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MUFA-SIRT1 signaling as a central node regulating healthspan

MUFA-SIRT1信号作为调节健康寿命的中心节点

基本信息

批准号：
10092409
负责人：
Douglas G Mashek
金额：
$ 31.57万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10092409
关键词：
Aging Animal Model Animals Attention Biogenesis Biological Biology Caloric Restriction Catabolism Cell Nucleus Cell physiology Charge Clinical Trials Data Deacetylation Development Diet Dietary Factors Dietary Fats Dietary Intervention Disease Dose FRAP1 gene Fasting Glean Gold Health Health Benefit Human Link Lipids Lipolysis Literature Longevity Machine Learning Macronutrients Nutrition Maps Mediating Mediterranean Diet Metabolism Mitochondria Modeling Monounsaturated Fatty Acids Mus Nutrient Nutritional Oils Olive oil preparation Olives - dietary Outcome Oxidation-Reduction PPAR alpha Pathway interactions Peptides Pharmacologic Substance Proteins Proteomics Reaction Research Resveratrol Role SIRT1 gene Signal Transduction Signaling Molecule Sirtuins Source Testing Therapeutic Time Work analog base cofactor deacylation detection of nutrient epidemiology study healthspan healthy aging improved innovation interest middle age mutant mouse model novel nutrient deprivation polyphenol prevent red wine response

项目摘要

PROJECT SUMMARY Macronutrients serve a multitude of roles beyond provision of energy, with numerous nutrients and/or their downstream metabolites acting as signaling molecules to coordinate cellular metabolism and function. Indeed, numerous nutrient sensing pathways (e.g. mTOR, AMPK and sirtuins) have evolved allowing us to respond to specific nutrients/metabolites, which in turn impacts healthspan. Sirtuins are largely thought to be driven by redox, whereby high levels of NAD, a cofactor in the sirtuin reaction and indicator of low energy charge, drives sirtuin-catalyzed deacylation of target proteins. SIRT1, the most-studied sirtuin, is a key nutrient sensing node that regulates a plethora of cellular functions to promote lifespan extension and healthy aging. As a result, there is immense interest in the use of SIRT1 activating compounds (STACs) to prevent or treat a wide range of aging-related disease. The links between dietary macronutrients, nutrient sensing and healthspan have historically focused upon caloric or protein restriction with limited attention given to dietary lipids. However, a small and growing body of literature has linked monounsaturated fatty acids (MUFAs) to improved healthspan. In addition to positive effects on lifespan and healthy aging in model organisms, dietary MUFAs have been linked to wide-ranging health benefits in epidemiological studies and, since they are a primary constituent of olive oil, thought to contribute to the benefits of the Mediterranean Diet. Despite these studies, little is known about the biological underpinnings through which MUFAs elicit their beneficial health effects. We have previously shown that lipid droplet catabolism (i.e. lipolysis) increases SIRT1 and downstream PGC-1a/PPAR- a signaling as a means to increase mitochondrial biogenesis and function during times of nutrient deprivation. Our preliminary data show for the first time that MUFAs released specifically from lipolysis are trafficked to the nucleus where they allosterically activate SIRT1 towards select acetylated peptide substrates. This discovery makes MUFAs the first-known endogenous allosteric activators of SIRT1. Moreover, we show that MUFAs activate SIRT1 through a similar mechanism to resveratrol suggesting that MUFA signaling may modulate the response to exogenous SIRT1 activators. Based on these preliminary data, the objective of this application is to further characterize the role of MUFAs as endogenous SIRT1 activators. We hypothesize that MUFAs selectively activate SIRT1 to modulate the response to numerous dietary interventions known to impact healthspan. To test our objective, we propose the following aims: Aim 1: To define how MUFAs modulate SIRT1 substrate selectivity. Aim 2: To characterize the SIRT1-dependent effects of MUFAs/olive oil on healthspan. Aim 3: To determine the contribution of MUFAs in mediating the response to STACs or caloric restriction. Upon completion of the proposes studies, we will have further expanded our understanding of SIRT1 biology allowing for refined approaches to activate SIRT1 to promote healthy aging.

项目总结