Growth hormone in adipose dysfunction and senescence

Growth hormone (GH) is an important modulator of maturation, adiposity, and metabolism in mammals. It also has profound effects on age-related disease onset and healthspan [1]. GH-deficient and-resistant mice have up to a 78% increase in maximum lifespan and are protected from age-related metabolic dysfunction and cancer [2]. Although lifespan does not appear to be extended in humans with GH resistance, these individuals are protected from a variety of age-related pathologies, particularly diabetes and cancer [3]. Several mechanisms have been proposed and likely contribute to the pro-survival effects of curtailed GH action, including enhanced stress resistance, xenobiotic metabolism, and insulin sensitivity in combination with reduced inflammation [1]. In contrast, both mice and humans with excess GH develop phenotypes indicative of premature aging and have greater disease burden and mortality risk [1, 2]. Furthermore, mice and humans with altered GH action also display profound changes in adipose tissue homeostasis and lipid distribution. GH-deficient and-resistant mice preferentially deposit lipid in subcutaneous adipose depots, whereas humans with Laron Syndrome exhibit markedly increased subcutaneous and visceral adiposity [1, 2]. Despite the development of obesity, the overwhelming majority of these mice and human subjects are safeguarded from metabolic dysfunction. Conversely, transgenic GH-overexpressing mice and human acromegaly patients remain lean throughout life, yet often develop insulin resistance and an elevated pro-inflammatory status [1]. These observations suggest GH may accelerate declines in adipose tissue homeostasis, which has previously been linked with age-related perturbations in systemic inflammation and metabolism [4]. Adipose tissue functional capacity declines with advancing age [4]. This deterioration is particularly evident in subcutaneous depots, which promotes increased visceral adiposity, ectopic lipid deposition, and concomitant metabolic disturbances. Preadipocyte proliferation and differentiation potential are curtailed with aging and result in reduced lipid deposition in subcutaneous adipose tissue [4]. Pro-inflammatory cytokines, chemokines, and extracellular matrix proteases are believed to play a central role in preadipocyte dysfunction and adipose tissue remodeling with aging. Senescent cells, which possess a highly pro-inflammatory secretome, accumulate in adipose tissue with advancing age, and thus, have emerged as a potential contributor to adipose tissue dysfunction [4]. Interestingly, the elimination of senescent cells preserves adipose tissue mass and enhances healthspan in mice with an accelerated aging phenotype [5]. Given that GH-deficient and-resistant mice appear to be protected from age-related lipid redistribution and metabolic dysfunction, we hypothesized that GH action would be predictive of subcutaneous adipose tissue lipid storage capacity and senescent cell burden. To test …