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The reproductive-cell cycle theory of aging: An update
Craig S. Atwood
a,b,c,
⁎, Richard L. Bowen
d
a
Geriatric Research, Education and Clinical Center, Veterans Administration Hospital and Department of Medicine, University of Wisconsin, Madison, WI 53705, USA
b
Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
c
School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Joondalup, 6027 WA, Australia
d
Duke University, Department of Family Medicine, Raleigh, NC 27615, USA
abstractarticle info
Article history:
Received 13 August 2010
Received in revised form 6 September 2010
Accepted 9 September 2010
Available online 17 September 2010
Section Editor: Kurt Borg
Keywords:
Aging
Reproductive hormones
Endocrine dyscrasia
Dyotic signaling
Age-related diseases
Cell cycle re-entry
Hypothalamic-pituitary-gonadal axis
Menopause
Andropause
Senescence
Hormone replacement therapy
The Reproductive-Cell Cycle Theory posits that the hormones that regulate reproduction act in an antagonistic
pleiotrophic manner to control aging via cell cycle signaling; promoting growth and development early in life
in order to achieve reproduction, but later in life, in a futile attempt to maintain reproduction, become
dysregulated and drive senescence. Since reproduction is the most important function of an organism from
the perspective of the survival of the species, if reproductive-cell cycle signaling factors determine the rate of
growth, determine the rate of development, determine the rate of reproduction, and determine the rate of
senescence, then by definition they determine the rate of aging and thus lifespan. The theory is able to
explain: 1) the simultaneous regulation of the rate of aging and reproduction as evidenced by the fact that
environmental conditions and experimental interventions known to extend longevity are associated with
decreased reproductive-cell cycle signaling factors, thereby slowing aging and preserving fertility in a hostile
reproductive environment; 2) two phenomena that are closely related to species lifespan—the rate of growth
and development and the ultimate size of the animal; 3). the apparent paradox that size is directly
proportional to lifespan and inversely proportional to fertility between species but vice versa within a species;
4). how differing rates of reproduction between species is associated with differences in their lifespan; 5).
why we develop aging-related diseases; and 6). an evolutionarily credible reason for why and how aging
occurs—these hormones act in an antagonistic pleiotrophic manner via cell cycle signaling; promoting growth
and development early in life in order to achieve reproduction, but later in life, in a futile attempt to maintain
reproduction, become dysregulated and drive senescence (dyosis). In essence, the Reproductive-Cell Cycle
Theory can explain aging in all sexually reproductive life forms.
Published by Elsevier Inc.
1. Background
The basic premise of the Reproductive-Cell Cycle Theory of Aging is
that the hormones that regulate reproduction act in an antagonistic
pleiotrophic manner to control aging via cell cycle signaling; promoting
growth and development early in life in order to achieve reproduction,
but later in life, in a futile attempt to maintain reproduction, become
dysregulated and drive senescence (Bowen and Atwood, 2004). The
theory evolved following the conceptualization of a new definition of
aging (that aging is any change in an organism over time), coupled with
data indicating that endocrine dyscrasia associated with menopause
and andropause led to aberrant mitogenic/differentiative (dyotic)
signaling that drives the re-entry of post-mitotic neurons into an
abortive cell cycle leading to cellular dysfunction and death (reviewed
in: Atwood et al., 2005; Atwoodand Bowen, submitted). The theorywas
first presented at the Pennington Symposium in 2003 (Atwood et al.,
2003) and subsequently published September, 2004 in Gerontology
(Bowen and Atwood, 2004).
Aging can be conceptualized according to the following logic. From a
reductionistic viewpoint we are nothing more than a complex
combination of chemical reactions; aging therefore has to be a result
of changes in these chemical reactions. If we were able to halt all
molecular movement and thereby stop these chemical reactions, then
we no longer age (such as following cryopreservation of embryos).
Using the definition of agingas any change in an organism over time,we
are able to assess how changes over time affect all stages of life, not just
the end of life. By understanding the major changes in an organism over
time, and what drives these changes, we can understand what controls
‘aging’. The major change in an organism over time is the chemical
reactions that result in a single cell (zygote) developing into a
multicellular organism containing trillionsof cells. This process requires
three major cellular events: division (growth), differentiation (cell
function) and apoptosis (cell death). An organism requires cell growth
Experimental Gerontology 46 (2011) 100–107
⁎Corresponding author. University of Wisconsin-Madison Medical School, Wm S.
Middleton Memorial VA (GRECC 11G), 2500 Overlook Terrace, Madison, WI 53705,
USA. Tel.: +1 608 256 1901x11664; fax: + 1 608 280 7291.
E-mail address: csa@medicine.wisc.edu (C.S. Atwood).
0531-5565/$ –see front matter. Published by Elsevier Inc.
doi:10.1016/j.exger.2010.09.007
Contents lists available at ScienceDirect
Experimental Gerontology
journal homepage: www.elsevier.com/locate/expgero
in order to grow larger, cell differentiation in order to specify cell fate
and providefunction, and cell death in order to specifyorganismal shape
and remove dysfunctional cells. If aging is equivalent to change, and the
major changes are cell division, differentiation anddeath, then whatever
controls these cellular processes controls aging. We have argued that
hormones of the hypothalamic-pituitary-gonadal axis regulate cell
division, differentiation and death, and therefore regulate growth and
development early in life in order to achieve reproduction, but as
reproductive function begins to decline the associated endocrine
dyscrasia (dyotic signaling) drives our senescent phenotype, age-
related diseases and ultimately removes non-reproductive individuals
from the gene pool. In this review we will present published and new
data supporting these contentions.
2. Evidence for the Reproductive-Cell Cycle Theory of Aging
2.1. Growth and development during embryogenesis and beyond
The role of reproductive hormones in regulating maternal systems
involved in the maintenance of the endometrium, blastocyst attach-
ment and synctiotrophoblast proliferation into the endometrium, as
well as preventing ovulation and preparing the immune, metabolic
and psychological systems of the mother for pregnancy are well
described (Larson et al., 2003). Until recently however the general
notion that reproductive hormones regulate embryonic growth and
development had not been examined. Based on the following findings
we examined the role of human chorionic gonadotropin (hCG) and
progesterone (P
4
) in the growth and development of the early embryo
(Gallego et al., 2008). These findings included: 1) hCG is dramatically
elevated post-conception by the early embryo (zygote, morula,
and blastocyst); 2) hCG, and the adult homolog luteinizing hormone
(LH) have powerful mitogenic properties (Cole, 2009). hCG and LH
share 83% amino acid sequence homology and bind a common
receptor with similar affinity (Fiddes and Talmadge, 1984); 3) post-
menopausal elevations in circulating LH promote mitotic-related
biochemical, cellular and pathological changes in Alzheimer's disease
(AD) (see Section 2.3); and 4) the lipophilic sex steroid P
4
is greatly
elevated early in pregnancy.
Using human embryonic stem cells (hESC) as a model of early
human embryogenesis and neurogenesis (Xia and Zhang, 2009), hCG
secreted by the trophoblastic layer of the blastocyst and later the
placenta (Gallego et al., 2008; Zhuang and Li, 1991), was demon-
strated to signal via LHCG receptors (LHCGR) to promote hESC
division and their differentiation into embryoid bodies, a structure
akin to an in vitro blastocyst (Gallego et al., 2008). hCG also rapidly
upregulated steroidogenic acute regulatory protein-mediated trans-
port of cholesterol and the synthesis of P
4
. This was found to be
essential for the formation of neuroectodermal rosettes, a structure
predominantly composed of neural precursor cells akin to those that
form the neural tube (Xia and Zhang, 2009). These data suggested that
the paracrine/juxtacrine signaling of hCG for mobilization of choles-
terol for P
4
production by the epiblast/synctiotrophoblast following
conception is essential for human blastulation and neurulation
(Atwood and Vadakkadath Meethal, 2011). P
4
receptor (and estrogen
receptor) expression is upregulated early in embryogenesis (see:
Sauter et al., 2005). Although largely unstudied, the hormonal
regulation of apoptotic mechanisms is likely involved in cell death
during embryogenesis (Zupanc, 1999). This paracrine/juxtacrine
signaling by extraembryonic tissues is the commencement of trophic
support by placental tissues in the growth and development of the
human embryo.
The reproductive hormone induction of blastulation and neurula-
tion, together with the identification of receptors for HPG axishormones
in all tissues of the body (reviewed in Bowen and Atwood, 2004;
Vadakkadath Meethal and Atwood, 2005) suggests that reproductive
hormones may dictate the growth and development of these tissues not
only during embryogenesis, but also in the fetus, neonate, child,
adolescent and adult. Both LH and P
4
have well described proliferative
and differentiation properties during these stages of life (e.g. Berndt
et al., 2006, 2009; Cole, 2009; Zygmunt et al., 2002). As an example of
HPG hormone regulation of post-embryonic life, P
4
has been shown to
regulate organogenesis during puberty and adulthood; P
4
is obligatory
for the development of the tertiary ducts on the mammary gland, and
the physiological differentiation of the lobuloalveolar system from the
lobular buds during puberty and adulthood (Atwood et al., 2000).
Moreover, in the adult, P
4
promotes neurogenesis (Wang et al., 2005),
angiogenesis and arteriogenesis (Rogers et al., 2009), and formation of
the placenta and bones (Prior, 1990).
The pivotal roles of 17β-estradiol (E
2
), activins and GnRH in
growth and development during fetal and later stages of life also have
been reported (e.g. Asashima et al., 2008). Similarly, hCG promotes
angiogenesis by inducing the up-regulation of vascular endothelial
growth factor (Berndt et al., 2006; Licht et al., 2002; Zygmunt et al.,
2002) and P
4
(Rogers et al., 2009). Recent data demonstrate that
physiological concentrations of hCG (10–400 IU/ml) significantly
enhance pericyte sprouting and migration and give rise to the
maturation and coverage of endothelial capillaries (Berndt et al.,
2009). Moreover, in the adult brain, subcutaneous administration of
LH has been shown to induce neurogenesis in the hippocampus of the
adult mouse (Mak et al., 2007), while in sheep there is evidence that
GnRH directly, or indirectly via LH, induces neurogenesis in the
hippocampus (Hawken et al., 2009). Similarly, the P
4
metabolite
allopregnanolone has been shown to significantly promote neurogen-
esis by increasing rat neuroprogenitor cell proliferation and human
neural stem cell proliferation (Wang et al., 2005). Sex steroids also
regulate synapse turnover in the CA1 region of the hippocampus
during the 4-day estrous cycle of the female rat. Similarly, sex
hormones regulate mammary epithelial cell proliferation and death
during reproduction (Atwood et al., 1995) and the estrous/menstrual
cycle (Lamote et al., 2004).
The growth and differentiation properties of LH/hCG described
above are likely mediated in conjunction with P
4
. Thus, hormones of
the reproductive axis appear to have pivotal functions in the adult for
the maintenance of tissues. We propose that these hormones regulate
the proliferation and differentiation of resident totipotent stem cells
in tissues throughout the body. During the reproductive phase this
would provide optimal tissue function in order to maximize the
likelihood of successful reproduction. That reproductive hormones
normally regulate growth and development in tissues of the adult is
consistent with the demise of body tissues and function with the
dysregulation of these HPG hormones later in life.
2.2. The adult reproductive period
Reproductive hormones mediate growth and development of the
embryo into a neonate that develops into a child, who then proceeds
through puberty to gain reproductive function in the adolescent and
adult. The regulation of reproduction by the hormones of the HPG axis
has been well characterized over the last 90 years (Larson et al.,
2003). The period of maximum reproductive and optimal HPG
function correlates with the time of least change and slowest rate of
aging. However, with the gradual decline in gonadal sex steroid
production in the case of men, and the more abrupt decline in the case
of women, there is a loss of hypothalamic feedback inhibition that
stimulates GnRH and gonadotropin production (Larson et al., 2003).
In addition, the decrease in gonadal production of inhibins at this time
results in decreased activin receptor inhibition, and together with the
increase in bioavailable activin leads to a further increase in the
secretion of GnRH and gonadotropins (reviewed in: Bowen and
Atwood, 2004). Thus, the lack of negative feedback from the ovary/
testis (P
4
,E
2
, testosterone (T), other sex steroids and inhibins) is
responsible for the unopposed and marked elevations in the secretion
101C.S. Atwood, R.L. Bowen / Experimental Gerontology 46 (2011) 100–107
of GnRH and gonadotropins with ovarian and testicular senescence.
Although post-reproductive endocrine dyscrasia, including the eleva-
tions in GnRH/gonadotropins, have been recognized for decades, their
implications for human health and longevity only began to be
elucidated in the early 2000s (Bowen et al., 2000, 2002, 2004b) and
is the subject of the next section.
2.3. Endocrine dyscrasia associated with gonadal cellloss initiatessenescence
and age-related diseases
The importance of understanding the etiology of aging-related
diseases is indicated by the fact that age-related diseases account
for ~80% of all deaths, the remainder being largely the result of
accidents and infections, the later being positively correlated with age
(CDC National Vital Statistics Report, 2009).
While appropriate HPG hormone signaling is necessary for normal
growth and development during embryogenesis, fetal life, childhood,
adolescence, and for the maintenance of brain health during adult
reproductive life, the unopposed elevations in GnRH, gonadotropin
(LH and follicle-stimulating hormone (FSH)) and activin signaling
with the loss of sex steroids and inhibins following menopause and
during andropause might be expected to lead to dysregulation of cell
cycle events given the proliferation and differentiation properties of
these hormones (Bowen and Atwood, 2004; Cole, 2009; Gallego et al.,
2008, 2009). We have termed the signaling resulting from reproduc-
tive endocrine dyscrasia as ‘dyotic signaling’. In women, this signaling
commences around the time of menopause (~51 years of age), while
in men andropause commences around 30 years of age in men, as
T levels decline 1% every year between the ages of 30 to 80 (Fig. 1A;
Belanger et al., 1994) with corresponding increases in circulating
gonadotropins. Thus, males are under the influence of these lower T
levels and higher LH levels for many decades before they fall into what
is defined as hypogonadism (the clinical definition of andropause).
Accumulating molecular, epidemiological and clinical evidence points
towards reproductive endocrine dyscrasia-induced cell cycle changes
as being at the heart of age-related diseases such as AD/dementia
(Atwood et al., 2005), stroke (Wilson et al., 2008), osteoporosis
(Sun et al., 2006), heart disease (Lee et al., 2009) and cancer. The basis
for this association included the identification of receptors for HPG
axis hormones in all tissues of the body (reviewed in: Bowen and
Atwood, 2004; Vadakkadath Meethal and Atwood, 2005).
2.3.1. Epidemiological/observational evidence
Evidence that reproductive endocrine dyscrasia lies at the heart of
aging related diseases is suggested by the findings that, in women with
later menopause, there is a reduced risk for developing cardiovascular
disease, calcifications in the aorta , atherosclerosis, cognitive decline and
bone fractures (see: Ossewaarde et al., 2005). The risk of colorectal cancer
also is decreased, and despite an increase in death from uterine and
ovarian cancer with increasing age at menopause, the net effect of later
menopause is an increased lifespan (Ossewaarde et al., 2005). Converse-
ly, early reproductive endocrine dyscrasia occurring naturally or induced
by unilateral or bilateral oophorectomy in premenopausal women, is
associated with increased risk of developing dementia, cognitive decline,
stroke, fatal and non-fatal coronary heart disease, Parkinsonism,
osteoporosis, hip fracture, lung cancer, depression and anxiety (e.g.
Gleason et al., 2005; Parker et al., 2009; Rocca et al., 2006). Indeed, the
increased prevalence of cognitive disease in women correlates with the
abrupt earlier loss of gonadal function (reviewed in: (Gleason et al.,
2005). Prospective cohort studies indicate E
2
replacement therapy
reduces the incidence and delays the onset of cognitive decline in
women and men. It should be noted that similar protection is not always
afforded by the use of non-physiological estrogens such as conjugated
equine estrogens (see Section 2.3.2). Similarly, suppression of circulating
gonadotropins (and sex steroids) with GnRH agonist therapy halves the
risk of death from AD (Bowen et al., 2004a; D'Amico et al., 2010),
suggesting elevations in gonadotropins drive cognitive decline.
Breast and ovarian cancer are the only age-related diseases where
risk decreases with early reproductive endocrine dyscrasia, i.e.
following oophorectomy (Parker et al., 2009). Conversely, early
menarche, higher numbers of ovulatory cycles, nulliparity and late
menopause are associated with increased risk for female reproductive
cancers (Parsa and Parsa, 2009).
2.3.2. Experimental evidence
Experimental evidence from both humans and animal intervention
studies using hormone replacement therapies and gonadectomy, and
correlations of circulating hormones levels with disease risk, clearly in-
dicate that reproductive endocrine dyscrasia is centralto the development
of age-related diseases. There is considerable evidence that physiological
hormone replacement therapies delay the onset, halt the progression and
even reverse the course of age-related diseases. Unfortunately, experi-
mental evidence from hormone replacement therapy studies has been
confounded by the use of non-physiologically and non-biochemically relevant
hormone replacement therapies. Clearly non-physiological forms of sex
steroid replacement (e.g. conjugated equine estrogens, medroxyproges-
terone, and other steroid analogs), that have different biochemical
structures and signaling, are not always useful in preventing age-related
diseases or conditions (Nilsen et al., 2006; Santen et al., 2010). This review
will focus only on physiologically relevant hormone replacement
therapies (i.e. E
2
,P
4
and T as they relate to disease and longevity).
Below we illustrate the importance of reproductive endocrine dyscrasia in
the etiology of the major human age-related diseases.
2.3.2.1. Dementia/Alzheimer's disease/cognitive health. Dementia
accounts for 3% of deaths in the USA (CDC National Vital Statistics
Report, 2009) although by the age of 85 ~45% of the population has
some form of dementia. AD accounts for ~70% of all dementia cases
and is characterized neurologically by progressive memory loss,
impairments in behavior, language, and visuo-spatial skills.
Fig. 1. (A) Changes in HPGhormones during andropausein men. (B) Model of changes in
HPG hormones following hormone replacement therapy in men during aging. HRT in
males suppresses hypothalamic GnRH production and circulating LH and FSH, but not to
early reproductive levels, perhaps as a result of decreased circulating inhibin with age.
102 C.S. Atwood, R.L. Bowen / Experimental Gerontology 46 (2011) 100–107
Supplementation with E
2
has been demonstrated in 3 case-controlled
and 5 uncontrolled intervention studies to improve cognition in
women with AD (reviewed in: Gleason et al., 2005). Similarly,
supplementation with T has been demonstrated in 1 case-controlled
intervention study to improve cognition in men with AD (Tan and Pu,
2003). Moreover, E
2
has been shown to improve the cognition of
cognitively normal post-menopausal women in 12 of 15 studies (3
studies indicated no difference; Gleason et al., 2005).
Suppression of gonadotropins and sex steroids following GnRH
agonist treatment (‘chemical castration’) has been shown to induce
abrupt, mild, cognitive deficits in premenopausal women, deficits that
were reversed by simultaneous administration of E
2
(Sherwin and
Tulandi, 1996). However, similar treatment in post-menopausal
women, where circulating sex steroids are already low, after 48 weeks
stabilized cognitive decline (AD Assessment Scale-cognitive subscale,
AD Cooperative Study—Clinical Global Impression of Change) and
activities of daily living (AD Cooperative Study/Activitiesof Daily Living)
(http://www.secinfo.com/d14D5a.z6483.htm,pp.56–64; http://clini-
caltrials.gov/ct/show/NCT00076440?order=6). In men, a recent small
study demonstrated that suppression of androgens and gonadotropins
with GnRH agonists significantly improved memory after 6 months
(Nedelec et al., 2009). The preservation of global cognitive performance
with GnRH-agonist-induced androgen and gonadotropin suppression
suggests a negative impact of gonadotropins on the brain (Bryan et al.,
2010). In this respect, the decapeptide Cetrorelix, a GnRH antagonist
that inhibits gonadotropin and sex steroid secretion, corrected the
impairment of the memory consolidation caused by Aβ25–35 in mice,
and had anxiolytic and antidepressive properties (Telegdy et al., 2009).
Support for reproductive endocrine dyscrasia in promoting
cognitive decline is evidenced by the negative correlation between
serum E
2
in women with AD (Manly et al., 2000); the negative
correlation between serum T in men with AD; and the positive
correlation between serum gonadotropins (LH and FSH) and cognitive
impairment and AD (reviewed in: Verdile et al., 2008).
In animals, P
4
and/or E
2
, and androgen treatments, have been shown
to improve learning and memory in tasks mediated by the prefrontal
cortex and/or hippocampusof aged rodents and ovariectomized rodents
(see studies performed by Frye, Walf and colleagues, e.g. Frye and Walf,
2009). Moreover, numerous studies have shown P
4
limits tissue damage
and improves functional outcome after blunt traumatic brain injury
(TBI),stroke, spinalcord injury, diabetic neuropathies, and other typesof
acute neuroinjury (Stein et al., 2008). Importantly, a recent Phase IIa
clinical trial reported 4 days of post-TBI intravenous P
4
reduced mortality
by more than 50% in moderately to severely injured human patients and
enhances functional outcomes at 30 days for the moderately injured
(Wright et al., 2007). P
4
is currently being tested in Phase III clinical trials
for the treatment of traumatic brain injury (Stein et al., 2008).
2.3.2.1.1. Mechanistic evidence for endocrine dyscrasia driving late-onset
AD. Considerable evidence exists that AD is a disease of aberrant, albeit
unsuccessful, re-entry of post-mitotic neurons into the cell cycle, resulting
in synapse contraction and neuron death (see: Wang et al., 2009 for
review). There is growing evidence that the elevation in LH that
accompanies the decline in sex steroids with aging induces this aberrant
re-entry of post-mitotic neurons into an abortive cell cycle in AD
(reviewed in Atwood and Bowen, submitted). Specifically, the mitogenic
functions of LH (see Section 2.1) appear to be mediated by the
upregulation of AβPP processing towards the amyloidogenic pathway
(Bowen et al., 2004a) and by activation/translocation of Cdk5, a key
regulator of cell cycle progression. Aβ, the major component of amyloid
deposits in the AD brain, has been demonstrated in a number of studies to
promote neuron proliferation, while the translocation of Cdk5 between
the cytoplasm and nucleus regulates tau phosphorylation cell cycle
progression (reviewed in Atwood and Bowen, submitted). Endocrine
dyscrasia (dyotic signaling) induced changes in AβPP and Cdk5
metabolism may therefore be responsible for inducing cell cycle
reactivation and apoptotic death of post-mitotic neurons.
2.3.2.2. Coronary heart disease (CHD). CHD accounts for 26% of all
deaths in the USA and is more prevalent in males, although the
incidence in women catches up to that of men after menopause,
consistent with the more abrupt endocrine dyscrasia in females (CDC
National Vital Statistics Report, 2009). Numerous studies indicate an
inverse relationship between serum T levels and cardiovascular disease
(reviewed in (Yeap, 2010). T use has shown some beneficial effects on
arterial reactivity, myocardial perfusion and angina frequency in the
prevention/treatment of CHD. Conversely, there is an increased risk of
cardiovascular disease in men receiving androgen deprivation therapies
for prostate cancer (Keating et al., 2010). In women, observational and
clinical trials of E
2
supplementation have been shown to decrease the
risk for CHD (reviewed in: Dubey et al., 2005).
2.3.2.2.1. Mechanistic evidence for endocrine dyscrasia driving CHD.
Like AD, there is evidence in CHD that vascular smooth muscle cell
proliferation is a primary cause of atherosclerosis (Lusis, 2000). hCG/LH
have been shown to promote angiogenesis (Zygmunt et al., 2002), but
whether this induces aberrant cell cycle re-entry leading to atheroscle-
rosis remains to be confirmed. Intriguingly, LHCGR are present on
endothelial and vascular smooth muscle cells (Berndt et al., 2006; Lei
et al., 1992; Toth et al., 2001) and recent evidence suggests that
reactivation of the cell cycle in cardiomyocytes can lead to severe
hypertrophic cardiomyopathy followed by ventricular dysfunction and
ultimately death from congestive heart failure (Lee et al., 2009).
2.3.2.3. Cerebrovascular disease. Stroke accounts for 5.7% of deaths in the
USA (CDC National Vital Statistics Report, 2009). In men, serum T
concentration is significantly inversely correlated with stroke severity,
infarct size and 6-month mortality, while high serum LH, high serum E
2
and low serum T4 were risk factors for stroke in men (Elwan et al., 1990).
This is consistent with the increased risk of stroke in men receiving
androgen deprivation therapies for prostate cancer (Keating et al., 2010).
Paradoxically, in women, higher circulating E
2
is associated with
increased risk of stroke (Lee et al., 2010). Although the data is contentious,
exogenous E
2
alone or together with P
4
(or its retroisomer dydrogester-
one) are generally either protective or neutral for stroke risk (Carwile et
al., 2009). These results illustrate the requirement for complete, rather
than partial, rebalancing of the HPG axis.
2.3.2.3.1. Mechanistic evidence for endocrine dyscrasia driving
cerebrovascular disease. Like other tissues, the localization of HPG
hormone receptors to endothelial cells and smooth muscle cells of the
cerebrovasculature (Berndt et al., 2006; Lei et al., 1992; Toth et al., 2001)
suggests a role for these hormones in maintaining the dynamic structure
of the vasculature and the blood brain barrier (BBB). Indeed, hCG
promotes angiogenesis by inducing vascular endothelial growth factor
up-regulation (Berndt et al., 2006; Licht et al., 2002; Zygmunt et al.,
2002). Endocrine dyscrasia induced by ovariectomy in mice leads to a
breakdown in the selective permeability of the BBB, as evidenced by an
increase in Evan's blue dye extravasation into the brain and a
redistribution of the gap-junction protein connexin-43 (Cx43) along
the extracellular microvascular endothelium (Wilson et al., 2008).
Changes in the selective permeability of the BBB following menopause
have been suggested to result from suppressed sex steroids (Bake and
Sohrabji, 2004) and elevated LH or GnRH (or at least an increase in the
ratio of LH/GnRH:sex steroids; Wilson et al., 2008). Thus, endocrine
dyscrasia associated withaging appears responsible for the alterationsin
cerebrovascular structure and function observed in aging and stroke.
2.3.2.4. Osteoporosis. Osteoporosis or low bone mass is present in 55% of
people aged 50 and older in the USA, with 80% being women (National
Osteoporosis Foundation, USA; http://www.nof.org/). Albright et al.
(1941) postulated almost 70 years ago that osteoporosis in aging
women was related to the endocrine dyscrasia associated with
menopause and demonstrated that E
2
treatment improved calcium
balance in postmenopausal women. Lindsay et al. (1976) subsequently
validated the original Albright hypothesis by demonstrating that the
103C.S. Atwood, R.L. Bowen / Experimental Gerontology 46 (2011) 100–107
accelerated bone loss incurred by ovariectomy could be prevented by E
2
therapy (Khosla, 2010). The aging-related decline in E
2
levels also has
been proven to lead to calcium loss in men (Khosla, 2010). More recently,
it has been demonstrated that the loss of E
2
may not be as important as the
concurrent increase in circulating FSH in promoting calcium loss following
ovariectomy/menopause (Sun et al., 2006; Zaidi et al., 2009). Despite
stable circulating E
2
during late-perimenopause, increasing circulating
FSH correlates with a profound increase in the rate of bone loss (Randolph
et al., 2004; Sowers et al., 2006).
2.3.2.4.1. Mechanistic evidence for endocrine dyscrasia driving
osteoporosis. Mechanistic evidence for FSH as mediating bone loss
comes from studies indicating that FSH increases osteoclastogenesis
and bone resorption, and from in vivo studies indicating that despite
having E
2
deficiency, FSH-receptor-null mice have normal bone mass
(Sun et al., 2006; Wu et al., 2007). Further, in vivo studies indicate that
FSHβmutant mice (~50% reduction in circulating FSH) display a high
bone mass despite being eugonadal, due to reduced bone resorption
(Sun et al., 2006). Similarly, hypogonadal FSHβ
−/−
mice also fail to
lose bone despite severe hypogonadism. Moreover, aromatase
−/−
mice, a model for chronic hypogonadism, display a doubling of
resorption surfaces in the presence of high FSH, whereas ERα
−/−
β
−/−
or GnRH
mut
hpg mice, in which estrogen deficiency is as severe but is
not accompanied by high FSH levels, do not show the expected
increases in bone resorption (Miyaura et al., 2001; Sims et al., 2002).
Effects of E
2
on bone metabolism are also clearly important perhaps as
an antiresorptive agent; deletion of ERαin osteoclasts result in bone
loss and increased resorption in the face of normal FSH levels
(Nakamura et al., 2007), while GnRH agonists cause high turnover
bone loss despite reduced FSH levels (Sanyal et al., 2008). Together
these data indicate that the ratio of FSH to E
2
may dictate bone
resorption, with an increase in the ratio promoting bone resorption.
These data also suggest a potential role for GnRH signaling. Evidence
also exists for inhibins A and B, which decline following menopause in
women and with aging in men, as regulating bone metabolism.
2.3.2.5. Cancer. Like other aging-related diseases, the incidence of nearly
all cancers increases (Rubin et al., 2010) with aging-related reproductive
endocrine dyscrasia, implying the loss of sex steroid and inhibin signaling
together with the elevation in gonadotropin/GnRH/activin signaling as
driving aberrant cell proliferation and neoplasia. Indeed, balancing of the
HPG axis with sex steroid supplementation prior to neoplasia appears to
prevent the increased risk of reproductive and other cancers associated
with endocrine dyscrasia. For example, in men, a recent meta-analysis
indicated no increase in prostate cancer risk, or any other adverse effect,
of T therapy (Fernandez-Balsells et al., 2010). Likewise, in weighing the
studies performed in menopausal/post-menopausal women supplemen-
ted with physiologically relevant sex steroids, i.e. E
2
or E
2
+P
4
/
dydrogesterone, there is minimal risk of reproductive cancers, although
there is an increased risk for certain unphysiological sex steroids (e.g.
Fournier et al., 2008). Sex steroid ablation or antagonism has been
demonstrated in many cancer types, particularly reproductive tissue
cancers of both male and female, to inhibit cancer progression (Folkerd
and Dowsett, 2010), indicating an important role for sex steroids in
neoplasia once a malignancy has developed.
2.3.2.5.1. Mechanistic evidence for endocrine dyscrasia driving
cancer. There is a large body of evidence generated over the last
60 years describing the proliferative, differentiative and apoptotic role
of reproductive hormones on cell fate and cancer (Russo and Russo,
2007). Although endocrine dyscrasia may not induce mutagenesis/
chromosomal abnormalities, it could act to simply increase the rate of
cellular division and the statistical likelihood of developing a
mutation/chromosomal abnormality. Such changes could inhibit
apoptotic mechanisms and enhance neoplasia, or modulate cell
adhesion and enhance metastasis (Simon et al., 2009). In particular,
the gonadotropins and GnRH have well described proliferative
functions, while sex steroids and activins have well described
differentiation functions (see Section 2.1), and an increase in the
ratio of these mitogenic versus differentiative hormones is postulated
to drive aberrant cell proliferation (Bowen and Atwood, 2004). Such a
mechanism of altered HPG hormone signaling also could operate
during childhood; the peak years of an organ system's increase in size
correlate with peak years of cancer incidence (Rubin et al., 2010)
when mitogenic signals are high. Likewise, the number of ovulatory
cycles positively correlates with reproductive cancer risk (Parsa and
Parsa, 2009), indicative of HPG hormone-induced proliferation of
epithelial stem cells, and their regression, during each menstrual cycle
(Soderqvist et al., 1997) and the progressive increase in the likelihood
of mutations/chromosomal abnormalities during cell division. Impor-
tantly, endocrine dyscrasia could drive neoplasia and/or metastasis
via epigenetic mechanisms (Prins et al., 2007; Greer et al., 2010).
In summary, the data presented in this section indicates that the
more dysregulated the HPG axis (i.e. the lower the concentration of sex
steroids/inhibins and the higher the concentration of gonadotropins/
GnRH/activins), the more quickly a person is to develop aging-related
diseases. Conversely, maintaining HPG hormones in balance is associ-
ated with decreased disease risk. The increased prevalence of most
aging-related diseases in men before 70 years of age (Mercuro et al.,
2001) are likely due to the fact that andropause commences earlier in
men than menopause in women (e.g. Belanger et al., 1994). The decline
in T/inhibins and elevation of gonadotropins/GnRH/activins in men are
therefore not without consequences in the first decades of andropause,
i.e. between 30–60 years of age, and likely explain the increased
incidence of many aging-related diseases compared with women. The
in vitro and in vivo evidence for distinct effects of sex steroids and
gonadotropins ondiseases of aging, in which sex steroids act to promote
cell differentiative functions, and gonadotropins/GnRH act to promote
cell proliferation (anti-differentiative) creates a paradigm shift in our
understanding of the mechanisms by which reproductive endocrine
dyscrasia (i.e. dyotic signaling) promotes aging-related diseases. Taken
together, these data strongly support endocrine dyscrasia and the
subsequent loss of cell cycle control as causative mechanisms for the
development of aging diseases and death.
2.4. HPG endocrine dyscrasia correlates with longevity
Like aging-related diseases, there are strong epidemiological and
mechanistic correlates between aging-related reproductive endocrine
dyscrasia and longevity in humans.
2.4.1. Epidemiological evidence
Most importantly, ~10 human studies have shown that higher age at
menopause is associated with prolonged female lifespan (e.g. Helle et al.,
2005). In this context, advanced age atlast pregnancy is associated with
improved longevity (see Appendix A in: Helle et al., 2005). In addition,
delaying of an entire reproductive effort to late ages covaries with the
enhanced post-reproductive survival of mothers (Helle et al., 2002).
Consistent with this data, brothers of women conceiving in their 40s or
50s live longer (Smith et al., 2009). Likewise, early age at menarche
(before age 12 yr, and likely early age at menopause), is correlated with
increased risk of cardiovascular morbidity and mortality, and overall
mortality in women (Lakshman et al., 2009). Conversely, a recent study
found a 4.5% reduced mortality per year increase in age at menarche
(Jacobsen et al., 2009).
In this connection, compared with ovarian conservation, bilateral
oophorectomy at the time of hysterectomy for benign disease is associated
with an increased risk of morbidity and mortality (Rocca et al., 2006).
Oophorectomy is not associated with increased survival at any age (Parker
et al., 2009).
2.4.2. Experimental evidence
The most compelling evidence in humans for reproductive endo-
crine dyscrasia regulating longevity comes fromepidemiologicalstudies
104 C.S. Atwood, R.L. Bowen / Experimental Gerontology 46 (2011) 100–107
of estrogen replacement therapy use after menopause. Partial balancing
of the HPG axis with estrogen therapy (decreasing gonadotropin/GnRH
production) extends longevity. Over fifteen studies have demonstrated
areduction in the risk of mortality in those taking estrogen replacement
therapies (reviewed in: Paganini-Hill et al., 2006), particularly those
who took HRT under 60 years (Salpeter et al., 2004). These studies
consistently show a 20% to 50% decrease in mortality among users of
estrogens. Recently, Paganini-Hill et al. (2006) reported increased
longevity even in older users of post-menopausal estrogen therapy.
In animals, re-establishment of the negative feedback loops in the
HPG axis of post-reproductive mice (22 months of age) following
transplantation of reproductively viable ovaries from young mice
(3 months of age) has been demonstrated to extend lifespan by up to
40% (Cargilletal.,2003;Masonetal.,2009). This method of HRT allows
reestablishment of the entire HPG axis (i.e. replacement of both sex
steroids and inhibins leading to suppression of gonadotropins, GnRH
and activins). Gonad manipulation in model organisms provides strong
evidence for a direct link between reproduction and longevity (Arantes-
Oliveira et al., 2002). In the hermaphroditic worm Caenorhabditis
elegans, neonatal ablation of the gonadal germ line cells while leaving
the somatic gonad intact results inincreased life span, but removalof the
entire gonad yielded no change in life span (Hsin and Kenyon, 1999).
Ablation of the germ line must be prior to germ line stem cell
proliferation for lifespan extension to occur (Arantes-Oliveira et al.,
2002). However, no extension of lifespan was found following ablation
of the germ line in Drosophila melanogaster (Barnes et al., 2006).
Characterization and quantitation of the endocrine signals in these
animal models might help explain the discrepant results regarding
longevity. In this respect, our own data indicate that suppression of
GnRHR signaling in C. elegans significantly decreases reproduction 46%
and prolongs lifespan~15% (23% at lower temperature) compared with
wild-type worms (Vadakkadath Meethal et al., 2006; Vadakkadath
Meethal and Atwood, unpublished data). Studies in D. melanogaster also
indicate thatmodulation of ecdysone signaling modulates lifespan. Flies
heterozygous for inactivating mutations in theligand binding domain or
DNA binding domain of ecdysone receptor show robust (typically 20–
50%) lifespan-extension (Simon et al., 2003).
3. Halting the aging process
According to the definition that aging is change, the reproductive
period is therefore the time of least change in function, and represents
the time of slowest aging. Together with the abundant evidence that
endocrine dyscrasia induces the senescent phenotype, mimicking the
levels of reproductive-cell cycle signaling factors during the repro-
ductive period of life would be one possible intervention that would
extend longevity. Strategies to reverse dyotic signaling have been
previously described (Atwood et al., 2005). In short, they consist of
reestablishing circulating concentrations of HPG axis hormones to
that of the young reproductive adult in terms of concentration and
perhaps cyclicity. Since aging-related reproductive endocrine dyscra-
sia results from the loss of sex steroid and inhibin production by the
gonads, strategies to supplement with these hormones is warranted.
Current interventions are limited to those members of the HPG axis
that are pharmacologically available, i.e. sex steroids. Sex steroids
decrease hypothalamic GnRH production and circulating LH and FSH,
but not to early reproductive levels (Fig. 1B;Lind et al., 1978), perhaps
as a result of decreased circulating inhibin (Boepple et al., 2008).
Treatments that increase circulating sex steroids (HRT) and decrease
gonadotropin/GnRH have been demonstrated to extend human
longevity (Paganini-Hill et al., 2006), while supplementation of the
inhibin α-subunit also is expected to extend longevity, although such
a treatment is not currently available.
Alternatively, since modalities that suppress HPG axis signaling
also extend longevity, another strategy would be to suppress the
reproductive axis. Elegant studies performed by Arthur Everitt at the
University of Sydney in the 1960s demonstrated that the removal of
the anterior pituitary (hypophysectomy) results in a decrease in
reproductive function, delayed senescence and increased healthspan
and lifespan (Everitt and Burgess, 1976). While hypophysectomy and
other modalities such as caloric restriction, cold or exercise stress that
suppress HPG axis hormones may not be favored by most, it is
possible using GnRH agonists and antagonists to suppress most
hormones of the axis, and certainly the elevation in GnRH/gonado-
tropin signaling that promotes our aged phenotype (Wilson et al.,
2007).
While these types of intervention should be effective, the real
question is why does reproductive function deteriorate in the first
place? If there were a way to decrease the rate of follicle depletion or
increase the number of viable follicles (i.e. decrease the rate of
follicular atresia or increase basal oocyte reserves in women; decrease
the rate of Sertoli/Leydig stem cell loss or increase basal Sertoli/Leydig
stem cell reserves) one should be able to maintain HPG axis balance
and delay senescence without decreasing growth, delaying the onset
of puberty or decreasing fertility. This could be achieved with cellular/
organ replacement (grafting) based technologies, such as has been
reported for mice (Cargill et al., 2003; Mason et al., 2009). The idea of
an elixir emanating from the gonads to prevent aging is not new.
While the pharmaceutical industry spends billions of dollars
developing bandaids (drugs) for aging related diseases, it can be
argued based on the above epidemiological, biological and clinical
evidence that restoration of the HPG axis would afford more protection
and better treatment than most drugs currently in development or on
the market.
4. Strengths of the Reproductive-Cell Cycle Theory of Aging
The Reproductive-Cell Cycle Theory is able to explain 1) the
simultaneous regulation of the rate of aging and reproduction as
evidenced by the fact that environmental conditions and experimen-
tal interventions known to extend longevity are associated with
decreased reproductive-cell cycle signaling factors, thereby slowing
aging and preserving fertility in a hostile reproductive environment;
2) two phenomena that are closely related to species lifespan—the
rate of growth and development and the ultimate size of the animal;
3) the apparent paradox that size is directly proportional to
lifespan and inversely proportional to fertility between species but
vice versa within a species; 4) how differing rates of reproduction
between species is associated with differences in their lifespan; 5)
why we develop aging-related diseases; and 6) an evolutionarily
credible reason why and how aging occurs—these hormones act in an
antagonistic pleiotrophic manner via cell cycle signaling; promoting
growth and development early in life in order to achieve reproduc-
tion, but later in life, in a futile attempt to maintain reproduction,
become dysregulated and drive senescence (dyosis). The Reproduc-
tive-Cell Cycle Theory explains aging in all sexually reproductive life
forms. This is supported by the fact that HPG axis hormones and
receptors are evolutionarily conserved throughout reproductive
organisms, orthologs having been identified in flies (D. melanogaster),
worms (C. elegans), yeast (Saccharomyces cerevisiae) and plants (see:
Bowen and Atwood, 2004; Vadakkadath Meethal et al., 2006).
Therefore, from the perspective of survival of the species, since
reproduction is the most important function of an organism, if
reproductive-cell cycle signaling factors determine the rate of growth,
determine the rate of development, determine the rate of reproduc-
tion, and determine the rate of senescence, then by definition they
determine the rate of aging and thus lifespan.
Acknowledgements
We thank the editors of this special issue, Holly Brown–Borg, Ph.D.
and Kurt Borg, Ph.D., for their invitation to write this review, and Holly
105C.S. Atwood, R.L. Bowen / Experimental Gerontology 46 (2011) 100–107
Brown–Borg for inviting CSA to present parts of this paper at the 10th
International Symposium on Neurobiology and Neuroendocrinology
of Aging in Bregenz, Austria. Due to space limitations, reviews
(or example references) are often cited instead of primary or all
references. We apologize to those colleagues whose work we could
not cite. This is Geriatrics Research, Education and Clinical Center VA
paper # 2010–21.
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