Highlighted Grant: Elevating NAD+ Levels in Brain May Improve Aging, Prevent Alzheimer’s Disease

Bill Chen, PhD, professor of Medicine in the UPMC Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine and deputy director for Drug Development at the Aging Institute of the University of Pittsburgh and UPMC, and Stacey Rizzo, PhD, associate professor of Neurobiology in the UPMC Division of Geriatric Medicine and deputy director for Pre-Clinical Studies at the Aging Institute, are the recipients of a new National Institutes of Health-funded U01 award from the National Institute on Aging. For this award, Dr. Chen and Dr. Rizzo will develop therapeutics for age-related diseases or conditions, including Alzheimer’s disease prevention.

The single greatest risk factor for Alzheimer’s disease (AD) is chronological age. As the global population ages, the incidence of memory loss, cognitive decline, and frank AD cases is expected to rapidly increase. This age-dependent increase in AD diagnosis, along with concerns for memory loss and cognitive decline, has fueled intense interest in the development of strategies to slow or reverse aspects of brain aging.

As we age, there is a decline in energy metabolism in the brain. One enzyme involved in energy metabolism, called nicotinamide adenine dinucleotide (NAD⁺), has been shown to decline in aging brains and is also associated with cell death and cognitive impairment. Studies in animal models of aging and AD have shown that restoring youthful NAD+ levels improves cognitive function. Although NAD+ supplements are available at grocery and health food stores, they metabolize very quickly and don’t easily get into the brain.

The Aging Institute Drug Discovery group has discovered novel molecules that activate an enzyme in the brain called nicotinamide phosphoribosyltransferase (NAMPT), which regulates NAD+ levels. These novel molecules can be taken orally and achieve sustained augmentation of NAD+ levels in the brain.  Studies in animal models of aging and AD are in progress to test the efficacy of these compounds to improve cognitive function.

Dr. Rizzo and Dr. Chen have assembled a team of experts in drug discovery, Alzheimer’s disease biology, and preclinical translational studies, including Toren Finkel, MD, PhD, and Yuan Liu, PhD, from the Aging Institute, and University of Pittsburgh Alzheimer’s Disease Research Center’s Oscar Lopez, MD, and Tommy Karikari, PhD. Together, the team aims to advance these compounds into clinical trials within the next five years