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J Gerontol A Biol Sci Med Sci. 2019 Mar 13. pii: glz069. doi: 10.1093/gerona/glz069. [Epub ahead of print]

Brain Protein Synthesis Rates in the UM-HET3 Mouse Following Treatment with Rapamycin or Rapamycin with Metformin.

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Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, Oklahoma 73104.
Department of Health and Exercise Science, Colorado State University, Fort Collins CO 80523-1582.
Department of Pathology and Paul F. Glenn Center, University of Michigan, 3001 BSRB, Box 2100, Ann Arbor, MI 48109-2100.


Treatment with the mTOR inhibitor, rapamycin (RAP), alone and in combination with the antidiabetic drug, metformin (RAP+MET), extends lifespan in mice. The mechanisms underlying lifespan extension are unclear. One possibility is improved capacity for proteostatic maintenance. We have previously characterized peripheral protein synthesis rates following treatment with RAP. However, it is unknown if RAP+MET elicits similar changes, or if either treatment affects protein synthesis in the brain. We hypothesized that 8 weeks of treatment with RAP and RAP+MET would alter brain protein synthesis rates to reflect proteostatic processes. Using the stable isotopic tracer, deuterium oxide (D2O), we demonstrate in UM-HET3 mice that protein synthesis rates measured in whole brain were unaffected by treatment in young male mice, whereas RAP+MET decreased mitochondrial protein synthesis in young females. Conversely, RAP increased mitochondrial protein synthesis rates in older females. Activity through the AMPK/mTOR pathway was affected in a sex-specific manner in young mice, and minimal changes were observed in the older cohort. Thus, we establish D2O for measurements of biogenesis in the brain. These results provide initial insights into the effects of RAP and RAP+MET on brain protein synthesis. Additionally, these data emphasize that responses to slowed-aging treatments vary with sex and age.


Biology of Aging; Deuterium Oxide; Mitochondria; Protein; mTOR


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