CD38 and Aging: NAD⁺ Decline, Inflammation, and Metabolic Dysfunction
What Is CD38?
CD38 is a transmembrane enzyme with NADase activity that increases with age, particularly on immune cells. It plays a central role in regulating nicotinamide adenine dinucleotide (NAD⁺), a critical coenzyme involved in energy production and DNA repair. As CD38 levels rise, NAD⁺ is depleted, contributing to mitochondrial dysfunction, chronic inflammation, and metabolic decline¹.
CD38 and NAD⁺ Metabolism
CD38 is one of the primary enzymes responsible for breaking down NAD⁺ in mammalian tissues. Because NAD⁺ levels naturally decline with age, increased CD38 activity accelerates this process and contributes to reduced cellular function².
In addition to consuming NAD⁺ directly, CD38 also degrades key NAD⁺ precursors such as nicotinamide mononucleotide (NMN), limiting the cell’s ability to replenish NAD⁺ stores³.
Age-Related Increase in CD38
CD38 expression increases significantly with age across multiple tissues, including liver, adipose tissue, spleen, and skeletal muscle³.
This rise in CD38 activity is closely linked to age-associated metabolic changes and declining cellular energy availability.
CD38, Inflammation, and the Immune System
CD38 expression is strongly influenced by the immune system. Pro-inflammatory signals, including factors associated with the senescence-associated secretory phenotype (SASP), induce CD38 expression on immune cells⁴.
This creates a feedback loop (see below) in which inflammation increases CD38 activity, leading to further NAD⁺ depletion, which in turn promotes additional metabolic dysfunction and inflammatory signaling.
Targeting CD38
In preclinical models, inhibition of CD38 has been shown to restore NAD⁺ levels, improve mitochondrial function, and enhance metabolic health. These effects suggest that CD38 is a promising target for interventions aimed at preserving cellular energy and function during aging⁵.
Summary - Why CD38 Matters for Longevity
CD38 occupies a central position in aging biology by linking immune activation, NAD⁺ metabolism, and mitochondrial function.
As CD38 activity increases with age, NAD⁺ availability declines, impairing energy production, reducing DNA repair capacity, and weakening cellular resilience.
From a longevity perspective, regulating CD38 activity may help preserve NAD⁺ levels, improve metabolic stability, and reduce chronic inflammation, all of which are critical for maintaining cellular function over time.
Footnotes
1 CD38 and age-related NAD decline https://pubmed.ncbi.nlm.nih.gov/27052143/
2 NAD metabolism in aging and disease https://pubmed.ncbi.nlm.nih.gov/29719225/
3 CD38, NAD⁺ metabolism, and aging https://pubmed.ncbi.nlm.nih.gov/33727743/
4 SASP-driven CD38 expression and NAD decline https://pubmed.ncbi.nlm.nih.gov/32737480/
5 CD38 inhibition and metabolic function https://pubmed.ncbi.nlm.nih.gov/29670298/
