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Hormonal and Metabolic Changes of Aging and the Influence of Lifestyle Modifications

      Abstract

      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.

      Abbreviations and Acronyms:

      AE (aerobic exercise), AET (AE training), BMD (bone mineral density), CR (caloric restriction), DHEA (dehydroepiandrosterone), DHEA-S (DHEA sulfate), GH (growth hormone), HIIT (high-intensity interval training), IGF-1 (insulinlike growth factor 1), RE (resistance exercise), RET (RE training), SHBG (sex hormone–binding globulin), T (testosterone), VO2max (maximum oxygen consumption)
      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.
      • Ortman J.M.
      • Velkoff V.A.
      • Hogan H.
      An Aging Nation: The Older Population in the United States.
      Worldwide, the number of people aged 65 and older is projected to be 1.6 billion by 2050.
      • Roberts A.W.
      • Ogunwole S.U.
      • Blakeslee L.
      • Rabe M.A.
      The Population 65 Years and Older in the United States: 2016.
      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.
      • Olshansky S.J.
      From lifespan to healthspan.
      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.
      • Lamberts S.W.
      • van den Beld A.W.
      Van Der Lely A-J. The endocrinology of aging.
      Menopause is associated with an abrupt loss of estrogen and progesterone production in women at middle age following the cessation of ovarian function.
      • Greendale G.A.
      • Lee N.P.
      • Arriola E.R.
      The menopause.
      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.
      • Stachowiak G.
      • Pertyński T.
      • Pertyńska-Marczewska M.
      Metabolic disorders in menopause.
      ,
      • Polotsky H.N.
      • Polotsky A.J.
      Metabolic implications of menopause.
      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,
      • Weiss L.W.
      • Cureton K.J.
      • Thompson F.N.
      Comparison of serum testosterone and androstenedione responses to weight lifting in men and women.
      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.
      • Guarner-Lans V.
      • Rubio-Ruiz M.E.
      • Pérez-Torres I.
      • Baños de MacCarthy G.
      Relation of aging and sex hormones to metabolic syndrome and cardiovascular disease.
      Thus, identifying strategies to mitigate the deleterious effects of andropause, adrenopause, and somatopause remain a high priority as the aging population continues to grow.
      Figure thumbnail gr1
      Figure 1Decline in hormone production with age. A, There is a gradual and consistent decline in testosterone (T) production with each year of age in men beginning around the third decade of life. Free T, the most biologically active form of T, declines at nearly twice the rate of total T. B, Plasma levels of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) sharply decline at birth until the age of approximately 6 to 7 years. A sharp increase in the levels of DHEA and DHEA-S occurs until approximately the third decade of life. Dehydroepiandrosterone and DHEA-S then gradually decline until death in men and women, with a slightly steeper decline in DHEA-S compared with DHEA. C, Insulinlike growth factor 1 (IGF-1) consistently decreases with age beginning around the third decade of life in men and women. Pulsatile release of growth hormone throughout the day maintains plasma IGF-1 levels through production in and secretion from the liver.
      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.
      • Goldman D.P.
      • Cutler D.
      • Rowe J.W.
      • et al.
      Substantial health and economic returns from delayed aging may warrant a new focus for medical research.
      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.
      • Holmes S.J.
      • Shalet S.M.
      Which adults develop side-effects of growth hormone replacement?.
      • Rhoden E.L.
      • Morgentaler A.
      Risks of testosterone-replacement therapy and recommendations for monitoring.
      • Basaria S.
      • Coviello A.D.
      • Travison T.G.
      • et al.
      Adverse events associated with testosterone administration.
      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
      • Janssen J.A.M.J.L.
      Impact of physical exercise on endocrine aging.
      ,
      • Giannoulis M.G.
      • Martin F.C.
      • Nair K.S.
      • Umpleby A.M.
      • Sonksen P.
      Hormone replacement therapy and physical function in healthy older men: time to talk hormones?.
      and caloric restriction (CR),
      • Witte A.V.
      • Fobker M.
      • Gellner R.
      • Knecht S.
      • Flöel A.
      Caloric restriction improves memory in elderly humans.
      • Ingram D.K.
      • Weindruch R.
      • Spangler E.L.
      • Freeman J.R.
      • Walford R.L.
      Dietary restriction benefits learning and motor performance of aged mice.
      • Fontán-Lozano Á.
      • Sáez-Cassanelli J.L.
      • Inda M.C.
      • et al.
      Caloric restriction increases learning consolidation and facilitates synaptic plasticity through mechanisms dependent on NR2B subunits of the NMDA receptor.
      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

      Testosterone

      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.
      • Kim H.H.
      Regulation of gonadotropin-releasing hormone gene expression.
      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.
      • Midzak A.S.
      • Chen H.
      • Papadopoulos V.
      • Zirkin B.R.
      Leydig cell aging and the mechanisms of reduced testosterone 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.
      • Vingren J.L.
      • Kraemer W.J.
      • Ratamess N.A.
      • Anderson J.M.
      • Volek J.S.
      • Maresh C.M.
      Testosterone physiology in resistance exercise and training: the up-stream regulatory elements.
      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.
      • Hobbs C.J.
      • Jones R.E.
      • Plymate S.R.
      The effects of sex hormone binding globulin (SHBG) on testosterone transport into the cerebrospinal fluid.
      Testosterone also binds to albumin in the blood, but the movement of T is less restricted by albumin and reaches the intracellular compartment.
      • Pardridge W.M.
      • Mietus L.J.
      Transport of steroid hormones through the rat blood-brain barrier: primary role of albumin-bound hormone.
      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.
      • Gobinet J.
      • Poujol N.
      • Sultan C.
      Molecular action of androgens.
      Activation of this hypothalamic-pituitary-gonadal axis has a robust anabolic effect, increasing muscle mass and strength, promoting muscle protein synthesis, and increasing bone mineral density (BMD).
      • Urban R.J.
      • Bodenburg Y.H.
      • Gilkison C.
      • et al.
      Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis.
      • Bhasin S.
      • Storer T.W.
      • Berman N.
      • et al.
      The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men.
      • Snyder P.J.
      • Peachey H.
      • Hannoush P.
      • et al.
      Effect of testosterone treatment on bone mineral density in men over 65 years of age.
      The term hypogonadism is used to describe the clinical condition of low levels of serum T and its associated symptoms of decreased libido, loss of muscle and bone mass, depression, and anemia.
      • Rhoden E.L.
      • Morgentaler A.
      Risks of testosterone-replacement therapy and recommendations for monitoring.
      Some or all of these features of hypogonadism are present in a milder but variable extent in older men.
      The anabolic effect of T is reduced during aging because of a gradual and consistent decline in circulating T that begins around the third to fourth decade of life in men,
      • Harman S.M.
      • Metter E.J.
      • Tobin J.D.
      • Pearson J.
      • Blackman M.R.
      Longitudinal effects of aging on serum total and free testosterone levels in healthy men.
      ,
      • Matsumoto A.M.
      Andropause: clinical implications of the decline in serum testosterone levels with aging in men.
      also known as andropause. Approximately 40% to 50% of men over the age of 80 have T levels below that of normal healthy young individuals.
      • Harman S.M.
      • Metter E.J.
      • Tobin J.D.
      • Pearson J.
      • Blackman M.R.
      Longitudinal effects of aging on serum total and free testosterone levels in healthy men.
      ,
      • Kaufman J.M.
      • Vermeulen A.
      Declining gonadal function in elderly men.
      By the third decade, both men and premenopausal women experience a decline in DHEA and DHEA-S,
      • Zumoff B.
      • Strain G.W.
      • Miller L.K.
      • Rosner W.
      Twenty-four-hour mean plasma testosterone concentration declines with age in normal premenopausal women.
      which can serve as precursors for the production of androgenic hormones such as T.
      • Labrie F.
      • Bélanger A.
      • Cusan L.
      • Candas B.
      Physiological changes in dehydroepiandrosterone are not reflected by serum levels of active androgens and estrogens but of their metabolites: intracrinology.
      The decline in total and free T levels in men occurs at a rate of approximately 1% and 2% per year, respectively (Figure 1A).
      • Feldman H.A.
      • Longcope C.
      • Derby C.A.
      • et al.
      Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts Male Aging Study.
      ,
      • Travison T.G.
      • Araujo A.B.
      • Kupelian V.
      • O’Donnell A.B.
      • McKinlay J.B.
      The relative contributions of aging, health, and lifestyle factors to serum testosterone decline in men.
      Even though women have a considerably lower level of T, they too experience reductions in bioavailable T with age.
      • Fabbri E.
      • An Y.
      • Gonzalez-Freire M.
      • et al.
      Bioavailable testosterone linearly declines over a wide age spectrum in men and women from the Baltimore Longitudinal Study of Aging.
      In men, this decline in T has been suggested to be due to a combination of both defective gonadotropin-releasing hormone secretion and Leydig cell responsiveness.
      • Mulligan T.
      • Iranmanesh A.
      • Kerzner R.
      • Demers L.W.
      • Veldhuis J.D.
      Two-week pulsatile gonadotropin releasing hormone infusion unmasks dual (hypothalamic and Leydig cell) defects in the healthy aging male gonadotropic axis.
      The biologically active forms of T (free T and albumin-bound T) decrease at a greater rate than SHBG-bound or total T during aging,
      • Orwoll E.
      • Lambert L.C.
      • Marshall L.M.
      • et al.
      Testosterone and estradiol among older men.
      likely because of the age-associated increase in SHBG.
      • Harman S.M.
      • Metter E.J.
      • Tobin J.D.
      • Pearson J.
      • Blackman M.R.
      Longitudinal effects of aging on serum total and free testosterone levels in healthy men.
      ,
      • Gray A.
      • Feldman H.A.
      • McKinlay J.B.
      • Longcope C.
      Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Aging Study.
      ,
      • Leifke E.
      • Gorenoi V.
      • Wichers C.
      • Von Zur Mühlen A.
      • Von Büren E.
      • Brabant G.
      Age-related changes of serum sex hormones, insulin-like growth factor-1 and sex-hormone binding globulin levels in men: cross-sectional data from a healthy male cohort.
      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.

      Dehydroepiandrosterone

      Approximately 75% to 90% of DHEA is produced in the adrenal cortex
      • Davis S.R.
      • Panjari M.
      • Stanczyk F.Z.
      Clinical review: DHEA replacement for postmenopausal women.
      and converted to DHEA-S, its sulfated form, by hydrosteroid sulfatases.
      • Kroboth P.D.
      • Salek F.S.
      • Pittenger A.L.
      • Fabian T.J.
      • Frye R.F.
      DHEA and DHEA-S: a review.
      The remaining approximately 10% to 25% of DHEA production occurs in the testes, ovaries, and brain.
      • Mannella P.
      • Simoncini T.
      • Caretto M.
      • Genazzani A.R.
      Dehydroepiandrosterone and cardiovascular disease.
      The secretion of DHEA-S, the most abundant circulating steroid hormone,
      • Montanini V.
      • Simoni M.
      • Chiossi G.
      • et al.
      Age-related changes in plasma dehydroepiandrosterone sulphate, cortisol, testosterone and free testosterone circadian rhythms in adult men.
      is synchronized with the secretion of cortisol in response to corticotropin-releasing hormone and adrenocorticotropic hormone.
      • Pavlov E.P.
      • Harman S.M.
      • Chrousos G.P.
      • Loriaux D.L.
      • Blackman M.R.
      Responses of plasma adrenocorticotropin, cortisol, and dehydroepiandrosterone to ovine corticotropin-releasing hormone in healthy aging men.
      ,
      • Parker Jr., C.R.
      • Azziz R.
      • Potter H.D.
      • Boots L.R.
      Adrenal androgen production in response to adrenocorticotropin infusions in men.
      After traveling through the circulation and arriving at peripheral tissues, DHEA-S can be metabolized back to DHEA by sulfohydrolase.
      • Kishimoto Y.
      • Hoshi M.
      Dehydroepiandrosterone sulphate in rat brain: incorporation from blood and metabolism in vivo.
      Dehydroepiandrosterone sulfate essentially serves as a large and stable plasma reservoir for later conversion to DHEA.
      • Mannella P.
      • Simoncini T.
      • Caretto M.
      • Genazzani A.R.
      Dehydroepiandrosterone and cardiovascular disease.
      Dehydroepiandrosterone serves as a precursor to many androgenic and estrogenic hormones.
      • Labrie F.
      • Bélanger A.
      • Cusan L.
      • Candas B.
      Physiological changes in dehydroepiandrosterone are not reflected by serum levels of active androgens and estrogens but of their metabolites: intracrinology.
      ,
      • Young J.
      • Couzinet B.
      • Nahoul K.
      • et al.
      Panhypopituitarism as a model to study the metabolism of dehydroepiandrosterone (DHEA) in humans.
      ,
      • Mortola J.F.
      • Yen S.S.
      The effects of oral dehydroepiandrosterone on endocrine-metabolic parameters in postmenopausal women.
      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.
      • Mannella P.
      • Simoncini T.
      • Caretto M.
      • Genazzani A.R.
      Dehydroepiandrosterone and cardiovascular disease.
      After birth, DHEA and DHEA-S levels sharply decline and do not begin to increase until around 7 to 9 years of age.
      • Mannella P.
      • Simoncini T.
      • Caretto M.
      • Genazzani A.R.
      Dehydroepiandrosterone and cardiovascular disease.
      ,
      • Šulcová J.
      • Hill M.
      • Hampl R.
      • Stárka L.
      Age and sex related differences in serum levels of unconjugated dehydroepiandrosterone and its sulphate in normal subjects.
      By age 20 to 30 years, DHEA and DHEA-S levels reach their peak and steadily decline at a rate of approximately 2% to 3% per year in both men and women (Figure 1B).
      • Feldman H.A.
      • Longcope C.
      • Derby C.A.
      • et al.
      Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts Male Aging Study.
      ,
      • Rainey W.E.
      • Carr B.R.
      • Sasano H.
      • Suzuki T.
      • Mason J.I.
      Dissecting human adrenal androgen production.
      ,
      • Orentreich N.
      • Brind J.L.
      • Rizer R.L.
      • Vogelman J.H.
      Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood.
      The age-related trend in DHEA is unique from any other steroid hormone and suggests that the signals to produce DHEA are distinct from signals for the production of other hormones.
      • Rainey W.E.
      • Carr B.R.
      • Sasano H.
      • Suzuki T.
      • Mason J.I.
      Dissecting human adrenal androgen production.
      Men have around 2 times greater DHEA-S than women,
      • Labrie F.
      • Bélanger A.
      • Cusan L.
      • Candas B.
      Physiological changes in dehydroepiandrosterone are not reflected by serum levels of active androgens and estrogens but of their metabolites: intracrinology.
      but women have been reported to have greater levels of DHEA.
      • Mannella P.
      • Simoncini T.
      • Caretto M.
      • Genazzani A.R.
      Dehydroepiandrosterone and cardiovascular disease.
      ,
      • Šulcová J.
      • Hill M.
      • Hampl R.
      • Stárka L.
      Age and sex related differences in serum levels of unconjugated dehydroepiandrosterone and its sulphate in normal subjects.
      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.
      • Hartman M.L.
      • Faria A.C.
      • Vance M.L.
      • Johnson M.L.
      • Thorner M.O.
      • Veldhuis J.D.
      Temporal structure of in vivo growth hormone secretory events in humans.
      • Takahashi Y.
      • Kipnis D.M.
      • Daughaday W.H.
      Growth hormone secretion during sleep.
      • Ho K.Y.
      • Veldhuis J.D.
      • Johnson M.L.
      • et al.
      Fasting enhances growth hormone secretion and amplifies the complex rhythms of growth hormone secretion in man.
      Negligible amounts of GH are produced in between the 10 to 15 secretory bursts that can occur during a 24-hour period.
      • Hartman M.L.
      • Faria A.C.
      • Vance M.L.
      • Johnson M.L.
      • Thorner M.O.
      • Veldhuis J.D.
      Temporal structure of in vivo growth hormone secretory events in humans.
      The primary positive and negative regulators of the pulsatile secretion of GH are GH-releasing hormone and somatostatin, respectively.
      • Tannenbaum G.S.
      • Ling N.
      The interrelationship of growth hormone (GH)-releasing factor and somatostatin in generation of the ultradian rhythm of GH secretion.
      Ghrelin, an endogenous ligand of the GH secretagogue receptor, is also a potent stimulant of GH secretion.
      • Khatib N.
      • Gaidhane S.
      • Gaidhane A.M.
      • et al.
      Ghrelin: ghrelin as a regulatory Peptide in growth hormone secretion.
      Growth hormone–releasing hormone is secreted by the hypothalamus in response to low levels of GH and IGF-1, and the response to GH-releasing hormone is inhibited by IGF-1,
      • Hartman M.L.
      • Clayton P.E.
      • Johnson M.L.
      • et al.
      A low dose euglycemic infusion of recombinant human insulin-like growth factor I rapidly suppresses fasting-enhanced pulsatile growth hormone secretion in humans.
      providing a negative feedback loop for GH secretion.
      • Roelfsema V.
      • Clark R.G.
      The growth hormone and insulin-like growth factor axis: its manipulation for the benefit of growth disorders in renal failure.
      The magnitude of GH pulses peaks during puberty and subsequently declines at a gradual rate of approximately 1% to 2% per year until death in men and women.
      • Finkelstein J.W.
      • Roffwarg H.P.
      • Boyar R.M.
      • Kream J.
      • Hellman L.
      Age-related change in the twenty-four-hour spontaneous secretion of growth hormone.
      • Iranmanesh A.
      • Lizarralde G.
      • Veldhuis J.D.
      Age and relative adiposity are specific negative determinants of the frequency and amplitude of growth hormone (GH) secretory bursts and the half-life of endogenous GH in healthy men.
      • Corpas E.
      • Harman S.M.
      • Blackman M.R.
      Human growth hormone and human aging.
      Once released into the blood, GH signals the production and release of IGF-1 by binding to the GH receptor on the plasma membrane of the liver and other peripheral tissues.
      • Le Roith D.
      • Bondy C.
      • Yakar S.
      • Liu J.-L.
      • Butler A.
      The somatomedin hypothesis: 2001.
      ,
      • Ohlsson C.
      • Mohan S.
      • Sjögren K.
      • et al.
      The role of liver-derived insulin-like growth factor-I.
      Insulinlike growth factor 1 is a primary mediator of cellular growth
      • Adams G.R.
      Invited Review: Autocrine/paracrine IGF-I and skeletal muscle adaptation.
      and a critical component of human postnatal development. Like GH, serum IGF-1 increases with age until puberty and then gradually declines into old age (Figure 1C).
      • Corpas E.
      • Harman S.M.
      • Blackman M.R.
      Human growth hormone and human aging.
      ,
      • Laron Z.
      The GH-IGF1 axis and longevity: the paradigm of IGF1 deficiency.
      The reduction in GH and IGF-1 in healthy aging adults is primarily due to a reduction in the amplitude of the GH secretion, not a reduction in the frequency of secretory bursts or the half-life of GH.
      • Veldhuis J.D.
      • Erickson D.
      • Iranmanesh A.
      • Miles J.M.
      • Bowers C.Y.
      Sex-steroid control of the aging somatotropic axis.
      The decrease in GH and IGF-1 with age has been termed somatopause and appears to have a robust impact on metabolic health.
      • Lombardi G.
      • Tauchmanova L.
      • Di Somma C.
      • et al.
      Somatopause: dismetabolic and bone effects.
      ,
      • Anawalt B.D.
      • Merriam G.R.
      Neuroendocrine aging in men: andropause and somatopause.

      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
      Potential age-related metabolic consequences of:
      Reduced testosteroneReduced DHEAReduced growth hormone
      • ↑ Subcutaneous and visceral fat
      • ↑ Risk for obesity
      • ↓ Insulin sensitivity
      • ↑ Risk for type 2 diabetes
      • ↑ High blood pressure
      • ↑ Triglycerides
      • ↑ Risk of metabolic syndrome
      • ↓ Muscle mass
      • ↓ Strength
      • ↓ Bone density
      • ↑ Body fat mass
      • ↑ Waist-to-hip ratio
      • ↓ Lean body mass
      • V˙O2max
      • ↑ Risk of cardiovascular disease
      • ↑ Risk of ischemic heart disease
      • ↓ Bone density
      • ↑ Risk for obesity
      • ↑ Visceral adipose tissue
      • ↓ Lean body mass
      • ↓ Strength
      • ↑ Risk of metabolic syndrome
      • ↑ Risk of cardiovascular disease
      • ↓ Bone density
      DHEA = dehydroepiandrosterone; V˙O2max = maximum oxygen consumption; ↑ = increased; ↓ = decreased.
      Figure thumbnail gr2
      Figure 2Schematic diagram of the influence of aging on metabolism. Aging results in a decline in anabolic hormone production and, as is true for much of the older population, a habitual decline in physical activity. This decrease in physical activity results in lower daily energy expenditure, leading to increased rates of obesity in the older population. Moreover, both hormonal dysregulation and reduced physical activity influence the reduction in muscle mass that occurs with age, also known as sarcopenia. The increased rates of obesity in aging combined with the development of sarcopenia can have devastating consequences on metabolism. After the development of insulin resistance, obesity and sarcopenia can result in an increased risk for type 2 diabetes, hypertension, and hyperlipidemia. These metabolic disturbances are known to lead to the development of cardiovascular disease and dementia. Importantly, positive lifestyle modifications such as regular exercise and healthy diet can combat multiple nodes in this process and are critical for healthy aging and the prevention of metabolic disease.

      Body Composition/Obesity

      Percent fat mass is an important predictor of metabolic disease.
      • Zeng Q.
      • Dong S.-Y.
      • Sun X.-N.
      • Xie J.
      • Cui Y.
      Percent body fat is a better predictor of cardiovascular risk factors than body mass index.
      ,
      • Bosy-Westphal A.
      • Geisler C.
      • Onur S.
      • et al.
      Value of body fat mass vs anthropometric obesity indices in the assessment of metabolic risk factors.
      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.
      • Svartberg J.
      • Agledahl I.
      • Figenschau Y.
      • Sildnes T.
      • Waterloo K.
      • Jorde R.
      Testosterone treatment in elderly men with subnormal testosterone levels improves body composition and BMD in the hip.
      A significant negative association has also been observed between obesity and T levels by multiple groups,
      • Kelly D.M.
      • Jones T.H.
      Testosterone and obesity.
      • Glass A.R.
      • Swerdloff R.S.
      • Bray G.A.
      • Dahms W.T.
      • Atkinson R.L.
      Low serum testosterone and sex-hormone-binding-globulin in massively obese men.
      • Allan C.A.
      • McLachlan R.I.
      Androgens and obesity.
      emphasizing the metabolic importance of maintaining T production with age. Lower DHEA-S levels have been associated with greater body fat,
      • Hernández-Morante J.J.
      • Pérez-de-Heredia F.
      • Luján J.A.
      • Zamora S.
      • Garaulet M.
      Role of DHEA-S on body fat distribution: gender- and depot-specific stimulation of adipose tissue lipolysis.
      increased waist-to-hip ratio,
      • Haffner S.M.
      • Valdez R.A.
      • Stern M.P.
      • Katz M.S.
      Obesity, body fat distribution and sex hormones in men.
      and decreased percent lean body mass
      • Abbasi A.
      • Duthie Jr., E.H.
      • Sheldahl L.
      • et al.
      Association of dehydroepiandrosterone sulfate, body composition, and physical fitness in independent community-dwelling older men and women.
      in men over the age of 60. An inverse correlation between DHEA and body mass index has also been found, suggesting that DHEA may increase lipolytic capacity and decrease body fat.
      • De Pergola G.
      • Giagulli V.A.
      • Garruti G.
      • et al.
      Low dehydroepiandrosterone circulating levels in premenopausal obese women with very high body mass index.
      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
      • Salomon F.
      • Cuneo R.C.
      • Hesp R.
      • Sönksen P.H.
      The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency.
      ,
      • Binnerts A.
      • Swart G.R.
      • Wilson J.P.
      • et al.
      The effect of growth hormone administration in growth hormone deficient adults on bone, protein, carbohydrate and lipid homeostasis, as well as on body composition.
      is also associated with reduced GH secretion during aging. In fact, 40 weeks of GH administration decreases visceral adipose volume in obese individuals.
      • Attallah H.
      • Friedlander A.L.
      • Nino-Murcia M.
      • Hoffman A.R.
      Effects of growth hormone and pioglitazone in viscerally obese adults with impaired glucose tolerance: a factorial clinical trial.
      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.
      • Redman L.M.
      • Heilbronn L.K.
      • Martin C.K.
      • et al.
      Effect of calorie restriction with or without exercise on body composition and fat distribution.
      • Racette S.B.
      • Weiss E.P.
      • Villareal D.T.
      • et al.
      Washington University School of Medicine CALERIE Group
      One year of caloric restriction in humans: feasibility and effects on body composition and abdominal adipose tissue.
      • Fontana L.
      • Meyer T.E.
      • Klein S.
      • Holloszy J.O.
      Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans.
      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.
      • Rochon J.
      • Bales C.W.
      • Ravussin E.
      • et al.
      CALERIE Study Group
      Design and conduct of the CALERIE study: comprehensive assessment of the long-term effects of reducing intake of energy.
      ,
      • Ravussin E.
      • Redman L.M.
      • Rochon J.
      • et al.
      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].
      In rodents, it has been well established that CR can improve metabolic health and significantly extend life span.
      • Weindruch R.
      • Walford R.L.
      Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence.
      ,
      • Weindruch R.
      • Walford R.L.
      • Fligiel S.
      • Guthrie D.
      The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake.
      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.
      • Schulte D.M.
      • Hahn M.
      • Oberhäuser F.
      • et al.
      Caloric restriction increases serum testosterone concentrations in obese male subjects by two distinct mechanisms.
      In obese adults who lost approximately 30 kg of body mass, GH secretion was more than 2-fold greater than that in obese individuals who did not lose weight.
      • Rasmussen M.H.
      • Hvidberg A.
      • Juul A.
      • et al.
      Massive weight loss restores 24-hour growth hormone release profiles and serum insulin-like growth factor-I levels in obese subjects [published correction appears in J Clin Endocrinol Metab. 1995;80(8):2446].
      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.

      Insulin Sensitivity

      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,
      • Wild S.
      • Roglic G.
      • Green A.
      • Sicree R.
      • King H.
      Global prevalence of diabetes: estimates for the year 2000 and projections for 2030.
      ,
      • Boyle J.P.
      • Honeycutt A.A.
      • Narayan K.M.
      • et al.
      Projection of diabetes burden through 2050: impact of changing demography and disease prevalence in the U.S.
      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,
      • Svartberg J.
      • Agledahl I.
      • Figenschau Y.
      • Sildnes T.
      • Waterloo K.
      • Jorde R.
      Testosterone treatment in elderly men with subnormal testosterone levels improves body composition and BMD in the hip.
      reduced quantitative insulin sensitivity check index score,
      • Muller M.
      • Grobbee D.E.
      • den Tonkelaar I.
      • Lamberts S.W.J.
      • van der Schouw Y.T.
      Endogenous sex hormones and metabolic syndrome in aging men.
      ,
      • Patel S.M.
      • Ratcliffe S.J.
      • Reilly M.P.
      • et al.
      Higher serum testosterone concentration in older women is associated with insulin resistance, metabolic syndrome, and cardiovascular disease.
      and lower Homeostatic Model Assessment for Insulin Resistance values.
      • Yeap B.B.
      • Chubb S.A.P.
      • Hyde Z.
      • et al.
      Lower serum testosterone is independently associated with insulin resistance in non-diabetic older men: the Health In Men Study.
      Additionally, endogenous GH levels are positively associated with insulin sensitivity in elderly individuals.
      • Johansson J.-O.
      • Fowelin J.
      • Landin K.
      • Lager I.
      Bengtsson B-Å. Growth hormone-deficient adults are insulin-resistant.
      ,
      • Hew F.L.
      • Koschmann M.
      • Christopher M.
      • et al.
      Insulin resistance in growth hormone-deficient adults: defects in glucose utilization and glycogen synthase activity.
      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.
      • Mitchell L.E.
      • Sprecher D.L.
      • Borecki I.B.
      • Rice T.
      • Laskarzewski P.M.
      • Rao D.C.
      Evidence for an association between dehydroepiandrosterone sulfate and nonfatal, premature myocardial infarction in males.
      • Herrington D.M.
      Dehydroepiandrosterone and coronary atherosclerosis.
      • Herrington D.M.
      • Gordon G.B.
      • Achuff S.C.
      • et al.
      Plasma dehydroepiandrosterone and dehydroepiandrosterone sulfate in patients undergoing diagnostic coronary angiography.
      Feldman et al
      • Feldman H.A.
      • Johannes C.B.
      • Araujo A.B.
      • Mohr B.A.
      • Longcope C.
      • McKinlay J.B.
      Low dehydroepiandrosterone and ischemic heart disease in middle-aged men: prospective results from the Massachusetts Male Aging Study.
      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.
      • Houmard J.A.
      • Tanner C.J.
      • Slentz C.A.
      • Duscha B.D.
      • McCartney J.S.
      • Kraus W.E.
      Effect of the volume and intensity of exercise training on insulin sensitivity.
      In fact, even a single bout of exercise can enhance insulin-stimulated glucose uptake in whole muscle tissue
      • Richter E.A.
      • Garetto L.P.
      • Goodman M.N.
      • Ruderman N.B.
      Muscle glucose metabolism following exercise in the rat: increased sensitivity to insulin.
      • Cartee G.D.
      • Young D.A.
      • Sleeper M.D.
      • Zierath J.
      • Wallberg-Henriksson H.
      • Holloszy J.O.
      Prolonged increase in insulin-stimulated glucose transport in muscle after exercise.
      • Wojtaszewski J.F.P.
      • Hansen B.F.
      • Gade J.
      • et al.
      Insulin signaling and insulin sensitivity after exercise in human skeletal muscle.
      and individual muscle fibers.
      • Cartee G.D.
      • Arias E.B.
      • Yu C.S.
      • Pataky M.W.
      Novel single skeletal muscle fiber analysis reveals a fiber type-selective effect of acute exercise on glucose uptake.
      ,
      • Pataky M.W.
      • Yu C.S.
      • Nie Y.
      • et al.
      Skeletal muscle fiber type-selective effects of acute exercise on insulin-stimulated glucose uptake in insulin-resistant, high-fat-fed rats.
      Unfortunately, insulin sensitivity is typically reduced with age.
      • Davidson M.B.
      The effect of aging on carbohydrate metabolism: a review of the English literature and a practical approach to the diagnosis of diabetes mellitus in the elderly.
      In older adults, those who partake in aerobic exercise (AE) 5 or more days per week have greater insulin sensitivity than do those who exercise 1 day per week or less.
      • Amati F.
      • Dubé J.J.
      • Coen P.M.
      • Stefanovic-Racic M.
      • Toledo F.G.S.
      • Goodpaster B.H.
      Physical inactivity and obesity underlie the insulin resistance of aging.
      In a separate study, our group previously found that insulin-induced glucose disposal was greater in aerobically trained older and young individuals than in their sedentary counterparts.
      • Lanza I.R.
      • Short D.K.
      • Short K.R.
      • et al.
      Endurance exercise as a countermeasure for aging [published correction appears in Diabetes. 2012;61(10):2653].
      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).
      • Robinson M.M.
      • Dasari S.
      • Konopka A.R.
      • et al.
      Enhanced protein translation underlies improved metabolic and physical adaptations to different exercise training modes in young and old humans.
      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,
      • Hurel S.J.
      • Koppiker N.
      • Newkirk J.
      • et al.
      Relationship of physical exercise and ageing to growth hormone production [published correction appears in Clin Endocrinol (Oxf). 2000;53(3):401].
      ,
      • Copeland J.L.
      • Chu S.Y.
      • Tremblay M.S.
      Aging, physical activity, and hormones in women—a review.
      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.
      • Larson-Meyer D.E.
      • Heilbronn L.K.
      • Redman L.M.
      • et al.
      Effect of calorie restriction with or without exercise on insulin sensitivity, β-cell function, fat cell size, and ectopic lipid in overweight subjects.
      ,
      • Weiss E.P.
      • Racette S.B.
      • Villareal D.T.
      • et al.
      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.
      • Johnson M.L.
      • Distelmaier K.
      • Lanza I.R.
      • et al.
      Mechanism by which caloric restriction improves insulin sensitivity in sedentary obese adults.
      ,
      • Menshikova E.V.
      • Ritov V.B.
      • Dube J.J.
      • et al.
      Calorie restriction-induced weight loss and exercise have differential effects on skeletal muscle mitochondria despite similar effects on insulin sensitivity.
      Another study found that insulin sensitivity is negatively associated with percent body fat and waist-to-hip ratio but that age is not significantly associated with insulin sensitivity,
      • Coon P.J.
      • Rogus E.M.
      • Drinkwater D.
      • Muller D.C.
      • Goldberg A.P.
      Role of body fat distribution in the decline in insulin sensitivity and glucose tolerance with age.
      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.
      • Masoro E.J.
      • Shimokawa I.
      • Yu B.P.
      Retardation of the aging processes in rats by food restriction.
      • Zheng Y.
      • Zhang W.
      • Pendleton E.
      • et al.
      Improved insulin sensitivity by calorie restriction is associated with reduction of ERK and p70S6K activities in the liver of obese Zucker rats.
      • Sharma N.
      • Castorena C.M.
      • Cartee G.D.
      Greater insulin sensitivity in calorie restricted rats occurs with unaltered circulating levels of several important myokines and cytokines.
      Long-term CR in rats results in elevated Leydig cell production of T in old age,
      • Chen H.
      • Luo L.
      • Liu J.
      • Brown T.
      • Zirkin B.R.
      Aging and caloric restriction: effects on Leydig cell steroidogenesis.
      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.

      Aerobic Capacity

      Age is associated with a decline in aerobic capacity (maximum oxygen consumption [V˙O2max]). Maximum oxygen consumption is highly dependent on both the amount of mitochondria and the oxidative capacity of the mitochondria in skeletal muscle.
      • Hoppeler H.
      • Weibel E.R.
      Limits for oxygen and substrate transport in mammals.
      • Lindstedt S.L.
      • Wells D.J.
      Skeletal muscle mitochondria: the aerobic gate?.
      • Larson-Meyer D.E.
      • Newcomer B.R.
      • Hunter G.R.
      • Hetherington H.P.
      • Weinsier R.L.
      31P MRS measurement of mitochondrial function in skeletal muscle: reliability, force-level sensitivity and relation to whole body maximal oxygen uptake.
      Multiple groups have reported a decrease in skeletal muscle mitochondrial content and function with age.
      • Short K.R.
      • Bigelow M.L.
      • Kahl J.
      • et al.
      Decline in skeletal muscle mitochondrial function with aging in humans.
      • Barazzoni R.
      • Short K.R.
      • Nair K.S.
      Effects of aging on mitochondrial DNA copy number and cytochrome c oxidase gene expression in rat skeletal muscle, liver, and heart.
      • Welle S.
      • Bhatt K.
      • Shah B.
      • Needler N.
      • Delehanty J.M.
      • Thornton C.A.
      Reduced amount of mitochondrial DNA in aged human muscle.
      The aging-associated decrease in mitochondrial content and function can result in reduced V˙O2max, which is a strong predictor of early mortality.
      • Ladenvall P.
      • Persson C.U.
      • Mandalenakis Z.
      • et al.
      Low aerobic capacity in middle-aged men associated with increased mortality rates during 45 years of follow-up [published correction appears in Eur J Prev Cardiol. 2017;24(4):NP2].
      In older men, low T is associated with low V˙O2max and low levels of muscle oxidative phosphorylation genes, suggesting that low T induces reductions in mitochondrial capacity.
      • Pitteloud N.
      • Mootha V.K.
      • Dwyer A.A.
      • et al.
      Relationship between testosterone levels, insulin sensitivity, and mitochondrial function in men.
      Corroborating this association, mice that are treated with exogenous T have transcriptionally up-regulated mitochondrial biogenesis.
      • Usui T.
      • Kajita K.
      • Kajita T.
      • et al.
      Elevated mitochondrial biogenesis in skeletal muscle is associated with testosterone-induced body weight loss in male mice.
      Further, low T levels in humans are associated with elevated mitochondrial reactive oxygen species (H2O2) production and enhanced inflammatory markers.
      • Rovira-Llopis S.
      • Bañuls C.
      • de Marañon A.M.
      • et al.
      Low testosterone levels are related to oxidative stress, mitochondrial dysfunction and altered subclinical atherosclerotic markers in type 2 diabetic male patients.
      Together these results support the notion that the maintenance of T levels during aging augments V˙O2max via maintenance of mitochondrial function. Higher levels of DHEA are also associated with increased V˙O2max during aging,
      • Abbasi A.
      • Duthie Jr., E.H.
      • Sheldahl L.
      • et al.
      Association of dehydroepiandrosterone sulfate, body composition, and physical fitness in independent community-dwelling older men and women.
      which may be due to elevated mitochondrial biogenesis in response to high levels of T.
      • Guo W.
      • Wong S.
      • Li M.
      • et al.
      Testosterone plus low-intensity physical training in late life improves functional performance, skeletal muscle mitochondrial biogenesis, and mitochondrial quality control in male mice.
      Because DHEA is the primary precursor for conversion to T,
      • Labrie F.
      • Bélanger A.
      • Luu-The V.
      • et al.
      DHEA and the intracrine formation of androgens and estrogens in peripheral target tissues: its role 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 V˙O2max is not independently associated with IGF-1 levels during aging.
      • Haydar Z.R.
      • Blackman M.R.
      • Tobin J.D.
      • Wright J.G.
      • Fleg J.L.
      The relationship between aerobic exercise capacity and circulating IGF-1 levels in healthy men and women.
      Four weeks of GH administration at either high or low doses did not alter V˙O2max in healthy young volunteers.
      • Berggren A.
      • Ehrnborg C.
      • Rosén T.
      • Ellegård L.
      • Bengtsson B.-A.
      • Caidahl K.
      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.
      • Short K.R.
      • Moller N.
      • Bigelow M.L.
      • Coenen-Schimke J.
      • Nair K.S.
      Enhancement of muscle mitochondrial function by growth hormone.
      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 V˙O2max.
      Despite the reduction in V˙O2max with age, exercise training can prevent the loss of aerobic capacity in older adults. In a study by Holloszy’s group,
      • Rogers M.A.
      • Hagberg J.M.
      • Martin III, W.H.
      • Ehsani A.A.
      • Holloszy J.O.
      Decline in VO2max with aging in master athletes and sedentary men.
      V˙O2max 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 V˙O2max in sedentary individuals was approximately 12% per decade, whereas in age-matched aerobically trained master athletes, only a 5.5% reduction in V˙O2max per decade was observed. Because aging is highly associated with reduced mitochondrial function due to decreasing mitochondrial DNA and increased DNA oxidation,
      • Short K.R.
      • Bigelow M.L.
      • Kahl J.
      • et al.
      Decline in skeletal muscle mitochondrial function with aging in humans.
      it has been suggested that the declining capacity of mitochondria to produce adenosine triphosphate during aging may contribute to insulin resistance and reduced physical function that occur with age.
      • Short K.R.
      • Bigelow M.L.
      • Kahl J.
      • et al.
      Decline in skeletal muscle mitochondrial function with aging in humans.
      However, AE training (AET) can prevent the loss in mitochondrial function with age. Lanza et al
      • Lanza I.R.
      • Short D.K.
      • Short K.R.
      • et al.
      Endurance exercise as a countermeasure for aging [published correction appears in Diabetes. 2012;61(10):2653].
      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).
      • Robinson M.M.
      • Dasari S.
      • Konopka A.R.
      • et al.
      Enhanced protein translation underlies improved metabolic and physical adaptations to different exercise training modes in young and old humans.
      However, despite the improvements in mitochondria in older trained individuals, the beneficial effect of exercise cannot completely maintain V˙O2max at levels observed in young individuals.
      • Robinson M.M.
      • Dasari S.
      • Konopka A.R.
      • et al.
      Enhanced protein translation underlies improved metabolic and physical adaptations to different exercise training modes in young and old humans.
      The age-associated decline in maximal heart rate is typically reported to be unaltered by exercise training,
      • Hawkins S.A.
      • Wiswell R.A.
      Rate and mechanism of maximal oxygen consumption decline with aging: implications for exercise training.
      • Heath G.W.
      • Hagberg J.M.
      • Ehsani A.A.
      • Holloszy J.O.
      A physiological comparison of young and older endurance athletes.
      • Pollock M.L.
      • Foster C.
      • Knapp D.
      • Rod J.L.
      • Schmidt D.H.
      Effect of age and training on aerobic capacity and body composition of master athletes.
      • Tanaka H.
      • Monahan K.D.
      • Seals D.R.
      Age-predicted maximal heart rate revisited.
      but some evidence suggests that the decline in maximal heart rate with age can be attenuated by vigorous exercise.
      • Gries K.J.
      • Raue U.
      • Perkins R.K.
      • et al.
      Cardiovascular and skeletal muscle health with lifelong exercise.
      • Everman S.
      • Farris J.W.
      • Bay R.C.
      • Daniels J.T.
      Elite distance runners: a 45-year follow-up.
      • Trappe S.
      • Hayes E.
      • Galpin A.
      • et al.
      New records in aerobic power among octogenarian lifelong endurance athletes.
      It appears that stroke volume and oxygen extraction can be maintained by exercise training during aging.
      • Heath G.W.
      • Hagberg J.M.
      • Ehsani A.A.
      • Holloszy J.O.
      A physiological comparison of young and older endurance athletes.
      ,
      • Hagberg J.M.
      • Allen W.K.
      • Seals D.R.
      • Hurley B.F.
      • Ehsani A.A.
      • Holloszy J.O.
      A hemodynamic comparison of young and older endurance athletes during exercise.
      Thus, there is a possible dissociation between aging-associated declines in V˙O2max 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 V˙O2max. 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,
      • Koch L.G.
      • Kemi O.J.
      • Qi N.
      • et al.
      Intrinsic aerobic capacity sets a divide for aging and longevity.
      it is reasonable to speculate that CR is also related to V˙O2max. In fact, 2 years of 25% CR in humans results in a significant increase in relative V˙O2max (mL/kg per min) compared with ad libitum controls.
      • Racette S.B.
      • Rochon J.
      • Uhrich M.L.
      • et al.
      Effects of two years of calorie restriction on aerobic capacity and muscle strength.
      In rodents, 40% CR prevents the age-associated decline in muscle mitochondrial function
      • Hepple R.T.
      • Baker D.J.
      • McConkey M.
      • Murynka T.
      • Norris R.
      Caloric restriction protects mitochondrial function with aging in skeletal and cardiac muscles.
      ,
      • Hepple R.T.
      • Baker D.J.
      • Kaczor J.J.
      • Krause D.J.
      Long-term caloric restriction abrogates the age-related decline in skeletal muscle aerobic function.
      and aerobic capacity.
      • Hepple R.T.
      • Baker D.J.
      • Kaczor J.J.
      • Krause D.J.
      Long-term caloric restriction abrogates the age-related decline in skeletal muscle aerobic function.
      Moreover, 40% CR in rodents also leads to lower heart mitochondrial H2O2 production,
      • Gredilla R.
      • Sanz A.
      • Lopez-Torres M.
      • Barja G.
      Caloric restriction decreases mitochondrial free radical generation at complex I and lowers oxidative damage to mitochondrial DNA in the rat heart.
      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,
      • Lanza I.R.
      • Zabielski P.
      • Klaus K.A.
      • et al.
      Chronic caloric restriction preserves mitochondrial function in senescence without increasing mitochondrial biogenesis.
      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.
      • Lexell J.
      • Henriksson-Larsén K.
      • Winblad B.
      • Sjöström M.
      Distribution of different fiber types in human skeletal muscles: effects of aging studied in whole muscle cross sections.
      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.
      • Baumgartner R.N.
      • Waters D.L.
      • Gallagher D.
      • Morley J.E.
      • Garry P.J.
      Predictors of skeletal muscle mass in elderly men and women.
      Longitudinal data revealed that when older men (~65 years old) were evaluated after a 12-year follow-up (at ~77 years old), there was a significant decline in muscle cross-sectional area and strength,
      • Frontera W.R.
      • Hughes V.A.
      • Fielding R.A.
      • Fiatarone M.A.
      • Evans W.J.
      • Roubenoff R.
      Aging of skeletal muscle: a 12-yr longitudinal study.
      and T consistently declines during this age range.
      • Harman S.M.
      • Metter E.J.
      • Tobin J.D.
      • Pearson J.
      • Blackman M.R.
      Longitudinal effects of aging on serum total and free testosterone levels in healthy men.
      ,
      • Matsumoto A.M.
      Andropause: clinical implications of the decline in serum testosterone levels with aging in men.
      In elderly men, low T levels are associated with reduced muscle strength.
      • Häkkinen K.
      • Pakarinen A.
      Muscle strength and serum testosterone, cortisol and SHBG concentrations in middle-aged and elderly men and women.
      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.
      • Mobley C.B.
      • Mumford P.W.
      • Kephart W.C.
      • et al.
      Effects of testosterone treatment on markers of skeletal muscle ribosome biogenesis.
      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
      • Salomon F.
      • Cuneo R.C.
      • Hesp R.
      • Sönksen P.H.
      The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency.
      ,
      • Cuneo R.C.
      • Salomon F.
      • Wiles C.M.
      • Sönksen P.H.
      Skeletal muscle performance in adults with growth hormone deficiency.
      and decreased strength.
      • Cuneo R.C.
      • Salomon F.
      • Wiles C.M.
      • Sönksen P.H.
      Skeletal muscle performance in adults with growth hormone deficiency.
      The loss of GH production in aging results in reduced circulating IGF-1, which is an important regulator of muscle mass and strength during aging.
      • Carter C.S.
      • Ramsey M.M.
      • Sonntag W.E.
      A critical analysis of the role of growth hormone and IGF-1 in aging and lifespan.
      Insulinlike growth factor 1 regulates muscle mass via Akt-mediated signaling, inhibiting forkhead box type O (FoxO) transcription factors and the ubiquitin-proteasome system.
      • Stitt T.N.
      • Drujan D.
      • Clarke B.A.
      • et al.
      The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors.
      Further, IGF-1 increases mammalian target of rapamycin signaling, resulting in increased ribosomal translation of transcriptome to proteins.
      • Ma X.M.
      • Blenis J.
      Molecular mechanisms of mTOR-mediated translational control.
      Thus, both T and GH are important regulators of muscle mass and strength during aging.
      Sarcopenia, the loss of muscle mass with age, and reduced strength are well-known symptoms of normal aging.
      • Doherty T.J.
      Invited review: aging and sarcopenia.
      ,
      • Lexell J.
      • Taylor C.C.
      • Sjöström M.
      What is the cause of the ageing atrophy? total number, size and proportion of different fiber types studied in whole vastus lateralis muscle from 15- to 83-year-old men.
      Thankfully, RE can attenuate and partially reverse the decline in muscle mass that is observed in older adults,
      • Bickel C.S.
      • Cross J.M.
      • Bamman M.M.
      Exercise dosing to retain resistance training adaptations in young and older adults.
      ,
      • Kosek D.J.
      • Kim J.-S.
      • Petrella J.K.
      • Cross J.M.
      • Bamman M.M.
      Efficacy of 3 days/wk resistance training on myofiber hypertrophy and myogenic mechanisms in young vs. older adults.
      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.
      • Bickel C.S.
      • Cross J.M.
      • Bamman M.M.
      Exercise dosing to retain resistance training adaptations in young and older adults.
      ,
      • Kosek D.J.
      • Kim J.-S.
      • Petrella J.K.
      • Cross J.M.
      • Bamman M.M.
      Efficacy of 3 days/wk resistance training on myofiber hypertrophy and myogenic mechanisms in young vs. older adults.
      Although HIIT modestly increases muscle mass, it is not nearly as effective at improving muscle strength as RET.
      • Robinson M.M.
      • Dasari S.
      • Konopka A.R.
      • et al.
      Enhanced protein translation underlies improved metabolic and physical adaptations to different exercise training modes in young and old humans.
      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.

      Bone Health

      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.
      • Riggs B.L.
      • Wahner H.W.
      • Dunn W.L.
      • Mazess R.B.
      • Offord K.P.
      • Melton III, L.J.
      Differential changes in bone mineral density of the appendicular and axial skeleton with aging: relationship to spinal osteoporosis.
      ,
      • Riggs B.L.
      • Wahner H.W.
      • Seeman E.
      • et al.
      Changes in bone mineral density of the proximal femur and spine with aging: differences between the postmenopausal and senile osteoporosis syndromes.
      The declines in bone mass and density with age are accompanied by a drastically increased risk for fractures,
      • Cummings S.R.
      • Browner W.
      • Black D.
      • et al.
      Bone density at various sites for prediction of hip fractures.
      which are associated with increasingly greater risk for mortality after the age of 60.
      • Keene G.S.
      • Parker M.J.
      • Pryor G.A.
      Mortality and morbidity after hip fractures.
      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,
      • Pouilles J.M.
      • Tremollieres F.
      • Ribot C.
      The effects of menopause on longitudinal bone loss from the spine.
      ,
      • Ahlborg H.G.
      • Johnell O.
      • Nilsson B.E.
      • Jeppsson S.
      • Rannevik G.
      • Karlsson M.K.
      Bone loss in relation to menopause: a prospective study during 16 years.
      the influence of T, DHEA, and GH on BMD in aging men is not as clear. Although Meier et al
      • Meier D.E.
      • Orwoll E.S.
      • Keenan E.J.
      • Fagerstrom R.M.
      Marked decline in trabecular bone mineral content in healthy men with age: lack of association with sex steroid levels.
      found no relationship between T levels and BMD in healthy older men, others have reported a positive association between T and BMD in elderly men
      • Murphy S.
      • Khaw K.T.
      • Cassidy A.
      • Compston J.E.
      Sex hormones and bone mineral density in elderly men.
      and postmenopausal women.
      • van Geel T.A.C.M.
      • Geusens P.P.
      • Winkens B.
      • Sels J.-P.J.E.
      • Dinant G.-J.
      Measures of bioavailable serum testosterone and estradiol and their relationships with muscle mass, muscle strength and bone mineral density in postmenopausal women: a cross-sectional study.
      However, Slemenda et al
      • Slemenda C.W.
      • Longcope C.
      • Zhou L.
      • Hui S.L.
      • Peacock M.
      • Johnston C.C.
      Sex steroids and bone mass in older men: positive associations with serum estrogens and negative associations with androgens.
      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.
      • Kenny A.M.
      • Prestwood K.M.
      • Marcello K.M.
      • Raisz L.G.
      Determinants of bone density in healthy older men with low testosterone levels.
      Furthermore, in GH-deficient adults, levels of GH are significantly associated with BMD.
      • Carroll P.V.
      • Christ E.R.
      • Bengtsson B.Å.
      • et al.
      Growth Hormone Research Society Scientific Committee
      Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review.
      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.
      • Bass S.
      • Pearce G.
      • Bradney M.
      • et al.
      Exercise before puberty may confer residual benefits in bone density in adulthood: studies in active prepubertal and retired female gymnasts.
      • McKay H.A.
      • Petit M.A.
      • Schutz R.W.
      • Prior J.C.
      • Barr S.I.
      • Khan K.M.
      Augmented trochanteric bone mineral density after modified physical education classes: a randomized school-based exercise intervention study in prepubescent and early pubescent children.
      • Grimston S.K.
      • Willows N.D.
      • Hanley D.A.
      Mechanical loading regime and its relationship to bone mineral density in children.
      Although exercise may only exert minimal increases in BMD in adulthood, it can certainly attenuate the decline in BMD that is associated with age.
      • Bocalini D.S.
      • Serra A.J.
      • dos Santos L.
      • Murad N.
      • Levy R.F.
      Strength training preserves the bone mineral density of postmenopausal women without hormone replacement therapy.
      Aerobic exercise, especially exercise such as running that produces a physical loading impact on bone, has been found to maintain bone health.
      • Michel B.A.
      • Lane N.E.
      • Björkengren A.
      • Bloch D.A.
      • Fries J.F.
      Impact of running on lumbar bone density: a 5-year longitudinal study.
      ,
      • MacDougall J.D.
      • Webber C.E.
      • Martin J.
      • et al.
      Relationship among running mileage, bone density, and serum testosterone in male runners.
      Resistance exercise training, especially that which encompasses the both upper and lower body exercises, has a profoundly positive impact on BMD.
      • Bocalini D.S.
      • Serra A.J.
      • dos Santos L.
      • Murad N.
      • Levy R.F.
      Strength training preserves the bone mineral density of postmenopausal women without hormone replacement therapy.
      ,
      • Layne J.E.
      • Nelson M.E.
      The effects of progressive resistance training on bone density: a review.
      Thus, for the maintenance of bone health and reducing the risk of fractures in aging, both AE and RE are highly recommended for older individuals.

      Cognitive Processes

      Aging is associated with cognitive decline, even in the absence of dementia.
      • Levy R.
      Aging-associated cognitive decline [published correction appears in Int Psychogeriatr. 1994;6(2):133].
      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
      • Bentourkia M.
      • Bol A.
      • Ivanoiu A.
      • et al.
      Comparison of regional cerebral blood flow and glucose metabolism in the normal brain: effect of aging.
      and can initiate a chain of deleterious metabolic derangements in the brain that may highly impact cognition. Increased oxidative protein damage in the brain
      • Forster M.J.
      • Dubey A.
      • Dawson K.M.
      • Stutts W.A.
      • Lal H.
      • Sohal R.S.
      Age-related losses of cognitive function and motor skills in mice are associated with oxidative protein damage in the brain.
      and decreased brain mitochondrial enzyme activity
      • Navarro A.
      • Boveris A.
      The mitochondrial energy transduction system and the aging process.
      are both associated with aging. Moreover, neuroinflammation has also been highly associated with cognitive aging.
      • Ownby R.L.
      Neuroinflammation and cognitive aging.
      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.
      • Ruegsegger G.N.
      • Vanderboom P.M.
      • Dasari S.
      • et al.
      Exercise and metformin counteract altered mitochondrial function in the insulin-resistant brain.
      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
      • Rogers R.L.
      • Meyer J.S.
      • Mortel K.F.
      After reaching retirement age physical activity sustains cerebral perfusion and cognition.
      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.
      • Colcombe S.J.
      • Kramer A.F.
      • Erickson K.I.
      • et al.
      Cardiovascular fitness, cortical plasticity, and aging.
      What are the mechanisms responsible for the beneficial effect of AET on cognition in older adults? Some suggest that improved blood flow and oxygen delivery are responsible for these changes.
      • Guiney H.
      • Lucas S.J.
      • Cotter J.D.
      • Machado L.
      Evidence cerebral blood-flow regulation mediates exercise-cognition links in healthy young adults.
      ,
      • Brown A.D.
      • McMorris C.A.
      • Longman R.S.
      • et al.
      Effects of cardiorespiratory fitness and cerebral blood flow on cognitive outcomes in older women.
      Others have provided evidence that improved brain mitochondrial function following AET can improve brain metabolism,
      • Ruegsegger G.N.
      • Vanderboom P.M.
      • Dasari S.
      • et al.
      Exercise and metformin counteract altered mitochondrial function in the insulin-resistant brain.
      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,
      • Chang Y.-K.
      • Pan C.-Y.
      • Chen F.-T.
      • Tsai C.-L.
      • Huang C.-C.
      Effect of resistance-exercise training on cognitive function in healthy older adults: a review.
      ,
      • Best J.R.
      • Chiu B.K.
      • Hsu C.L.
      • Nagamatsu L.S.
      • Liu-Ambrose T.
      Long-term effects of resistance exercise training on cognition and brain volume in older women: results from a randomized controlled trial.
      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,
      • Cassilhas R.C.
      • Lee K.S.
      • Fernandes J.
      • et al.
      Spatial memory is improved by aerobic and resistance exercise through divergent molecular mechanisms.
      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
      • Witte A.V.
      • Fobker M.
      • Gellner R.
      • Knecht S.
      • Flöel A.
      Caloric restriction improves memory in elderly humans.
      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.
      • Yang F.
      • Chu X.
      • Yin M.
      • et al.
      mTOR and autophagy in normal brain aging and caloric restriction ameliorating age-related cognition deficits.
      In these same mice, it was observed that hippocampal autophagy processes were up-regulated during CR,
      • Yang F.
      • Chu X.
      • Yin M.
      • et al.
      mTOR and autophagy in normal brain aging and caloric restriction ameliorating age-related cognition deficits.
      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
      • Sanz A.
      • Caro P.
      • Ibañez J.
      • Gómez J.
      • Gredilla R.
      • Barja G.
      Dietary restriction at old age lowers mitochondrial oxygen radical production and leak at complex I and oxidative DNA damage in rat brain.
      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.
      • Bassil N.
      • Alkaade S.
      • Morley J.E.
      The benefits and risks of testosterone replacement therapy: a review.
      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).
      • Snyder P.J.
      • Bhasin S.
      • Cunningham G.R.
      • et al.
      Testosterone Trials Investigators
      Effects of testosterone treatment in older men.
      These trials and other independent studies found that T administration in elderly men resulted in improvements in sexual function,
      • Cunningham G.R.
      • Stephens-Shields A.J.
      • Rosen R.C.
      • et al.
      Testosterone treatment and sexual function in older men with low testosterone levels.
      ,
      • Cunningham G.R.
      • Stephens-Shields A.J.
      • Rosen R.C.
      • et al.
      Association of sex hormones with sexual function, vitality, and physical function of symptomatic older men with low testosterone levels at baseline in the Testosterone Trials.
      lean body mass,
      • Tenover J.S.
      Effects of testosterone supplementation in the aging male.
      ,
      • Page S.T.
      • Amory J.K.
      • Bowman F.D.
      • et al.
      Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T.
      physical function,
      • Bhasin S.
      • Ellenberg S.S.
      • Storer T.W.
      • et al.
      Effect of testosterone replacement on measures of mobility in older men with mobility limitation and low testosterone concentrations: secondary analyses of the Testosterone Trials.
      strength,
      • Urban R.J.
      • Bodenburg Y.H.
      • Gilkison C.
      • et al.
      Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis.
      ,
      • Page S.T.
      • Amory J.K.
      • Bowman F.D.
      • et al.
      Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T.
      ,
      • Sih R.
      • Morley J.E.
      • Kaiser F.E.
      • Perry III, H.M.
      • Patrick P.
      • Ross C.
      Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial.
      protein synthesis,
      • Urban R.J.
      • Bodenburg Y.H.
      • Gilkison C.
      • et al.
      Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis.
      cholesterol,
      • Tenover J.S.
      Effects of testosterone supplementation in the aging male.
      ,
      • Page S.T.
      • Amory J.K.
      • Bowman F.D.
      • et al.
      Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T.
      ,
      • Mohler III, E.R.
      • Ellenberg S.S.
      • Lewis C.E.
      • et al.
      The effect of testosterone on cardiovascular biomarkers in the Testosterone Trials [published correction appears in J Clin Endocrinol Metab. 2020;105(1):384-5].
      and bone density.
      • Snyder P.J.
      • Kopperdahl D.L.
      • Stephens-Shields A.J.
      • et al.
      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]).
      • Chen X.
      • Li X.
      • Huang H.
      • Li X.
      • Lin J.
      Effects of testosterone on insulin receptor substrate-1 and glucose transporter 4 expression in cells sensitive to insulin [in Chinese].
      • Salehzadeh F.
      • Rune A.
      • Osler M.
      • Al-Khalili L.
      Testosterone or 17β-estradiol exposure reveals sex-specific effects on glucose and lipid metabolism in human myotubes.
      • Sato K.
      • Iemitsu M.
      • Aizawa K.
      • Ajisaka R.
      Testosterone and DHEA activate the glucose metabolism-related signaling pathway in skeletal muscle.
      • Bergamini E.
      • Bombara G.
      • Pellegrino C.
      The effect of testosterone on glycogen metabolism in rat levator ani muscle.
      However, some groups have reported that T replacement in older men does not provide significant benefits in strength
      • Harman S.M.
      • Blackman M.R.
      The effects of growth hormone and sex steroid on lean body mass, fat mass, muscle strength, cardiovascular endurance and adverse events in healthy elderly women and men.
      • Giannoulis M.G.
      • Jackson N.
      • Shojaee-Moradie F.
      • et al.
      The effects of growth hormone and/or testosterone on whole body protein kinetics and skeletal muscle gene expression in healthy elderly men: a randomized controlled trial.
      • Nair K.S.
      • Rizza R.A.
      • O'Brien P.
      • et al.
      DHEA in elderly women and DHEA or testosterone in elderly men.
      • Giannoulis M.G.
      • Sonksen P.H.
      • Umpleby M.
      • et al.
      The effects of growth hormone and/or testosterone in healthy elderly men: a randomized controlled trial.
      or cognition,
      • Resnick S.M.
      • Matsumoto A.M.
      • Stephens-Shields A.J.
      • et al.
      Testosterone treatment and cognitive function in older men with low testosterone and age-associated memory impairment.
      increases coronary artery plaque formation,
      • Budoff M.J.
      • Ellenberg S.S.
      • Lewis C.E.
      • et al.
      Testosterone treatment and coronary artery plaque volume in older men with low testosterone.
      and is consistently found to have no effect on insulin sensitivity.
      • Nair K.S.
      • Rizza R.A.
      • O'Brien P.
      • et al.
      DHEA in elderly women and DHEA or testosterone in elderly men.
      ,
      • Basu R.
      • Dalla Man C.
      • Campioni M.
      • et al.
      Effect of 2 years of testosterone replacement on insulin secretion, insulin action, glucose effectiveness, hepatic insulin clearance, and postprandial glucose turnover in elderly men.
      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.
      • Rhoden E.L.
      • Morgentaler A.
      Risks of testosterone-replacement therapy and recommendations for monitoring.
      ,
      • Basaria S.
      • Coviello A.D.
      • Travison T.G.
      • et al.
      Adverse events associated with testosterone administration.
      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.
      • Calof O.M.
      • Singh A.B.
      • Lee M.L.
      • et al.
      Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials.
      Presumably, lower doses of T may not exert such adverse health effects, but unfortunately, low-dose T does not have physiologically relevant beneficial effects on health.
      • Nair K.S.
      • Rizza R.A.
      • O'Brien P.
      • et al.
      DHEA in elderly women and DHEA or testosterone in elderly men.
      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.
      • Tenover J.L.
      Experience with testosterone replacement in the elderly.
      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.
      • Sato K.
      • Iemitsu M.
      • Aizawa K.
      • Ajisaka R.
      Testosterone and DHEA activate the glucose metabolism-related signaling pathway in skeletal muscle.
      ,
      • Sato K.
      • Iemitsu M.
      • Aizawa K.
      • Ajisaka R.
      DHEA improves impaired activation of Akt and PKC ζ/λ-GLUT4 pathway in skeletal muscle and improves hyperglycaemia in streptozotocin-induced diabetes rats.
      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,
      • Minghetti P.
      • Cilurzo F.
      • Casiraghi A.
      • Montanari L.
      • Santoro A.
      Development of patches for the controlled release of dehydroepiandrosterone.
      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,
      • Nair K.S.
      • Rizza R.A.
      • O'Brien P.
      • et al.
      DHEA in elderly women and DHEA or testosterone in elderly men.
      ,
      • Jankowski C.M.
      • Gozansky W.S.
      • Kittelson J.M.
      • Van Pelt R.E.
      • Schwartz R.S.
      • Kohrt W.M.
      Increases in bone mineral density in response to oral dehydroepiandrosterone replacement in older adults appear to be mediated by serum estrogens.
      ,
      • Villareal D.T.
      • Holloszy J.O.
      • Kohrt W.M.
      Effects of DHEA replacement on bone mineral density and body composition in elderly women and men.
      these increases are not as large as those produced by other therapies. The collective literature suggests that DHEA therapy has no significant effect on muscle mass and strength
      • Dayal M.
      • Sammel M.D.
      • Zhao J.
      • Hummel A.C.
      • Vandenbourne K.
      • Barnhart K.T.
      Supplementation with DHEA: effect on muscle size, strength, quality of life, and lipids.
      ,
      • Villareal D.T.
      • Holloszy J.O.
      DHEA enhances effects of weight training on muscle mass and strength in elderly women and men.
      or insulin sensitivity.
      • Mortola J.F.
      • Yen S.S.
      The effects of oral dehydroepiandrosterone on endocrine-metabolic parameters in postmenopausal women.
      ,
      • Nair K.S.
      • Rizza R.A.
      • O'Brien P.
      • et al.
      DHEA in elderly women and DHEA or testosterone in elderly men.
      ,
      • Casson P.R.
      • Santoro N.
      • Elkind-Hirsch K.
      • et al.
      Postmenopausal dehydroepiandrosterone administration increases free insulin-like growth factor-I and decreases high-density lipoprotein: a six-month trial.
      • Panjari M.
      • Bell R.J.
      • Jane F.
      • Adams J.
      • Morrow C.
      • Davis S.R.
      The safety of 52 weeks of oral DHEA therapy for postmenopausal women.
      • Basu R.
      • Dalla Man C.
      • Campioni M.
      • et al.
      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].
      Long-term (24-month) DHEA administration in older people, which elevated DHEA levels to that in the high-normal range for young people, did not result in improvements in body fat or muscle mass.
      • Nair K.S.
      • Rizza R.A.
      • O'Brien P.
      • et al.
      DHEA in elderly women and DHEA or testosterone in elderly men.
      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,
      • Davis S.R.
      • Panjari M.
      • Stanczyk F.Z.
      Clinical review: DHEA replacement for postmenopausal women.
      but another group reported elevated high-density lipoprotein cholesterol and decreased low-density lipoprotein cholesterol and plasma triglycerides in postmenopausal women.
      • Lasco A.
      • Frisina N.
      • Morabito N.
      • et al.
      Metabolic effects of dehydroepiandrosterone replacement therapy 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.
      • Kawano H.
      • Yasue H.
      • Kitagawa A.
      • et al.
      Dehydroepiandrosterone supplementation improves endothelial function and insulin sensitivity in men.
      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.
      Since the seminal publication by Rudman et al
      • Rudman D.
      • Feller A.G.
      • Nagraj H.S.
      • et al.
      Effects of human growth hormone in men over 60 years old.
      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
      • Rudman D.
      • Feller A.G.
      • Cohn L.
      • Shetty K.R.
      • Rudman I.W.
      • Draper M.W.
      Effects of human growth hormone on body composition in elderly men.
      and cholesterol
      • Feldt-Rasmussen U.
      • Wilton P.
      • Jonsson P.
      KIMS Study Group, KIMS International Board
      Aspects of growth hormone deficiency and replacement in elderly hypopituitary adults.
      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.
      • Liu H.
      • Bravata D.M.
      • Olkin I.
      • et al.
      Systematic review: the safety and efficacy of growth hormone in the healthy elderly.
      Moreover, although GH replacement may provide minor benefits in body composition to healthy elderly individuals, it does not improve strength, V˙O2max, BMD, lipid levels, or fasting glucose concentration.
      • Liu H.
      • Bravata D.M.
      • Olkin I.
      • et al.
      Systematic review: the safety and efficacy of growth hormone in the healthy elderly.
      ,
      • Lange K.H.W.
      • Andersen J.L.
      • Beyer N.
      • et al.
      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.
      • Giannoulis M.G.
      • Jackson N.
      • Shojaee-Moradie F.
      • et al.
      The effects of growth hormone and/or testosterone on whole body protein kinetics and skeletal muscle gene expression in healthy elderly men: a randomized controlled trial.
      ,
      • Giannoulis M.G.
      • Sonksen P.H.
      • Umpleby M.
      • et al.
      The effects of growth hormone and/or testosterone in healthy elderly men: a randomized controlled trial.
      ,
      • Lange K.H.W.
      • Andersen J.L.
      • Beyer N.
      • et al.
      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.
      • Papadakis M.A.
      • Grady D.
      • Black D.
      • et al.
      Growth hormone replacement in healthy older men improves body composition but not functional ability.
      • Blackman M.R.
      • Sorkin J.D.
      • Münzer T.
      • et al.
      Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial.
      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.
      • Cook D.
      • Yuen K.C.J.
      • Biller B.M.K.
      • Kemp S.F.
      • Vance M.L.
      American Association of Clinical Endocrinologists medical guidelines for clinical practice for growth hormone use in growth hormone-deficient adults and transition patients – 2009 update.

      Impact of Lifestyle Modifications on Hormone Production in Aging

      Aging is associated with a decrease in physical activity levels.
      • Bijnen F.C.
      • Feskens E.J.
      • Caspersen C.J.
      • Mosterd W.L.
      • Kromhout D.
      Age, period, and cohort effects on physical activity among elderly men during 10 years of follow-up: the Zutphen Elderly Study.
      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.
      • Verbrugge L.M.
      • Gruber-Baldini A.L.
      • Fozard J.L.
      Age differences and age changes in activities: Baltimore Longitudinal Study of Aging.
      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.
      • Little R.M.D.
      • Paterson D.H.
      • Humphreys D.A.
      • Stathokostas L.
      A 12-month incidence of exercise-related injuries in previously sedentary community-dwelling older adults following an exercise intervention.
      ,
      • Stathokostas L.
      • Theou O.
      • Little R.M.D.
      • Vandervoort A.A.
      • Raina P.
      Physical activity-related injuries in older adults: a scoping review.
      Frailty is a commonly reported adverse effect of CR in the aging population, which can likely be offset by maintaining dietary protein intake.
      • Katsanos C.S.
      • Kobayashi H.
      • Sheffield-Moore M.
      • Aarsland A.
      • Wolfe R.R.
      A high proportion of leucine is required for optimal stimulation of the rate of muscle protein synthesis by essential amino acids in the elderly.
      Frailty in older adults can also be drastically reduced by combined AE and RE.
      • Villareal D.T.
      • Aguirre L.
      • Gurney A.B.
      • et al.
      Aerobic or resistance exercise, or both, in dieting obese older adults.
      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,
      • Kraemer W.J.
      • Häkkinen K.
      • Newton R.U.
      • et al.
      Acute hormonal responses to heavy resistance exercise in younger and older men.
      • Häkkinen K.
      • Pakarinen A.
      • Kraemer W.J.
      • Newton R.U.
      • Alen M.
      Basal concentrations and acute responses of serum hormones and strength development during heavy resistance training in middle-aged and elderly men and women.
      • Ahtiainen J.P.
      • Hulmi J.J.
      • Kraemer W.J.
      • et al.
      Heavy resistance exercise training and skeletal muscle androgen receptor expression in younger and older men.
      • Baker J.R.
      • Bemben M.G.
      • Anderson M.A.
      • Bemben D.A.
      Effects of age on testosterone responses to resistance exercise and musculoskeletal variables in men.
      • Smilios I.
      • Pilianidis T.
      • Karamouzis M.
      • Parlavantzas A.
      • Tokmakidis S.P.
      Hormonal responses after a strength endurance resistance exercise protocol in young and elderly males.
      • Häkkinen K.
      • Pakarinen A.
      • Newton R.U.
      • Kraemer W.J.
      Acute hormone responses to heavy resistance lower and upper extremity exercise in young versus old men.
      but this effect is worn off by approximately 2 hours postexercise.
      • Paunksnis M.R.
      • Evangelista A.L.
      • La Scala Teixeira C.V.
      • et al.
      Metabolic and hormonal responses to different resistance training systems in elderly men.
      It appears that a low intensity or low volume of short-duration RE does not result in as robust an effect on T levels as high-intensity or high-volume exercise.
      • Häkkinen K.
      • Pakarinen A.
      • Newton R.U.
      • Kraemer W.J.
      Acute hormone responses to heavy resistance lower and upper extremity exercise in young versus old men.
      ,
      • Häkkinen K.
      • Pakarinen A.
      Acute hormonal responses to heavy resistance exercise in men and women at different ages.
      • Nicklas B.J.
      • Ryan A.J.
      • Treuth M.M.
      • et al.
      Testosterone, growth hormone and IGF-I responses to acute and chronic resistive exercise in men aged 55-70 years.
      • Kostka T.
      • Patricot M.C.
      • Mathian B.
      • Lacour J.-R.
      • Bonnefoy M.
      Anabolic and catabolic hormonal responses to experimental two-set low-volume resistance exercise in sedentary and active elderly people.
      • Roberts M.D.
      • Dalbo V.J.
      • Hassell S.E.
      • Kerksick C.M.
      The expression of androgen-regulated genes before and after a resistance exercise bout in younger and 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,
      • Kraemer W.J.
      • Häkkinen K.
      • Newton R.U.
      • et al.
      Acute hormonal responses to heavy resistance exercise in younger and older men.
      possibly explaining the larger absolute increases in strength that are observed in young men following RET compared with older men.
      • Newton R.U.
      • Häkkinen K.
      • Häkkinen A.
      • McCormick M.
      • Volek J.
      • Kraemer W.J.
      Mixed-methods resistance training increases power and strength of young and older men.
      ,
      • Welle S.
      • Thornton C.
      • Statt M.
      Myofibrillar protein synthesis in young and old human subjects after three months of resistance training.
      However, RET, which increases muscle strength, does not result in elevated basal levels of T in middle-aged or older men.
      • Häkkinen K.
      • Pakarinen A.
      • Kraemer W.J.
      • Newton R.U.
      • Alen M.
      Basal concentrations and acute responses of serum hormones and strength development during heavy resistance training in middle-aged and elderly men and women.
      ,
      • Nicklas B.J.
      • Ryan A.J.
      • Treuth M.M.
      • et al.
      Testosterone, growth hormone and IGF-I responses to acute and chronic resistive exercise in men aged 55-70 years.
      ,
      • Häkkinen K.
      • Kraemer W.J.
      • Pakarinen A.
      • et al.
      Effects of heavy resistance/power training on maximal strength, muscle morphology, and hormonal response patterns in 60-75-year-old men and women.
      • Häkkinen K.
      • Pakarinen A.
      Serum hormones and strength development during strength training in middle-aged and elderly males and females.
      • Craig B.W.
      • Brown R.
      • Everhart J.
      Effects of progressive resistance training on growth hormone and testosterone levels in young and elderly subjects.
      Resistance exercise training does appear, however, to increase the effect of a short bout of high-intensity exercise on free and total T.
      • Lovell D.I.
      • Cuneo R.
      • Wallace J.
      • McLellan C.
      The hormonal response of older men to sub-maximum aerobic exercise: the effect of training and detraining.
      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
      Reference, yearExercise durationExercise detailsSexAge (y)Effect of exercise on T
      Craig et al,
      • Craig B.W.
      • Brown R.
      • Everhart J.
      Effects of progressive resistance training on growth hormone and testosterone levels in young and elderly subjects.
      1989
      Training (12 wk)Progressive whole-body REMale63±1↔ In resting T following RET
      Häkkinen & Pakarinen,
      • Häkkinen K.
      • Pakarinen A.
      Serum hormones and strength development during strength training in middle-aged and elderly males and females.
      1994
      Training (12 wk)Progressive whole-body REMale and femaleMale: 64-73 Female: 66-73↔ In free or total resting T post-RET in elderly persons
      Häkkinen & Pakarinen,
      • Häkkinen K.
      • Pakarinen A.
      Acute hormonal responses to heavy resistance exercise in men and women at different ages.
      1995
      Single bout5 Sets of 10 reps (at ∼10-RM) for 3 exercises (bench press, leg press, sit-ups)Male and femaleMale: 68±3 Female: 69±3↔ In T immediately following RET in elderly persons
      Nicklas et al,
      • Nicklas B.J.
      • Ryan A.J.
      • Treuth M.M.
      • et al.
      Testosterone, growth hormone and IGF-I responses to acute and chronic resistive exercise in men aged 55-70 years.
      1995
      Both single bout and training (16 wk)Progressive whole-body REMale60±4Resting T ↔ after RET. In both trained and untrained men, T was ↔ after a single bout of RE
      Häkkinen et al,
      • Häkkinen K.
      • Pakarinen A.
      • Newton R.U.
      • Kraemer W.J.
      Acute hormone responses to heavy resistance lower and upper extremity exercise in young versus old men.
      1998
      Single boutUpper body, lower body, or both upper and lower body REMale70±4↑ In total and free T only occurred when lower-body exercises were included
      Kraemer et al,
      • Kraemer W.J.
      • Häkkinen K.
      • Newton R.U.
      • et al.
      Acute hormonal responses to heavy resistance exercise in younger and older men.
      1998
      Single bout4 Sets of 10-RM squatsMale62±3.2T was ↑ immediately and up to 30 min following RE
      Hakkinen, 2000
      • Häkkinen K.
      • Pakarinen A.
      • Kraemer W.J.
      • Newton R.U.
      • Alen M.
      Basal concentrations and acute responses of serum hormones and strength development during heavy resistance training in middle-aged and elderly men and women.
      Both single bout and Training (24 wk)Progressive whole body REmale and femalemale:72 ± 3 female:67 ± 3Trained and untrained men ↑ total and free T after a single bout of RE. Only trained women increase free T after a single bout of RE. Resting T is ↔ by RET
      Häkkinen et al,
      • Häkkinen K.
      • Kraemer W.J.
      • Pakarinen A.
      • et al.
      Effects of heavy resistance/power training on maximal strength, muscle morphology, and hormonal response patterns in 60-75-year-old men and women.
      2002
      Training (24 wk)Progressive whole-body REMale and femaleMale: 65±5 Female: 64±4↔ In basal T concentrations in elderly women or men after RET
      Kostka et al,
      • Kostka T.
      • Patricot M.C.
      • Mathian B.
      • Lacour J.-R.
      • Bonnefoy M.
      Anabolic and catabolic hormonal responses to experimental two-set low-volume resistance exercise in sedentary and active elderly people.
      2003
      Single boutLow-volume RE: 6-16 reps of leg extensions at 30%-70% of 1-RMMale and femaleMale: 71±5 Female: 71±4↔ In T concentrations in elderly women or men immediately after a single low-volume bout of RE
      Baker et al,
      • Baker J.R.
      • Bemben M.G.
      • Anderson M.A.
      • Bemben D.A.
      Effects of age on testosterone responses to resistance exercise and musculoskeletal variables in men.
      2006
      Single boutWhole body: 3 sets, 10 reps at 80% of 1-RM for 6 exercisesMale65±1Total and free T ↑ immediately post-RE but was returned to baseline by 15 min post-RE
      Smilios et al,
      • Smilios I.
      • Pilianidis T.
      • Karamouzis M.
      • Parlavantzas A.
      • Tokmakidis S.P.
      Hormonal