Simply supplementing with NMN may not yield obvious effects—because it’s not just about "hard supplementation"; you need to enable its effective circulation in the body! To maximize NAD+ production and anti-aging benefits, NMN should be scientifically combined with specific ingredients, targeting key steps in NAD+ synthesis and metabolism. Below are the 4 critical points for boosting NAD+ and 7 "golden partners" for NMN.
1. The "Salvage Pathway" of NAD+
Approximately 80% of NAD+ (nicotinamide adenine dinucleotide) in the human body is produced via the "salvage pathway."
Think of NAD+ as water in a reservoir with an automatic filtration and recycling system: water enters through an inlet, is used, and the spent water is recycled back into the reservoir via the filtration system.
With aging, the reservoir leaks severely and the recycling system malfunctions, causing NAD+ levels to drop. Supplementing NMN is like adding water to the reservoir, but it doesn’t fix the aging-related issues of the reservoir itself—hence the effects are slow and mild.
2. 4 Key Focus Areas to Boost NAD+
Four critical "sites" are essential for optimizing the NAD+ "reservoir":
01 NAMPT
NAMPT is the rate-limiting enzyme responsible for regenerating NAD+. It converts nicotinamide (NAM), a byproduct of NAD+ metabolism, back into NMN, which then reforms NAD+—acting as the reservoir’s recycling filter.
Ingredients that increase NAMPT expression (enhancing NAD+ recycling) include:
- Resveratrol (a favorite pairing with NMN among anti-aging enthusiasts like David A. Sinclair)
- Rutin
- Alpha-lipoic acid
- PQQ (pyrroloquinoline quinone, with additional health benefits)
02 CD38
CD38 is the main "leakage point" of the NAD+ reservoir. This enzyme consumes NAD+ to support immune function, but age-related immune aging leads to excessive CD38 synthesis. This not only triggers chronic inflammation and autoimmune diseases but also wastes large amounts of NAD+, impairing the function of NAD-dependent proteins (e.g., SIRT1 for metabolism, PARP1 for DNA repair, SARM1 for neuronal protection).
Natural ingredients that inhibit excessive CD38 expression (repairing the "leak") include:
- Apigenin
- Quercetin (both with multiple additional health benefits)
03 NNMT
After NAD+ is consumed by enzymes like CD38 and SIRT1, it becomes NAM. NAM has two fates:
- Converted back to NMN via NAMPT (recycling);
- Methylated by NNMT to form methylnicotinamide, exiting the salvage pathway (loss).
This pathway has two risks: reduced NAD+ regeneration due to NAM loss, and depletion of methyl groups (critical for epigenetic regulation and anti-aging).
Solutions:
- Inhibit NNMT to retain NAM in the salvage pathway (e.g., EGCG, epigallocatechin gallate from green tea).
- Supplement methyl donors to replenish losses (e.g., trimethylglycine (TMG), S-adenosylmethionine (SAMe)).
04 NADH/NAD+ Ratio
The NADH/NAD+ ratio regulates cellular energy metabolism and redox status. A low ratio supports normal cell function (typical in young cells), while a high ratio promotes aging and disease (typical in aged cells).
Ingredients that lower the NADH/NAD+ ratio (improving NAD+ utilization) include:
- Coenzyme Q10 (CoQ10)
- PQQ
- Alpha-lipoic acid
- Ergothioneine
These compounds act in metabolic pathways like mitochondrial electron transport chain, glycolysis, and the TCA cycle to convert NADH back to NAD+.
3. Promoting NMN Entry into Cells
Cutting-edge NMN supplements often add small amounts of sodium to enhance cellular absorption:
- NMN was previously thought to enter cells only after converting to NR (nicotinamide riboside), but the NMN transporter Slc12a8 was discovered in mice—confirmed to exist in humans too.
- Slc12a8 requires sodium to transport NMN directly into cells.
- Exercise further increases Slc12a8 expression (more transport channels), making NMN supplementation combined with exercise highly effective.
Key Finding
Growing research confirms that NMN combined with other active ingredients yields synergistic effects. Laboratory data shows that compound NMN formulas (e.g., with PQQ) can boost NAD+ levels by over 200% compared to single-ingredient NMN.
References
[1] Henderson, J.D., Quigley, S.N.Z., Chachra, S.S., et al. The use of a systems approach to increase NAD+ in human participants. npj Aging, 10, 7 (2024). https://doi.org/10.1038/s41514-023-00134-0[2] Gardell, S.J., Hopf, M., Khan, A., et al. Boosting NAD+ with a small molecule that activates NAMPT. Nat Commun, 10, 3241 (2019). https://doi.org/10.1038/s41467-019-11078-z[3] Lan F, Weikel KA, Cacicedo JM, Ido Y. Resveratrol-Induced AMP-Activated Protein Kinase Activation Is Cell-Type Dependent: Lessons from Basic Research for Clinical Application. Nutrients, 9(7):751 (2017). https://doi.org/10.3390/nu9070751[4] Imai SI. NAD World 3.0: the importance of the NMN transporter and eNAMPT in mammalian aging and longevity control. NPJ Aging, 11(1):4 (2025). https://doi.org/10.1038/s41514-025-00192-6[5] Camacho-Pereira, J., et al. CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism. Cell Metabolism, 23(6):1127–1139.[6] Sharma A, Chabloz S, Lapides RA, et al. Potential Synergistic Supplementation of NAD+ Promoting Compounds as a Strategy for Increasing Healthspan. Nutrients, 15(2):445 (2023). https://doi.org/10.3390/nu15020445[7] Xiao W, Wang RS, Handy DE, Loscalzo J. NAD(H) and NADP(H) Redox Couples and Cellular Energy Metabolism. Antioxid Redox Signal, 28(3):251–272 (2018). https://doi.org/10.1089/ars.2017.7216