Senolytics + NAD+ Precursors: Complete Longevity Stack

Expert Summary

NAD+ decline with aging is driven by two mechanisms: reduced synthesis and increased consumption (primarily by CD38 in senescent immune cells). Senolytics eliminate the highest CD38-expressing cells, reducing the NAD+ drain. NMN/NR replenishes the pool. Quercetin inhibits CD38 directly. This three-pronged approach addresses all major NAD+ decline mechanisms simultaneously.

Key Facts

• CD38 in senescent cells: Senescent macrophages and adipose tissue macrophages (M1-polarized) express 10–15x more CD38 than young counterparts. CD38 consumes NAD+ at >100 nmol/mg protein/hour — far exceeding synthesis rates.
• PARP in senescent cells: Senescent cells have persistent DNA damage that continuously activates PARP (Poly-ADP ribose polymerase), another major NAD+ consumer. PARP activation in senescent cells may consume 20–40% of cellular NAD+.
• Senolytic → NAD+ restoration: By eliminating the highest CD38 and PARP-active cells, senolytics measurably reduce NAD+ consumption — a mechanism confirmed in aged mouse tissues post-senolytic treatment.
• NMN/NR → replenishment: NMN (250–500 mg/day) consistently raises blood NAD+ by 40–100% in human trials. Adding this replenishment to reduced consumption creates the largest possible net NAD+ gain.
• Quercetin's CD38 role: Quercetin inhibits CD38 enzymatic activity at ~20 μM (phytosome-achievable). This provides NAD+ protection between senolytic cycles when senescent cells may be partially re-accumulating.
• Protocol: NMN 250–500 mg morning (daily). Quercetin phytosome 200–300 mg daily. Fisetin 20 mg/kg × 2 days monthly (senolytic). Spermidine 2–4 mg daily (autophagy/prevention).

Recommended Products

Frequently Asked Questions

Which should I prioritize if budget allows only one: NMN or fisetin?

If you are over 50 with established senescent cell burden: fisetin (monthly protocol) addresses the root cause. If you are under 40 with low senescent burden: NMN addresses the NAD+ decline driving early aging. Combine as budget allows.

How do I know if my NAD+ is improving from senolytics?

Blood NAD+ (whole blood) can be measured via specialized testing (Jinfiniti, Alive by Science). Before-and-after testing (post-senolytic cycle at 4 weeks) can confirm the expected NAD+ increase from senescent cell clearance.

Scientific References

• Camacho-Pereira J et al. CD38 dictates age-related NAD decline and mitochondrial dysfunction. Cell Metabolism. 2016. PMID: 27304511
• Yousefzadeh MJ et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018. PMID: 30279143