Does Rapamycin Treatment Alter Age-Associated Changes in Liver Proteome Profile of a Unique Non-Human Primate Model?

The common marmoset ( Callithrix jacchus) is a small, short-lived non-human primate, which has an analogous physiology to humans making it more suitable to elucidate mechanisms involved in the development of human diseases, particularly with aging. The objectives of this study were to identify for the first time whether 1) there are age-related changes in liver proteome profile of the marmoset, and 2) these changes can be reversed by rapamycin, a drug known to slow aging in rodents. We based these objectives on our own previously observed significant age-associated changes in specific lipid classes in serum and liver tissues of marmosets. We hypothesized that the liver proteome of marmosets will be altered with age, and treatment with rapamycin will prevent many of these age-associated changes. To test our hypothesis, we performed liver tissue proteomics to identify proteins that change with age. Our data reveal that the liver proteome of the old untreated marmosets is distinct compared to that of the young untreated or the old animals treated with rapamycin. Interestingly, we find a significant increase in the enzyme ceramidase (ASAH1) in old marmosets treated with rapamycin compared to the old untreated animals. Rapamycin treatment increased ceramidase levels in old marmosets to that observed in young untreated animals. Ceramidase mediates the hydrolysis of ceramides. Our lipidomic results previously revealed that there is an age-associated increase in hepatic ceramides which is significantly reduced upon treatment of marmosets with rapamycin. Accumulation of ceramides has been linked to insulin resistance, mitochondrial dysfunction, inflammation, and activation of triglyceride storage which results in the development and progression of diseases like nonalcoholic fatty liver disease (NAFLD). Taken together, our results suggest that treatment with rapamycin increases hepatic ceramidase levels which may reduce age-associated increases in ceramide levels and consequently lead to improved hepatic function and reduced lipid accumulation. Further analysis of the hepatic proteome profile revealed a decrease in choline phosphotransferase (CHPT1) and fetuin A in young untreated animals or old animals treated with rapamycin compared to old untreated animals. Choline phosphotransferase (CHPT1) catalyzes the synthesis of phosphatidylcholine which is a regulator of cell membrane integrity while fetuin A is a proinflammatory protein produced by hepatocytes. Both these proteins also play important roles in the development of NAFLD. We are now performing pathway analysis to narrow down the pathways that may play an important role in age-associated hepatic fat accumulation, a critical step in the development of NAFLD. This work was supported by NIA/NIH 1R21 AG067164-01 (AK, AS) and a NIA/NIH P30AG044271 San Antonio Claude D. Pepper Older Americans Independence Center, PESC Pilot Grant Award (AK). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.