madman
Super Moderator
Growth Hormone and Aging (2023)
Camille Hage, MD, MPH, Roberto Salvatori, MD
BACKGROUND
The number of people aged 60 and older outnumbers children younger than 5 years.’ For the first time in history, life expectancy exceeds 60 years worldwide.' The United Nations General Assembly has declared the upcoming decade as a decade of healthy aging to improve older people’s lives. An increasing number of anti-aging methods have been proposed to halt or slow senescence. These methods aim to establish a healthy life with a functional capacity that enables well-being in older age. One particular area of interest has been somatopause, a term that describes the expected decline in growth hormone (GH) secretion that occurs with age. Today, with the availability of recombinant GH, restoring GH to youthful levels in otherwise normal older adult populations has been an area of focus for many healthcare researchers. This study aims to elucidate the current knowledge and novel advances of GH in the aging population.
DISCUSSION
Physiology of Growth Hormone GH (somatotropin) is produced by somatotroph cells in the anterior pituitary gland. The GH gene (GH1) is located on chromosome 17g22 (OMIM: 139250, NBClgenelD: 2688). Mutations or deletions in this gene result in congenital GHD. The arcuate nucleus in the hypothalamus stimulates GH secretion via GH-releasing hormone (GHRH) transported through the hypothalamo-hypophyseal portal system targeting the GHRH receptor (GHRHR) in the pituitary. The GH secretion is inhibited by somatostatin (GH-inhibiting hormone) produced by neuroendocrine neurons in the ventromedial nucleus of the hypothalamus. A third hormone (ghrelin), secreted mainly by the enteroendocrine cells of the gastrointestinal tract (predominantly in the stomach), induces GH secretion. GH has a distinctive pulsatile secretion that is mostly mediated by a reduction in tonic inhibition by somatostatin.” GH is secreted mostly at night, starting shortly after the onset of sleep in association with the first phase of slow-wave sleep (SWS) (stages Il and IV). GH’s sleep-related secretion primarily depends on the increased release of GHRH.® GH is also produced in non-pituitary cells, mainly in the colon and the breast, with a possible role in regulating local cell proliferation.
*Some effects of GH are direct, whereas others are indirectly mediated by systemic (primarily produced in the liver) or locally produced insulin-like growth factor | (IGFI). Circulating IGF-I inhibits GH secretion by the pituitary somatotroph cells with a negative feedback loop.®
GH acts by binding to the GH receptor (GHR), a class 1 cytokine receptor with 638 amino acids forming three domains.® Upon attaching to GH, the extracellular domain undergoes a conformational change, followed by phosphorylation and activation of STATS5 through Janus kinase 2.”* The GHR gene consists of nine coding exons and several additional exons in the 5’ UTR. Of note, two major isoforms of GHR differ by the absence of exon 3 encoding the extracellular domain of GHR. Its absence gives rise to GHR lacking 22 amino acids in the extracellular domain.”'®
In healthy adults, GH increases lipolysis and lipid oxidation, stimulates protein synthesis, antagonizes the effect of insulin, and causes phosphate, water, and sodium retention.’" In addition, it can maintain cardiac function, glucose homeostasis, bone mineralization, appropriate balance of adipose lipogenesis and lipolysis, and skeletal muscle anabolism.
After growth is completed, the secretion of GH decreases over time, starting early in adult life.'*'* Effectively, the daily secretion of GH in adults falls by about 50% every 7 years after turning 18 to 25 years.'” This reduction seems to be due to the loss of nocturnal sleep-related GH pulses.'® In addition, a decline in pituitary responsiveness to GHRH and pituitary or hypothalamic responsiveness to ghrelin is observed with aging."® The reduction in GH secretion parallels an increase in adiposity with aging.'” The decrease in sex steroid hormones, physical fitness, sleep quality, and nutritional status. that occur during aging are all correlated with a decline in GH secretion, without proof of causality. Consequently, somatopause remains hard to define as it occurs as part of the normal aging process.
GH decrease is associated with (but not necessarily caused by) significant changes in body composition. However, one cannot help noticing that the physiologic changes seen with aging are similar to those observed in young individuals with organic GHD. Most studies on somatopause focus on a few markers, such as lean body mass, total fat, muscle strength, and bone mineral density. Although musculoskeletal impairment has been associated with aging, extreme cases are seldom seen in normal somatopause.’® Similarly, the temporal association between somatopause and increased adiposity remains a central topic of interest with a significant lack of established causal-effect relationships. Aging is associated with a modified body fat distribution and a decreased lipolytic responsiveness to GH, while GH release can be reduced by the increased amount of abdominal fat, creating a vicious cycle of increased fat mass that promotes reduction in GH in older adults.'®
GH has effects on bone, either directly or mediated by IGF-I, stimulating osteoblast proliferation as well as osteoclast differentiation.” Although bone loss associated with aging is multifactorial, the age-related decline in GH contributes to reduced bone turnover. Replacing GH may not necessarily improve bone density with age-related bone loss, but in a therapeutic context (meaning in adults with proven GH deficiency), it has shown signs of possible protective effect, with a decrease in the risk of fracture and osteopenia.”!
GH, through IGF-1, has a role in maintaining cognitive function. Several positive associations in healthy older individuals between the circulating levels of IGF-I and different neuropsychological tests of intelligence have been demonstrated.?*>* However, the detailed roles of GH and IGF-I in the adult human brain remain unclear as the overall effects of somatopause on learning and memory are still unidentified.
Although somatopause is a naturally occurring phenomenon, it remains important to distinguish it from true GHD caused by hypothalamic or pituitary pathologic processes, such as tumors, infarcts, inflammation, head trauma, or radiation. Most acquired GHD cases present more severe physical defects than normal aging, such as increased cardiovascular risk and bone fragility, unfavorable fat/lean mass ratio, reduced muscle strength, and psychological deficiencies (impaired quality of life, social isolation).”® Therefore, if suspected, GHD should be ruled out via measurement of serum IGF-I or GH provocative testing. It is vital to notice that although a low serum IGF-I (<—2.0 standard deviation score) in the appropriate clinical scenario is strongly suggestive of GHD (particularly if additional pituitary hormone deficits are present), a normal IGF-I level does not rule it out, particularly in men. Therefore, GH stimulation tests are often needed to establish the diagnosis of GHD. Such tests can use different stimuli and their interpretation (notably depending on body mass index) requires knowledge of the performance, accuracy, and limitations of each secretagogue. A review of the available GH stimulation tests and their interpretation and cutoff points are given in Table 1.2°
*Mice Model of Growth Hormone Deficiency or Resistance
*Human Models of Congenital Growth Hormone Deficiency or Resistance
*Growth Hormone Replacement
SUMMARY
The U.S. Food and Drug Administration approved recombinant GH in 1985 as replacement therapy for adults with hypothalamic-pituitary disease and confirmed GHD on biochemical testing. Thirty years ago, an editorial in the New England Journal of Medicine that accompanied the Rudman article wondered about the potential benefits of GH in older subjects without proven GHD.”® Although anti-aging medicine has become a multimillion-dollar industry with significant economic, health, and societal costs, at present, there is no evidence of long-term beneficial effects of GH treatment in healthy older adults, and GH should only be prescribed for clinically approved indications.”*"
Camille Hage, MD, MPH, Roberto Salvatori, MD
BACKGROUND
The number of people aged 60 and older outnumbers children younger than 5 years.’ For the first time in history, life expectancy exceeds 60 years worldwide.' The United Nations General Assembly has declared the upcoming decade as a decade of healthy aging to improve older people’s lives. An increasing number of anti-aging methods have been proposed to halt or slow senescence. These methods aim to establish a healthy life with a functional capacity that enables well-being in older age. One particular area of interest has been somatopause, a term that describes the expected decline in growth hormone (GH) secretion that occurs with age. Today, with the availability of recombinant GH, restoring GH to youthful levels in otherwise normal older adult populations has been an area of focus for many healthcare researchers. This study aims to elucidate the current knowledge and novel advances of GH in the aging population.
DISCUSSION
Physiology of Growth Hormone GH (somatotropin) is produced by somatotroph cells in the anterior pituitary gland. The GH gene (GH1) is located on chromosome 17g22 (OMIM: 139250, NBClgenelD: 2688). Mutations or deletions in this gene result in congenital GHD. The arcuate nucleus in the hypothalamus stimulates GH secretion via GH-releasing hormone (GHRH) transported through the hypothalamo-hypophyseal portal system targeting the GHRH receptor (GHRHR) in the pituitary. The GH secretion is inhibited by somatostatin (GH-inhibiting hormone) produced by neuroendocrine neurons in the ventromedial nucleus of the hypothalamus. A third hormone (ghrelin), secreted mainly by the enteroendocrine cells of the gastrointestinal tract (predominantly in the stomach), induces GH secretion. GH has a distinctive pulsatile secretion that is mostly mediated by a reduction in tonic inhibition by somatostatin.” GH is secreted mostly at night, starting shortly after the onset of sleep in association with the first phase of slow-wave sleep (SWS) (stages Il and IV). GH’s sleep-related secretion primarily depends on the increased release of GHRH.® GH is also produced in non-pituitary cells, mainly in the colon and the breast, with a possible role in regulating local cell proliferation.
*Some effects of GH are direct, whereas others are indirectly mediated by systemic (primarily produced in the liver) or locally produced insulin-like growth factor | (IGFI). Circulating IGF-I inhibits GH secretion by the pituitary somatotroph cells with a negative feedback loop.®
GH acts by binding to the GH receptor (GHR), a class 1 cytokine receptor with 638 amino acids forming three domains.® Upon attaching to GH, the extracellular domain undergoes a conformational change, followed by phosphorylation and activation of STATS5 through Janus kinase 2.”* The GHR gene consists of nine coding exons and several additional exons in the 5’ UTR. Of note, two major isoforms of GHR differ by the absence of exon 3 encoding the extracellular domain of GHR. Its absence gives rise to GHR lacking 22 amino acids in the extracellular domain.”'®
In healthy adults, GH increases lipolysis and lipid oxidation, stimulates protein synthesis, antagonizes the effect of insulin, and causes phosphate, water, and sodium retention.’" In addition, it can maintain cardiac function, glucose homeostasis, bone mineralization, appropriate balance of adipose lipogenesis and lipolysis, and skeletal muscle anabolism.
After growth is completed, the secretion of GH decreases over time, starting early in adult life.'*'* Effectively, the daily secretion of GH in adults falls by about 50% every 7 years after turning 18 to 25 years.'” This reduction seems to be due to the loss of nocturnal sleep-related GH pulses.'® In addition, a decline in pituitary responsiveness to GHRH and pituitary or hypothalamic responsiveness to ghrelin is observed with aging."® The reduction in GH secretion parallels an increase in adiposity with aging.'” The decrease in sex steroid hormones, physical fitness, sleep quality, and nutritional status. that occur during aging are all correlated with a decline in GH secretion, without proof of causality. Consequently, somatopause remains hard to define as it occurs as part of the normal aging process.
GH decrease is associated with (but not necessarily caused by) significant changes in body composition. However, one cannot help noticing that the physiologic changes seen with aging are similar to those observed in young individuals with organic GHD. Most studies on somatopause focus on a few markers, such as lean body mass, total fat, muscle strength, and bone mineral density. Although musculoskeletal impairment has been associated with aging, extreme cases are seldom seen in normal somatopause.’® Similarly, the temporal association between somatopause and increased adiposity remains a central topic of interest with a significant lack of established causal-effect relationships. Aging is associated with a modified body fat distribution and a decreased lipolytic responsiveness to GH, while GH release can be reduced by the increased amount of abdominal fat, creating a vicious cycle of increased fat mass that promotes reduction in GH in older adults.'®
GH has effects on bone, either directly or mediated by IGF-I, stimulating osteoblast proliferation as well as osteoclast differentiation.” Although bone loss associated with aging is multifactorial, the age-related decline in GH contributes to reduced bone turnover. Replacing GH may not necessarily improve bone density with age-related bone loss, but in a therapeutic context (meaning in adults with proven GH deficiency), it has shown signs of possible protective effect, with a decrease in the risk of fracture and osteopenia.”!
GH, through IGF-1, has a role in maintaining cognitive function. Several positive associations in healthy older individuals between the circulating levels of IGF-I and different neuropsychological tests of intelligence have been demonstrated.?*>* However, the detailed roles of GH and IGF-I in the adult human brain remain unclear as the overall effects of somatopause on learning and memory are still unidentified.
Although somatopause is a naturally occurring phenomenon, it remains important to distinguish it from true GHD caused by hypothalamic or pituitary pathologic processes, such as tumors, infarcts, inflammation, head trauma, or radiation. Most acquired GHD cases present more severe physical defects than normal aging, such as increased cardiovascular risk and bone fragility, unfavorable fat/lean mass ratio, reduced muscle strength, and psychological deficiencies (impaired quality of life, social isolation).”® Therefore, if suspected, GHD should be ruled out via measurement of serum IGF-I or GH provocative testing. It is vital to notice that although a low serum IGF-I (<—2.0 standard deviation score) in the appropriate clinical scenario is strongly suggestive of GHD (particularly if additional pituitary hormone deficits are present), a normal IGF-I level does not rule it out, particularly in men. Therefore, GH stimulation tests are often needed to establish the diagnosis of GHD. Such tests can use different stimuli and their interpretation (notably depending on body mass index) requires knowledge of the performance, accuracy, and limitations of each secretagogue. A review of the available GH stimulation tests and their interpretation and cutoff points are given in Table 1.2°
*Mice Model of Growth Hormone Deficiency or Resistance
*Human Models of Congenital Growth Hormone Deficiency or Resistance
*Growth Hormone Replacement
SUMMARY
The U.S. Food and Drug Administration approved recombinant GH in 1985 as replacement therapy for adults with hypothalamic-pituitary disease and confirmed GHD on biochemical testing. Thirty years ago, an editorial in the New England Journal of Medicine that accompanied the Rudman article wondered about the potential benefits of GH in older subjects without proven GHD.”® Although anti-aging medicine has become a multimillion-dollar industry with significant economic, health, and societal costs, at present, there is no evidence of long-term beneficial effects of GH treatment in healthy older adults, and GH should only be prescribed for clinically approved indications.”*"
