The role of chronic inflammation (inflammaging)
Chronic low-grade inflammation, known as 'inflammaging', is a major factor in the age-related increase of CD38. As the body ages, pro-inflammatory molecules like TNF-α and IFN-γ increase, activating CD38 in cells such as macrophages. This activation involves transcription factors like NF-κB, which upregulate the CD38 gene. This process creates a cycle where inflammation boosts CD38, which then lowers NAD+, further promoting inflammation and accelerating aging.
Cellular senescence and the SASP connection
Cellular senescence, a state of irreversible cell cycle arrest, also contributes to increased CD38 through the Senescence-Associated Secretory Phenotype (SASP). Senescent cells release a mix of inflammatory factors (SASP) that induce CD38 expression in surrounding non-senescent cells, particularly macrophages and endothelial cells. This link between senescent cell accumulation and CD38 upregulation contributes significantly to the decline in NAD+ seen with age.
The NAD+ decline and its impact on sirtuins
Elevated CD38 activity accelerates the breakdown of NAD+, a molecule essential for numerous metabolic functions. This shift in the balance between NAD+ synthesis and degradation leads to reduced NAD+ levels. This decline negatively affects sirtuins (SIRTs), NAD+-dependent enzymes that regulate metabolism and cellular resilience. Lower NAD+ reduces sirtuin activity, disrupting processes like DNA repair and stress resistance, contributing to metabolic issues, oxidative stress, and mitochondrial dysfunction in aging. For instance, studies in aged mice link increased CD38 to NAD+ depletion and mitochondrial problems via SIRT3.
Comparing CD38 with other NAD+-consuming pathways
Understanding CD38's role can be enhanced by comparing it to other NAD+-consuming enzymes:
| Feature | CD38 | PARP1 | Sirtuins |
|---|---|---|---|
| Primary Function | Major NAD+ glycohydrolase, consuming NAD+ and precursors | NAD+-consuming enzyme for DNA repair | NAD+-dependent deacetylase, regulates cellular stress responses |
| Change with Age | Significantly increases in expression and activity | Activated by DNA damage, but increase is less pronounced than CD38 | Activity declines due to reduced NAD+ availability |
| Catalytic Efficiency | Highly efficient at consuming NAD+, particularly ecto-cellular NAD+ and its precursors | Efficient consumer in response to DNA damage, primarily intracellular | Activity is limited by the availability of NAD+ substrate |
| Link to Inflammation | Expression is strongly induced by inflammatory cytokines and SASP factors | Can be activated in response to oxidative stress, but not directly induced by inflammation in the same manner as CD38 | Their function is impaired by NAD+ decline, contributing to a pro-inflammatory state |
| Location | Expressed on the cell surface (ecto-enzyme) and intracellularly | Primarily located in the cell nucleus | Located in various cellular compartments, including mitochondria |
The vicious cycle of CD38, inflammation, and NAD+ depletion
The age-related rise in CD38 is part of a harmful feedback loop:
- Aging-related stress: Stressors over time cause senescent cell buildup and chronic inflammation.
- SASP and CD38 induction: SASP factors from senescent cells and inflammatory cytokines significantly increase CD38, especially in immune and endothelial cells.
- NAD+ degradation: High CD38 activity rapidly depletes NAD+ levels.
- Sirtuin impairment: Reduced NAD+ hinders protective sirtuins, vital for metabolic health and mitochondria.
- Accelerated aging and inflammation: This metabolic disruption increases oxidative stress and inflammation, accelerating age-related decline.
This cycle identifies CD38 as a key player in age-related decline. More details on CD38's role in NAD+ metabolism and aging can be found in specialized reviews, such as those available on the National Institutes of Health (NIH) website, which describe its complex functions.
Conclusion
The increase of CD38 with age is a central aspect of aging, connected to inflammation and cellular senescence. Factors from senescent cells and chronic inflammation drive CD38 overexpression. CD38's consumption of NAD+ lowers its levels, which in turn impairs sirtuin activity and key protective pathways. The resulting metabolic dysfunction and cellular stress worsen inflammation, creating a feedback loop that accelerates physiological decline. These findings suggest CD38 is a potential target for therapies aimed at mitigating age-related conditions, with ongoing research exploring inhibitors to restore NAD+ and promote healthier aging.
