PROJECT SUMMARY Nutrient sensing pathways (mTOR, AMPK, sirtuins) are core components underlying the aging process, linking post-translation modifications critical to cellular function to environmental factors. To date, research in this area has largely focused on interventions such as caloric or protein restriction that drive lifespan or slow aging-related morbidities. An emerging area of research derived from these intervention studies highlights the potential of fat catabolism, the lipolytic degradation of triacylglycerol stored within lipid droplets (LDs), as a major factor during the aging process. Despite accumulating evidence for a beneficial role of lipolysis, the mechanism that links lipolysis to healthspan is poorly understood. Dr. Charles Najt recently identified the LD protein perilipin 5 (PLIN5) to be the critical link between lipolysis and the nutrient sensor SIRT1; loss of PLIN5 ablated adipose-triglyceride lipase (ATGL)-mediated activation of SIRT1. Our published and preliminary data show that in response to cAMP/PKA signaling, which is driven by fasting or caloric restriction (CR), PLIN5 binds and transports monounsaturated FAs (MUFAs) produced from lipolysis to the nucleus. Once in the nucleus, MUFAs liberated from PLIN5 allosterically activate SIRT1. These results provide an underlying mechanism explaining the growing body of literature that has linked MUFAs to improved healthspan. Yet, while CR or intermittent fasting, interventions shown to increase healthspan, increase PLIN5 expression, little is known about the direct role of PLIN5 in healthspan or longevity. A few studies indicate Plin5 expression peaks around middle age, slowly decreasing over time or drastically decreases in oxidative tissues during metabolic disease, yet the cause of these changes or the impact of decreased Plin5 expression is unknown. This is a significant gap in knowledge as PLIN5 has been shown to mitigate metabolic disease but its ability to influence health or lifespan has yet to be established. In the current proposal we aim to fill this gap in knowledge, providing significant results directly linking PLIN5 lipid signaling and metabolic flexibility to healthy aging. We hypothesize that PLIN5 signaling in the nucleus is critical for maintaining metabolic health during aging, whereas breakdown of this signaling axis results in age-related morbidities, decreasing healthspan. Moreover, we propose that maintaining PLIN5 signaling throughout life, will increase healthspan and enhance dietary interventions. This hypothesis is significant as no study to date has determined the role of PLIN5 during aging or what role it has in healthspan promoting interventions such as the Mediterranean Diet, which is considered the ideal diet for healthy aging. By focusing on a novel niche in lipid signaling and directly relating PLIN5 to health and lifespan, we are establishing strong fundamental biology that is extremely relevant to healthy aging. The proposed studies are well-aligned with the funding areas listed as of special interest in aging, allowing the applicant to progress to independent investigator status in a new and growing field.

NARRATIVE The goal of this application is to dissect out the unique functions of Perilipin5 and its role in healthspan and longevity-inducing interventions. This work is a significant as Perilipin5 has been shown to mitigate metabolic disease but its ability to influence health or lifespan has yet to be established. By focusing on a novel niche in lipid signaling and directly relating Perilipin5 to health and lifespan, we are establishing strong fundamental biology that is extremely relevant to healthy aging and healthspan promoting interventions.