Modulating NAD+ metabolism, from bench to bedside

Abstract

Discovered in the beginning of the 20^th century, nicotinamide adenine dinucleotide (NAD⁺) has evolved from a simple oxidoreductase cofactor to being an essential cosubstrate for a wide range of regulatory proteins that include the sirtuin family of NAD⁺-dependent protein deacylases, widely recognized regulators of metabolic function and longevity. Altered NAD⁺ metabolism is associated with aging and many pathological conditions, such as metabolic diseases and disorders of the muscular and neuronal systems. Conversely, increased NAD⁺ levels have shown to be beneficial in a broad spectrum of diseases. Here, we review the fundamental aspects of NAD⁺ biochemistry and metabolism and discuss how boosting NAD⁺ content can help ameliorate mitochondrial homeostasis and as such improve healthspan and lifespan.

Keywords: aging; metabolic disorders; neurodegeneration; nicotinamide adenine dinucleotide; poly ADP‐ribose polymerase.

Figure 1. Pathways modulating NAD⁺ content in mammals

Intermediates of the amidated and deamidated routes are depicted in yellow and green, respectively. NAD ⁺‐consuming enzymes competing with sirtuins for NAD ⁺ availability are depicted in orange. Purple color indicates metabolites not recycled in the NAD ⁺ synthesis pathway.

Figure 2. Therapeutic potential of NAD ⁺ boosting in humans based on findings in animal studies

NAFLD, non‐alcoholic fatty liver disease; AFLD, alcoholic fatty liver disease.