantitative relationships between
longevity and these phenotypic features or levels of
messenger RNA for the examined genes exhibit a ‘ceil-
ing’ or a ‘f loor’ eff ect with changes greater than those
measured in Ames dwarf or GHRKO mice having no

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additional effect on aging and lif espan.
The importance of GH signaling in the control of
murine lifespan is f urther emphasized by the evidence
that disruption of signaling events ‘downstream’ from
GH and its receptor also extends longevity. Early f ind-
ings of extended longevity of female mice heterozygous
for the deletion of IGF-1 receptor [40] were confirmed
and extended in f urther studies [41]. A recent report
documented extension of lifespan of f emale mice by
inducing IGF-1 deficiency before weaning or during
adulthood [42]. Major increase of longevity was seen
in mice in which amount of bioavailable IGF-1 was
reduced at the tissue level by germline or adult dis-
ruption of the gene coding for pregnancy associated
plasma protein A, an enzyme degrading IGF-1 binding
protein [43,44]. Significant and reproducible extension
of longevity was also produced by pharmacological
suppression of the activity of mechanistic target of
rapamycin a kinase regulated by GH and IGF1 with a
major role in RNA translation, protein synthesis, and
cell g r ow th [4 5].
Importantly, conclusions concerning pro-aging effects
of normal or elevated GH based on studies in mutant,
gene knockout, transgenic, or drug treated mice ap-
pear to apply to genetically normal mice and to other
mammalian species. Multiple studies reported negative
association of adult body size (a strongly GH- and IGF-
1-dependemt trait) with longevity in comparisons of
dif ferent mouse strains, selected lines, and individual
animals [46-48]. Similar associations were documented
in rats [49], domestic dogs [50,51], and horses [52]. Hu-
man studies addressing this issue with be discussed
later in the article.
MECHANISMS OF EXTENDED
LONGEVITY OF ANIMALS WITH
GROWTH HORMONE-RELATED
MUTATIONS
The demonstration of a remarkable extension of lon-
gevity in GH-deficient and GH-resistant mice prompted
a search for mechanisms linking GH signaling with
Table 1. Mechanisms of extended healthspan and longevity in GH-deficient and GH-resistant mice (details and references in the text)
Mechanisms related to somatic growth
• Reduced hepatic IGF-1 expression and circulating IGF-1 levels
• Reduced mTORC1 signaling and mRNA translation; increased autophagy
• Reduced growth rate and adult body size
Mechanisms related to glucose homeostasis and lipid metabolism
• Hypoinsulinemia combined with enhanced insulin sensitivity
• Increased utilization of fatty acids; reduced hepatic and serum levels of lipids
• Reduced hepatic lipogenesis
Mechanisms related to cell senescence and low-grade chronic inflammation
• Reduced levels of pro-inflammatory cytokines: IL-1b, IL-6, TNF-α
• Increased levels of adiponectin
• Inhibition of NLRP3 inflammasome
• Reduced burden of senescent cells
Mechanisms related to stress resistance and repair
• Improved antioxidant defenses and reduced reactive oxygen species production
• Altered glutathione metabolism
• Increased cellular and whole animal resistance to toxins and a variety of stresses
• Improved maintenance of stem cell populations
Mechanisms related to energy metabolism
• Increased brown adipose tissue mass and activity; white adipose tissue ‘browning’; increased thermogenesis
• Increased utilization of lipids vs. carbohydrates as energy source
• Increased oxygen consumption per unit of total or lean body mass
Miscellaneous mechanism
• Hypogonadotropism and delayed puberty
• Increased hepatic hydrogen sulfide (H2S) production
• Suppression of age-related epigenetic changes
• Altered microRNA profiles
GH: growth hormone, IGF-1: insulin-like growth factor-1, mTORC1: mechanistic target of rapamycin complex 1, IL: interleukin, TNF-α: tumor ne-
crosis factor-α.

Andrzej Bartke: Growth Hormone and Aging: Updated Review
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the rate of aging. Detailed characterization of the phe-
notypic characteristics of these long-lived GH-related
mutants [31-33] together with analysis of their pro-
files of gene expression [53-55] and their responses to
dietary, hormonal, surgical, or pharmacological inter-
ventions [29,56-60] led to the identification of multiple
candidate mechanisms of the extension of healthspan
and lifespan in these animals (Table 1). T he pictu re
that emerges f rom these studies suggests interplay of
multiple interacting mechanisms that translate severe
reduction (or absence) of GH signals into a healthy
‘longevous’ phenotype resembling, but not identical to,
the phenotype of animals subjected to chronic calorie
restriction. Some of the interactions between various
mechanisms of delayed and/or slower aging in GH-
deficient and GH-resistant mice are shown in Fig. 1.
Interpretation of the findings that identify likely
mechanisms of slower or delayed aging is complicated
because mechanisms can be very dif ficult to separate
from the symptoms (‘biomarkers’) or consequences of
aging, and firm evidence of causality is difficult to
obtain. However, GH-deficient and GH-resistant mice
are uniquely suitable for identifying mechanistic links
between GH and longevity and, more broadly, for stud-
ies of the mechanisms of mammalian aging. Because
their propensity for extreme longevity is inherited as
fully recessive trait and heterozygous carriers of these
mutations as well as homozygous males are f ertile, it is
a standard practice to use a breeding scheme in which
mutant and normal offspring are born in the same
litter. This makes it possible to compare animals that
shared the same uterine environment, maternal care
and provision of nutrients, as well as every detail of
laboratory environment, and genetic background, and
differ only by the presence or absence of two copies of
the loss-of-function mutation at a particular chromo-
somal site. Moreover, since their extended longevity
is genetically determined, it is possible to study these
mutants as well as the matched control (wild type)
animals when they are young and their physiological
characteristics are not impacted by the process of ag-
ing and only minimally (or not at all) impacted by the
diff erences in life expectancy [61].
Our laboratory is particularly interested in the role
of reduced chronic low-grade inflammation in adipose
tissue [62,63] and in the central nervous system [64], the
combination of reduced insulin levels and enhanced in-
sulin sensitivity [65], and the alterations in thermogen-
esis and energy metabolism [66] as mechanisms linking
reduced GH signaling with extensions of healthspan
and lifespan. We are also pursuing the question of pos-
sible differences in the role of GH at dif ferent stages
of the life history in the control of aging. The evidence
available to date indicates that GH actions during the
rapid peri-pubertal growth may have major impact on
longevity [67], but GH signaling during adult lif e also
plays a role [68]. We will return to this issue in the last
(closing) section of this article.
GH signals Longevity
Peripheral
IGF-1
Cancer
incidence
mTORC1
signaling
Insulin
secretion
Stress
resistance
Antioxidant
enzymes
Inflammation
Cell
senescence
Insulin
sensitivity
Adiponectin
level
Fig. 1. Key mechanisms mediating the effects of reduced growth hormone (GH) signaling on aging and longevity (↓decrease, ↑increase). IGF-1:
insulin-like growth factor-1, mTORC1: mechanistic target of rapamycin complex 1.

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GROWTH HORMONE AND HUMAN
LONGEVITY
The initial evidence for a role of GH signaling in the
control of human aging was largely indirect and often
considered controversial. Samaras [69] reported numer-
ous examples of a negative correlation of longevity
with height, a GH-dependent trait. However, some ex-
amples of taller people living longer were also reported
[70]. Subsequent studies provided new examples of
longer survival of shorter people [71] and uncovered as-
sociation of polymorphism of genes coding for GH, IGF-
1, IGF-1 receptor and their downstream targets, with
exceptional longevity [33,71-74].
Reports of remarkably extended longevity in di-
minutive mice lacking GH or GHR increased interest
in aging of humans with the same genetic defects or
with dwarfism of dif ferent etiologies but few clear
answers emerged f rom these studies. Although some
individuals with isolated GHD resulting f rom muta-
tions af fecting GH releasing hormone, genetic hypopi-
tuitarism (including GHD) resulting from Prop1 loss of
function mutations, or with GH resistance (the Laron
syndrome) attained very old age, average longevity did
not appear to be altered by these mutations [75-78]. In
one study, isolated GHD was associated with mark-
edly reduced longevity [79]. Intriguingly, reduced lon-
gevity also characterizes patients with pathologically
increased GH levels in the syndrome of acromegaly
[80,81]. The rare syndrome of gigantism with excessive
GH secretion starting before maturation appears to be
associated with very high risk of early mortality, al-
though the evidence consists primarily f rom case stud-
ies [82,83] and media reports. Increased risk of diabetes,
cardiovascular disease and cancer associated with ac-
romegaly resembles the effects of chronological age on
the incidence of these disease and, thus, could perhaps
be interpreted as an indication of accelerated aging.
Transgenic mice with a massive increase in circulating
GH levels due to ectopic expression of heterologous GH
genes exhibit a signif icant, often dramatic, reduction of
longevity along with multiple symptoms of accelerated
aging [84 ].
Research conducted during the last decade provided
a considerable amount of new evidence for the role
of GH in human aging. Study of a large cohort of
American men of Japanese ancestry conf irmed earlier
reports of negative association of height (a GH-related
trait) and longevity, and indicated that this association
was most pronounced in the eighth and ninth decades
of life [71]. Importantly, this study also demonstrated
that height is negatively associated with the FOXO3
longevity allele and positively associated with fasting
blood insulin levels, both of which have been mecha-
nistically related to the process of aging in humans
and other species. Detailed analysis of pulsatile pat-
tern of GH relates in serum samples collected every 10
minutes for 24 hours, revealed that offspring of long-
lived families which are themselves genetically predis-
posed to increased longevity secrete less GH than their
spouses or partners [85]. Moreover, GH secretion in
these individuals was more tightly controlled [85].
In a different cohort of long-lived people, Milman et
al [86] demonstrated negative association of circulat-
ing IGF-1 levels and survival in nonagenarian women.
Ben-Avraham et al [87] recently reported increased
longevity of men homozygous for a mutation of GH
receptor. Reduced serum levels of IGF-1 in these indi-
viduals were consistent with reduced GH signaling but,
unexpectedly, they were taller than men without this
mutation. Tanisawa et al [88] approached the relation-
ship between growth and longevity by comparing the
frequency of height increasing alleles in large cohorts
of centenarians and control subjects. This interesting
approach removes some important confounders, such
as nutrition and childhood diseases, that can influence
adult height. The results revealed inverse association
between height-increasing alleles and extreme longev-
ity in Japanese women [88].
There is also considerable evidence that mutations
which disrupt GH signaling in humans of fer signif i-
cant protection from various age-associated diseases.
Early observations of reduced cancer risk in individu-
als with Laron dwarf syndrome (genetic GH resistance)
[89] were followed by demonstration that members of
a large cohort of Laron dwarfs in Ecuador are almost
completely protected from cancer and diabetes [78].
More recently, these individuals were also shown to
have increased adiponectin levels and enhanced insu-
lin sensitivity in spite of greater percentage of body fat
[90], enhanced cognitive performance and structural
features of the brain hippocampus and other brain
regions resembling younger unaf fected relatives [91].
Aguiar-Oliveira et al [77] reported that individuals
with isolated GHD in Brazil are remarkably protected
from atherosclerosis in spite of unfavorable serum

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lipid profiles and frequent obesity, that they tend to ‘age
well’, in terms of physical appearance and f itness and
can survive to an advanced age with one becoming a
centenarian (Aguiar-Oliveira, personal communication).
Discrepancies between the findings in different co-
horts of individuals with genetic defects in GH signal-
ing are diff icult to explain. Rarity of these genetic syn-
dromes precludes recruitment of large cohorts needed
for critical analysis of mortality rates, median, and
maximal longevity. The impact of genomic, lifestyle,
and medical care differences between the ethnically
diverse and geographically distant populations exam-
ined in these studies could, of course, be suspected, but
explanations based on these differences would, at this
point, be entirely speculative. It is also unclear why the
protection from cancer, diabetes, and atherosclerosis in
the affected individuals is not associated with a clear
increase in life expectancy. A relatively high incidence
of alcoholism and accidental deaths among the GH-
resistant individuals in Ecuador [78] may provide at
least a partial explanation. It also hints at a possible
interaction of this syndrome with social, behavioral,
and environmental factors, an issue that would seem
to merit further studies.
CONCLUSION: OVERVIEW; WHAT DO
WE KNOW AND WHAT ARE THE KEY
UNANSWERED QUESTIONS?
The impact of GH actions on longevity of laboratory
mice is major, consistent and well documented, and
some of the f indings obtained in these animals clearly
apply to other mammalian species, including humans.
Still, inconsistencies and controversies abound. Promi-
nent among them is the issue of dif ferences between
findings concerning longevity in mice and humans.
However, pathological GH excess is associated with
comor bidities and reduced longevity in both species.
Negative association of GH levels and adult body size
(a GH-dependent trait) with longevity was reported in
multiple studies in both species, but these relationships
are much more pronounced and consistent in mice.
What could be the reasons? The most obvious differ-
ences are that human growth and adult height are
inf luenced by nutrition, childhood disease, and access
to healthcare (all related to the birth cohort and socio-
economic status), and human longevity is impacted by
smoking, dietary and exercise habits, alcohol and drug
use, traffic and industrial accidents, murder, and sui-
cide, while none of these factors can impact the results
of experimental studies of aging in mice. Another im-
portant difference that we are currently evaluating is,
perhaps surprisingly, the diff erence in environmental
(ambient) temperature. Laboratory mice are routinely
housed at room temperature and it is easy f or us to
forget that this represents a comfortable indoor tem-
perature f or humans wearing light clothing and it is
much below the thermoneutral and the preferred tem-
perature for mice, which is approximately 30°C (86°F)
[92]. We have shown that major metabolic diff erences,
as well as differences in gene expression profiles, be-
tween normal (wild type) mice and long-lived mice
with diminished GH signaling disappear or are greatly
reduced when the mice are housed in a thermoneutral
environment [93, unpublished data]. Thus, we should
probably not expect full consistency between findings
obtained in humans living in an environment close to
thermoneutrality and in mice exposed to a constant
cold stress [94,95].
In trying to reconcile some seemingly inconsistent
findings concerning GH and aging in different species,
it may also be necessary to consider that the question,
‘does GH promote or prevent aging?’ is overly simplis-
tic. Emerging evidence suggests that the impact of
GH on aging is not the same at different stages of lif e
history. For example, interesting studies conducted in
the Sonntag laboratory in dwarf rats suggests that GH
signals have a positive effect on longevity during de-
velopment, but a negative impact later on, most likely
by increasing the risk of cancer [96]. However, results
of GH replacement therapy in juvenile GH-deficient
mice suggest that the absence of GH signals during
development importantly contributes to the remark-
able extended longevity of these mutants [67]. The
mechanisms by which early-life changes in GH signals
inf luence adult phenotype, aging, and longevity are al-
most certainly epigenetic. This intriguing possibility is
indirectly supported by the recently reported impact of
Ames dwarf ism on the epigenetic signatures of aging
[97,98], and clearly deserves further study. However,
the lifespan of the dwarf mice was not completely nor-
malized (‘rescued’) by early-life GH therapy, suggesting
that adult GH levels are also involved in the control
of aging. A recent report that disrupting GHR gene in
adult female mice extends their longevity [68] provides
direct evidence for the role of GH signaling during

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adult life in the control of mammalian aging.
It is also interesting to consider that the evidence for
delayed puberty, reduced fecundity, and extended lifes-
pan of GH-deficient and GH-resistant mice f its perfect-
ly into the concept of antagonistic pleiotropy proposed
many years ago [99]. Genes related to the somatotropic
signaling promote growth, sexual maturation, and fe-
cundity, the key elements of evolutionary f itness and,
thus, their actions would have been selected for in the
course of evolution, even though later in life they may
have detrimental effects on disease risk and survival.
This concept likely applies broadly to the genetic con-
trol of aging and fits remarkably well with the rather
counterintuitive findings that most of the strong
‘longevity genes’ discovered in various organisms are
either loss-of -function mutations or mutations that
reduce the level of gene expression. Much work will be
needed to identify the role of somatotropic signaling at
dif ferent stages of life history in the control of aging,
risks of age-related disease and longevity. We believe
that studies of the role of GH in aging in different spe-
cies, the mechanisms involved, and the interactions of
these mechanisms with environmental factors will lead
to new insights with signif icant implications for both
individual and public health.
ACKNOWLEDGEMENTS
Writing of this article and our recent and current
studies of this topic were supported by NIA (NIH) via
grants R01AG019899 and R21AG051869. We apologize
to those whose work pertinent to the issues discussed
was not cited due to limitations of the format or to in-
advertent omissions.
Disclosure
The author has no potential conflicts of interest to disclose.
Author Contribution
Article conception & design: Bartke A. Data acquisition:
Bartke A. Data analysis and interpretation: Bartke A. Writing
of the manuscript: Bartke A. Receiving grant: Bartke A. Ap-
proval of final manuscript: Bartke A.
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