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We hypothesized that rapamycin (Rapa), acarbose (ACA), which both increase mouse lifespan, and 17α‐estradiol, which increases lifespan in males (17aE2) all share common intracellular signaling pathways with long‐lived Snell dwarf, PAPPA‐KO, and Ghr−/− mice. The long‐lived mutant mice exhibit reduction in mTORC1 activity, declines in cap‐dependent mRNA translation, and increases in cap‐independent translation (CIT). Here, we report that Rapa and ACA prevent age‐related declines in CIT target proteins in both sexes, while 17aE2 has the same effect only in males, suggesting increases in CIT. mTORC1 activity showed the reciprocal pattern, with age‐related increases blocked by Rapa, ACA, and 17aE2 (in males only). METTL3, required for addition of 6‐methyl‐adenosine to mRNA and thus a trigger for CIT, also showed an age‐dependent increase blunted by Rapa, ACA, and 17aE2 (in males). Diminution of mTORC1 activity and increases in CIT‐dependent proteins may represent a shared pathway for both long‐lived‐mutant mice and drug‐induced lifespan extension in mice., ACA, Rapamycin and 17alfa Estradiol downregulate mTORC1 activity and upregulation of the Cap‐Independent Translation leading to increases in the levels of cap‐Independent associated proteins (involved in mitochondrial function and stress resistance), suggesting a possible mechanism for lifespan extension.

Weight loss is an effective intervention for diminishing disease burden in obese older adults. Pharmacological interventions that reduce food intake and thereby promote weight loss may offer effective strategies to reduce age-related disease. We previously reported that 17α-estradiol (17α-E2) administration elicits beneficial effects on metabolism and inflammation in old male mice. These observations were associated with reduced calorie intake. Here, we demonstrate that 17α-E2 acts through pro-opiomelanocortin (Pomc) expression in the arcuate nucleus (ARC) to reduce food intake and body mass in mouse models of obesity. These results confirm that 17α-E2 modulates appetite through selective interactions within hypothalamic anorexigenic pathways. Interestingly, some peripheral markers of metabolic homeostasis were also improved in animals with near complete loss of ARC Pomc transcription. This suggests that 17α-E2 might have central and peripheral actions that can beneficially affect metabolism cooperatively or independently. Fil: Steyn, Frederik J.. University of Queensland Centre for Clinical Research; Australia. Royal Brisbane & Women’s Hospital; Australia. Wesley Medical Research; Australia Fil: Ngo, Shyuan T.. University of Queensland Centre for Clinical Research; Australia. Royal Brisbane & Women’s Hospital; Australia. Wesley Medical Research; Australia. University of Queensland; Australia Fil: Chen, Vicky Ping. Mayo Clinic; Estados Unidos Fil: Bailey Downs, Lora C.. University of Oklahoma Health Sciences Center; Estados Unidos Fil: Xie, Teresa Y.. University of Queensland; Australia Fil: Ghadami, Martin. University of Queensland; Australia Fil: Brimijoin, Stephen. Mayo Clinic; Estados Unidos Fil: Freeman, Willard M.. University of Oklahoma Health Sciences Center; Estados Unidos Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. University of Michigan Medical School; Estados Unidos Fil: Low, Malcolm J.. University of Michigan Medical School; Estados Unidos Fil: Stout, Michael B.. University of Oklahoma. Health Sciences Center; Estados Unidos