Effects of rapamycin on growth hormone receptor knockout mice

Abstract

It is well documented that inhibition of mTORC1 (defined by Raptor), a complex of mechanistic target of rapamycin (mTOR), extends life span, but less is known about the mechanisms by which mTORC2 (defined by Rictor) impacts longevity. Here, rapamycin (an inhibitor of mTOR) was used in GHR-KO (growth hormone receptor knockout) mice, which have suppressed mTORC1 and up-regulated mTORC2 signaling, to determine the effect of concurrently decreased mTORC1 and mTORC2 signaling on life span. We found that rapamycin extended life span in control normal (N) mice, whereas it had the opposite effect in GHR-KO mice. In the rapamycin-treated GHR-KO mice, mTORC2 signaling was reduced without further inhibition of mTORC1 in the liver, muscle, and s.c. fat. Glucose and lipid homeostasis were impaired, and old GHR-KO mice treated with rapamycin lost functional immune cells and had increased inflammation. In GHR-KO MEF cells, knockdown of Rictor, but not Raptor, decreased mTORC2 signaling. We conclude that drastic reduction of mTORC2 plays important roles in impaired longevity in GHR-KO mice via disruption of whole-body homeostasis.

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

“…Average longevity of GHRKO mice housed at 23°C in the current study resembled the values measured in the previous studies (Bonkowski et al, ; Coschigano, Clemmons, Bellush, & Kopchick, ; List et al, ). Similarly, longevity of WT mice from the same strain housed at 23°C appears to resemble the values recorded in the previous studies (Bonkowski et al, ; Fang et al, ). Interestingly, data available to date suggest that chronic housing at 30°C has no, or very little, impact on the longevity of WT mice from this genetically heterogeneous strain.…”

“…GHRKO mice are GH‐resistant, small, obese, hypoinsulinemic, and highly insulin sensitive. We have previously reported that at 23°C, GHRKO mice had improved glucose metabolism indicated by lower fasting glucose, improved glucose clearance (measured by glucose tolerance test [GTT]), and insulin sensitivity (measured by insulin tolerance test [ITT]) compared to wild‐type mice (Bonkowski et al, ; Bonkowski, Rocha, Masternak, Al Regaiey, & Bartke, ; Fang et al, ). Here, glucose homeostasis was examined at 13 months of age after housing at 30°C for approximately 1 year postweaning.…”

“…GTT or ITT was carried out as described previously (Fang et al, ). Sixteen‐hour‐fasted mice underwent GTT by intraperitoneal (i.p.)…”

Anti-Aging Effects of Calorie Restriction (CR) and CR Mimetics Based on the Senoinflammation Concept

“…In addition, mTOR promotes growth and aging in C. elegans [167], D. melanogaster [168], S. cerevisiae [169], as well as in mice [170,171] and rat [172,173] models. Further, it modulates glucose and lipid metabolism [174,175]. Rapamycin prevents insulin resistance in humans [176], reduces insulin resistance in hyperinsulinemia rats [177,178], and normalizes glucose metabolism in diabetic mice [179,180].…”

Mammalian Target of Rapamycin

“…In fact, many of these diseases have been associated with dysregulation of mTOR signaling, importantly through imbalanced dietary intake. 7e9 More evidence for the role of diet in regulating mTOR signaling comes from studies of calorie restriction, which have been shown to extend life span, 10 in a diverse array of eukaryotes ranging from yeasts to humans. 11,12 Therefore, gaining a deeper understanding of mTOR's role and function in these poorly defined processes is critical to understanding disease pathogenesis in tissues where mTOR plays a central role.…”