With advancing age, the function of hematopoietic stem cells (HSCs)—the "seed cells" of the blood system—gradually declines, a phenomenon known as "HSC aging." This decline directly impairs the production and balance of blood cells, triggering a cascade of health issues: compromised immunity (e.g., reduced T/B lymphocytes and weakened infection resistance), anemia, and increased risk of hematological diseases. Closely linked to accumulated DNA damage, telomere shortening, metabolic disorders, and deteriorating bone marrow microenvironment, HSC aging poses a significant threat to health. 
 
Recently, researchers from the University of California published a study titled "An NAD⁺-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging" in the journal *Nature Aging*. The research reveals that aberrant activation of the NAD⁺ metabolizing enzyme CD38 is a key driver of HSC aging, and targeted interventions to elevate NAD⁺ levels can significantly reverse the aging phenotype—offering a novel target for anti-aging therapies.

（Article screenshot）

Core Findings: NAD⁺—The Cornerstone of HSC Function
NAD⁺ emerges as a critical metabolite for maintaining HSC function. As a core coenzyme for cellular energy metabolism (e.g., glycolysis, oxidative phosphorylation) and DNA repair, NAD⁺ levels decline markedly with age. In HSCs, NAD⁺ sustains stem cell function through three key mechanisms: 
1. Energy supply**: Supports mitochondrial ATP production to fuel HSC activity. 
2. Epigenetic regulation**: Activates longevity proteins such as SIRT1/3/7, preserving genomic stability. 
3. Antioxidant defense**: Modulates redox balance to mitigate oxidative stress. 
 
CD38: An Age-Dependent Regulator of HSCs
The study confirms CD38 exerts age-specific control over HSCs: 
Young HSCs (3-month-old mice): Moderate CD38 expression enhances mitochondrial Ca²⁺ influx, boosts tricarboxylic acid (TCA) cycle activity, increases ATP production, and promotes HSC proliferation—sustaining basal hematopoietic demand. 


（Young experimental subject CD38 promotes HSC proliferation）
 
Aged HSCs (24-month-old mice): Excessive CD38 activation triggers a sharp 50%+ drop in NAD⁺ levels (Figure 3a), leading to insufficient sirtuin activity, disrupted TCA cycles, reduced ATP generation, myeloid-biased differentiation, and progressive hematopoietic dysfunction. 


（Overactivated CD38 depleting NAD⁺ caused HSC aging）
 
Intervention Efficacy: Reversing HSC Aging via CD38 Inhibition or NAD⁺ Supplementation 
Treating aged HSCs with CD38 inhibitors or NAD⁺ precursors (e.g., NMN) reversed the aging phenotype, with key outcomes including: 
Restored NAD⁺ levels: Reaching 80–90% of those in young HSCs. 
Enhanced hematopoietic reconstitution: Significantly increased peripheral blood leukocytes and lymphocytes, improved bone marrow hematopoietic capacity, and reversed myeloid-biased differentiation. 
Mitochondrial repair: Reduced oxidative stress and restored mitochondrial membrane potential. 


（before intervention" (aged HSC pathology) vs. "after NAD⁺ precursor/CD38 inhibitor treatment）
 
The NAD⁺-CD38-Sirtuins Axis: A Central Regulator of HSC Aging
The study summarizes the axis’s core role: 
Young state: Moderate CD38 activation drives Ca²⁺ signaling, supporting mitochondrial metabolism and HSC proliferation. 
Aged state: Excessive CD38 activation → NAD⁺ depletion → sirtuin inactivation → mitochondrial damage → HSC functional decline. 
Intervention strategy: Inhibiting CD38 or supplementing NAD⁺ restores NAD⁺ levels, reactivates sirtuins, and reverses the aging process. 
 
This research not only highlights the central role of NAD⁺ metabolism in HSC aging but also provides a theoretical basis for developing NAD⁺-targeted anti-aging drugs. Notably, the combination of NAD⁺ precursors (e.g., NMN, NADH) with CD28 inhibitors may represent a novel strategy to improve age-related hematopoietic function and immunity. 
 
References 
Song Z, Park SH, Mu WC, et al. An NAD⁺-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging. *Nat Aging*. 2024 Oct;4(10):1384-1393.