In aging research, NAD+ metabolism acts as a hub—many processes, including cellular senescence, are closely linked to it. Additionally, the characteristic decline of NAD+ levels with age has made it a key target for aging intervention.
1. Cellular NAD+ Metabolism
NAD+ is widely present in the cytoplasm, mitochondria, and nucleus. Under the action of glycohydrolases (CD38, CD157, SARM1), Sirtuins proteins (protein deacylases), and PARPs proteins, it is ultimately converted into the byproduct NAM (nicotinamide).
Subsequently, the body maintains the relative stability of intracellular NAD+ levels through the NAM recycling pathway and the de novo synthesis pathway using multiple precursor substances. However, aging can disrupt the balance between NAD+ synthesis and consumption.
As a "co-factor" for over 300 biochemical enzymes, NAD+ regulates multiple cellular processes, including cell metabolism, redox homeostasis, genomic stability, epigenetic regulation, chromatin remodeling, and autophagy. A deficiency in NAD+ will inevitably lead to functional abnormalities.
Note on Key Reactions:
- Sirtuins: Catalyze the conversion of NAD+ to NAM, while deacetylating proteins (from acetylated to deacetylated states), producing acetyl-ADPR as a byproduct.
- PARPs: Convert NAD+ to NAM, modifying unmodified proteins into mono(ADP-ribosyl)ated or poly(ADP-ribosyl)ated proteins.
- CD38/CD157/SARM1: Exhibit glycohydrolase activity (converting NAD+ to NAM and ADPR) and ADP-ribosyl cyclase activity (converting NAD+ to NAM and cADPR). CD38 also participates in base-exchange reactions (at acidic pH) to convert NAD(P)+ to NAM and NA (nicotinic acid), and degrades NMN/NR to NAM.
2. NAD+-Dependent Aging Mechanisms
Over the past two decades, numerous high-quality studies have confirmed the importance of NAD+ homeostasis for healthy aging and longevity. Abnormal declines in NAD+ levels may lead to the following four bodily abnormalities:
#1 Metabolic Dysfunction
NAD+ levels are significantly reduced in obese individuals, who are more susceptible to type 2 diabetes, cardiovascular diseases, non-alcoholic fatty liver disease, atherosclerosis, stroke, and cancer. Supplementation with NAD+ precursors can effectively activate Sirtuins proteins, helping obese patients restore metabolic health.
Epigenetic & Circadian Rhythm Link:
- In young individuals: SIRT1 (a member of Sirtuins) and NAMPT (a key enzyme in NAD+ synthesis) maintain normal circadian rhythm regulation, ensuring balanced expression of metabolism-related genes.
- In aging individuals: Circadian rhythm regulation is disrupted or lost. Reduced SIRT1 activity and altered CLOCK/BMAL1 (circadian clock proteins) function lead to abnormal gene expression, further exacerbating NAD+ decline and metabolic disorders.
#2 Immune Cell Dysfunction
Inflammation is recognized as a hallmark of aging and a major driver of diseases, affecting systemic metabolism (e.g., glucose/lipid uptake and insulin sensitivity). Maintaining sufficient NAD+ levels helps restore the innate and adaptive immune functions of organisms.
Supplementing NAD+ or inhibiting NAD+ consumption (especially regulating the activity of CD38 and PARPs) reduces the production of pro-inflammatory cytokines. Additionally, it enhances immune cell function and delays immune aging by upregulating the NAD+–SIRT1–FOXO1 axis.
#3 Cellular Senescence
Senescent cells disrupt tissue homeostasis by increasing the secretion of SASP (senescence-associated secretory phenotype), interfering with stem cell regeneration, impairing tissue/wound repair, and exacerbating inflammation. Increasing intracellular NAD+ levels helps restore mitochondrial function and extend the healthy lifespan of cells.
#4 Neurodegenerative Diseases
Most neurodegenerative diseases (e.g., Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis) are closely associated with reduced NAD+ levels. Multiple lines of evidence support the neuroprotective role of NAD+, which prevents axonal degeneration. Supplementation with NAD+ precursors (e.g., NR, NMN) helps maintain NAD+ levels in tissues and systems, and may improve memory and cognitive function.
Mechanistic Snapshot in Aging:In elderly individuals, elevated CD38 and PARP1 activity accelerates NAD+ consumption (converting NAD+ to NAM). This leads to impaired mitochondrial metabolism in T cells, imbalanced polarization of M1/M2 macrophages (pro-inflammatory M1 macrophages dominate), increased pro-inflammatory cytokines, excessive inflammatory responses, accumulation of senescent cells (and SASP secretion), and ultimately exacerbates tissue damage.
3. Background on NAD+ Research
Evandro F. Fang, Associate Professor of Molecular Gerontology at the University of Oslo and Akershus University Hospital (Norway), focuses on the molecular mechanisms underlying mitophagy (cellular clearance of damaged/aged mitochondria) and the role of the NAD+-mitophagy/autophagy axis in healthy aging and Alzheimer’s disease (AD) inhibition. He has participated in 5 NAD+-based clinical trials, aiming to develop novel and safe biological strategies for promoting healthier and longer human lifespans.
His research laboratory’s website: https://evandrofanglab.com/
