NMN (Nicotinamide Mononucleotide)

Strong preclinical evidence. Human trials show improved insulin sensitivity and muscle function. Long-term outcomes still being studied. David Sinclair research widely cited. UPDATE (August 2026): A Nature Aging 2026 meta-analysis of more than 15,000 human DNA methylation profiles across 17 tissues (Jacques et al., with Horvath, Gladyshev and Teschendorff) used network analysis to separate tightly connected age-associated gene clusters that beneficial interventions do NOT move from a more modifiable cluster linked to NAD+ metabolism - the authors frame this as supporting NAD+ as a candidate therapeutic node in aging. This is meaningful as network-level evidence that NAD+ metabolism sits in an addressable part of the aging epigenome. It is NOT evidence that NMN or any NAD+ precursor supplement improves human aging outcomes; the analysis is cross-sectional and descriptive, with no supplementation arm. Separately, a peer-reviewed systematic review of 27 human nutrition trials (Ageing Research Reviews 2026) found that dietary supplement evidence for moving cellular-senescence biomarkers remains limited and heterogeneous. UPDATE (August 9, 2026): Two peer-reviewed papers this cycle bear on the sirtuin/NAD rationale, and both cut against over-reading it. (1) Nature Aging 2026 (Mu, Barthez et al.; D. Chen, Netea and Verdin labs) shows the mitochondrial deacetylase SIRT3 — highly expressed in hematopoietic stem cells and lost with age — suppresses an HSC response to aging that installs maladaptive trained immunity in myeloid progeny; HSC-specific SIRT3 overexpression improved HSC function and attenuated age-related declines in cognition and motility in distant tissues. This is a genuinely important relocation of inflammaging upstream to a trained stem-cell compartment, but SIRT3 was raised by transgenic overexpression in mice. There is no demonstration that NMN, NR or any NAD+ precursor raises HSC SIRT3 activity or reproduces any part of this phenotype. (2) Nature Aging 2026 (Cole, Buj et al.) identifies fructose as a metabolic component of the chemotherapy-induced SASP that drives ovarian-cancer cell detachment and metastatic dissemination specifically through inhibition of an NAD-SIRT-SREBP axis. That places NAD-sirtuin signalling inside a pro-dissemination pathway in an oncology context — preclinical and model-specific, but a reason for caution rather than confidence about NAD+ loading in patients with active or recent malignancy. UPDATE (September 20, 2026): A peer-reviewed measurement result that directly affects how NMN response is monitored. Nature Metabolism 2026;8:1282-1290 (Tretowicz, Schomakers et al.; Houtkooper lab, Amsterdam UMC) quantified NAD+ across seven independent human cohorts with a rigorously validated UHPLC-high-resolution MS method designed to account for real-world analytical variability, and found whole-blood NAD+ STABLE with chronological age and UNCHANGED by lifestyle interventions - while responding as expected to nicotinamide riboside supplementation. The authors conclude that blood NAD+ is not a useful biomarker of ageing or lifestyle, and that much of the previously reported age-related decline is plausibly assay variability. Scope this carefully: the paper does not refute tissue or intracellular NAD+ decline, does not test NMN specifically, and does not evaluate any clinical outcome of precursor supplementation - the mechanistic NAD+ rationale summarised above is untouched. What it does remove is the common practice of using a blood NAD+ level as a biological-age readout or as proof that a precursor is working; a supplement-induced rise demonstrates absorption, not benefit. Balancing this, GeroScience 2026 (Itabashi Longitudinal Study on Aging, 16 Sept 2026) reported that among 529 community-dwelling Japanese adults aged 65+, the 32 (6.0%) meeting revised J-CHS frailty criteria had lower median whole-blood NAD+ than non-frail participants, robust to adjustment for age, sex and fasting time and to spline, Firth penalised-likelihood and haematological sensitivity analyses. This is the clearest human association to date between circulating NAD+ and a functional outcome, and it is a legitimate reason to keep the axis under study - but it is cross-sectional with only 32 frail participants, reverse causation is unaddressed, and it tests no supplement. Human NMN evidence remains limited to short-duration surrogate endpoints.

Evidence Scale