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Increased life expectancy combined with the aging baby boomer generation has resulted in an unprecedented global expansion of the elderly population. The growing population of older adults and increased rate of age-related chronic illness has caused a substantial socioeconomic burden. The gradual and progressive age-related decline in hormone production and action has a detrimental impact on human health by increasing risk for chronic disease and reducing life span. This article reviews the age-related decline in hormone production, as well as age-related biochemical and body composition changes that reduce the bioavailability and actions of some hormones. The impact of hormonal changes on various chronic conditions including frailty, diabetes, cardiovascular disease, and dementia are also discussed. Hormone replacement therapy has been attempted in many clinical trials to reverse and/or prevent the hormonal decline in aging to combat the progression of age-related diseases. Unfortunately, hormone replacement therapy is not a panacea, as it often results in various adverse events that outweigh its potential health benefits. Therefore, except in some specific individual cases, hormone replacement is not recommended. Rather, positive lifestyle modifications such as regular aerobic and resistance exercise programs and/or healthy calorically restricted diet can favorably affect endocrine and metabolic functions and act as countermeasures to various age-related diseases. We provide a critical review of the available data and offer recommendations that hopefully will form the groundwork for physicians/scientists to develop and optimize new endocrine-targeted therapies and lifestyle modifications that can better address age-related decline in heath.
Aging is inevitable and is the single most important modulator of human life span and health span. The substantially increased morbidity and mortality associated with advancing age contribute to the higher socioeconomic cost of care of the older population. An unavoidable consequence of increased life expectancy is an expansion of the older population. In 2012, it was estimated that there were approximately 43.1 million people aged 65 and older in the United States, and this number is projected to reach 83.7 million by the year 2050.
The abrupt increase in life span that has occurred since the turn of the 20th century has prompted scientists, health care organizations, and national leadership to develop approaches aimed at extending quality of life and reducing late-onset diseases of aging.
It is therefore critical to understand the “normal” age-related changes in human physiology and the underpinnings of these changes. Multiple age-related hormonal and metabolic changes greatly contribute to the principal age-related chronic diseases and decline in physiologic functions, which include atherosclerosis, hypertension, diabetes, hyperlipidemia, obesity, sarcopenia, osteoporosis, thrombogenesis, chronic inflammation, and decline in immune functions. Another emerging health concern of aging is a decline in brain function, which is mostly related to the development of degenerative brain diseases that cause cognitive decline in the form of various types of dementias. Interestingly, the development of cognitive decline during aging is more prevalent in people with metabolic problems. Aging adversely affects not only hormonal secretions but also their biological availability (eg, sex hormones) and their effects on targeted organs (eg, insulin resistance). One of the most important questions is whether any or all of the hormonal and metabolic changes that occur with age are preventable and/or reversible. In addition, many metabolic changes, especially those related to hormonal actions, are related to lifestyle modifications that are common as people become older. In this review, we will attempt to critically summarize the hormonal and metabolic changes that occur with age and whether and/or how these age-related alterations can be prevented or slowed down, thus benefitting the welfare of humanity.
Hormone Changes With Age
A number of terms have been used to describe the loss of hormone production and their secretory patterns as we age including menopause, andropause, adrenopause, and somatopause.
Although the sudden decline in female sex hormone production in menopause has a clear consequence on cardiometabolic health, this review will focus on the adverse health effects of the gradual loss of hormones during aging. For more information regarding the influence of menopause on metabolism in elderly women, we refer readers to other comprehensive reviews.
In men, a gradual decline in testosterone (T), termed andropause, begins at around 20 to 30 years of age and persists until death (Figure 1A). Women also experience decreased T with age, but the T level in women is approximately 10 times lower than that in men,
and thus, the effects of lower T during aging may be more detrimental in men. Because of the greater decline in T in men, most studies in this area have been performed in men; therefore, generalizing of the effects of andropause across sexes should be considered carefully. Adrenopause is characterized by reduced secretion of dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) with advanced age (Figure 1B). Somatopause is the term used to describe a decline in pulsatile secretion of growth hormone (GH), resulting in reduced insulinlike growth factor 1 (IGF-1) that occurs with age (Figure 1C). It has been suggested that the altered hormonal profile that is associated with aging plays a critical role in the onset of many metabolic complications that also come with advancing age.
Thus, identifying strategies to mitigate the deleterious effects of andropause, adrenopause, and somatopause remain a high priority as the aging population continues to grow.
A widely held notion is that approaches for combating the decline in endocrine function observed during aging may improve the quality of life of elderly people. Additionally, if strategies that successfully improve endocrine function in the elderly population can improve quality of life, then a substantial burden on the national and global economy should be lessened.
In recent decades, hormone replacement therapy has garnered substantial attention because of promising findings, but apparently, preventing an age-related decline in hormones by exogenous replacement is associated with increased risk for adverse effects in older adults.
The controversies and conflicting results on hormone replacement have more recently discouraged physicians from prescribing hormone therapy in most healthy older people. In contrast, the emerging data from multiple studies show the indisputable beneficial effects of lifestyle changes, especially exercise
in mitigating many age-related physical and cognitive declines.
The current review presents an overview of the major metabolic consequences of normal aging, many of which are associated with the decline or alteration of endocrine function. Specifically, we address the metabolic outcomes of andropause, adrenopause, and somatopause. Further, we discuss the efficacy and complications of hormone replacement therapy and lifestyle changes, especially exercise, as interventions for treating the age-related declines in metabolic function. By summarizing the collective literature regarding the major hormone-associated metabolic complications that occur during aging, we hope to provide the groundwork for physicians and scientists to develop and optimize new endocrine-targeted therapies and lifestyle modifications that can better address metabolic health concerns during aging.
Reduction of Hormone Availability and Action Related to Age
The pulsatile secretion of gonadotropin-releasing hormone from the hypothalamus results in the release of luteinizing hormone and follicle-stimulating hormone from the anterior pituitary gland.
Luteinizing hormone then binds with specific high affinity to luteinizing hormone receptors on the plasma membrane of testicular Leydig cells in men and of theca cells in women, leading to a cascade of signaling events that results in T synthesis.
Because T is a steroid hormone and cannot be stored in the cells where it is produced, it is immediately secreted into the circulation. Once in the circulation, approximately 98% to 99% of T associates with hydrophilic binding partners.
The remaining 1% to 2% of free T is the most biologically active form of T. Sex hormone–binding globulin (SHBG) is the primary binding protein for T and reduces the transport of T into the cell, thus inhibiting its biological action.
After transport through the circulation, T exerts its effect by binding to the intracellular androgen receptor, which subsequently is transported as the androgen receptor–T complex to the nucleus where it induces gene transcription.
The increase in SHBG and SHBG-bound T reduces the mobility and effectiveness of endogenously produced T. Thus, not only is T production reduced during aging, but also a greater proportion of the T that is produced is less effective.
Approximately 75% to 90% of DHEA is produced in the adrenal cortex
Thus, low levels of DHEA or DHEA-S result in an even greater dysregulation of the overall hormonal profile. In fact, around 30% of androgens in men and around 75% of estrogens in premenopausal women are produced from the conversion of DHEA/DHEA-S steroids.
The cause of these sex-related differences is unknown.
Growth Hormone and IGF-1
Also referred to as somatotropin, GH is a peptide hormone that is synthesized and secreted by the anterior pituitary gland, which initiates signaling processes involved in the growth of nearly all tissues in the human body. Growth hormone is released in a pulsatile fashion, with the largest peak in GH observed soon after slow wave sleep and numerous smaller peaks in GH observed shortly after meals.
Metabolic and Physical Performance Decline of Aging Related to Hormone Changes and Lifestyle Changes
The reduction in hormone production that commonly occurs with age can influence a variety of metabolic processes (Table 1). As a consequence, physiologic outcomes that are major risk factors for diabetes and metabolic abnormalities are negatively affected. Moreover, the habitual decline in physical activity that occurs with aging can exacerbate these metabolic abnormalities (Figure 2). In this section, we discuss some of the physiologic outcomes related to the hormonal changes of aging. However, the association between hormonal changes and these physiologic outcomes cannot be fully delineated from the influence that lifestyle changes (ie, physical activity and diet) may also have on these outcomes. Therefore, we also address the influence of positive lifestyle modifications, such as increased physical activity and reduced caloric intake, on important health-related outcomes during aging.
Table 1Potential Age-Related Metabolic Consequences of Reduced Testosterone (Andropause), DHEA (Adrenopause), and Growth Hormone (Somatopause) Based on Both Human Observational Studies and Rodent Studies
Altered body composition, particularly loss of lean tissue (especially muscle mass), and increased obesity (accumulation of body fat) become more evident with age and can have profound effects on metabolism. The decline in hormone production that is associated with age may play a critical role in the increased fat mass and decrease in lean tissue that occur with age. For example, it has been observed in elderly (60- to 80-year-old) men with subnormal T levels that subcutaneous and visceral fat mass are elevated when compared with elderly men with normal T levels.
It is logical to speculate that because DHEA serves as a precursor to multiple androgens, such as T, that the beneficial effects of higher endogenous DHEA may be due, at least in part, to an elevation in T production. Increased adiposity
Taken together, these data highlight the roles of T, DHEA, and GH in substrate metabolism and storage and suggest that dysregulation of these important hormones in aging might result in deleterious effects on body composition, an important indicator of metabolic health.
Caloric restriction has been reported to robustly improve body composition and reduce obesity.
Thus, CR has been touted as an exceptional strategy for improving health and life span. In fact, some researchers have explored the feasibility of performing long-term CR studies in humans to assess its effect on multiple health parameters.
CALERIE Study Group A 2-year randomized controlled trial of human caloric restriction: feasibility and effects on predictors of health span and longevity [published correction appears in J Gerontol A Biol Sci Med Sci. 2016;71(6):839-840].
Caloric restriction can also improve hormonal regulation. In obese males who were calorically restricted for 3 months, total T levels were significantly increased, concomitant with a large decrease in body fat.
These findings suggest that CR is a modifiable lifestyle factor that may improve hormonal regulation and result in improved body composition, a major risk factor for metabolic disease. However, it is unclear if the beneficial effect of CR on body composition requires the improvement in hormonal production. If hormonal improvements are necessary for the CR effect on metabolism, then future therapies and drugs aimed at improving body composition via CR-related mechanisms should also target these important hormones for an optimal improvement in metabolic health.
Reduced insulin sensitivity is an essential precursor in the development of type 2 diabetes. Insulin resistance, type 2 diabetes, and associated clustering of cardiometabolic changes including dyslipidemia, hypertension, and increased thrombogenesis are significant risk factors for cardiovascular disease and all-cause mortality. The rates of type 2 diabetes and insulin resistance are substantially greater in the elderly population compared with young adults,
leading to greater risk for cardiovascular events. It is logical to speculate that the reduction in anabolic hormone production that occurs with age may play a role in the reduction in insulin sensitivity that is also commonly observed with age. In elderly men, lower T levels are associated with reduced insulin sensitivity as indicated by higher glucose levels during an oral glucose tolerance test,
The decline in T production and reduction in GH with age, therefore, may have a significant influence on reducing insulin sensitivity. Low levels of both DHEA and DHEA-S are associated with elevated risk of cardiovascular disease.
reported that in 40- to 70-year-old men in the lowest quartile for plasma DHEA or DHEA-S, there was a significantly greater risk for ischemic heart disease. Reduced endogenous GH secretion during aging gives rise to a number of negative metabolic outcomes that collectively result in elevated risk for cardiometabolic morbidity and mortality, which are deleterious consequences of aging. However, the mechanisms that are responsible for the decline in insulin sensitivity and increased cardiovascular disease risk with age are not entirely clear.
Increasing physical activity level is a simple lifestyle modification that can have a robust impact on health in older populations. Exercise training can significantly improve insulin sensitivity.
Importantly, this study found that there were no age-related differences in insulin sensitivity, suggesting that the commonly observed age-related reduction in insulin sensitivity is likely due to reductions in physical activity rather than aging per se. Furthermore, insulin sensitivity can be improved, irrespective of age, by either AE or resistance exercise (RE).
These data support the provocative idea that simply maintaining activity levels in old age can completely prevent the commonly observed reductions in insulin sensitivity with age. Of course, aging may introduce other symptoms that limit an individual’s ability to remain physically active, indirectly affecting insulin sensitivity. Because it has been well documented that exercise/physical activity can help to maintain normal hormone production with age,
it is possible that the maintenance of insulin sensitivity in older individuals by exercise is mediated by the maintenance of hormonal production.
Another lifestyle change that can help to maintain insulin sensitivity in aging is CR. Reducing caloric intake to approximately 75% to 80% of baseline energy requirements has been found to maintain insulin sensitivity in overweight middle-aged humans.
Washington University School of Medicine CALERIE Group Improvements in glucose tolerance and insulin action induced by increasing energy expenditure or decreasing energy intake: a randomized controlled trial.
Two separate studies have reported that even in the absence of improvements in mitochondrial content and oxidative capacity, CR designed to reduce body weight by 10% within 16 weeks in obese humans can significantly improve insulin sensitivity.
suggesting that weight loss (which can be aggressively achieved by CR) may be crucial for improving insulin sensitivity with age. A number of studies have reported that life span is extended and insulin sensitivity is improved in older rodents that are subjected to approximately 40% CR.
suggesting that hormone production mediates the effect of CR on insulin sensitivity in old age. However, because these studies in rats typically employ approximately 40% CR, which is unfeasible for most humans, it will be critical to determine if the same effects are observed in humans with modest reductions in caloric intake that do not reduce mood and quality of life. It will also be important to determine if CR-induced alterations in hormone production or CR per se are responsible for improvements in human insulin sensitivity.
Age is associated with a decline in aerobic capacity (maximum oxygen consumption ). Maximum oxygen consumption is highly dependent on both the amount of mitochondria and the oxidative capacity of the mitochondria in skeletal muscle.
Together these results support the notion that the maintenance of T levels during aging augments via maintenance of mitochondrial function. Higher levels of DHEA are also associated with increased during aging,
the beneficial effect of DHEA on aerobic capacity during aging may be due to the maintenance of T levels. Interestingly, although IGF-1 levels decline with age, at least one group has reported that is not independently associated with IGF-1 levels during aging.
Short-term administration of supraphysiological recombinant human growth hormone (GH) does not increase maximum endurance exercise capacity in healthy, active young men and women with normal GH-insulin-like growth factor I axes.
However, short-term GH administration in healthy young humans, which increases IGF-1, promotes an increase in mitochondrial oxidative capacity and the abundance of various mitochondrial genes in skeletal muscle.
Therefore, the influence of GH/IGF-1 and aerobic capacity is unclear, since mitochondrial adaptations to GH are present in the absence of any detectable changes in functional aerobic capacity. However, the influences of other anabolic hormones, especially T, clearly have a robust impact on .
Despite the reduction in with age, exercise training can prevent the loss of aerobic capacity in older adults. In a study by Holloszy’s group,
was measured in older adults (~62 years old) who were either sedentary or aerobically trained master athletes before and after an 8-year follow-up. The reduction in in sedentary individuals was approximately 12% per decade, whereas in age-matched aerobically trained master athletes, only a 5.5% reduction in per decade was observed. Because aging is highly associated with reduced mitochondrial function due to decreasing mitochondrial DNA and increased DNA oxidation,
found that the normal age-related decline in mitochondrial oxidative capacity is not present in AE-trained older individuals. In fact, much of the decline in mitochondria, especially mitochondrial content and respiration, can be reversed by 3 months of high-intensity interval training (HIIT).
Thus, there is a possible dissociation between aging-associated declines in and cardiac output/mitochondrial function. It will be important to clearly identify which factors prevent long-term exercise training from completely reversing the decline in . Furthermore, it will also be important to know if the declines in these cardiac functions are irreversible.
The many effects that CR has on metabolism have prompted researchers to study the impact of CR on longevity. Because aerobic capacity is a strong predictor of life span,
reducing mitochondrial damage and extending life span. Lifelong CR in mice can completely prevent the age-related loss of mitochondrial oxidative capacity and efficiency without increasing mitochondrial content,
suggesting that CR preserves mitochondrial function by maintaining its existing components, not by replacing damaged mitochondria with new mitochondria. However, it is important to make the distinction that CR has not been found to improve mitochondrial function, but rather, CR may prevent the age-associated decline in mitochondria. Understanding the mechanisms by which CR maintains mitochondrial integrity during aging will be important for optimizing the therapeutic potential of this robust lifestyle practice.
Muscle Mass and Strength
Both muscle mass and strength decline with age. Postmortem studies performed in relatively healthy people in Sweden originally reported lower muscle cross-sectional area in older people.
In particular, this study reported a significant reduction in the number of muscle fibers expressing the type II myosin heavy chain (known as fast-twitch muscle fibers) in older compared with young individuals. Cross-sectional data in 60- to 90-year-old men and women revealed a significant age-related decline in muscle mass and strength, which corresponds to a reduction in T.
Orchiectomized rats, which have drastically reduced T, display muscle atrophy and reduced muscle ribosome content, but treating orchiectomized rats with T recovers muscle ribosome content to normal values.
Therefore, at least in rodents, T plays an important role in maintaining muscle mass during aging through regulating ribosomal content, which is critical for protein synthesis. However, the effects of low T in elderly human populations on ribosomal biogenesis, capacity, and content have yet to be evaluated. It also remains to be determined whether maintaining T levels during aging is critical for the conservation of muscle mass and strength via ribosomal biogenesis. Reductions in GH secretion also result in a loss of lean body mass
although HIIT and AE can also modestly increase muscle mass. In fact, RE training (RET) can increase muscle mass and strength in older individuals who were previously sedentary, but not to the same extent as younger people.
Factors that restrict the capacity of older adults to partake in RET such as increased soreness, risk for injury, and joint pain may be critical barriers that limit the benefits of RET. Although reduced muscle mass and strength may be partially due to reduced activity in aging, inactivity does not completely explain muscle loss with age.
After reaching peak BMD by the third decade of life, a consistent decline in bone mass and BMD occurs in both men and women with advancing age, with a steeper decline in women, especially after menopause.
The correlation between bone loss and declining hormone production with age has sparked investigations into the influence of hormones such as T, DHEA, and GH on the maintenance of bone health with age. Although estrogen deficiency in postmenopausal women is clearly linked to increased osteoporosis with age,
have reported that both T and DHEA are negatively associated with BMD in older men. These confounding results leave uncertainty in the relationship between T levels in aging and bone health. However, at least in hypogonadal men, T is clearly significantly correlated with BMD.
Therefore, since hormone deficiency is increasingly prevalent in older adults and bone loss occurs more rapidly with T or GH deficiency, positive lifestyle strategies for combating declines in hormonal secretion should be considered for the maintenance of bone health.
Consistent lifelong exercise has been known to build and maintain bone health. In childhood, the loading impact of physical exercise has been reported to have a significant impact on the increase in BMD.
Although the mechanisms responsible for this decline are not completely understood, mounting evidence continues to point toward metabolic derangements in the brain as the culprit for cognitive declines associated with age. Brain glucose metabolism significantly declines in old age
These and other age-related effects in the brain are likely due to altered fuel metabolism. When brain glucose metabolism is disturbed in mice using an insulin receptor antagonist, brain mitochondrial structure and function are dramatically impaired.
It is likely that maintenance of metabolism, specifically mitochondrial metabolism, in the brain can combat the age-related decline in cognitive function. As with other deleterious aging-associated outcomes, positive lifestyle modifications have been found to prevent or reduce the cognitive decline with age.
Exercise is convincingly beneficial for cognitive health with age. For example, in a 4-year prospective longitudinal study, Rogers et al
found that older adults approaching retirement (~65 years of age) who either continued working or retired and began a regular physical activity routine had significantly better cognitive test scores than those who retired and did not remain physically active. Older adults who underwent AET for 3 months increased functional capacity of key attentional aspects of the brain, but the sedentary control group did not.
potentially leading to improved cognition. Perhaps multiple mechanisms are responsible for the cognitive improvements following AET. It is also important to note that RET has also been found to improve cognitive functioning in older adults,
but the mechanisms of its effect are even less clear than those for AET. Aerobic excerise and RE can independently improve cognition, but the brain signaling processes that occur after each type of exercise are distinct,
suggesting that AET and RET have different mechanisms of action. Understanding how both RET and AET can improve/maintain brain function with aging will be a critical step for prescribing therapies and creating drugs that mitigate the effects of aging on the brain.
Caloric restriction is another lifestyle modification that can improve cognitive function in older adults. Witte et al
reported that in healthy older people (mean age, 60.5 years), 3 months of 30% CR significantly improved verbal memory scores. Age-dependent cognitive deficits that are observed in ad libitum-fed mice are absent in mice that are 30% calorically restricted.
suggesting that the process of removing damaged and dysfunctional proteins is crucial for maintaining cognitive function during aging. It is reasonable to speculate that these processes of improved protein turnover in the brain can enhance brain mitochondrial structure and function. Supporting this idea, Sanz et al
reported that 40% CR in older rats results in reduced brain mitochondrial H2O2 production and lower oxidative damage to nuclear DNA. Thus, the metabolic processes that occur in the brain in response to CR can have a substantial beneficial effect during aging and therefore may reduce cognitive decline.
Impact of Hormone Replacement in Aging
Testosterone replacement therapy has been introduced as a mode for treating many of the metabolic deficiencies that come with age. Various methods of T replacement such as oral tablets, mucoadhesives, injections, transdermal patches or cream, and subdermal implants have been used and are reported to provide multiple health benefits to hypogonadal men.
Of course, the various forms of T replacement have distinct advantages and disadvantages. For example, injectable T is relatively inexpensive, but the prescribed weekly injections result in peaks in T soon after the injections that are supraphysiologic and dips in T by the end of the week. Transdermal patches or cream provide a steady and consistent lower dose of T but may result in skin irritation or inadequate absorption. Regardless of the administration method, T replacement has been found to provide a variety of health benefits. The Testosterone Trials, a multicenter set of randomized trials across 12 clinical sites, tested the effect of T administration in 790 elderly men on 7 different primary outcomes (sexual function, physical function, vitality, cardiovascular health, bone health, cognitive function, and anemia).
Effect of testosterone treatment on volumetric bone density and strength in older men with low testosterone: a controlled clinical trial [published corrections appear in JAMA Intern Med. 2017;177(4):600 and JAMA Intern Med. 2019;179(3):457].
Potentially explaining some of the positive effects of T on human health, studies using cell culture and rodent models reveal that T administration increases the activity of glycolytic enzymes (hexokinase, phosphofructokinase, and glycogen synthase) and up-regulates the expression of genes and proteins involved in glucose metabolism (IRS1, IRS2, SLC2A4 [previously GLUT4], PPARG [for expansion of gene symbols, see www.genenames.org]).
The disparate findings regarding efficacy of T replacement and its effect on metabolic health have created some controversy, especially considering the potential risks associated with T replacement treatment. Some of the risks associated with T therapy include exacerbation of prostate cancer, cardiovascular-related events, hepatotoxicity, erythrocytosis, sleep apnea, and dermatological issues.
A meta-analysis analyzing adverse events of T therapy reported that in those who received T replacement therapy compared with placebo, the odds of development of a prostate event or having a hematocrit level greater than 50% were 1.78 and 3.69 times greater, respectively.
The duration of T replacement in most previous studies ranged from approximately 1 to 36 months, but the adverse effects of longer-duration T replacement therapy have yet to be assessed. Moreover, most studies evaluating the effect of T replacement are performed in relatively healthy elderly men. However, those who likely stand to benefit the most from T replacement therapy are the frail elderly, yet the beneficial and adverse effects of T replacement in this population are largely unknown.
Although the efficacy of T replacement therapy remains under question, some have postulated that treatment with the T precursor DHEA may provide improvements in health without negative effects. Studies in cultured skeletal muscle cells and rodents have suggested that DHEA administration can increase the expression of the glucose transporter GLUT4 and key glycolytic enzymes phosphofructokinase and hexokinase.
However, findings from studies examining the influence of DHEA administration in humans are less promising. Dehydroepiandrosterone has been introduced as an “antiaging” therapy via ingestible tablets or transdermal patches. Although both of these modes of administration of DHEA clearly elevate plasma DHEA and DHEA-S levels,
the beneficial effect on metabolism in the elderly population is underwhelming. In older men and postmenopausal women, although DHEA administration has been reported to produce very minor elevations in BMD,
Two years of treatment with dehydroepiandrosterone does not improve insulin secretion, insulin action, or postprandial glucose turnover in elderly men or women [published correction appears in Diabetes. 2007;56(5):1486].
Conflicting findings regarding DHEA administration and cholesterol have been reported. One group found that DHEA administration seems to lower high-density lipoprotein cholesterol in postmenopausal women,
It has been suggested that DHEA supplementation may improve vascular endothelial function and cardiovascular disease, but no long-term (multiple year) studies have evaluated the impact of DHEA therapy on cardiovascular health.
The current literature suggests that DHEA may have minor metabolic health benefits, but long-term adverse effects are not completely known. Thus, DHEA supplementation should be prescribed with caution and should be terminated immediately at the onset of any adverse effects.
30 years ago in the New England Journal of Medicine reporting that GH replacement in elderly men resulted in increased lean body mass and decreased fat mass, multiple groups have evaluated the efficacy of GH replacement in older men and women. Subsequently, other groups have also found that GH therapy can improve body composition
in GH-deficient older adults. These initial promising findings in GH-deficient adults prompted the promotion of GH replacement by the medical industry in older adults (without clinical GH deficiency) with little regard for the potential negative effects. Growth hormone replacement has been associated with increased risk for adverse events such as soft tissue edema, carpal tunnel syndrome, glucose intolerance, type 2 diabetes, joint pain, and gynecomastia in healthy older adults.
GH administration changes myosin heavy chain isoforms in skeletal muscle but does not augment muscle strength or hypertrophy, either alone or combined with resistance exercise training in healthy elderly men.
It has also been suggested that the improvements in lean body mass following GH administration may be due to elevated water retention, which artificially increases values for lean body mass using certain methods for computing lean body mass. This issue is corroborated by the fact that although increases in lean body mass are observed after GH treatment, often no effect of muscular strength is observed in healthy older individuals.
GH administration changes myosin heavy chain isoforms in skeletal muscle but does not augment muscle strength or hypertrophy, either alone or combined with resistance exercise training in healthy elderly men.
Thus, the efficacy and safety of GH replacement in the healthy aging population remains controversial. Based on the collective literature, the use of GH replacement for nonmedical conditions such as aging is now strongly discouraged by the American Association of Clinical Endocrinologists.
In general, this change in physical activity with age appears to be at least partially due to declines in occupational activity that are not offset by increases in leisure activity, especially on retirement.
Unlike hormone replacement therapies, increased physical activity levels and calorically restricted diets in older adults rarely result in negative effects. Although fear of injury is a commonly reported barrier to exercise in the older population, multiple studies have reported that older adults are not at an increased risk for exercise-related injuries.
The minimal risks that are posed by exercise or CR in the aging population are greatly outweighed by the positive impact that these lifestyle modifications can have on overall health. In particular, the following section describes the influence that regular physical exercise can have on hormone production in the aging population.
A single bout of RE has been reported to increase endogenous T production in older men,
Not surprisingly, the beneficial effects of RE (improved muscle mass and strength, elevated muscle protein synthesis, and increased BMD) are similar to the primary reported functions of T on metabolism. Compared with older men, young men have a greater increase in total and free T in response to a short bout of RE,
Thus, the repeated effect of multiple short bouts of RE on T level, rather than RET per se, may underlie the beneficial effect of RE on metabolic health in older men. Table 2 summarizes the notable literature that assesses the effects of short-term or long-term RE on endogenous T production in older men and women.
Table 2Summary of Notable Studies That Examined the Single-bout and Training Effect of Resistance Exercise on Endogenous Testosterone Levels in Elderly Men and Women