NAD+ and sirtuins in aging and disease

Abstract

Nicotinamide adenine dinucleotide (NAD(+)) is a classical coenzyme mediating many redox reactions. NAD(+) also plays an important role in the regulation of NAD(+)-consuming enzymes, including sirtuins, poly-ADP-ribose polymerases (PARPs), and CD38/157 ectoenzymes. NAD(+) biosynthesis, particularly mediated by nicotinamide phosphoribosyltransferase (NAMPT), and SIRT1 function together to regulate metabolism and circadian rhythm. NAD(+) levels decline during the aging process and may be an Achilles' heel, causing defects in nuclear and mitochondrial functions and resulting in many age-associated pathologies. Restoring NAD(+) by supplementing NAD(+) intermediates can dramatically ameliorate these age-associated functional defects, counteracting many diseases of aging, including neurodegenerative diseases. Thus, the combination of sirtuin activation and NAD(+) intermediate supplementation may be an effective antiaging intervention, providing hope to aging societies worldwide.

Keywords: NAD(+); nicotinamide mononucleotide; nicotinamide phosphoribosyltransferase; nicotinamide riboside; poly-ADP-ribose polymerases; sirtuins.

Figure 1

Various uses of NAD⁺ for canonical redox and NAD⁺-consuming enzymatic reactions. Whereas NAD⁺ is converted to NADH by many metabolic enzymes (a), it is also used as a cosubstrate for NAD⁺-consuming enzymes, such as poly-ADP-ribose polymerases (PARPs) (b), sirtuins (c), and CD38/157 ectoenzymes (d).

Figure 2

NAD⁺ biosynthetic pathways in various organisms. (a) The de novo pathway from tryptophan and the salvage pathway through nicotinamide (NIC) and nicotinic acid (NA) in the budding yeast Saccharomyces cerevisiae. These pathways are also conserved in invertebrates. Pnc1, nicotinamidase; Npt1, nicotinic acid phosphoribosyltransferase; Nma1, 2, nicotinic acid mononucleotide adenylyltransferase 1, 2; Qns1, NAD synthetase; Qpt1, quinolinic acid phosphoribosyltransfease; Nrk1, nicotinamide ribose kinase 1; Pho5, 8, phosphatase 5, 8; Urh1, Pnp1, nucleosidases; Nnt1, nicotinamide-N-methyltransferase. (b) NAD⁺ biosynthetic pathways in mammals. In mammals, NAD⁺ can be synthesized from tryptophan, nicotinic acid (NA) and nicotinamide (NIC) (two forms of vitamin B3), and nicotinamide riboside (NR). NIC is a predominant NAD⁺ precursor in mammals. The de novo pathway and the NAD⁺ biosynthetic pathway from nicotinic acid are evolutionarily conserved, whereas the NAD⁺ biosynthetic pathway from nicotinamide is mediated by nicotinamide phosphoribosyltransferase (Nampt). While multiple enzymes break NAD⁺ into nicotinamide and ADP-ribose, only sirtuins are shown in this figure. The resultant NIC is also converted to 1-methylnicotinamide by nicotinamide-N-methyltransferase (Nnmt). Mammals have two NR kinases (Nrk1 and 2) and ecto-5′-nucleotidase CD73 to produce NMN and NR, respectively. NaMN, nicotinic acid mononucleotide; NMN, nicotinamide mononucleotide.

Figure 3

Synthesis of NAD⁺ is regulated by the circadian clock and declines with age. The oscillating clock consists of the heterodimeric complex of core circadian transcription factors BMAL1 and CLOCK. The BMAL1/CLOCK complex controls the Nampt gene encoding the key NAD⁺ biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT), rendering NAD⁺ production and SIRT1 activity circadian in peripheral tissues. SIRT1 negatively regulates the transcriptional activity of the BMAL1/CLOCK complex, completing a novel circadian-regulatory feedback loop. In the suprachiasmatic nucleus (SCN), SIRT1 also regulates Bmal1 and Clock expression levels via the complex with PGC-1α and RORα. Chronic inflammation, particularly induced by inflammatory cytokines such as TNF-α, might affect NAMPT-mediated NAD⁺ biosynthesis and BMAL1/CLOCK-mediated circadian transcription in peripheral tissues and the SCN, causing a decline in the amplitude of the circadian clock with age.

Figure 4

Electron transport via NADH generates NAD⁺ in mitochondria and may decline with age. In young mitochondria, NADH, made by the citric acid cycle, readily donates its electrons to complex I of the electron transport chain (ETC) and thereby generates NAD⁺. During the aging process, DNA damage accumulates in the nucleus, causing PARP activation and NAD⁺ reduction. Consequently, SIRT1 activity is reduced, resulting in increased PGC-1α acetylation and decreased TFAM levels. These nuclear events might reduce mitochondrial function in old mitochondria by affecting mitochondrial complex I and other mitochondrial components, or blocking the entry of electrons from NADH into the ETC, thereby creating an NAD deficiency.