The Central Role of CD38 as an NADase
CD38 is a multifunctional glycoprotein expressed on the surface of many cells, particularly immune cells. It has both enzymatic and receptor functions, but its role as a powerful NADase—an enzyme that breaks down NAD+—is central to its influence on aging. Nicotinamide adenine dinucleotide (NAD+) is a fundamental coenzyme found in all living cells, essential for a myriad of biochemical processes, including energy metabolism, DNA repair, and the activation of longevity-associated proteins called sirtuins.
With increasing chronological age, the expression and enzymatic activity of CD38 have been shown to increase in various tissues in both mice and humans, including the liver, fat tissue, and spleen. This rise in CD38 effectively acts like a metabolic drain, accelerating the depletion of NAD+ reserves within the body's cells.
The Vicious Cycle: CD38, Senescence, and Inflammation
Scientific evidence points to a self-reinforcing loop involving CD38, cellular senescence, and inflammation that drives aging. Cellular senescence is a state of irreversible growth arrest that cells enter under stress, but they often remain metabolically active and can secrete a cocktail of pro-inflammatory factors known as the Senescence-Associated Secretory Phenotype (SASP).
- SASP-Induced Upregulation of CD38: The inflammatory molecules released by senescent cells directly trigger the upregulation of CD38 expression and activity in surrounding non-senescent cells, such as macrophages and endothelial cells.
- NAD+ Depletion: The heightened CD38 activity then degrades NAD+, reducing its availability for NAD-dependent processes, including sirtuin activity.
- Compromised DNA Repair: Crucial NAD+-dependent enzymes like PARP1, which help repair DNA damage, become less active due to low NAD+ levels. This leads to an accumulation of cellular damage, which can, in turn, drive more cells into senescence.
- Chronic Inflammation: The resulting NAD+ depletion and accumulation of senescent cells amplify the body's chronic, low-grade inflammation, a phenomenon known as “inflammaging”. This ongoing inflammation further elevates CD38, perpetuating the cycle.
Consequences of CD38-Driven NAD+ Depletion
- Mitochondrial Dysfunction: NAD+ is critical for maintaining mitochondrial function. The decline in NAD+ caused by CD38 activity impairs mitochondrial respiration, reduces ATP production, and increases oxidative stress, a central feature of aging.
- Metabolic Derangements: Decreased NAD+ impacts metabolic processes, contributing to age-related conditions such as insulin resistance, glucose intolerance, and obesity.
- Cardiovascular and Kidney Disease: Research has linked elevated CD38 to vascular aging, kidney dysfunction, and heart disease, particularly due to its effects on NAD+ levels and calcium signaling.
- Muscular and Neurological Decline: NAD+ decline affects muscle function, endurance, and can contribute to neurological issues. Mouse studies have shown that inhibiting CD38 can improve muscle performance in aged animals.
Clinical Research and Therapeutic Potential
The discovery of CD38's pivotal role has sparked intense research into therapeutic strategies aimed at inhibiting its activity. Studies, primarily in mouse models, have shown promising results from genetic ablation or pharmacological inhibition of CD38.
Comparison of Normal Aging vs. CD38 Inhibition
| Feature | Normal Aging (High CD38) | CD38 Inhibition (Reduced CD38) |
|---|---|---|
| NAD+ Levels | Significantly decreased with age | Preserved or increased with age |
| Mitochondrial Function | Impaired, less efficient energy production | Restored, higher respiratory capacity |
| Inflammation | Increased chronic, low-grade systemic inflammation | Reduced inflammaging |
| Metabolic Health | Decline (e.g., glucose intolerance, insulin resistance) | Improved metabolic parameters, better glucose tolerance |
| Physical Performance | Decreased exercise capacity, muscle dysfunction | Improved muscle function and endurance |
Small-molecule CD38 inhibitors, such as 78c, have demonstrated the ability to increase NAD+ levels, activate pro-longevity factors, and improve physiological markers in aged mice. For example, one study showed that treating aged mice with 78c improved glucose tolerance and exercise performance.
The Interplay of CD38 and NAD+ Precursors
CD38's influence also extends to NAD+ replacement therapies involving precursors like nicotinamide mononucleotide (NMN). The enzyme has been shown to degrade NMN, a common supplement, in vivo. This suggests that the high levels of CD38 in aging may reduce the effectiveness of NAD+ precursors by consuming them before they can be converted into NAD+ inside the cells. This finding has significant implications for optimizing NAD+ boosting strategies, possibly by combining CD38 inhibitors with NAD+ precursor supplementation.
The Broader Implications for Healthspan
Ultimately, the role of CD38 in aging highlights the deep connection between NAD+ metabolism, inflammation, and age-related decline. The accumulation of CD38 is driven by age-related inflammatory cues and contributes to NAD+ depletion, which in turn impairs the function of NAD+-dependent sirtuins, resulting in poorer metabolic function, increased oxidative stress, and accelerated aging at a cellular level. Targeting CD38 activity represents a promising avenue not just for extending lifespan, but more importantly, for improving healthspan—the period of life spent in good health. Continuing research is necessary to fully understand the mechanisms and to translate these findings into safe and effective therapies for humans.
For more on ongoing aging research, you can explore the work done at institutions like the Robert and Arlene Kogod Center on Aging at Mayo Clinic.
