Table 1. Mechanisms of extended healthspan and longevity in GH-deficient and GH-resistant mice (details and references in the text).

Mechanisms related to somatic growth

· Reduced hepatic IGF-1 expression and circulating IGF-1 levels

· Reduced mTORC1 signaling and mRNA translation; increased autophagy

· Reduced growth rate and adult body size

Mechanisms related to glucose homeostasis and lipid metabolism

· Hypoinsulinemia combined with enhanced insulin sensitivity

· Increased utilization of fatty acids; reduced hepatic and serum levels of lipids

· Reduced hepatic lipogenesis

Mechanisms related to cell senescence and low-grade chronic inflammation

· Reduced levels of pro-inflammatory cytokines: IL-1b, IL-6, TNF-α

· Increased levels of adiponectin

· Inhibition of NLRP3 inflammasome

· Reduced burden of senescent cells

Mechanisms related to stress resistance and repair

· Improved antioxidant defenses and reduced reactive oxygen species production

· Altered glutathione metabolism

· Increased cellular and whole animal resistance to toxins and a variety of stresses

· Improved maintenance of stem cell populations

Mechanisms related to energy metabolism

· Increased brown adipose tissue mass and activity; white adipose tissue ‘browning’; increased thermogenesis

· Increased utilization of lipids vs. carbohydrates as energy source

· Increased oxygen consumption per unit of total or lean body mass

Miscellaneous mechanism

· Hypogonadotropism and delayed puberty

· Increased hepatic hydrogen sulfide (H2S) production

· Suppression of age-related epigenetic changes

· Altered microRNA profiles

GH: growth hormone, IGF-1: insulin-like growth factor-1, mTORC1: mechanistic target of rapamycin complex 1, IL: interleukin, TNF-α: tumor necrosis factor-α.