Lifespan of long‐lived growth hormone receptor knockout mice was not normalized by housing at 30°C since weaning

Abstract

Growth hormone receptor knockout (GHRKO) mice are remarkably long‐lived and have improved glucose homeostasis along with altered energy metabolism which manifests through decreased respiratory quotient (RQ) and increased oxygen consumption (VO2). Short‐term exposure of these animals to increased environmental temperature (eT) at 30°C can normalize their VO2 and RQ. We hypothesized that increased heat loss in the diminutive GHRKO mice housed at 23°C and the consequent metabolic adjustments to meet the increased energy demand for thermogenesis may promote extension of longevity, and preventing these adjustments by chronic exposure to increased eT will reduce or eliminate their longevity advantage. To test these hypotheses, GHRKO mice were housed at increased eT (30°C) since weaning. Here, we report that contrasting with the effects of short‐term exposure of adult GHRKO mice to 30°C, transferring juvenile GHRKO mice to chronic housing at 30°C did not normalize the examined parameters of energy metabolism and glucose homeostasis. Moreover, despite decreased expression levels of thermogenic genes in brown adipose tissue (BAT) and elevated core body temperature, the lifespan of male GHRKO mice was not reduced, while the lifespan of female GHRKO mice was increased, along with improved glucose homeostasis. The results indicate that GHRKO mice have intrinsic features that help maintain their delayed, healthy aging, and extended longevity at both 23°C and 30°C.

Effects of GH/IGF on the Aging Mitochondria

“…Accordingly, the long-lived GHRKO and Ames mice exhibit improved glucose homeostasis and energy metabolism evidenced by decreased respiratory quotient (RQ) and increased oxygen consumption (VO 2 ). In contrast, bGH mice, with high GH/IGF-1 levels show decreased VO(2) and increased RQ [30,32,33]. Taken together, these animal models suggest that diminished GH/IGF-1 activity improves mitochondrial flexibility and increases the capacity for fat oxidation.…”

“…Taken together, these animal models suggest that diminished GH/IGF-1 activity improves mitochondrial flexibility and increases the capacity for fat oxidation. Interestingly, a recent study found that housing the GHRKO mice at thermoneutral temperature (30 • C) resulted in decreased expression of thermogenic genes in brown adipose tissue (BAT) and elevated core body temperature [32]. However, these mice still maintained their extended longevity phenotype at 30 • C [32], suggesting an intrinsic advantage of mitochondrial function in the GHRKO mice.…”

“…Interestingly, a recent study found that housing the GHRKO mice at thermoneutral temperature (30 • C) resulted in decreased expression of thermogenic genes in brown adipose tissue (BAT) and elevated core body temperature [32]. However, these mice still maintained their extended longevity phenotype at 30 • C [32], suggesting an intrinsic advantage of mitochondrial function in the GHRKO mice. Together, congenital decreases in the GH/IGF signaling in genetically modified mice were associated with reduced levels of ROS, upregulated activity of the mitochondrial ETC, and overall enhanced mitochondrial function [31,34].…”

Energy Metabolism and Aging

“…We are currently investigating the effect of long-term exposure to different eTs on aging-sensitive traits and longevity of wild-type and GH-mutant mice. We have recently reported that life-long exposure to increased (thermoneutral) temperature does not eliminate the longevity advantage of GH-resistant Ghr-/- mice [ 34 ].…”

Genes in human obesity loci are causal obesity genes in C. elegans

“…However, daf-2 mutant animals are resistant to age-related decline and long lived [88][89][90]. Consistently, even though GH receptor knockout (GHRKO) mice have increased fat mass and decreased lean mass, they show improved insulin sensitivity and are long lived [91]. Therefore, to establish an informative model of DIO in C. elegans, it is critical to test whether the increase in fat levels correlates with detrimental effects on health.…”