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Conference Report
Endocrinology of Aging

Johannes D. Veldhuis, MD

[Medscape Diabetes & Endocrinology, 2000. © 2000 Medscape, Inc.
http://endocrine.medscape.com/Medscape/endocrinology/journal/2000/v02.n03/mde0315.veld/pnt-mde0315.veld.html ]

Introduction

The endocrine system regulates body composition, fat deposition, skeletal mass, muscle strength, metabolism, body weight, and physical well being. Multiple endocrine changes evolve with aging in all species and, not surprisingly, some of the physiologic manifestations of aging are related to the effects of declining hormone levels.

One of the earliest investigations into the possible role of the endocrine system in the aging process was conducted by Charles Edward Brown-Séquard (1817-1894), a French-educated physician and Professor of Physiology and Neuropathology at Harvard. At the age of 72 years, Brown-Séquard injected himself intramuscularly with the aqueous extracts of testicular tissue from young dogs and guinea pigs. In 1889, he proclaimed that this treatment produced an increase in grip strength and sexual vigor and advocated the medical use of testicular extracts as a means to prolong life.

In humans, aging is associated with a decrease in the gonadal production of estrogen in females (menopause) and testosterone in males (andropause); the adrenal production of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) (adrenopause); and a decrease in the activity of growth hormone (GH)/insulin-like growth factor (IGF) axis (somatopause). As a result, hormone replacement regimens are being developed as a strategy to delay or prevent some of the consequences of aging. However, in some cases the use of hormone replacement therapy for this purpose is controversial. This article highlights pivotal new concepts in the endocrinology of aging, as discussed at a recent Serono Symposium, Endocrinology of Aging, held on October 27-30, 1999, in Tempe, Arizona.

Biologic Origins of Aging

There is limited evidence that genetics plays a role in the aging process per se, although the genomic complement regulates longevity. Aging at the molecular level can be viewed as a stochastic process resulting from increased disorderliness of intra- and intercellular regulatory mechanisms. This results in reduced robustness of the organism to intercurrent stress and disease. The notion of greater disorderliness in aging is also evident at the whole organismic level, as illustrated by the erosion of the orderly neuroendocrine feedback regulation of the secretion of GH, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and adrenocorticotropin hormone (ACTH).[1]

Aging Cells

At the cellular level, several processes are involved in the physiology of aging and the development of some aging-related diseases. Apoptosis, a word coined in 1972, signifies the process of nontraumatic and noninflammatory cell death -- and the opposite of cell mitosis -- that balances cell proliferation and thus maintains homeostasis. This theme was adumbrated as early as the late 1800s in studies of ovarian follicular atresia. Specific gene products either promote (Bax) or oppose (Bcl-2) regulated cell death via mitochondrial effects.[2] Dysregulation of apoptosis has been implicated in the development of diseases that are more prevalent in older individuals, such as cancer and the neurodegenerative disorders (Alzheimer's and Parkinson's disease).

Telomeres have also been implicated in the regulation of cellular senescence. Telomeres consist of tandem repeats of a short nucleotide sequence and are located on the ends of chromosomes. Their length limits the total number of attainable cell generations in a tissue or organ (the so-called "end-replication" problem -- the inability of DNA polymerase to completely replicate the 3_ end of linear DNA). It has been speculated that the limited proliferative potential of human cells is a result of the telomere shortening that occurs during DNA synthesis at each cell division. The extension of telomeres by the enzyme telomerase compensates for the loss of a few nucleotides of telomeric DNA during each cell cycle, essentially protecting and ensuring that the entire linear chromosome is completely replicated. As a result, telomere length is directly related to the number of cell generations. Transfection of human cells with the gene for telomerase has resulted in more than 400 population doublings. Thus, telomere renewal may be relevant in both cancer pathogenesis and the research of aging.[3]

Biochemical insults also arise within aging cells, in part from the action of reactive oxygen species generated and scavenged incompletely throughout the cell cycle. Aging-associated changes also occur between and among cells via alterations in the intercellular matrix, the intercellular exchange of trophic factors, the release of inflammatory cytokine mediators, and the degree of infiltration by other associated cell types (eg, glial interactions with neurons). However, it is not known why free-radical damage does not adversely affect certain cells (eg, gonadal germ cells).[4]

Animal Models of Aging

The tortoise and lobster exhibit remarkably few features of aging, albeit for reasons not yet known. In fruit flies, the activation of the methuselah gene confers approximately a 30% extension of longevity. In the laboratory rat, neuronal sprouting can be stimulated by either apolipoprotein (Apo) E-3 or Apo E-4, whose production is increased by estrogen.[5] Apo-E transgenic knockout mice do not exhibit neurite outgrowth in response to estrogen. This finding may be pertinent to estrogen's presumed role in the prevention of neuronal aging and Alzheimer's disease. Estrogen also induces glial fibrillary acidic protein in astrocytes and their abutment and retraction from regulatory gamma-aminobutyric acid (GABA)-producing terminals that synapse on gonadotropin-releasing hormone (GnRH) neurons in the young female rat, but not in older animals that have lost the capacity to generate an LH surge. The important new experimental concept of defective hormone-sensitive neuronal plasticity with aging will require further experimental appraisal.[5]

Ensemble View of Neuroendocrine Axis in Aging

The central nervous system (CNS) regulates the pituitary gland, which secretes hormones to target tissues that, in turn, produce substances that feed back on the hypothalamic-pituitary axis. This feedback-control network can be assessed via novel entropy statistics, which assess the ensemble synchrony of a feedback axis. Entropy calculations quantify the progressive age-related loss of orderliness of single-hormone secretion for GH, ACTH, LH, and insulin, as well as the erosion of coordinate 2-hormone secretion for ACTH-cortisol, LH-testosterone, LH-FSH, and LH-prolactin.[1] LH secretion, sleep-stage transitions, and nocturnal penile tumescence (NPT) oscillations also exhibit marked loss of synchrony with aging.

Unknown mechanisms link aging-related parallel declines in the GH-IGF-I axis (somatopause), gonadal axis (gonadopause), and adrenal androgen secretion (adrenopause). Epidemiologic studies reveal consistent decrements in adrenal androgen (DHEA and DHEA-S) secretion in aging men and women.[6-8] However, neither the basis for nor the medical implications of this attrition in the adrenal zona-fasciculata function are known.

Adrenopause: The Role of DHEA or DHEA-S in Aging

The enzymic machinery of the adrenal zona reticularis fails in aging men and women. However, the ability of the zona fasciculata to produce cortisol is preserved (based on ACTH infusion, insulin tolerance, and metyrapone testing). Mineralocorticoid and glucocorticoid receptors in the hippocampus are variably downregulated in aging humans. Excessive lifelong adrenal cortisol feedback on the brain may exacerbate the aging-associated loss in neuronal synapses and plasticity.

Extraglandular neurosteroids (typically progestin derivatives) produced by CNS astroglia regulate the activity of neuronal ion-channels (eg, via GABA-A receptors). The mechanisms by which neurosteroids interact with corticosteroids to modulate the cognitive and affective changes of aging have not been described.

Role of the Endocrine System in the Biologic Variability of Aging

The remarkable variability in the physical status of the healthy-aging population and in the progression of aging-related diseases, such as sarcopenia, osteopenia, and cognitive disorders, may reflect, in part, the natural polymorphisms of key catabolic and/or anabolic gene products. For example, molecular diversity in the glucocorticoid receptor may influence the relative effects of cortisol excess on tissue catabolism. Conversely, polymorphisms of the IGF-I receptor could be relevant in mediating interindividual differences in tissue atrophy in aging. A more systematic evaluation of this issue will require additional studies in various ethnic populations.[9]

Neuroendocrine Rhythms in Aging

Neuroendocrine rhythms are altered with aging. For example, although the role of melatonin in human aging is not known, the peak nighttime release of melatonin decreases by approximately 50% with aging. Other CNS timekeeping centers, such as the suprachiasmatic nuclei (SCN), show aging-dependent alterations, as reflected in changing 24-hour rhythms of GH, prolactin, cortisol, thyroid-stimulating hormone (TSH), GH, and LH. For example, over the age range of 18-80 years in humans, the secretion of cortisol, which is driven by ACTH, progressively exhibits an earlier maximum (phase advance), a higher late-day nadir, and a smaller variation in secretion over 24 hours.[10] In contrast, the 24-hour periodicity of cortisol secretion remains stable across the life span.[11] With aging, there is a blunting of the presleep peak of TSH. Levels of GH manifest a global (day and night) suppression of amplitude with aging.[10, 12]

Neurophysiologic outcomes, such as circadian temperature rhythms, tend to show phase advance and amplitude suppression with aging. Extended daylong and inter-diem monitoring of cardiovascular indices may identify patients at higher risk for arrhythmia or myocardial infarction. Knowledge of circadian rhythms has resulted in the development of chronopharmacotherapy, or timed drug delivery based on the circadian cycle of the patient, in an effort to obviate drug toxicity and enhance medication efficacy.[13]

Sleep Rhythms in Aging

Sleep fragmentation, prolonged sleep onset latency, and reduced rapid-eye movement activity are evident in older adults. Some GH-releasing hormones and peptides can trigger sleep in rats, rabbits, and humans.[14] The drugs gamma-hydroxybutyrate and ritanserine can induce both slow-wave sleep and GH secretion, at least in young adults, thereby relating sleep and GH release.[10] Conversely, the disordered sleep patterns associated with the sleep-apnea syndrome suppress GH secretion. The normal relationship between deep sleep and GH secretion may be eroded in aging. Sleep deprivation in young men elicits some of the same neuroendocrine and metabolic features of aging, such as elevated evening cortisol levels, higher sympathetic tone, and decreased glucose tolerance.

Aging and Diabetes Mellitus

At least 17% of individuals age 80 or older will develop type 2 diabetes mellitus. Adults with low insulin sensitivity (eg, relative insulin resistance) and reduced glucose effectiveness (eg, insulin-independent glucose removal rate) have approximately an 80% risk of developing type 2 diabetes mellitus over a period of 25 years.[15] In healthy-aging individuals, there is a progressive increase in fasting and especially in postprandial plasma glucose levels.[16] As we age, insulin secretion decreases to a variable degree and becomes disorderly.[17] Concomitantly, there is a progressive increase in peripheral resistance to insulin action.[18] In healthy individuals, the aging of enteroinsular axis shows remarkable between-subject heterogeneity; the underlying basis for this is not completely understood. For example, how the aging-related diabetogenic tendency is related to the aging-related increase in visceral obesity is not known. In addition, there are few data on how well glycosylated hemoglobin levels in healthy-aging individuals predict later development of clinical diabetes mellitus.[19]

Insulin Action in Aging

Biochemically, insulin activates receptor-dependent autophosphorylation as well as phosphorylation of tyrosine residues of multiple (as many as 10) insulin-receptor substrates (eg, IRS-1, IRS-2), and multiple isoforms of phosphatidylinositol-3 (PI-3) kinase. Further divergence of these signaling pathways imposes selective control of cellular glucose metabolism, protein and lipid turnover, cell replication and hypertrophy, and gene expression.

The use of transgenic mouse signaling gene-knockout models have identified a new multiplicity of possible molecular defects in type 2 diabetes mellitus as well as plausible loci of targeted drug interventions. For example, experimentally disabling the IRS-1 or IRS-2 genes promotes tissue insulin resistance and causes variable intrauterine growth retardation.[20] Albeit unproven, the pathogenetic sequence that culminates in type 2 diabetes could be driven by an ensemble of single-allele molecular polymorphisms, which cause progressive insulin resistance in muscle, liver, fat, and systemic hyperinsulinemia and eventual beta-cell failure.

The novel Cre-lox conditional gene knockout approach is being used to further explore some of these hypotheses. For example, tissue-specific disruption of the muscle insulin receptor promotes visceral fat accumulation and hypertriglyceridemia without producing overt type 2 diabetes mellitus; knockout of the liver insulin receptor promotes postprandial hyperglycemia and marked hyperinsulinemia; and disabling the beta-cell insulin receptor eliminates glucose (but not L-arginine)-stimulated insulin secretion, resulting in impaired glucose tolerance and type 2 diabetes mellitus.[21]

Glucagon-like Peptides in Aging

Glucagon-like peptide-1 (GLP-1), the main product of the posttranslational processing of proglucagon in the small intestine, is produced in response to a mixed meal. This peptide, along with GIP (gastric inhibitory peptide), may mediate much of the so-called 'incretin effect' (augmented postprandial insulin secretion following oral compared with intravenous glucose administration due to the effect of intestinal hormones). In the baboon, a specific GLP-1 antagonist blocks the incretin effect, and GLP-1 knockout mice show glucose intolerance. At the pancreatic beta cell, GLP-1 is a potent insulin secretagogue, defining GLP-1 as a new incretin.

Intravenous infusion of GLP-1 in healthy humans is a powerful insulin secretagogue that acts by potentiating the insulinotropic action of glucose. GLP-1 may exert other actions on the stomach and brain, such as delaying gastric emptying and inducing satiety, respectively. The slower gastric emptying delays nutrient entry to the intestine and thereby diminishes meal-induced glucose excursions. The pathophysiologic roles of reduced GLP-1 action, if any, in aging-associated glucose intolerance are not yet known. Although GLP-1 deficiency does not occur in type 2 diabetes, possible future therapeutic applications for GLP-1 may be to heighten insulin secretion, augment glucose disposal, and repress postprandial glucagon production.[22]

Leptin, Obesity, and Aging

Body mass index increases and visceral fat accumulates with age until early senescence. Levels of the nutritional signaling peptide leptin (mostly produced in white adipose tissue) increase pari passu. Leptin conveys signals to the hypothalamus about fat stores and, in response, hypothalamic efferents regulate food intake and energy expenditure.

Leptin inhibits the hypothalamic release of the orexigenic (appetite-inducing) peptide neuropeptide Y (NPY) and activates the sympathetic nervous system. The latter stimulates lipolysis in adipose tissue via the beta-3 adrenergic receptor, cAMP accumulation, and increased activity of mitochondrial uncoupling protein (UCP)-3, thus generating heat (which is dissipated) rather than ATP (which is stored).

In older animals, fasting suppresses circulating leptin concentrations and stimulates hypothalamic NPY secretion less effectively. In older rodents, leptin infusions also fail to augment energy expenditure as prominently. Thus, leptin-receptor signaling may be attenuated in aging.[23]

Menopause

The World Health Organization has defined the perimenopause as the interval preceding cessation of menses through 1 year after the last spontaneous bleeding cycle, which, according to the findings of the Massachusetts's Women's Health Study, is a mean span of about 3 1/2 years. There is still no known biochemical signal that reliably indicates the onset of menopause. However, serum FSH levels tend to rise in regularly menstruating late-premenopausal women (42-50 years of age). The pulsatility and the orderliness of LH release also change before menstrual cyclicity falters.[1] Estrogen secretion in the perimenopause is variable, and includes intervals of increased production. A greater stimulation by FSH may increase follicular aromatase activity and induce estrogen excess. Inhibin concentrations fall perimenopausally and contribute to heightened FSH release.

Hot flushes may precede the onset of anovulatory cycles in the perimenopause. Physical complaints, such as breast tenderness, irregular menstrual bleeding, hot flushes, and dyspareunia; and emotional concerns, such as disrupted sleep, fatigue, tension, and irritability, are equally represented among menopausal women in North America.[24] Some of the relevant physiologic effects of estrogen that ameliorate the consequences of menopause may be exerted via the 10 or more membrane (nongenomic) binding sites for estradiol, which regulate ion flow and kinase signaling. In addition, the alpha and recently cloned beta isoforms of the estrogen receptor mediate classical DNA-dependent interactions within the target cell. New designer estrogens, such as raloxifene (Evista), which act as selective estrogen-receptor modulators (SERMs), may or may not confer the same neurobiologic effects as estrogen.[5]

Individual Variations in Reproductive Aging in Women

Even in identical (monozygotic) twin pairs, there can be a 12- to 14-year discordance in the age of menopause, albeit 50% of twin pairs are concordant within 2 years. Thus, reproductive aging--even with identical genetic anlagen--shows stochastic and/or environmental variability. For the female gonadal axis, this stochastic element could originate from the nonuniformity among individuals in rates of prenatal oocyte and follicle survival. This view highlights the importance of the ovarian oocyte reserve. Clinically, premature menopause holds significant implications for the development of cardiovascular disease and osteopenia.[24]

The Aging Human Ovary

Females have a finite nonrenewable complement of oocytes. Hence, control of oocyte depletion is a critical determinant of the human female reproductive life span. A maximal oocyte population of 7 million is estimated to exist at 20 weeks gestation. Two million persist until birth, and there are 400,000 at the onset of puberty. Only approximately 400 oocytes are actually ovulated during a woman's reproductive years. Understanding the mechanisms that regulate the attrition of oocytes is critical for developing strategies that extend the reproductive life span, intervene in premature ovarian failure, and preserve threatened gonadal function in patients undergoing cancer chemotherapy.

Studies using selective transgenic mouse-knockout models have established important roles in germ cell/follicular preservation for sphingomyelinase, ceramide, Bcl-2, the proapoptotic protein Bax, and other apoptosis-modulating substances. For example, Bax promotes the atresia of primordial follicles, and hence knocking out Bax markedly extends the ovarian reproductive life span in mice and prolongs endogenous estrogen secretion by Graafian follicles.

Developing a molecular strategy that promotes follicular protection may limit premature menopause resulting from cytotoxic chemotherapy (eg, adriamycin, doxorubicin, x-rays, cyclophosphamide). On the other hand, gonadotropins and GH/IGF-I rescue more mature follicles by opposing granulosa-cell (not oocyte) death. Transforming growth-factor beta and Müllerian inhibiting substance are proapoptotic -- that is, they promote oocyte death.[2]

Endocrine Facets of Breast Cancer in Older Women

The incidence of breast cancer rises unidirectionally with age. The National Surgical Adjuvant Breast and Bowel Project compared 13,000 women treated for 5 years with placebo or with tamoxifen. Tamoxifen is a SERM that acts as an estrogen antagonist in breast tissue. Patients in the tamoxifen group achieved a 50% reduction in the cumulative rate of invasive breast cancer.

The estrogen receptor (ER) mediates growth-factor production and possible tumor gene induction in breast cells. Antiestrogens dimerize the ER but stabilize a corepressive (rather than coactivator) state, thereby blocking gene activation. Some of the growth-promoting effects of estrogen are mediated via local IGF-I production and/or the growth-factor receptor family (EGF, c-erbB-2). For example, estrogen requires IGF-I for maximal breast stimulation and stimulates genes involved in IGF-I signaling. Neutralization of IGF-I action by the overexpression of IGF-binding protein limits experimental breast tumor growth. Available clinical data do not relate GH replacement to increased breast cancer incidence.[25]

Andropause

Sexual dysfunction in the elderly male is primarily associated with erectile rather than ejaculatory dysfunction. The latter is more often drug induced or associated with prostate surgery. In the hypogonadal male, reduced libido is often accompanied by diminished well being and/or depression that may be relieved by androgen replacement.[26]

Cognitive decline, visceral obesity, osteopenia, and relative sarcopenia also accompany androgen deficiency in aging.[27] These conditions respond favorably to androgen supplementation, especially in men with very low testosterone levels.[28] Enhanced physical performance has not been established in this context. Few studies have examined whether testosterone supplementation enhances cognitive function in elderly men.[29] Although it appears that neoplastic transformation of prostate tissue is not elicited by physiologic testosterone repletion, proliferation of existing androgen-responsive carcinomas may be stimulated. Thus, a normal prostate-specific antigen (PSA) and prostatic digital examination should precede any androgen treatment in older individuals.

Testosterone supplementation may worsen sleep apnea, induce gynecomastia, elicit erythrocytosis, and elevate blood pressure. Thus, the long-term safety of androgen supplementation in healthy adults requires further study.

Endocrine Aspects of the Aging Prostate

Prostate volume increases progressively with age in eugonadal men. Albeit androgen-dependent, this propensity is also modulated by unknown environmental and genetic factors. Estradiol, IGF-I, IGF-II, fibroblast, and keratinocyte growth factors act locally to promote prostate epithelial and stromal growth. The number of cytosine, adenine, and guanine (CAG) repeats in the androgen-receptor gene may also correlate with intense prostate growth.[27]

Approximately 180,000 men are newly diagnosed with prostatic cancer each year, and 37,000 others die annually from this neoplasm. Occult prostate cancers are detectable in approximately 25% of men under age 40. The incidence is nearly 50% higher in African Americans, possibly because of the contribution of higher perinatal testosterone concentrations and other poorly defined genetic factors. Differences in 5-alpha reductase enzyme activity and adult testosterone concentrations do not explain this phenomenon.

The Aging GH Axis

Gender markedly influences GH secretion in young adults. Premenopausal women exhibit a 2-fold less rapid decline than men in daily GH production with increasing age. Young women also manifest less vulnerability to the suppressive effects of increased total body fat and reduced physical fitness on GH secretion.[30] Withdrawal of estrogen at menopause appears to eliminate much of this gender difference.

An important ongoing clinical issue relates to the uncertain role of sex-hormone deficiency in the aging-related impoverishment of GH and IGF-I production in women and men.[31] Preliminary data from clinical studies raise the possibility that combined GH and androgen repletion in older men can have an additive effect on increasing muscle mass.[30]

Short-term Experimental Use of GHRH in Older Adults

New clinical studies are appraising the effect of stimulating endogenous GH secretion in a manner that approximates physiologic levels (pulsatile and feedback-preserved). This strategy involves administration of GH-releasing hormone (GHRH) or GH-releasing peptide (GHRP)-like analogues.[32] New data indicate that treatment with GHRH can restore plasma IGF-I to levels found in young adults and is associated with little evident toxicity.[33-35] Body composition also improves. However, to date this treatment has not enhanced strength and physical aerobic capacity. Ongoing investigations are being conducted to evaluate the effects of combining GH, gonadal steroids, and/or GH secretagogues in older individuals. However, it appears that the relatively brief trials conducted thus far (eg, 6 months duration) may be inadequate to unveil the true spectrum of responses.[36]

Experimental Administration of recombinant human GH (rhGH) in Older Adults

New prospective interventions corroborate the dose-dependent restoration of plasma IGF-I concentrations by GH injections in older volunteers. Estrogen replacement in older women limits, but does not abolish, the ability of GH to stimulate IGF-I secretion. Treatment with GH consistently reduces visceral adiposity and increases muscle mass in men. Physical performance and maximal aerobic capacity most often do not change.[14]

Recent studies have successfully used lower doses of rhGH (3-10 mcg/kg/day, daily at night), which elicit fewer adverse events (eg, less fluid retention, carpal tunnel syndrome, gynecomastia, headache, bloating, pedal edema, or myalgias). The issue of whether long-term GH supplementation will stimulate neoplasia of the breast, prostate, or other tissues at increased risk for neoplasia in the elderly remains unclear.

New GH Secretagogues

Various peptidyl and nonpeptidyl compounds stimulate pulsatile GH secretion and increase plasma IGF-I concentrations in the elderly both acutely and over intervals of days to months without producing a clinically significant downregulation of GH responsiveness.[34] These novel agents include rhGHRH-1,44-amide and various members of the GHRP family.[14]

Individual GH secretagogues are uniformly less effective in older men and women. However, in older individuals, the coadministration of either GHRH or GHRP with L-arginine (an effector believed to restrain hypothalamic somatostatin secretion) stimulates GH secretion to levels approximating those of young adults.[37] A preliminary intervention study in elderly Dutch patients (>75 years of age) undergoing surgical repair of acute hip fractures suggests that perioperative short-term (6 weeks) rhGH treatment can accelerate recovery to premorbid quality of life.[9] This beneficial effect will need to be confirmed by additional studies.

Summary

Aging can be viewed as a stochastic process resulting from a greater disorderliness of regulatory mechanisms that results in reduced robustness of the organism to intercurrent stress and disease. The notion of greater disorderliness in aging is illustrated by the erosion of the orderly neuroendocrine feedback regulation of the secretion of LH, FSH, ACTH, and GH. These changes are manifested as menopause, andropause, adrenopause, and somatopause. Aging-related disruption of metabolic processes is associated with a higher prevalence of diseases such as type 2 diabetes and cancer in older individuals.

Although the dysregulation of neurohormone outflow from the CNS constitutes one of the earliest measurable facets of endocrine aging, many questions remain to be answered by aging research. What is the exact mechanism of CNS integrative failure? To what degree does peripheral endocrine gland insufficiency (eg, testis, ovary) contribute to disruption in the aging feedback-axis (eg, GnRH-LH)? What gender differences underlie the neuroendocrine changes that occur with aging? What is the contribution of the neuroregulatory alterations to the risk of frailty and/or eventual disability?

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Endocrinology of Aging

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