MUFA-SIRT1 signaling as a central node regulating healthspan

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Diet is a major regulator of most if not all aging-related diseases. The Mediterranean Diet is widely regarded as the gold standard of diets due to its ability to reduce a wide range of aging-related diseases resulting in improved healthspan. While numerous components of the Mediterranean Diet likely contribute to its health benefits, extra virgin olive oil has emerged as a major constituent underlying these effects. Indeed, both epidemiological and interventional studies have linked extra virgin olive oil consumption to improved health benefits including reductions in cognitive decline and neurodegenerative diseases. Extra virgin olive oil is largely comprised of oil enriched in monounsaturated fatty acids (MUFA) as well as a diverse class of phenolic compounds. Interestingly, both MUFAs and the many phenols found in extra virgin olive oil have been shown in pre-clinical and clinical trials to have positive effects on cognition and in the prevention of Alzheimer’s Disease and related dementias. Our laboratory has found the MUFAs are allosteric activators of sirtuin 1 (SIRT1), a key nutrient sensing protein that regulates a plethora of pathways controlling aging-related pathologies. Numerous phenols, including some found in extra virgin olive oil, also can activate SIRT1 to improve aging related outcomes and, as we have shown, these small molecules likely activate SIRT1 through the same mechanism as MUFAs. Thus, deciphering the health benefits of MUFAs vs non-lipid components in olive oil, and the extent to which SIRT1 allosteric activation mediates these effects, would greatly advance our understanding of the Mediterranean Diet, the health benefits of olive oil, and SIRT1 biology. In addition, MUFA signaling to SIRT1 occurs upon conditions that stimulate lipolysis such as fasting or caloric restriction suggesting that diet composition and eating patterns are co-dependent. Based upon these data, we hypothesize that MUFAs and extra virgin olive oil phenols will prevent declines in cognition and neurological impairments via SIRT1 activation and will modulate the effects of caloric restriction. To test our hypothesis, we will conduct the following two aims. 1) To test the effects of extra virgin olive oil MUFAs and phenols signaling via SIRT1 on aging-related neurodegeneration. In this aim, we will feed wild-type or SIRT1 E222K mice, which lack responsiveness to SIRT1 allosteric activators, diets enriched in olive oil with high or low phenolic content and comprehensively characterize neurological function and cognition. 2) To determine impact of olive oil and caloric restriction alone or in combination on neurodegeneration. We will feed middle- aged mice diets with low or high MUFA along under ad libitum or caloric restriction conditions to determine if the interaction between these two dietary interventions impacts cognition and neural function. We expect these studies to advance our understanding into how dietary lipids and caloric restriction impact the aging brain, which will help define new mechanisms underlying neurodegenerative diseases and open new therapeutic avenues targeting lipid metabolism.