Isolating the direct effects of growth hormone on lifespan and metabolism in mice

Abstract

Prior studies have shown that interrupting the growth hormone/insulin-like growth factor-I (GH/IGF-I) signaling axis extends laboratory mouse lifespan, but confounding effects of additional gene or hormone deficiencies that exist in commonly used models of GH/IGF-I interruption obscure the specific effect of GH on longevity. We address this issue by using mice with a specific knockout of the GH gene and show that both males and females on a mixed genetic background display extended lifespans resulting from GH deficiency. Our physiological assessment of these mice revealed that in addition to weighing significantly less and displaying significantly greater body fat (as a percentage of body weight), GH deficient mice display significant impairments in glucose metabolism and preferential fat utilization. These data provide strong evidence that GH deficiency is directly responsible for the altered nutrient utilization and extended lifespan that is commonly observed in mouse models of GH/IGF-I interruption.

Keywords: aging; growth hormone; lifespan; longevity regulation; metabolic health; mouse models.

FIGURE 1

Isolated GH deficiency extends lifespan. Kaplan–Meier survival curves for pooled sexes (a), all groups (b), male mice (c) and female mice (d). Statistical analyses of lifespans are provided in Table 1. WT = wild type; KO = GH knockout mice. N = 20 male WT; n = 22 male KO; n = 20 female WT; n = 21 female KO mice.

FIGURE 2

Physiological features of 18‐month‐old mice with isolated GH deficiency. Bodyweight of male (a) and female (b) mice at the indicated ages. Fat and lean mass as percentages of total bodyweight in male (c) and female (d) mice. 24‐h respiratory quotient (RQ; VCO₂/VO₂) measured during indirect calorimetry in male (e) and female (f) mice, with insets representing mean RQ during the dark or light phases as indicated. 24‐h glucose oxidation (GOx) normalized to bodyweight in male (g) and female (h) mice with insets representing mean GOx during dark or light phases as indicated. 24‐h fat oxidation (FOx) normalized to bodyweight in male (i) and female (j) mice with insets representing mean FOx during dark or light phases as indicated. 1 g/kg glucose tolerance test in overnight fasted male (k) and female (l) mice, with insets representing incremental area under the curve (iAUC) analysis where only values above baseline are considered. Data presented as mean ± SEM with points representing individual mice. *p < 0.05; **p < 0.01; ****p < 0.0001 as determined by two‐tailed t‐test with the welch correction applied or by Mann–Whitney U‐test (g, h, k, l). P‐values presented represent the main effect of genotype on fat or lean mass determined by ANCOVA with bodyweight as a covariate (c, d). N = 7–13 (a–d), 9–15 (e–j), or 9–13 (k, l) per group.