High intensity interval training and nicotinamide riboside treatment to enhance functional capacity and reduce frailty during aging Frailty is a condition of poor physiological reserve that increases susceptibility to falls, hospitalization, disability, and mortality. The incidence of frailty increases after the age 65, growing from 10% to as many as 50% of those 85 years or older; therefore over 9 million veterans are either frail or at risk for frailty. Exercise has proven benefits for frailty, yet older adults rarely attain the recommended 150 minutes a week of moderate intensity continuous exercise (MICT), as lack of time and fear of injury are the most common barriers. High intensity interval training (HIIT) is emerging as an alternative as it can safely provide strength and endurance benefits with lower time commitments than (MICT). Additionally, exercise can boost nicotinamide adenine dinucleotide (NAD+) levels, an essential co-enzyme for mitochondrial and cellular function that declines with aging. Supplementation with nicotinamide riboside (NR) can also increase NAD+, and both interventions are gaining support as a therapeutic strategy for aging and related conditions such as frailty. Therefore, the goals of this project are: 1) compare the impacts of HIIT versus MICT on physical performance, frailty, and lifespan, and 2) examine whether NR can augment the benefits in response to HIIT or MICT. HIIT ± nicotinamide riboside (NR) reduces frailty during aging. The premise for this study is based upon our recently published study demonstrating that a 10 minute long, 3-days a week HIIT regimen enhances physical performance and reduces frailty in aged mice 28 months of age (equivalent to a 65-80 year old human). The hypothesis of this proposal is that HIIT exercise will reduce frailty and increase lifespan, in a manner that is superior to MICT, and that these benefits will be enhanced with NR supplementation. To test this hypothesis, 24-month-old mice will be given HIIT or MICT regimens until end of life to assess survival benefits, while also being longitudinally assessed for improvement in physical performance and frailty. Next, in addition to HIIT or MICT, aged mice will receive placebo or NR supplementation and examined at 28 months of age to assess impacts upon muscle physiology, physical performance, and frailty. This study will provide a clinical trial blueprint for successful implementation of HIIT and NR supplementation in humans, thus permitting the development of personalized interventions that improve the quality of life of the aging veteran population.