EVIDENCE SUPPORTING CERAMIDE ACCUMULATION AS A NOVEL HALLMARK OF AGING

Abstract Aging is the single greatest risk factor for all major chronic diseases, and thus, understanding the biological mechanisms that modulate aging is critical for the development of health-maximizing interventions. Lipids are small hydrophobic molecules that not only serve as fundamental cellular components, but also act as important cellular signaling molecules, with well-established roles in nutrition, health, and disease. The first longevity gene discovered in yeast, i.e. the longevity-assurance gene (LAG1), encodes an enzyme that synthesizes ceramides, a lipid class that has been associated with insulin resistance, apoptosis, mitochondrial dysfunction, senescence, inflammation, sarcopenia, frailty, among other age-related pathways and phenotypes. Using a number of animal models and methodologies, we have amassed a significant amount of data that place ceramides as a novel major driver of aging. Specifically, we found that: (1) ceramides consistently accumulate with age in circulation and in multiple organs in multiple mouse strains and marmosets; (2) circulating ceramides are dramatically reduced in long-lived isolated growth hormone deficient mice; (3) hepatic ceramides are substantially reduced in old marmosets treated with rapamycin, a well-established anti-aging drug, through a mechanisms that seems to involve an acid ceramidase (ASAH1); (4) low doses of myriocin, a potent inhibitor of ceramide synthesis, improves healthspan (i.e. glucose homeostasis and grip strength) in WT C57BL/6J, Balb/c, and UM-HET3 mice fed with Western diet. In addition, preliminary data suggests that myriocin significantly extends lifespan in mice as well. Taken together, our results place ceramide accumulation as a novel driver of aging.