Impact of a Novel Secreted Enzyme J18 on Healthspan and Lifespan

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Project Summary/Abstract This proposal outlines an integrated training and research plan for Dr. Shangang Zhao to complete further academic training under the mentorship of Dr. Philipp E. Scherer and transition to an independent investigator specializing in the field of metabolism and geroscience. The overall objective of the research proposal is to explore the impact of a novel secreting protein, referred to as “J18” in healthspan and lifespan. Highly expressed in salivary glands both in mouse and human, large amounts of glycosylated J18 are secreted into saliva, an easily accessible biomaterial for multiple biomedical assays. J18 displays a unique pattern of regulation: Its level is increased in metabolically healthy states, such as fasting and calorie restriction, while decreased in metabolically adverse conditions, such as aging and obesity. With evidence accumulated from our J18 transgenic and knockout mouse models, we found that J18 is a novel lipid hydrolase, targeting on a unique lipid class to mediate its potent effects in promoting metabolic health. In addition, preliminary data suggest that increasing J18 level in our liver J18 transgenic mouse seems to prolong life span and deficiency of J18 in our J18 global KO mice reduces median life span. The basic principle of J18 physiology has been conserved remarkably well from mouse to human. These findings helped us define the physiological role of a previously unknown protein J18 in metabolic aspect. We will take advantage of our newly generated tissue specific transgenic and KO mouse models to manipulate systemic J18 level, along with the J18 targeted- unique lipid class, and will address: 1) saliva-derived J18 may be a potential and novel aging biomarker to allow easy prediction of an individual's life expectancy; 2) the impact of J18 in healthspan and lifespan. Combined, these studies will provide significant new insights into the physiological effects of J18 in healthspan and lifespan. The proposed role of J18 as a potential aging biomarker meets the urgent need for an easily assayable, validated and effective aging biomarker, and will greatly advance research in geroscience. Under the auspices of the University of Texas Southwestern Medical Center, along with the previous experience gained in studying the impact of adiponectin in healthspan, I will be mentored by internationally recognized leaders in the metabolism, and advised by the top aging experts, which will greatly facilitate the transition of my research career toward an independent investigator position.