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The anabolic applications of androgens in older adults with functional limitations (2022)
Arijeet K. Gattu · Anna L. Goldman · Ezgi Caliskan Guzelce · Francesca Galbiati · Shalender Bhasin
Abstract
Aging is associated with a progressive decrease in skeletal muscle mass, strength, and power, and impairment of physical function. Serum testosterone concentrations in men decrease with advancing age due to defects at all levels of the hypothalamic–pituitary–testicular axis. Testosterone administration increases skeletal muscle mass, strength, and power in older men with low or low normal testosterone levels, but the effects on performance-based measures of physical function have been inconsistent. Adequately powered randomized trials are needed to determine the long-term safety and efficacy of testosterone in improving physical function and quality of life in older adults with functional limitations.
1 Introduction
The remarkable increase in average life expectancy across the globe from the low 30 s during most of the nineteenth century to 72.6 years in 2019, largely as a result of improved sanitation, clean water supply, immunization, and treatment of infectious diseases, has focused attention on the high prevalence of functional limitations and physical disabilities associated with old age. Advancing age is associated with a slow but progressive loss of skeletal muscle mass and muscle strength, and impairment of physical function [1–3]. Muscle power (the rate of force generation) and muscle endurance also decline after age 50 years [4, 5]. Although the loss of skeletal muscle mass is associated with atrophy and loss of both type I and type II muscle fibers, there is a disproportionately greater loss of type II fast-twitch muscle fibers required for the generation of muscle power than type 1 slow-twitch muscle fibers [6–8]. The aerobic capacity declines 3 to 6% per decade in young adults but at a much faster rate in older adults, declining by as much as 20% per decade after age 70. Aging also is associated with a dynamic redistribution of body fat; a loss of subcutaneous fat and accumulation of fat in ectopic locations such as the visceral and the inter and intra-myocellular fat compartments contributes to an increased risk of metabolic disorders.
The pathophysiology of age-related loss of skeletal muscle mass and aerobic capacity is multifactorial: a decrease in muscle proteins, including myosin heavy chain and mitochondrial proteins [3], age-related decline in anabolic hormones (testosterone, growth hormone, and IGF-1), inflammation and oxidative stress, accumulation of mitochondrial mutations and mitochondrial dysfunction, genomic instability, telomere attrition, loss of proteostasis, altered nutrient sensing, and cellular and stem cell senescence contribute to the loss of muscle mass and strength [9]. The age-related loss of muscle mass, strength, and power, and impaired physical function are associated with an increased risk of physical disability, falls, fractures, metabolic disorders, diminished capacity to live independently in the community, and increased health care resource utilization. Thus, the development of interventions to prevent and treat the age-related impairment of physical function has emerged as a public health imperative.
Among the anabolic interventions that are being investigated for the prevention and treatment of age-related loss of skeletal muscle mass and physical function, androgens, especially testosterone, are among the leading candidates. The potential application of testosterone as an anabolic drug to prevent and treat the impairment of muscle performance and physical function associated with aging and chronic diseases is based on the hypotheses that 1, circulating testosterone levels decline with advancing age and contribute to the loss of skeletal muscle mass and performance; 2, that testosterone administration increases muscle mass, strength and physical function in older adults; and 3, that testosterone treatment of older men is safe. This review offers a critical appraisal of each of these hypotheses.
2 Age‑related decline in serum testosterone levels
3 Evidence of the anabolic effects of testosterone
4 Randomized trials of testosterone in older adults
5 Testosterone's effects in adults with chronic diseases
6 Safety of long‑term testosterone treatment
7 The mechanisms of testosterone's anabolic effects on the skeletal muscle and physical performance
8 Selective androgen receptor modulators
9 Synthesis and conclusions
There is compelling evidence that testosterone and other androgens increase skeletal muscle mass and maximal muscle strength. Testosterone treatment has also been shown to improve measures of physical function that are strongly associated with muscle strength, such as stair climbing speed and power. However, changes in other performance-based measures, such as walking speed, with replacement doses of testosterone have been modest and inconsistent across trials. It is possible that neuromuscular adaptations needed to induce physical functional improvements may require concomitant functional exercise training that includes elements of progressive resistance training, endurance training, gait training to improve mobility and reduce the risk of falls, balance training, task-specific training to improve the ability to perform activities of daily living, and cognitive behavioral training to increase adherence with exercise regimens. Larger adequately powered randomized trials of longer duration are needed to determine whether testosterone treatment of older men with functional limitations, when administered in conjunction with a multi-dimensional functional exercise training, can safely improve physical function and meaningfully improve how a person "functions and feels”.
Arijeet K. Gattu · Anna L. Goldman · Ezgi Caliskan Guzelce · Francesca Galbiati · Shalender Bhasin
Abstract
Aging is associated with a progressive decrease in skeletal muscle mass, strength, and power, and impairment of physical function. Serum testosterone concentrations in men decrease with advancing age due to defects at all levels of the hypothalamic–pituitary–testicular axis. Testosterone administration increases skeletal muscle mass, strength, and power in older men with low or low normal testosterone levels, but the effects on performance-based measures of physical function have been inconsistent. Adequately powered randomized trials are needed to determine the long-term safety and efficacy of testosterone in improving physical function and quality of life in older adults with functional limitations.
1 Introduction
The remarkable increase in average life expectancy across the globe from the low 30 s during most of the nineteenth century to 72.6 years in 2019, largely as a result of improved sanitation, clean water supply, immunization, and treatment of infectious diseases, has focused attention on the high prevalence of functional limitations and physical disabilities associated with old age. Advancing age is associated with a slow but progressive loss of skeletal muscle mass and muscle strength, and impairment of physical function [1–3]. Muscle power (the rate of force generation) and muscle endurance also decline after age 50 years [4, 5]. Although the loss of skeletal muscle mass is associated with atrophy and loss of both type I and type II muscle fibers, there is a disproportionately greater loss of type II fast-twitch muscle fibers required for the generation of muscle power than type 1 slow-twitch muscle fibers [6–8]. The aerobic capacity declines 3 to 6% per decade in young adults but at a much faster rate in older adults, declining by as much as 20% per decade after age 70. Aging also is associated with a dynamic redistribution of body fat; a loss of subcutaneous fat and accumulation of fat in ectopic locations such as the visceral and the inter and intra-myocellular fat compartments contributes to an increased risk of metabolic disorders.
The pathophysiology of age-related loss of skeletal muscle mass and aerobic capacity is multifactorial: a decrease in muscle proteins, including myosin heavy chain and mitochondrial proteins [3], age-related decline in anabolic hormones (testosterone, growth hormone, and IGF-1), inflammation and oxidative stress, accumulation of mitochondrial mutations and mitochondrial dysfunction, genomic instability, telomere attrition, loss of proteostasis, altered nutrient sensing, and cellular and stem cell senescence contribute to the loss of muscle mass and strength [9]. The age-related loss of muscle mass, strength, and power, and impaired physical function are associated with an increased risk of physical disability, falls, fractures, metabolic disorders, diminished capacity to live independently in the community, and increased health care resource utilization. Thus, the development of interventions to prevent and treat the age-related impairment of physical function has emerged as a public health imperative.
Among the anabolic interventions that are being investigated for the prevention and treatment of age-related loss of skeletal muscle mass and physical function, androgens, especially testosterone, are among the leading candidates. The potential application of testosterone as an anabolic drug to prevent and treat the impairment of muscle performance and physical function associated with aging and chronic diseases is based on the hypotheses that 1, circulating testosterone levels decline with advancing age and contribute to the loss of skeletal muscle mass and performance; 2, that testosterone administration increases muscle mass, strength and physical function in older adults; and 3, that testosterone treatment of older men is safe. This review offers a critical appraisal of each of these hypotheses.
2 Age‑related decline in serum testosterone levels
3 Evidence of the anabolic effects of testosterone
4 Randomized trials of testosterone in older adults
5 Testosterone's effects in adults with chronic diseases
6 Safety of long‑term testosterone treatment
7 The mechanisms of testosterone's anabolic effects on the skeletal muscle and physical performance
8 Selective androgen receptor modulators
9 Synthesis and conclusions
There is compelling evidence that testosterone and other androgens increase skeletal muscle mass and maximal muscle strength. Testosterone treatment has also been shown to improve measures of physical function that are strongly associated with muscle strength, such as stair climbing speed and power. However, changes in other performance-based measures, such as walking speed, with replacement doses of testosterone have been modest and inconsistent across trials. It is possible that neuromuscular adaptations needed to induce physical functional improvements may require concomitant functional exercise training that includes elements of progressive resistance training, endurance training, gait training to improve mobility and reduce the risk of falls, balance training, task-specific training to improve the ability to perform activities of daily living, and cognitive behavioral training to increase adherence with exercise regimens. Larger adequately powered randomized trials of longer duration are needed to determine whether testosterone treatment of older men with functional limitations, when administered in conjunction with a multi-dimensional functional exercise training, can safely improve physical function and meaningfully improve how a person "functions and feels”.
