# Research timeline and gaps: NAD Boosters and Human Function

Selected publication milestones, not an exhaustive history or discovery priority claim.

**2014 — Older diabetic observational survival associations vary with frailty and active-drug comparator.** [Original PMID25506599](https://pubmed.ncbi.nlm.nih.gov/25506599/).

**2016 — NR human pharmacokinetics establish exposure rather than older clinical benefit.** [Original PMID27721479](https://pubmed.ncbi.nlm.nih.gov/27721479/).

**2018 — Short NR crossover demonstrates circulating NAD augmentation and bounded vascular leads.** [Original PMID29599478](https://pubmed.ncbi.nlm.nih.gov/29599478/).

**2018 — Metformin older-tissue pathways supply physiological rather than lifespan evidence.** [Original PMID29383869](https://pubmed.ncbi.nlm.nih.gov/29383869/).

**2019 — Metformin/exercise interaction shows blunted fitness/metabolic adaptation in older adults.** [Original PMID30548390](https://pubmed.ncbi.nlm.nih.gov/30548390/).

**2019 — MASTERS separates blunted muscle growth from a nonsignificant strength trend.** [Original PMID31557380](https://pubmed.ncbi.nlm.nih.gov/31557380/).

**2019 — Aged human muscle metabolome responds to NR without changed bioenergetics.** [Original PMID31412242](https://pubmed.ncbi.nlm.nih.gov/31412242/).

**2020 — Single-dose NMN feasibility precedes chronic physical-outcome testing.** [Original PMID31685720](https://pubmed.ncbi.nlm.nih.gov/31685720/).

**2021 — Prediabetic-women NMN clamp physiology establishes its own endpoint and population.** [Original PMID33888596](https://pubmed.ncbi.nlm.nih.gov/33888596/).

**2021 — Young/middle-aged runner threshold effects coexist with peak-capacity nulls.** [Original PMID34238308](https://pubmed.ncbi.nlm.nih.gov/34238308/).

**2022 — Twelve-week older timing trial yields interactions and within-arm improvements, not clear pairwise efficacy.** [Original PMID35215405](https://pubmed.ncbi.nlm.nih.gov/35215405/).

**2022 — Older-men gait leads require supplier-switch, sample and multiplicity interpretation.** [Original PMID35927255](https://pubmed.ncbi.nlm.nih.gov/35927255/).

**2022 — NR/pterostilbene induced-muscle-injury trial gives a direct recovery null.** [Original PMID35998039](https://pubmed.ncbi.nlm.nih.gov/35998039/).

**2023 — Middle-aged NMN walking/exposure dose results remain separate from ≥60 efficacy.** [Original PMID36482258](https://pubmed.ncbi.nlm.nih.gov/36482258/).

**2023 — Older-diabetic impaired-function NMN primary tests are null at24weeks.** [Original PMID36443648](https://pubmed.ncbi.nlm.nih.gov/36443648/).

**2023 — MIB626 changes NAD and selected cardiometabolic measures with physical-performance nulls.** [Original PMID36740954](https://pubmed.ncbi.nlm.nih.gov/36740954/).

**2023 — Mouse isotope tracing challenges assumptions of widespread intact NMN uptake.** [Original PMID37446292](https://pubmed.ncbi.nlm.nih.gov/37446292/).

**2024 — A real secondary gait-time signal occurs alongside stepping, grip and SPPB nulls in older adults.** [Original PMID38789831](https://pubmed.ncbi.nlm.nih.gov/38789831/).

**2024 — NR-PAD supplies a genuine different-molecule walking positive with specific statistical limits.** [Original PMID38871717](https://pubmed.ncbi.nlm.nih.gov/38871717/).

**2024 — Metformin knee-OA adjunct trial retains a distinct pain/function positive.** [Original PMID38869746](https://pubmed.ncbi.nlm.nih.gov/38869746/).

**2025 — MET-PREVENT tests frail-older function directly and finds no gait benefit with tolerability concerns.** [Original PMID40147475](https://pubmed.ncbi.nlm.nih.gov/40147475/).

**2026 — Newer NR-MCI primary cognition remains null despite NAD rise.** [Original PMID42478598](https://pubmed.ncbi.nlm.nih.gov/42478598/).

**2026 — PERMET establishes a direct metformin-PAD walking null.** [Original PMID41205146](https://pubmed.ncbi.nlm.nih.gov/41205146/).

**2026 — DEMFOS distinguishes lifestyle efficacy from absent added metformin function.** [Original PMID42532077](https://pubmed.ncbi.nlm.nih.gov/42532077/).

**2026 — METFORAGING provides a longer biomarker primary null rather than human longevity evidence.** [Original PMID42023167](https://pubmed.ncbi.nlm.nih.gov/42023167/).

## Research gaps

Adequate prespecified objective-function replication and clinically interpretable effect size.

Independent verification of exact formulations, target-tissue NAD and necessary functional mediator.

Prospective baseline disease/function/sex and dose interactions rather than cross-trial subgroup narratives.

Complete missing-data, allocation-error and multiplicity audits across older trials.

Longer clinical functional trajectory, disease incidence and survival rather than biological-age algorithms.

Long-term safety and drug/exercise interactions with molecule-specific attribution.

## Boundary experiment

Randomize baseline-defined ≥60 adults to exact NMN formulation and matched placebo for24weeks, with gait/strength/capacity prespecified as primary or multiplicity-controlled co-primary, meaningful effect size and complete assignment-based analysis. Include prospectively defined healthy and impaired-function/diabetes strata with interaction testing, independent blinded assessors and proper allocation auditing. Measure muscle NAD and pathway controls separately, and extend functional/disease follow-up.