NAD+ in Aging: Molecular Mechanisms and Translational Implications

Abstract

The coenzyme NAD⁺ is critical in cellular bioenergetics and adaptive stress responses. Its depletion has emerged as a fundamental feature of aging that may predispose to a wide range of chronic diseases. Maintenance of NAD⁺ levels is important for cells with high energy demands and for proficient neuronal function. NAD⁺ depletion is detected in major neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, cardiovascular disease and muscle atrophy. Emerging evidence suggests that NAD⁺ decrements occur in various tissues during aging, and that physiological and pharmacological interventions bolstering cellular NAD⁺ levels might retard aspects of aging and forestall some age-related diseases. Here, we discuss aspects of NAD⁺ biosynthesis, together with putative mechanisms of NAD⁺ action against aging, including recent preclinical and clinical trials.

Keywords: DNA repair; NAD(+); aging; autophagy; clinical application; metabolism; mitophagy; neurodegenerative disorder; stem cell.

Figure 1.. NAD⁺ Biosynthetic Pathways.

NAD⁺ is synthesized via three major pathways in mammals; the de novo biosynthesis from Tryptophan (Trp) (to the left) in a total of 8 steps. Four steps are shown in this figure, including the conversion of tryptophan to formylkinurenine (FK), and a spontaneous reaction conversion of ACMS to quinolinic acid (Qa). Qa is then converted to NAMN by QPRT. The second pathway is the Preiss-Handler pathway initiated by the conversion of nicotinic acid (NA) to NAMN by NAPRT. NANM, an intermediate in both the de novo biosynthesis and the Preiss-Handler pathway is then converted to form NAAD by NMNATs. The link between Trp and NA shown here is the human pathway. The last step of these pathways is the conversion of NAAD to NAD⁺ by NADS. The third pathway is the Salvage pathway, generating NAD⁺ from nicotinamide riboside (NR), which also includes the recycling of NAM back to NAD⁺ via NMN. Extracellularly, NAD⁺ or NAM can be converted to NMN, which is in turn dephosphorylated to NR, possibly by CD73. NR is transported into the cell via unknown mechanism (possibly nucleoside transporters), where it is phosphorylated by the NRK1 or NRK2 forming NMN. NMN is then converted to NAD⁺ by NMNATs. The dashed lines indicate that the mechanism and involved proteins are not known. The lower part of the figure shows the major NAD⁺ consuming enzymes. From left: The cyclic ADP-ribose synthases (cADPRSs) CD38 and CD157 hydrolyze NAD⁺ to NAM; in addition, CD38 can degrade NMN to NAM, removing NMN from the NAD⁺ synthesis. PARPs, especially PARP1 and PARP2 use NAD⁺ as a co-substrate to PARylate target proteins, generating NAM as a by-product. The deacetylation activity of SIRTs SIRT1, SIRT3 and SIRT6 depend on NAD⁺, generating NAM as a byproduct, which can inhibit the activity of SIRTs. The enzyme NNMT methylates NAM, using SAM as a methyl-donor. This removes NAM from recycling, and indirectly affects NAD⁺ levels. Abbreviations: ACMS: 2-amino-3-carboxymuconate semialdehyde; cADPRSs: cyclic ADP-ribose synthases; FK: formylkinurenine; IDO: indoleamine 2,3-dioxygenase; Me-NAM: Methylated nicotinic acid mononucleotide; NA: nicotinic acid; NAAD: nicotinic acid adenine dinucleotide; NAD⁺: nicotinamide adenine dinucleotide; NADS: NAD⁺ synthase; NAM: nicotinamide; NAMN: nicotinic acid mononucleotide; NAMPT: nicotinamide phosphoribosyl transferase (including extracellular and intracellular ones); NAPRT: nicotinic acid phosphoribosyl-transferase; NMN: nicotinamide mononucleotide; NMNATs: nicotinic acid mononucleotide transferases; NR: nicotinamide riboside; NRKs: nicotinamide riboside kinases; PARPs: Poly(ADP-ribose) polymerases; QPRT: quinolinate phosphoribosyltransferases; SIRTs: sirtuins; SAM: S-adenosyl methionine; TDO: tryptophan 2,3-dioxygenase; Trp: tryptophan.