NAD+, Stacks, and Healthspan: What the Science Actually Says (and How to Use It Safely)

NAD+, Stacks, and Healthspan: What the Science Actually Says (and How to Use It Safely)

  • NAD+ is a cellular coenzyme that supports energy metabolism, DNA repair, circadian rhythm, and stress responses. Levels decline with age.
  • A 2023 peer-reviewed review in Nutrients proposes that combining NAD+ precursors (e.g., NMN or NR) with complementary compounds (e.g., resveratrol/pterostilbene, quercetin/apigenin [CD38 inhibition], CoQ10, betaine) may better sustain NAD+ signaling and downstream SIRT1 activity than taking a precursor alone.
  • Human data are promising but limited. Most synergy evidence is mechanistic or from animal studies; some human trials show NAD+ rises and modest functional benefits.
  • Safety and fit are personal. Start conservatively, monitor how you feel, and use labs where appropriate. See your clinician if you have medical conditions or take prescriptions.

Primary source: Sharma A, Chabloz S, Lapides RA, Roider E, Ewald CY. Potential Synergistic Supplementation of NAD+ Promoting Compounds as a Strategy for Increasing Healthspan. Nutrients. 2023;15(2):445. Open-access article.

First, a quick refresher: What is NAD+ and why does it matter?

Nicotinamide adenine dinucleotide (NAD+) is a coenzyme in every cell. It helps convert food to ATP, coordinates DNA repair, tunes sirtuins (SIRT1), supports mitochondrial health, and helps keep your body clock on time. Levels fall with age, in part due to higher activity of CD38, an enzyme that degrades NAD+. The review above frames a practical axis: CD38 → NAD+ → SIRT1. More CD38 → less NAD+ → lower SIRT1 activity; the stack idea tries to push back along that axis.

What the 2023 review suggests (in plain English)

The authors synthesize basic science, animal work, and early human studies and propose a combination (“stack”) approach:

  1. Top up NAD+

    • NMN or NR (dietary precursors) can raise NAD+ in blood/tissues in humans in several small trials. Reported benefits include improved muscle function, sleep/fatigue scores, and metabolic markers in some cohorts.

  2. Support SIRT1 and mitochondria

    • Stilbenes: resveratrol and pterostilbene can activate sirtuin-related pathways and show cognitive/cardiometabolic signals in humans (mixed results; dose and bioavailability matter).

    • CoQ10 may complement mitochondrial respiration and redox balance, with human data for cardiometabolic support and fatigue.

  3. Slow NAD+ breakdown (CD38 inhibition)

    • Flavonoids: quercetin, apigenin, luteolin show CD38-inhibiting activity in preclinical work and broad anti-inflammatory effects. Translational human data are still early.

  4. Mind the methylation budget

    • Converting some B3 forms through the salvage pathway uses methyl groups. Betaine (trimethylglycine) can help maintain methylation capacity in theory; human synergy data with NMN/NR remain limited.

Bottom line from the review: a smart combo may work better than a single ingredient, but robust human “superiority” trials are still needed to confirm real-world advantage.
Source: Sharma et al., 2023 (Nutrients). Link.

A practical, conservative “NAD+ stack” template (education only)

Not medical advice. Discuss with your clinician—especially if pregnant, nursing, on anticoagulants, glucose-lowering meds, chemo/immunotherapy, or have cancer history.

  • Phase 1 (4–8 weeks): establish baseline & tolerance

    • NMN or NR: start low (e.g., 150–300 mg/day), morning.

    • CoQ10 (ubiquinol): 100–200 mg/day with a meal.

    • Optional resveratrol: 75–200 mg/day with food if tolerated.

  • Phase 2 (weeks 9–16): consider synergy add-ons

    • Add a CD38-modulating flavonoid such as quercetin 250–500 mg/day or apigenin 50–100 mg/day (with food).

    • If you use high-dose NR/NAM products, consider betaine 500–1000 mg/day for methylation support.

  • Always pair with fundamentals: sleep, protein adequacy, resistance training, fiber/polyphenol-rich diet, and stress management—all support the same pathways naturally.

Why this order? You’ll learn how you respond to each layer, reduce confounders, and lower the risk of supplement-supplement or drug-supplement interactions.

What benefits are realistic?

  • Most consistent signal: Biochemical NAD+ increases with precursors.

  • Encouraging but variable: small improvements in fatigue, sleep quality, aerobic capacity, muscle function, and metabolic markers reported in select studies.

  • Speculative but mechanistically plausible: combining a precursor with a SIRT1-supporter (resveratrol/pterostilbene) and a CD38-modulator (quercetin/apigenin) may keep NAD+ elevated and signaling more robustly than a precursor alone—needs more human RCTs to confirm.

Primary evidence summary: Sharma et al., 2023 (Nutrients). Full text.

Safety notes & who should be cautious

  • Drug interactions: Resveratrol, quercetin, apigenin and others can affect CYP enzymes, platelet function, and glucose handling.

  • Cancer history: The review notes theoretical concerns (e.g., fueling NAD+ in certain contexts). Human risk is uncertain; discuss with your oncology team.

  • Surgery/bleeding risk: Pause polyphenols with antiplatelet effects pre-op if your doctor advises.

  • GI upset, headaches, flushing can occur when starting or at higher doses—titrate slowly.

Make it personal with testing (optional but helpful)

  • Before: capture baseline energy/fatigue, sleep, training output, and simple labs where appropriate (e.g., B12/folate, homocysteine, lipid panel, glucose/A1c).
  • After 8–12 weeks: reassess symptoms and, if used initially, re-check labs.
  • Keep a stack “diary”: dose, timing, how you feel, HRV/sleep from wearables—then adjust.

If you’re using Boomerang Kits: our Vitamin Panel (B-vitamins, etc.) and General Health/Thyroid panels can help identify correctable basics (e.g., B12 or iron issues) that meaningfully impact energy—often before you need a complex longevity stack.

Frequently asked questions

Is NMN better than NR?
Both are NAD+ precursors with human data. NMN is one enzymatic step from NAD+; NR converts to NMN first. Availability, price, and personal tolerance often decide.

Do I need resveratrol if I take NMN/NR?
Not strictly. The theory is that resveratrol/pterostilbene may enhance sirtuin signaling that depends on NAD+. Human synergy proof is still emerging.

What about CD38 inhibitors?
Compounds like quercetin and apigenin show CD38-inhibiting activity preclinically, which could slow NAD+ breakdown. Human outcome data are limited; use cautiously.

Primary review: Sharma A, Chabloz S, Lapides RA, Roider E, Ewald CY. Potential Synergistic Supplementation of NAD+ Promoting Compounds as a Strategy for Increasing Healthspan. Nutrients. 2023;15(2):445. doi:10.3390/nu15020445. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC9861325/


Building a smart, simple, and safe plan beats chasing every new longevity headline. If you experiment, start with foundations, consider a precursor (NMN or NR), then layer carefully (mitochondrial support, polyphenols, CD38 modulators)—measure, and collaborate with your clinician.

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