Journal of Aging Science

Role of NAD+ Metabolism in Aging and Longevity

Katrien Baelen^* Department of Public Health and Primary Care, Ghent University, Corneel Heymanslaan, Ghent, Belgium
^*Correspondence: Katrien Baelen, Department of Public Health and Primary Care, Ghent University, Corneel Heymanslaan, Ghent, Belgium, Email:

Received: 27-Feb-2025, Manuscript No. JASC-25-28490; Editor assigned: 01-Mar-2025, Pre QC No. JASC-25-28490 (PQ); Reviewed: 07-Mar-2025, QC No. JASC-25-28490; Revised: 14-Mar-2025, Manuscript No. JASC-25-28490 (R); Published: 28-Mar-2025, DOI: 10.35248/2329-8847.25.13.402

Description

Nicotinamide Adenine Dinucleotide (NAD⁺) is a vital coenzyme involved in numerous cellular processes, including energy metabolism, DNA repair and cellular signaling. NAD⁺ levels decline with age, contributing to metabolic dysfunction, increased susceptibility to age-related diseases and reduced lifespan. Understanding the role of NAD⁺ metabolism in aging and longevity provides insights into potential therapeutic strategies aimed at maintaining cellular homeostasis and promoting healthy aging.

NAD⁺ and cellular metabolism

NAD⁺ serves as an important cofactor in redox reactions, facilitating ATP production through glycolysis, the Tricarboxylic Acid (TCA) cycle and oxidative phosphorylation. Additionally, NAD⁺ is a substrate for several enzyme families that regulate aging and longevity, including sirtuins, poly(ADP-ribose) Polymerases (PARPs) and CD38/CD157 ectoenzymes.

Sirtuins: NAD⁺ dependent deacetylases that regulate mitochondrial function, genomic stability and metabolic health. SIRT1, SIRT3 and SIRT6 have been implicated in extending lifespan by enhancing stress resistance and reducing inflammation.

PARPs: DNA repair enzymes that consume NAD⁺ to maintain genomic integrity. While important for preventing mutations, excessive PARP activity can deplete cellular NAD⁺ pools.

CD38/CD157: Ectoenzymes that degrade NAD⁺ and regulate immune function. CD38 levels increase with age, accelerating NAD⁺ depletion and contributing to metabolic decline.

NAD⁺ decline and aging

Aging is associated with a progressive decline in NAD⁺ levels, primarily due to increased NAD⁺ consumption and decreased biosynthesis. This decline contributes to several hallmarks of aging:

Mitochondrial dysfunction: Reduced NAD⁺ impairs oxidative phosphorylation, leading to decreased ATP production and energy metabolism.

Genomic instability: Insufficient NAD⁺ compromises DNA repair mechanisms, increasing the risk of mutations and cellular senescence.

Inflammation and immune dysfunction: Elevated CD38 activity increases NAD⁺ depletion, promoting chronic inflammation and immune aging.

Metabolic dysregulation: NAD⁺ depletion impairs glucose and lipid metabolism, increasing the risk of age-related metabolic diseases.

Therapeutic strategies to boost NAD⁺ levels

Given the critical role of NAD⁺ in aging, several interventions have been explored to restore NAD⁺ levels and promote longevity:

NAD⁺ precursors: Supplementation with Nicotinamide Riboside (NR) and Nicotinamide Mononucleotide (NMN) has shown promise in increasing NAD⁺ levels, improving mitochondrial function and extending lifespan in preclinical models.

Caloric restriction and fasting: Dietary interventions enhance NAD⁺ biosynthesis and sirtuin activity, representing the benefits of longevity-promoting strategies.

CD38 inhibition: Reducing CD38 activity through pharmacological inhibitors or genetic interventions helps preserve NAD⁺ levels and mitigate age-related decline.

Exercise and lifestyle modifications: Physical activity has been shown to enhance NAD⁺ metabolism, improve mitochondrial health and extend healthspan.

Conclusion

NAD⁺ metabolism plays a fundamental role in aging and longevity by regulating mitochondrial function, genomic stability and cellular resilience. Targeting NAD⁺ decline through supplementation, lifestyle interventions and pharmacological approaches offers potential strategies for extending healthspan and delaying age-related diseases. Continued research into NAD⁺ metabolism will provide deeper insights into its therapeutic potential for promoting healthy aging.