{
  "cutoff": "2026-10-12",
  "note": "Selected publication milestones, not an exhaustive history or discovery priority claim.",
  "milestones": [
    {
      "pmid": "16507602",
      "year": "2006",
      "title": "A high proportion of leucine is required for optimal stimulation of the rate of muscle protein synthesis by essential amino acids in the elderly.",
      "doi": "10.1152/ajpendo.00488.2005",
      "url": "https://pubmed.ncbi.nlm.nih.gov/16507602/",
      "interpretation": "2006 acute EAA/leucine tracer experiments demonstrate composition-sensitive synthesis."
    },
    {
      "pmid": "22338078",
      "year": "2012",
      "title": "Bed rest impairs skeletal muscle amino acid transporter expression, mTORC1 signaling, and protein synthesis in response to essential amino acids in older adults.",
      "doi": "10.1152/ajpendo.00603.2011",
      "url": "https://pubmed.ncbi.nlm.nih.gov/22338078/",
      "interpretation": "2012 bed rest shows reduced anabolic response, linking inactivity to a physiological boundary."
    },
    {
      "pmid": "22889730",
      "year": "2012",
      "title": "Protein supplementation improves physical performance in frail elderly people: a randomized, double-blind, placebo-controlled trial.",
      "doi": "10.1016/j.jamda.2012.07.005",
      "url": "https://pubmed.ncbi.nlm.nih.gov/22889730/",
      "interpretation": "2012 nutrition-only frailty trial improves SPPB without mass gain."
    },
    {
      "pmid": "22770932",
      "year": "2012",
      "title": "Protein supplementation increases muscle mass gain during prolonged resistance-type exercise training in frail elderly people: a randomized, double-blind, placebo-controlled trial.",
      "doi": "10.1016/j.jamda.2012.05.020",
      "url": "https://pubmed.ncbi.nlm.nih.gov/22770932/",
      "interpretation": "2012 separate training trial increases lean mass without added strength or SPPB benefit."
    },
    {
      "pmid": "26170041",
      "year": "2015",
      "title": "Effects of a vitamin D and leucine-enriched whey protein nutritional supplement on measures of sarcopenia in older adults, the PROVIDE study: a randomized, double-blind, placebo-controlled trial.",
      "doi": "10.1016/j.jamda.2015.05.021",
      "url": "https://pubmed.ncbi.nlm.nih.gov/26170041/",
      "interpretation": "2015 PROVIDE retains secondary chair-rise and lean-mass positives with primary functional nulls."
    },
    {
      "pmid": "25646324",
      "year": "2015",
      "title": "A high whey protein-, leucine-, and vitamin D-enriched supplement preserves muscle mass during intentional weight loss in obese older adults: a double-blind randomized controlled trial.",
      "doi": "10.3945/ajcn.114.090290",
      "url": "https://pubmed.ncbi.nlm.nih.gov/25646324/",
      "interpretation": "2015 weight-loss formulation preserves lean mass without additional function."
    },
    {
      "pmid": "28166780",
      "year": "2017",
      "title": "Effect of a high protein diet and/or resistance exercise on the preservation of fat free mass during weight loss in overweight and obese older adults: a randomized controlled trial.",
      "doi": "10.1186/s12937-017-0229-6",
      "url": "https://pubmed.ncbi.nlm.nih.gov/28166780/",
      "interpretation": "2017 factorial weight-loss study reports modest achieved dose separation and endpoint-specific interactions."
    },
    {
      "pmid": "29532075",
      "year": "2018",
      "title": "Effect of Protein Intake on Lean Body Mass in Functionally Limited Older Men: A Randomized Clinical Trial.",
      "doi": "10.1001/jamainternmed.2018.0008",
      "url": "https://pubmed.ncbi.nlm.nih.gov/29532075/",
      "interpretation": "2018 controlled feeding tests above-RDA intake with no functional advantage in its enrolled group."
    },
    {
      "pmid": "30475969",
      "year": "2018",
      "title": "Protein supplementation improves muscle mass and physical performance in undernourished prefrail and frail elderly subjects: a randomized, double-blind, placebo-controlled trial.",
      "doi": "10.1093/ajcn/nqy214",
      "url": "https://pubmed.ncbi.nlm.nih.gov/30475969/",
      "interpretation": "2018 malnourished frailty dose trial identifies highest-dose mass and gait benefit."
    },
    {
      "pmid": "31734121",
      "year": "2020",
      "title": "Effect of Protein Supplementation on Physical Performance in Older People With Sarcopenia-A Randomized Controlled Trial.",
      "doi": "10.1016/j.jamda.2019.09.006",
      "url": "https://pubmed.ncbi.nlm.nih.gov/31734121/",
      "interpretation": "2020 year-long whey trial in sarcopenia reports functional nulls."
    },
    {
      "pmid": "33564844",
      "year": "2021",
      "title": "The effect of daily protein supplementation, with or without resistance training for 1 year, on muscle size, strength, and function in healthy older adults: A randomized controlled trial.",
      "doi": "10.1093/ajcn/nqaa372",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33564844/",
      "interpretation": "2021 CALM separates ineffective protein alone from effective heavy loading."
    },
    {
      "pmid": "34358827",
      "year": "2021",
      "title": "Supplement-based nutritional strategies to tackle frailty: A multifactorial, double-blind, randomized placebo-controlled trial.",
      "doi": "10.1016/j.clnu.2021.06.024",
      "url": "https://pubmed.ncbi.nlm.nih.gov/34358827/",
      "interpretation": "2021 PRO-Elderly finds no nutrition add-on to training."
    },
    {
      "pmid": "41805014",
      "year": "2026",
      "title": "Fermented Whey Protein Supplement Slows the Progression of Frailty and Sarcopenia Among Older Korean Adults: A Randomized Blinded Trial.",
      "doi": "10.1177/1096620X261430172",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41805014/",
      "interpretation": "2026 small fermented-whey trial supplies a positive multinutrient replication lead."
    },
    {
      "pmid": "40926079",
      "year": "2026",
      "title": "Resistance training, but not leucine, increased basal muscle protein synthesis and reversed frailty in older women consuming optimized protein intake.",
      "doi": "10.1007/s11357-025-01877-2",
      "url": "https://pubmed.ncbi.nlm.nih.gov/40926079/",
      "interpretation": "2026 adequate-intake older-women trial finds training benefits without added leucine."
    }
  ],
  "gaps": [
    "A universalabove-RDA targetcannotbe readfromanacuteMPS plateau or observational dietassociation.",
    "The relativecontributionofproteinquantity,quality,energy correction,vitaminD andexercise needsmatchedcomponent controls.",
    "Longterm musclefunction isnotidenticaltoDXA/BIA leanmass orbiochemicalanabolism.",
    "Achievedintake andbaselinefrailty/nutrition interactionsneed independentprospective replication;frailtyalone isnot aresponderdefinition.",
    "Medication-assistedweightloss protein/training evidence isstilldirectlyneeded;protocols do notvalidateallGLP-1muscle-loss mitigation claims.",
    "Renalstate,exposure duration andproduct ingredientsdefine safetyinference;short unchangedcreatinine isnotall-populationsafetyproof."
  ],
  "decisive_experiment": "A preregistered multicenter isocaloricproteinquantitytrial with0.8g/kg/day comparator and clearlyachieved higherintake, stratifiedbeforeoutcomes bynutrition/frailty andincluding a factorial resistance-training component; GLP-1treated adults needtheirown controlled stratum withmeasuredfunction."
}