Rapamycin treatment increases survival, autophagy biomarkers and expression of the anti‐aging klotho protein in elderly mice

Abstract

Abstract Previous investigations have demonstrated that treatment of animals with rapamycin increases levels of autophagy, which is a process by which cells degrade intracellular detritus, thus suppressing the emergence of senescent cells, whose pro‐inflammatory properties, are primary drivers of age‐associated physical decline. A hypothesis is tested here that rapamycin treatment of mice approaching the end of their normal lifespan exhibits increased survival, enhanced expression of autophagic proteins; and klotho protein—a biomarker of aging that affects whole organism senescence, and systemic suppression of inflammatory mediator production. Test groups of 24‐month‐old C57BL mice were injected intraperitoneally with either 1.5 mg/kg/week rapamycin or vehicle. All mice administered rapamycin survived the 12‐week course, whereas 43% of the controls died. Relative to controls, rapamycin‐treated mice experienced minor but significant weight loss; moreover, nonsignificant trends toward decreased levels of leptin, IL‐6, IL‐1β, TNF‐α, IL‐1α, and IGF‐1, along with slight elevations in VEGF, MCP‐1 were observed in the blood serum of rapamycin‐treated mice. Rapamycin‐treated mice exhibited significantly enhanced autophagy and elevated expression of klotho protein, particularly in the kidney. Rapamycin treatment also increased cardiomyocyte Ca2+‐sensitivity and enhanced the rate constant of force re‐development, which may also contribute to the enhanced survival rate in elderly mice.

Keywords

• aging
• autophagy
• klotho
• rapamycin
• senolytics