Pathobiochemistry of Aging and Neurodegeneration: Deregulation of NAD+ Metabolism in Brain Cells

Abstract

NAD+ plays a pivotal role in energy metabolism and adaptation to external stimuli and stressful conditions. A significant reduction in intracellular NAD+ levels is associated with aging and contributes to the development of chronic cardiovascular, neurodegenerative, and metabolic diseases. It is of particular importance to maintain optimal levels of NAD+ in cells with high energy consumption, particularly in the brain. Maintaining the tissue level of NAD+ with pharmacological tools has the potential to slow down the aging process, to prevent the development of age-related diseases. This review covers key aspects of NAD+ metabolism in terms of brain metabolic plasticity, including NAD+ biosynthesis and degradation in different types of brain cells, as well as its contribution to the development of neurodegeneration and aging, and highlights up-to-date approaches to modulate NAD+ levels in brain cells.

Keywords: NAD+; aging; brain; metabolism; neurodegeneration; nicotinamide adenine dinucleotide.

Figure 1

The principal metabolic pathways involved in the synthesis and degradation of NAD+ in cells. The synthesis of NAD+ primarily occurs through three main pathways: the de novo pathway, which involves tryptophan; the Preiss–Handler pathway, where nicotinic acid is used as a precursor of NAD+; and the salvage pathway, which utilizes nicotinamide. The degradation of NAD+ involves hydrolysis and consumption in various enzymatic reactions that play essential roles in cellular metabolism and signaling. The balance between synthesis and degradation is critical for maintaining cellular NAD+ levels, which are vital for energy metabolism and other physiological functions. ACMS—2-amino-3-carboxymuconate semialdehyde; ACMSD—a-amino-b-carboxymuconate-e-semialdehyde decarboxylase; ADPR—ADP ribose; AMS—a-aminomuconate-e-semialdeyde; cADPR—cyclic ADP ribose; CD157—cluster of differentiation 157; CD38—cluster of differentiation 38; IDO—indoleamine 2,3-dioxygenase; NA—nicotinamide; NaAD—nicotinic acid adenine dinucleotide; NAD+—nicotinamide adenine dinucleotide NAM—nicotinamide; NAMN—nicotinic acid mononucleotide; NAMPT—nicotinamide phosphoribosyltransferase; NAPRT—nicotinic acid phosphoribosyltransferase; NMN—nicotinamide mononucleotide; NMNAT1/2/3—Nicotinamide mononucleotide adenylyltransferase type 1/2/3; NR—nicotinamide riboside; NRK—nicotinamide ribonucleoside kinase; PARPs—poly(ADP-ribose) polymerase; QA—quinolinic acid; QPRT—quinolinate phosphoribosyltransferase; SARMs—selective androgen receptor modulators; SIRTs—sirtuins; TDO—tryptophan 2,3-dioxygenase; Try—Tryptophan.

Figure 2

Key aspects of NAD+ metabolism within the neurovascular unit. NAD+ metabolism is of vital importance for the optimal functioning of the neurovascular unit (NVU), exerting a significant influence on both neuronal health and vascular integrity. NAD+ is a vital component of the cellular respiration and ATP production processes in neurons and glial cells, thereby supporting their energy demands. NAD+ plays a role in protecting neurons from oxidative stress and excitotoxicity, enhancing cell survival through the activation of sirtuins and the promotion of DNA repair mechanisms. NAD+ exerts influence over inflammatory responses within the NVU by modulating the activity of immune cells, such as microglia, which can impact neurovascular integrity. In the blood–brain barrier (BBB), NAD+ is involved in maintaining endothelial cell function, regulating permeability, and supporting angiogenesis. Furthermore, NAD+ acts as a substrate for enzymes like PARPs and sirtuins, which are involved in signaling pathways that regulate cell survival, differentiation, and stress responses. ADP—adenosine diphosphate; AMP—adenosine monophosphate; ATP—adenosine triphosphate; cADPR—cyclic ADP ribose; CD157—cluster of differentiation 157; eNAMPT—intracellular nicotinamide phosphoribosyltransferase; FA—fatty acids; Glc—glucose; Gln—glutamine; Glu—glutamate; GLUT1—glucose transporter type I; iNAMPT—intracellular nicotinamide phosphoribosyltransferase; KB—ketone bodies; Lac—lactate; MCT1/2/4—Monocarboxylate transporter type 1/2/4; NA—nicotinamide; NaAD—nicotinic acid adenine dinucleotide; NAD+—nicotinamide adenine dinucleotide oxidized; NADH—nicotinamide adenine dinucleotide reduced; NADSYN1—NAD synthetase type 1; NaMN—nicotinic acid mononucleotide; NMN—nicotinamide mononucleotide; NMNAT1/2/3—Nicotinamide mononucleotide adenylyltransferase type 1/2/3; NR—nicotinamide riboside; PPi—bisphosphate; PRPP—phosphoribosyl pyrophosphate; Pyr—pyruvate; Quin—quinolinic acid.

Figure 3

The altered metabolism of NAD+ in neurodegeneration and aging. The altered metabolism of NAD+ in neurodegeneration and aging is characterized by a decline in NAD+ levels, which has a deleterious effect on cellular functions. In neurodegenerative disorders, reduced availability of NAD+ impairs energy production, DNA repair, and antioxidant defenses, thereby increasing neuronal vulnerability and cell death. Furthermore, this decline affects sirtuins, which regulate stress responses and inflammation, thereby exacerbating neuroinflammation and contributing to disease progression. Additionally, the process of aging serves to further exacerbate these issues. The reduction in NAD+ that occurs naturally with age disrupts the metabolic pathways that are essential for maintaining neuronal and vascular health. This ultimately results in the promotion of cognitive decline and neurodegenerative processes. ACMSD—a-amino-b-carboxymuconate-e-semialdehyde decarboxylase; AD—Alzheimer disease; ALS—amyotrophic lateral sclerosis; AxD—Alexander disease; ATP—adenosine triphosphate; BMAL—brain and muscle arnt-like protein 1; CD 37—cluster of differentiation 37; CLOCK—circadian locomotor output cycles kaput; ETC—electron transport chain; HD—Huntington disease; IDO—indoleamine 2,3-dioxygenase; NAM—nicotinamide; NAMPT—nicotinamide phosphoribosyltransferase; NLRP3—NOD-like receptor protein 3 inflammasome; NOX—NADPH oxidases; NRK—nicotinamide ribonucleoside kinase; PD—Parkinson disease; OXPOHS—oxidative phosphorylation; SIRT—silent information regulator protein; SARM—Sterile alpha and toll/interleukin receptor (TIR) motif–containing protein 1; QPRT—quinolinate phosphoribosyltransferase; TDO—tryptophan 2,3-dioxygenase.

Figure 4

NAD+-based modulation strategies with neuroprotective potential. The administration of NAD+ precursors has been demonstrated to elevate NAD+ levels, thereby enhancing mitochondrial function and cellular energy. The selective targeting of NAD+-converting enzymes such as PARP and CD38 can prevent the excessive consumption of NAD+ during cellular stress, thereby ensuring its continued availability for vital processes. Strategies to enhance the recycling of NAD+ from its metabolites can assist in maintaining cellular NAD+ levels and supporting neuroprotection. These strategies seek to restore cellular homeostasis, reduce neuroinflammation, and improve overall brain health, offering potential therapeutic avenues for age-related cognitive decline and neurodegenerative disorders.