NAD metabolism in aging and cancer

Abstract

NAD+ and its derivatives NADH, NADP+, and NADPH are essential cofactors in redox reactions and electron transport pathways. NAD serves also as substrate for an extensive series of regulatory enzymes including cyclic ADP-ribose hydrolases, mono(ADP-ribosyl)transferases, poly(ADP-ribose) polymerases, and sirtuin deacetylases which are O-acetyl-ADP-ribosyltransferases. As a result of the numerous and diverse enzymes that utilize NAD as well as depend on its synthesis and concentration, significant interest has developed in its role in a variety of physiologic and pathologic processes, and therapeutic initiatives have focused both on augmenting its levels as well as inhibiting some of its pathways. In this article, we examine the biosynthesis of NAD, metabolic processes in which it is involved, and its role in aging, cancer, and other age-associated comorbidities including neurodegenerative, cardiovascular, and metabolic disorders. Therapeutic interventions to augment and/or inhibit these processes are also discussed. Impact statement NAD is a central metabolite connecting energy balance and organismal growth with genomic integrity and function. It is involved in the development of malignancy and has a regulatory role in the aging process. These processes are mediated by a diverse series of enzymes whose common focus is either NAD’s biosynthesis or its utilization as a redox cofactor or enzyme substrate. These enzymes include dehydrogenases, cyclic ADP-ribose hydrolases, mono(ADP-ribosyl)transferases, poly(ADP-ribose) polymerases, and sirtuin deacetylases. This article describes the manifold pathways that comprise NAD metabolism and promotes an increased awareness of how perturbations in these systems may be important in disease prevention and/or progression.

Dysfunction of metabolic activity of bone marrow mesenchymal stem cells in aged mice

“… 40 Our results showed that NAD+/NADH ratio was decreased in 18 M BMSCs. Since abnormal NAD levels may lead to a variety of diseases, including aging process and inflammatory diseases, 41 , 42 , 43 we hypothesized that aging can weaken the mitochondrial function of BMSCs by reducing the proportion of NAD+. In addition, in eukaryotes, electrons received during glycolysis, oxidative phosphorylation, and oxidation of fatty acids are transferred to the electron transfer chain to form ATP.…”

Cancer treatment-induced NAD+ depletion in premature senescence and late cardiovascular complications

“…These conditions are now seen significantly more often among cancer survivors, years after their cancer diagnosis and treatment. NAD + biosynthetic and metabolic processes are mechanistically involved in aging, cancer, and many age-associated comorbidities [ 184 ] , and therapies aimed at raising intracellular NAD + may remedy accelerated aging and age-associated diseases in cancer survivors. In fact, there are several ongoing clinical studies examining supplementation with NAD + precursors as a therapeutic option for age-related diseases [ Table 1 ].…”

Nicotinamide mononucleotide ameliorates acute lung injury by inducing mitonuclear protein imbalance and activating the UPRmt

“…10,11 As a central cofactor, nicotinamide adenine dinucleotide (NAD + ) could modulate metabolic homeostasis and be a rate-limiting substrate for sirtuin deacetylases. 12 Multiple lines of evidence indicate that NAD + levels perform a crucial role in nuclear-mitochondrial interaction in aging. 6 In addition, the NAD + precursor NMN has been proven to enhance NAD + biosynthesis and ameliorate multiple pathologies in mouse disease models.…”