Nicotinamide adenine dinucleotide (NAD⁺) is a crucial coenzyme involved in numerous cellular processes, including energy metabolism, DNA repair, and cellular signaling. As organisms age, NAD⁺ levels decline, which has significant implications for cellular function and contributes to various age-related diseases. The primary mechanisms driving this decline include increased consumption by NAD⁺-dependent enzymes, chronic inflammation, and the accumulation of senescent cells. These changes impact cellular function by impairing metabolic processes, reducing DNA repair capacity, and promoting inflammation, ultimately affecting tissue homeostasis and organismal health.
Increased Consumption by NAD⁺-Dependent Enzymes
- Enzyme Hyperactivation: Aging is associated with the hyperactivation of NAD⁺-consuming enzymes such as sirtuins, poly(ADP-ribose) polymerases (PARPs), and CD38. This increased activity leads to a higher turnover of NAD⁺, contributing to its decline in tissues(Ipakchi, 2023) (Covarrubias et al., 2020).
- PARP1 and SIRT1 Axis: The formation of complexes between NAD⁺-binding protein DBC1 and PARP1 in aged organisms inhibits PARP activity, leading to increased DNA damage and reduced repair capacity. Supplementation with NAD⁺ precursors can disrupt these complexes, restoring PARP activity and reducing DNA damage(Mendelsohn & Larrick, 2017).
Chronic Inflammation and Senescence
- Inflammaging: Chronic, low-grade inflammation, or “inflammaging,” is a hallmark of aging. NAD⁺ levels decline in response to pro-inflammatory stimuli, which is exacerbated by the activity of PARPs. This decline limits the activity of sirtuins and PARPs, further promoting inflammation and cellular damage(Schultz et al., 2018).
- Senescent Cells and CD38: Senescent cells accumulate with age and secrete inflammatory cytokines that activate CD38+ macrophages. These macrophages express high levels of CD38, an NAD⁺-consuming enzyme, leading to further depletion of NAD⁺ in tissues(Covarrubias et al., 2020).
Impact on Cellular Function
- Metabolic Disruption: The decline in NAD⁺ affects metabolic pathways, including gluconeogenesis and insulin secretion, leading to metabolic disorders. NAD⁺ supplementation has been shown to improve these pathways in aged mice(Janssens et al., 2022).
- DNA Repair and Genomic Stability: Reduced NAD⁺ levels impair DNA repair mechanisms, such as nonhomologous end joining and homologous recombination, increasing genomic instability and susceptibility to age-related diseases like cancer(Mendelsohn & Larrick, 2017).
- Neuronal and Muscle Function: NAD⁺ is essential for neuronal function and muscle health. Its decline contributes to neurodegenerative diseases and sarcopenia, but supplementation with NAD⁺ precursors can ameliorate these effects(Lautrup et al., 2023) (Olimjonovna, 2022).
While the decline in NAD⁺ with age is well-documented, the exact mechanisms and their relative contributions to aging are still being elucidated. Some studies suggest that the decline is not due to impaired synthesis but rather increased consumption, as NAD⁺ biosynthetic flux remains stable in aged tissues(McReynolds et al., 2021). Additionally, interventions such as calorie restriction and exercise have been shown to mitigate NAD⁺ decline, highlighting the potential for lifestyle modifications to maintain NAD⁺ levels and promote healthy aging(Ji & Yeo, 2022).
