Mechanisms and Effects of NAD+ Modulation in Inflammation and Aging

Abstract

Levels of nicotinamide adenine dinucleotide (NAD+) fall during aging for reasons that are not fully understood. Caloric restriction, the most effective intervention to slow aging, prevents this fall, and pharmacological restoration of NAD+ levels slows or reverses many aspects of age-related disease. In Chapter 2, I identify the enzyme PARP14, induced by inflammation, as a novel driver of declining NAD+ levels. As chronic inflammation is a conserved characteristic of aging, we examined the effect of inflammatory stimuli on NAD+ levels in bone marrow-derived macrophages. Toll-like receptor agonists were found to induce a drop in NAD+ levels. Through pharmacological and genetic approaches, we identified PARP14 as necessary for such NAD+ destruction. We also identified a potent, synthetic NAD+ precursor, nicotinamide riboside hydride. PARP14 levels increase during sepsis and PARP14 inhibition or deletion restored NAD+ to normal levels in spleens of septic mice. PARP14 also increased during aging, and PARP14 inhibition restored splenic NAD+ to youthful levels. Our results suggest that PARP14 inhibitors and potent synthetic NAD+-precursors are promising drug candidates for the treatment of age-related diseases. In Chapter 3, I explore the interaction between NAD+ levels and expression levels of the sirtuin gene family on aspects of aging. Sirtuins are NAD+ sensors that promote health and longevity. We boosted the expression of the entire sirtuin gene family with adeno-associated viral vectors in 20-month old mice, in combination with dietary supplementation with the NAD+ precursor NMN. We observed a protection from body weight loss, a protection from muscle weight loss, and a trend towards increased longevity. In Chapter 4, I describe approaches to estimate biological age based on non-invasive assessment of frailty. We used the frailty index (FI) to assess frailty longitudinally in mice until their natural deaths, and created a model to predict chronological age, termed FRIGHT Age, and a model to predict mortality, termed the AFRAID score. These models may be useful as early indicators of the effectiveness of aging interventions. Taken together, this dissertation provides new insight into novel regulatory mechanisms and effects of NAD+ dynamics during inflammation and aging.