Aging increases the prevalence of nonalcoholic fatty liver disease (NAFLD) which is escalating markedly in the United States. NAFLD includes a spectrum of disorders ranging from hepatic steatosis to steatohepatitis and even hepatocellular carcinoma in individuals who do not have a history of alcohol abuse. NAFLD is also a rapidly rising indication for liver transplantation and is strongly associated with cardiovascular disease (CVD), which is the leading cause of death in these patients. Pathogenetic mechanisms involved in the development and progression of NAFLD are poorly understood and better mechanistic understanding could help identify new approaches for effective therapies. Previous studies delineating mechanisms involved in NAFLD have largely used rodent models which demonstrated that hepatic steatosis and activation of the mechanistic target of rapamycin (mTOR) pathway increases with aging. Unfortunately, rodents fail to recapitulate many of the features of this naturally-occurring human disease. The common marmosets (Callithrix jacchus) are small, short-lived nonhuman primates (NHP), which have a more analogous physiology to humans making them more suitable to elucidate mechanisms involved in the development of human disease, particularly with aging. Our group is currently testing whether rapamycin, an inhibitor of mTOR, can extend lifespan and improve healthy aging in the marmoset. A single study has previously reported NAFLD in marmosets; however, the design of this study made it challenging to interpret effects of the naturally-occurring disease in this model. Our aging marmoset cohort provides a unique well-controlled model for studying the effects of aging on NAFLD that cannot be performed in humans or rodents. Moreover, for the first time we can investigate the role of mTOR (through inhibition by rapamycin) on the progression of this disease in NHP, a major step in bridging the knowledge gap in translational potential. We hypothesize that hepatic steatosis and serum biomarkers of aberrant lipid metabolism and NAFLD in marmosets increase with aging and an anti- aging intervention can prevent or delay the development of NAFLD. To test our hypothesis, we propose the following:
Specific Aim 1) To determine the extent to which alterations in hepatic steatosis and structure, and changes in lipid metabolism occur with age in the common marmoset.
Specific Aim 2) To elucidate the extent to which a pharmaceutical intervention to the aging process affects the development of NAFLD in the marmoset. Liver and cardiac imaging as well as serum lipidomics and biomarkers of NAFLD will be measured in young and old marmosets, and the results compared with those in old marmosets treated with an anti-aging intervention rapamycin. Significance and Innovation: Results of the proposed studies will provide insights into the underlying mechanisms of aging and development of NAFLD. The successful establishment of this unique NHP model of age-related NAFLD, and identifying the effects of an anti-aging intervention, will drive novel pre-clinical interventions/treatment trials for NAFLD and associated diseases like CVD.
Delineating the mechanisms that drive the development of NAFLD with aging are a challenge with existing experimental models and as such there is a lack of effective therapies. In this exploratory research proposal, we will investigate for the first time the feasibility of the common marmoset as a novel non-human primate model of age-related NAFLD. In addition, we will use a cohort of marmosets undergoing an anti-aging intervention to initiate translational efforts towards delaying development and progression of NAFLD in human populations.
