Project Summary/Abstract: The overarching goal of Dr. Richardson’s research has been to identify the molecular pathways that lead to aging with the purpose of generating therapies that retard aging, delay/prevent age-related diseases, and improve the health of the elderly. His VA research has focused on the role oxidative stress and damage play in aging that has led to his recently funded VA Merit grant, which studies the role of inflammation in aging. Chronic, low-grade inflammation is a hallmark of aging and is a major risk factor for most age-related diseases, e.g., cancer, health disease, Alzheimer’s disease, etc. Necroptosis is a recently identified pathway of programmed necrosis that induces cell death through the lysis of cells, resulting in the release of damage-associated molecular patterns, which are potent inducers of inflammation. Using genetical manipulations that reduce necroptosis in mice, Dr. Richardson will determine if reducing necroptosis attenuates the age-related increase in chronic inflammation and leads to increased lifespan, improved healthspan, and reduced age-related pathology in the mice. Dr. Richardson also is PI on three NIH grants. His first NIH grant studies dietary Restriction (DR), which has been shown to increase the lifespan of a wide variety of organisms ranging from invertebrates to rodents. Therefore, DR has been viewed as a universal aging intervention. However, a study in 2010 reported that the genotype of an animal was a major determinant in the ability of the animal to respond to DR, e.g., two-thirds of the 41 recombinant inbred (RI) lines of mice studied either did not respond or showed reduced lifespan when fed DR. The overall goal of his NIH grant is to explore the interaction between genotype and the level of DR using four of the RI lines of mice reported to show a decrease in lifespan when fed a DR diet. The lifespan and pathology associated with aging is being measured in male and female mice fed either ad libitum or 60% ad libitum (DR). The current data indicate that in contrast to the previous report, DR increases the lifespan of the RI lines of mice, supporting the view that DR is a universal aging intervention. Dr. Richardson’s second NIH grant is in response to an RFA to develop measures of resilience in mice that can be surrogates for increased longevity and healthspan. He is developing four measures of resilience that are relatively simple, inexpensive, non-invasive, and can be performed in mice in vivo. Currently, his laboratory is studying the response of age, DR, and rapamycin on resilience to the following: treadmill exercise, recovery from anesthesia, carrageenan-induced inflammation, and recovery from oxidative stress. In a recently funded third NIH grant, Dr. Richardson is studying the potential role epigenetics plays in the anti-aging mechanism of DR. Recently, he showed that short-term DR induces changes in DNA methylation in intestinal mucosa in the promoter of the Nts 1 gene. Th...