Role of NAD+ in regulating cellular and metabolic signaling pathways

Abstract

Background: Nicotinamide adenine dinucleotide (NAD⁺), a critical coenzyme present in every living cell, is involved in a myriad of metabolic processes associated with cellular bioenergetics. For this reason, NAD⁺ is often studied in the context of aging, cancer, and neurodegenerative and metabolic disorders.

Scope of review: Cellular NAD⁺ depletion is associated with compromised adaptive cellular stress responses, impaired neuronal plasticity, impaired DNA repair, and cellular senescence. Increasing evidence has shown the efficacy of boosting NAD⁺ levels using NAD⁺ precursors in various diseases. This review provides a comprehensive understanding into the role of NAD⁺ in aging and other pathologies and discusses potential therapeutic targets.

Major conclusions: An alteration in the NAD⁺/NADH ratio or the NAD⁺ pool size can lead to derailment of the biological system and contribute to various neurodegenerative disorders, aging, and tumorigenesis. Due to the varied distribution of NAD⁺/NADH in different locations within cells, the direct role of impaired NAD⁺-dependent processes in humans remains unestablished. In this regard, longitudinal studies are needed to quantify NAD⁺ and its related metabolites. Future research should focus on measuring the fluxes through pathways associated with NAD⁺ synthesis and degradation.

Keywords: Aging; Cancer; Metabolism; NAD(+); Neurodegeneration; Sirtuins.

Graphical abstract

Figure 1

Representation of NAD⁺biosynthesis pathways. Biosynthesis pathways and cellular metabolism of NAD⁺. NAD precursors such as NR, NA, NAM, and Trp provided by diet can be converted into NAD via three pathways. In the Preiss-Handler pathway, NA is converted into NAMN by NAPRT, NAMN is converted into NAAD by NAD by NMNATs, and NAAD is converted into NAD by NADSYN. In the de novo synthesis pathway, Trp is converted into QA in a series of steps, which is then converted into NAD by forming NAMN and NAAD. In contrast, in the salvage pathway, NR and NAM provided by diet are converted into NAD by forming NMN by enzymes NAMPT and NRK [2]. The equilibrium in each subcellular compartment such as the nucleus and mitochondria is determined by NAD/NADH redox ratios. ETC is a significant contributor to the conversion of NADH into NAD. Additionally, NAD-consuming enzymes such as PARPs and sirtuins catalyze NAM production in subcellular compartments, which can be used for NAD synthesis via the salvage pathway.

Figure 2

Role of NAD in aging, neurodegeneration, and cancer. DNA damage caused by stress or aging activates PARP. PARP activation leads to reduced levels of cytosolic NAD and mitochondrial dysfunction, which contribute to aging and neurodegeneration. Any disturbance in levels of NAD⁺/NADH (redox homeostasis) can upregulate oncogenic signaling pathways, leading to tumorigenesis.

Figure 3

NAD⁺ depletion with increasing age is caused by several factors such as inefficient metabolism or protein consumption, increased activity of NAD⁺-consuming enzymes CD38/PARP, mitochondrial dysfunction, DNA damage, cellular dysfunction, and NAMPT depletion. NAD⁺ can be restored by manipulating enzymes in NAD⁺ synthesis pathways. The NAD⁺ concentration can be replenished by increasing the activity of NAMPT, niacin, NMN, and NR. Moreover, in many cases, inhibition of PARP/CD38 also helps restore NAD⁺.

Figure 4

Altered NAD metabolism is associated with neurodegeneration. Axonal injury leads to the activation of SARM1, which reduces NAD + levels and leads to axonal degeneration. The overexpression of NMNAT1 inhibits SARM1 and protects injured axons. NAD levels are associated with axonal degradation, and impairment in the KYN pathway causes fluctuations in KYN pathway metabolite levels, which impairs the neurotransmission process and leads to neurodegeneration and the development of neurological disorders [201].

Figure 5

The polyol pathway becomes highly active during hyperglycemia, leading to the massive production of NADH [202,203]. Consumption of NAD⁺ by PARPs results in NAD⁺ decline. During diabetes, accumulation of NADH and depletion of NAD⁺ leads to an increase in redox imbalance, which causes oxidative stress, decreased SIRT activity, decreased ATP production, and increased cell death.

Figure 6

NAD metabolism in cancer cells. Cancer cells rely on increased glycolysis rates for energy production and regenerate NAD⁺ by converting accumulating pyruvate into lactate to maintain glycolysis. Excess lactate accumulation in tumor cells increases the level of NADH relative to NAD and perturbs the NAD/NADH balance in cells [204]. In contrast, SIRT1 acts as an inactivator of HIFα and prevents its nuclear translocation. SIRT6 acts as a corepressor of HIFα to prevent the transcriptional process, and mitochondrial-localized SIRT3 suppresses ROS production.

Figure 7

Expression profiles of NAMPT in nine cancer types and corresponding normal tissues per the TCGA-GTEx GEPIA2 dataset.

Figure 8

Overall survival rates of patients in low- and high-NAMPT expression groups in nine cancer types (GBM, LUAD, LAML, LIHC, READ, PAAD, LGG, THYM, and DLBC) using the TCGA-GTEx GEPIA2 dataset.