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Medical disclaimer: This article reviews published biochemistry and aging research on NAD+ metabolism. It is not medical advice, diagnosis, or treatment. Not medical advice. Consult a qualified healthcare professional before changing your supplement regimen or any health-related practice.

TL;DR

• NAD+ is synthesized through three distinct routes: de novo from tryptophan via the kynurenine pathway, the Preiss-Handler pathway from nicotinic acid (niacin), and the salvage pathway from nicotinamide, NR, and NMN
• NMN and NR supplements address only the salvage pathway — they do not directly alter kynurenine pathway flux
• The kynurenine pathway bifurcates at kynurenine: one branch heads toward NAD+ synthesis via quinolinic acid and QPRT; the other generates neuroactive metabolites including kynurenic acid, with the balance determined by enzymatic activity ratios
• With age and chronic inflammation, IDO1 activity tends to increase while QPRT activity appears to decline in some tissues — potentially generating more quinolinic acid than aging tissue can efficiently convert to NAD+
• Japanese research programs have contributed to IDO1 biology, kynurenine metabolite measurement in aging cohorts, and NAMPT activity characterization in Japanese adult populations
• Calibration: the pathway biochemistry is well-established; translation to supplement strategies specifically targeting the kynurenine route remains a research-stage question with no human clinical trial data as of mid-2026

Why the pathway map matters

People who follow NAD+ biology long enough eventually reach a version of the same question: if cells have three ways to make NAD+, and NMN and NR only address one of those ways, what is happening in the other two?

The answer is mechanistically important and practically underappreciated in supplement discourse. Most commercial coverage of NAD+ focuses on the rate-limiting step in the salvage pathway — NAMPT (nicotinamide phosphoribosyltransferase), which converts nicotinamide to NMN. Bypass NAMPT by supplying NMN or NR directly, and NAD+ rises through a documented mechanism. That is what the Yoshino et al. 2021 (Science, PubMed 34407019) and Igarashi et al. 2022 (NPJ Aging) Keio-linked trials established at the biomarker level.

What that framing misses: a substantial portion of NAD+ in many tissues is produced from the essential amino acid tryptophan through a multi-step enzymatic cascade — the kynurenine pathway — and age-related changes in that cascade affect NAD+ homeostasis in ways salvage-pathway precursor supplementation does not directly address.

Three routes to NAD+

De novo: the kynurenine pathway from tryptophan

The longest and metabolically most complex route begins with tryptophan. The entry step is catalyzed by one of three enzymes: IDO1 (indoleamine 2,3-dioxygenase 1), IDO2, or TDO2 (tryptophan 2,3-dioxygenase), depending on tissue and physiological context. IDO1 is expressed broadly and is strongly induced by interferon-gamma and other inflammatory cytokines. TDO2 is primarily hepatic and responds to tryptophan availability. Both convert tryptophan to N-formylkynurenine, which is rapidly hydrolyzed to kynurenine by kynurenine formamidase.

From kynurenine, the pathway splits:

Branch toward NAD+. Kynurenine 3-monooxygenase (KMO) converts kynurenine to 3-hydroxykynurenine; kynureninase (KYNU) then generates 3-hydroxyanthranilic acid (3-HAA); 3-HAO converts 3-HAA to quinolinic acid (QUIN). Quinolinic acid is the substrate for QPRT (quinolinate phosphoribosyltransferase), which generates NaMN — the same intermediate the Preiss-Handler pathway reaches from niacin. From NaMN, NMNAT enzymes generate NAAD, then NADSYN1 generates NAD+.

Branch toward neuroactive metabolites. Kynurenine aminotransferases (KATs) convert kynurenine to kynurenic acid (KYNA), an antagonist at NMDA and alpha-7 nicotinic receptors with documented neuroprotective properties in some experimental contexts. The ratio between NAD+-producing flux through KMO and the KYNA-producing branch through KATs varies by tissue and is modulated by inflammatory state, substrate availability, and individual enzymatic expression levels.

Preiss-Handler pathway from nicotinic acid

Dietary niacin (nicotinic acid, vitamin B3) enters through nicotinic acid phosphoribosyltransferase (NAPRT), generating NaMN — the same intermediate as the last step before NAAD in the de novo pathway. This route is efficient for dietary niacin and bypasses the kynurenine complexity entirely. Nicotinamide (niacinamide) from the same B3 family enters at NAMPT, the salvage pathway rate-limiter.

Salvage pathway

Nicotinamide released from NAD+ consumption — via PARP, sirtuin deacylase, and cyclic ADP-ribose synthase reactions — is recycled through NAMPT → NMN → NAD+ via NMNAT. NR (nicotinamide riboside) bypasses NAMPT through NRK1/NRK2 kinases, converting to NMN directly. NMN taken as a supplement enters this pathway at the NMN stage, downstream of NAMPT. This is the supplement-targeted route, the most commercially characterized, and the one with the most human bioavailability data as of 2026.

Age-related changes in the kynurenine pathway

Two shifts appear to occur with age, and they work against each other from a NAD+ production standpoint.

IDO1 activity tends to increase. Chronic low-grade inflammation associated with aging — sometimes called inflammaging — drives sustained IDO1 induction via IFN-γ and related cytokines. Higher IDO1 activity channels more tryptophan into the kynurenine pathway rather than toward serotonin synthesis. On paper, more substrate entering the pathway would be expected to generate more NAD+.

QPRT activity appears to decline in some aged tissues. QPRT is the enzymatic bottleneck that determines how much quinolinic acid gets converted to NaMN rather than accumulating. Massudi et al. (2012, PLoS One, PubMed 22848578) documented that QPRT expression declines with age in human skeletal muscle. This finding — still limited to specific tissue types in a relatively small study — implies that aged tissue may generate more flux through the kynurenine pathway while being less capable of completing the conversion to NAD+. The net result in those tissues would be quinolinate accumulation rather than NAD+ synthesis, despite upstream IDO1 activity being elevated.

Quinolinate accumulation is not a neutral biochemical outcome in the context of neural tissue. Quinolinic acid is an endogenous NMDA receptor agonist; at sufficient concentrations in brain tissue it is associated with excitotoxic signaling. The concentrations observed in normal aging appear substantially lower than those documented in acute inflammatory and infectious conditions — including HIV-associated neurocognitive disorder, Huntington’s disease, and severe sepsis — where the QUIN-excitotoxicity connection is better characterized. Whether physiological-aging QUIN elevation reaches neurologically relevant concentrations independently of acute inflammatory episodes remains contested in the literature, and overstating this pathway’s contribution to age-associated cognitive change is not warranted by the current evidence base.

The more conservative reading: the kynurenine-to-NAD+ conversion efficiency may decrease with age through a QPRT-mediated bottleneck, independently of salvage pathway decline, and NMN or NR supplementation does not address that specific mechanism.

Japanese research contributions

Japan’s contribution to this field spans several institutional programs.

IDO1 biology and immune signaling. Japanese cancer immunology research has characterized IDO1 as an immunosuppressive mechanism in tumor microenvironments, where IDO1 induction by interferon-gamma depletes tryptophan and generates immunosuppressive kynurenine metabolites that blunt T-cell responses. This work — including programs at Kyoto University and the National Cancer Center Research Institute — overlaps with the aging biology question because the same IDO1-driven tryptophan depletion mechanism operates in chronic inflammatory contexts at lower magnitude. The mechanistic characterization of IDO1 induction pathways in these cancer programs has contributed to the broader understanding of how IDO1 responds to cytokine signaling, including cytokines elevated in aging tissue.

NAMPT characterization in Japanese cohorts. NAMPT exists in two forms: intracellular iNAMPT (the NAD+ biosynthesis enzyme) and secreted eNAMPT, which has proposed extracellular signaling roles. Research groups at Tohoku University and the National Center for Geriatrics and Gerontology (NCGG) have examined NAMPT and NAD+ metabolite levels in Japanese adult cohorts, contributing population-level reference data to an area where most published normative values come from Western study populations. Japan’s centenarian density — approximately 95,000 centenarians as of 2024 per Japan Statistics Bureau data — provides unusual access to extreme-longevity cohort subjects for comparative metabolomics.

Kynurenine metabolite ratios in cognitive aging. NCGG’s clinical research infrastructure has examined plasma kynurenine metabolite ratios — particularly the kynurenine-to-tryptophan ratio (KTR), a surrogate marker of IDO1 activity — in the context of age-related cognitive changes in Japanese adults. Elevated KTR is associated in epidemiological literature with systemic inflammatory markers, and prospective data suggest correlations with frailty progression and cognitive trajectories in older cohorts. Causal direction is not established in Japanese or other population cohorts through interventional designs; elevated KTR may reflect chronic inflammatory load that also affects cognitive outcomes rather than being a direct contributor through tryptophan depletion.

What the three-pathway view means for supplement strategy

The practical implication is specific. NMN and NR supply precursors at the salvage pathway entry point. They do not alter IDO1 activity, kynurenine flux distribution, or QPRT enzymatic capacity. In a scenario where salvage pathway decline is the primary driver of NAD+ depletion, adding NMN or NR addresses the relevant bottleneck. In a scenario where kynurenine pathway inefficiency via QPRT decline is the primary driver, adding salvage-pathway precursors may still raise NAD+ to some degree — the salvage pathway is not saturated at supplemental doses in published trials — but leaves the kynurenine-route limitation unaddressed.

No supplement product currently marketed to consumers specifically targets QPRT activity or IDO1 modulation for NAD+ support purposes. IDO1 inhibitors exist as pharmaceutical candidates in cancer immunotherapy — epacadostat being the best-characterized — but these are designed to reverse immunosuppression in tumor settings, not to support NAD+ synthesis in aging tissue, and their safety profile in healthy adults is not characterized for that indication.

Dietary context: tryptophan is the substrate for de novo NAD+ synthesis. Japanese dietary patterns emphasizing fish, tofu, natto, and fermented soy provide tryptophan from complete-protein food sources. Most dietary tryptophan is allocated to protein synthesis, with a fraction entering the kynurenine and serotonin pathways; the proportion entering de novo NAD+ synthesis is not a readily manipulable variable through dietary tryptophan increases alone. Niacin (B3) from food sources activates the Preiss-Handler pathway independently of both kynurenine and salvage routes; fish and fermented soy contribute dietary niacin as well as tryptophan.

For supplementation targeting the salvage pathway, the published human biomarker evidence remains the Yoshino 2021 and Igarashi 2022 NMN trials and the NR literature anchored in ChromaDex’s Tru Niagen program. Search ProHealth NMN supplement on Amazon and search Tru Niagen nicotinamide riboside on Amazon for products from manufacturers whose material appears in cited clinical literature. Neither addresses the kynurenine pathway; both address the salvage pathway with available human biomarker data.

If NAD+ support is something you are actively considering based on this research, the appropriate first step is a conversation with a clinician — particularly if you are on medications metabolized through pathways that NAD+ metabolism affects, or if your interest is driven by a specific health condition.

Where the evidence stands in mid-2026

The three-pathway architecture is established biochemistry, not hypothesis. The age-related changes in IDO1 activity and QPRT expression documented in published research are real findings with mechanistic plausibility. What they do not yet constitute is a basis for specific supplementation recommendations beyond the salvage-pathway evidence already accumulated for NMN and NR.

The honest position: kynurenine pathway dysregulation is a credible contributor to age-related NAD+ decline, distinct from and potentially additive to salvage pathway insufficiency. Measuring it — via KTR ratio or plasma kynurenine metabolite panels — is a research-grade tool available in some academic clinical settings, not a standard consumer-accessible biomarker. Addressing it pharmacologically requires either anti-inflammatory approaches that reduce IDO1 induction or QPRT-activating compounds that do not currently exist as characterized consumer products.

Following this area through primary literature is the most accurate information source: the NCGG programs, Japanese centenarian cohort metabolomics, and the expanding kynurenine metabolism in aging literature in journals including Aging Cell, GeroScience, and Cell Metabolism carry more signal than supplement product pages that reference kynurenine pathway research in support of NAD+ precursor products.

Related reading: Apigenin and CD38: the NAD+ degradation side covers enzymatic NAD+ consumption as the complementary half of the maintenance equation. Japan anti-aging clinical trials: Keio, Tokyo University, and TMDU covers the interventional trial landscape for salvage-pathway supplements.

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Sources: Massudi H, Grant R, Braidy N, et al. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS One. 2012;7(7):e42357. | Yoshino M, Yoshino J, Kayser BD, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science. 2021;372(6547):1224–1229. | Igarashi M, et al. Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels in healthy older men. NPJ Aging. 2022;8:5. | Cervenka I, Agudelo LZ, Ruas JL. Kynurenines: tryptophan’s metabolites in exercise, inflammation, and mental health. Science. 2017;357(6349):eaaf9794. | Platten M, Nollen EAA, Röhrig UF, Fallarino F, Opitz CA. Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration, and beyond. Nat Rev Drug Discov. 2019;18(5):379–401.

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• NAD+ Decline and Aging: What Japanese Research Shows
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• Japan Anti-Aging Clinical Trials 2025: NMN and NAD+