{
  "cutoff": "2026-10-13",
  "note": "Selected publication milestones, not an exhaustive history or discovery priority claim.",
  "milestones": [
    {
      "pmid": "25506599",
      "year": "2014",
      "title": "Frailty Attenuates the Impact of Metformin on Reducing Mortality in Older Adults with Type 2 Diabetes.",
      "doi": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/25506599/",
      "interpretation": "Older diabetic observational survival associations vary with frailty and active-drug comparator."
    },
    {
      "pmid": "27721479",
      "year": "2016",
      "title": "Nicotinamide riboside is uniquely and orally bioavailable in mice and humans.",
      "doi": "10.1038/ncomms12948",
      "url": "https://pubmed.ncbi.nlm.nih.gov/27721479/",
      "interpretation": "NR human pharmacokinetics establish exposure rather than older clinical benefit."
    },
    {
      "pmid": "29599478",
      "year": "2018",
      "title": "Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults.",
      "doi": "10.1038/s41467-018-03421-7",
      "url": "https://pubmed.ncbi.nlm.nih.gov/29599478/",
      "interpretation": "Short NR crossover demonstrates circulating NAD augmentation and bounded vascular leads."
    },
    {
      "pmid": "29383869",
      "year": "2018",
      "title": "Metformin regulates metabolic and nonmetabolic pathways in skeletal muscle and subcutaneous adipose tissues of older adults.",
      "doi": "10.1111/acel.12723",
      "url": "https://pubmed.ncbi.nlm.nih.gov/29383869/",
      "interpretation": "Metformin older-tissue pathways supply physiological rather than lifespan evidence."
    },
    {
      "pmid": "30548390",
      "year": "2019",
      "title": "Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults.",
      "doi": "10.1111/acel.12880",
      "url": "https://pubmed.ncbi.nlm.nih.gov/30548390/",
      "interpretation": "Metformin/exercise interaction shows blunted fitness/metabolic adaptation in older adults."
    },
    {
      "pmid": "31557380",
      "year": "2019",
      "title": "Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double-blind, placebo-controlled, multicenter trial: The MASTERS trial.",
      "doi": "10.1111/acel.13039",
      "url": "https://pubmed.ncbi.nlm.nih.gov/31557380/",
      "interpretation": "MASTERS separates blunted muscle growth from a nonsignificant strength trend."
    },
    {
      "pmid": "31412242",
      "year": "2019",
      "title": "Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures.",
      "doi": "10.1016/j.celrep.2019.07.043",
      "url": "https://pubmed.ncbi.nlm.nih.gov/31412242/",
      "interpretation": "Aged human muscle metabolome responds to NR without changed bioenergetics."
    },
    {
      "pmid": "31685720",
      "year": "2020",
      "title": "Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men.",
      "doi": "10.1507/endocrj.EJ19-0313",
      "url": "https://pubmed.ncbi.nlm.nih.gov/31685720/",
      "interpretation": "Single-dose NMN feasibility precedes chronic physical-outcome testing."
    },
    {
      "pmid": "33888596",
      "year": "2021",
      "title": "Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women.",
      "doi": "10.1126/science.abe9985",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33888596/",
      "interpretation": "Prediabetic-women NMN clamp physiology establishes its own endpoint and population."
    },
    {
      "pmid": "34238308",
      "year": "2021",
      "title": "Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study.",
      "doi": "10.1186/s12970-021-00442-4",
      "url": "https://pubmed.ncbi.nlm.nih.gov/34238308/",
      "interpretation": "Young/middle-aged runner threshold effects coexist with peak-capacity nulls."
    },
    {
      "pmid": "35215405",
      "year": "2022",
      "title": "Effect of 12-Week Intake of Nicotinamide Mononucleotide on Sleep Quality, Fatigue, and Physical Performance in Older Japanese Adults: A Randomized, Double-Blind Placebo-Controlled Study.",
      "doi": "10.3390/nu14040755",
      "url": "https://pubmed.ncbi.nlm.nih.gov/35215405/",
      "interpretation": "Twelve-week older timing trial yields interactions and within-arm improvements, not clear pairwise efficacy."
    },
    {
      "pmid": "35927255",
      "year": "2022",
      "title": "Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men.",
      "doi": "10.1038/s41514-022-00084-z",
      "url": "https://pubmed.ncbi.nlm.nih.gov/35927255/",
      "interpretation": "Older-men gait leads require supplier-switch, sample and multiplicity interpretation."
    },
    {
      "pmid": "35998039",
      "year": "2022",
      "title": "A randomized placebo-controlled trial of nicotinamide riboside and pterostilbene supplementation in experimental muscle injury in elderly individuals.",
      "doi": "10.1172/jci.insight.158314",
      "url": "https://pubmed.ncbi.nlm.nih.gov/35998039/",
      "interpretation": "NR/pterostilbene induced-muscle-injury trial gives a direct recovery null."
    },
    {
      "pmid": "36482258",
      "year": "2023",
      "title": "The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial.",
      "doi": "10.1007/s11357-022-00705-1",
      "url": "https://pubmed.ncbi.nlm.nih.gov/36482258/",
      "interpretation": "Middle-aged NMN walking/exposure dose results remain separate from ≥60 efficacy."
    },
    {
      "pmid": "36443648",
      "year": "2023",
      "title": "Effects of nicotinamide mononucleotide on older patients with diabetes and impaired physical performance: A prospective, placebo-controlled, double-blind study.",
      "doi": "10.1111/ggi.14513",
      "url": "https://pubmed.ncbi.nlm.nih.gov/36443648/",
      "interpretation": "Older-diabetic impaired-function NMN primary tests are null at24weeks."
    },
    {
      "pmid": "36740954",
      "year": "2023",
      "title": "Nicotinamide Adenine Dinucleotide Augmentation in Overweight or Obese Middle-Aged and Older Adults: A Physiologic Study.",
      "doi": "10.1210/clinem/dgad027",
      "url": "https://pubmed.ncbi.nlm.nih.gov/36740954/",
      "interpretation": "MIB626 changes NAD and selected cardiometabolic measures with physical-performance nulls."
    },
    {
      "pmid": "37446292",
      "year": "2023",
      "title": "Triple-Isotope Tracing for Pathway Discernment of NMN-Induced NAD+ Biosynthesis in Whole Mice.",
      "doi": "10.3390/ijms241311114",
      "url": "https://pubmed.ncbi.nlm.nih.gov/37446292/",
      "interpretation": "Mouse isotope tracing challenges assumptions of widespread intact NMN uptake."
    },
    {
      "pmid": "38789831",
      "year": "2024",
      "title": "Ingestion of β-nicotinamide mononucleotide increased blood NAD levels, maintained walking speed, and improved sleep quality in older adults in a double-blind randomized, placebo-controlled study.",
      "doi": "10.1007/s11357-024-01204-1",
      "url": "https://pubmed.ncbi.nlm.nih.gov/38789831/",
      "interpretation": "A real secondary gait-time signal occurs alongside stepping, grip and SPPB nulls in older adults."
    },
    {
      "pmid": "38871717",
      "year": "2024",
      "title": "Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial.",
      "doi": "10.1038/s41467-024-49092-5",
      "url": "https://pubmed.ncbi.nlm.nih.gov/38871717/",
      "interpretation": "NR-PAD supplies a genuine different-molecule walking positive with specific statistical limits."
    },
    {
      "pmid": "38869746",
      "year": "2024",
      "title": "Metformin as adjuvant therapy in obese knee osteoarthritis patients.",
      "doi": "10.1007/s10787-024-01495-y",
      "url": "https://pubmed.ncbi.nlm.nih.gov/38869746/",
      "interpretation": "Metformin knee-OA adjunct trial retains a distinct pain/function positive."
    },
    {
      "pmid": "40147475",
      "year": "2025",
      "title": "Metformin and physical performance in older people with probable sarcopenia and physical prefrailty or frailty in England (MET-PREVENT): a double-blind, randomised, placebo-controlled trial.",
      "doi": "10.1016/j.lanhl.2025.100695",
      "url": "https://pubmed.ncbi.nlm.nih.gov/40147475/",
      "interpretation": "MET-PREVENT tests frail-older function directly and finds no gait benefit with tolerability concerns."
    },
    {
      "pmid": "42478598",
      "year": "2026",
      "title": "A phase-II randomized controlled pilot study of nicotinamide riboside supplementation in older adults with amnestic mild cognitive impairment.",
      "doi": "10.1002/alz.71605",
      "url": "https://pubmed.ncbi.nlm.nih.gov/42478598/",
      "interpretation": "Newer NR-MCI primary cognition remains null despite NAD rise."
    },
    {
      "pmid": "41205146",
      "year": "2026",
      "title": "Metformin to Improve Walking Performance in Lower Extremity Peripheral Artery Disease: The PERMET Randomized Clinical Trial.",
      "doi": "10.1001/jama.2025.21358",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41205146/",
      "interpretation": "PERMET establishes a direct metformin-PAD walking null."
    },
    {
      "pmid": "42532077",
      "year": "2026",
      "title": "Metformin added to lifestyle intervention for physical function in older adults with obesity (DEMFOS trial): a randomised controlled trial.",
      "doi": "10.1016/j.lanhl.2026.100883",
      "url": "https://pubmed.ncbi.nlm.nih.gov/42532077/",
      "interpretation": "DEMFOS distinguishes lifestyle efficacy from absent added metformin function."
    },
    {
      "pmid": "42023167",
      "year": "2026",
      "title": "Metformin and epigenetic age in non-diabetic older people with HIV in Madrid (METFORAGING): a double-blind, randomised, placebo-controlled, pilot trial.",
      "doi": "10.1016/j.eclinm.2026.103874",
      "url": "https://pubmed.ncbi.nlm.nih.gov/42023167/",
      "interpretation": "METFORAGING provides a longer biomarker primary null rather than human longevity evidence."
    }
  ],
  "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."
  ],
  "decisive_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."
}