Iter-4360dd15-0006-transcript
第 6 轮执行轨迹
→ call search_memory({"limit":10,"query":"4360dd15 rapamycin human trials endpoint PMC review Table 1"}) → call list_recent({"n":10})
→ call list_by_tag({"limit":20,"tag":"4360dd15"})
【tool:search_memory】
{"ok": true, "results": [{"title": "Iter-4360dd15-0004-transcript", "tags": "iteration transcript", "modified": "20260424174235000", "preview": "!! 第 4 轮执行轨迹
→ call search_memory({\"limit\":10,\"query\":\"4360dd15 rapamycin human trial systematic review PMC endpoints trial names primary endpoint\"}) 【tool:search_memory】 {\"ok\": true, \"results\": [{\"title\": \"Iter-4360dd15-0004-transcript\", \"tags\": \"iteration transcript\", \"modified\": \"20260424174235000\", \"preview\": \"!! 第 4 轮执行轨迹 → call search_memory({\"limit\":8,\"query\":\"4360dd15 rapamycin human trial systematic review endpoints safety\"}) 【tool:search_memory】 {\"ok\": true, \"results\": [{\"title\": \"Iter-4360dd15-0002-transcript\", \"tag【tool:list_recent】
{"ok": true, "items": [{"title": "Iter-4360dd15-0005-reflection", "modified": "20260424174404000", "tags": "iteration reflection"}, {"title": "NEXT_FOCUS", "modified": "20260424174404000", "tags": "pinned focus"}, {"title": "先把异质证据拆成逐试验清单", "modified": "20260424174404000", "tags": "lesson evidence human-trials rapamycin"}, {"title": "Iter-4360dd15-0005-transcript", "modified": "20260424174400000", "tags": "iteration transcript"}, {"title": "Rapamycin human trials: completed studies table from PMC review", "modified": "20260424174352000", "tags": "knowledge fact 4360dd15"}, {"title": "Iter-4360dd15-0004-reflection", "modified": "20260424174242000", "tags": "iteration reflection"}, {"title": "先用可访问二级来源拼表", "modified": "20260424174242000", "tags": "lesson evidence retrieval human-trials"}, {"title": "Iter-4360dd15-0004-transcript", "modified": "20260424174235000", "tags": "iteration transcript"}, {"title": "Iter-4360dd15-0004-critique-rapamycin-evidence", "modified": "20260424174226000", "tags": "lesson critique 4360dd15"}, {"title": "Iter-4360dd15-0003-reflection", "modified": "20260424173853000", "tags": "iteration reflection"}]}
【tool:list_by_tag】
{"ok": true, "items": [{"title": "Rapamycin human trials: completed studies table from PMC review", "modified": "20260424174352000"}, {"title": "Iter-4360dd15-0004-critique-rapamycin-evidence", "modified": "20260424174226000"}, {"title": "Rapamycin human trials: extracted endpoints and outcomes from the 2024 systematic review review pass 1", "modified": "20260424173529000"}, {"title": "Human longevity interventions evidence maturity matrix 2026-04-25", "modified": "20260424173237000"}]}
→ call read_note({"title":"NEXT_FOCUS"})
→ call read_note({"title":"Rapamycin human trials: completed studies table from PMC review"})
→ call read_note({"title":"Rapamycin human trials: extracted endpoints and outcomes from the 2024 systematic review review pass 1"})
【tool:read_note】
{"ok": true, "title": "NEXT_FOCUS", "tags": "pinned focus", "text": "!! 下轮焦点（来自 mission `4360dd15` · Iter-0005）\n\n下一轮只做一件事：从 PMC 综述及其参考文献中逐条提取 rapamycin 人体试验名称和每项的主要终点。"}
【tool:read_note】
{"ok": true, "title": "Rapamycin human trials: completed studies table from PMC review", "tags": "knowledge fact 4360dd15", "text": "!! PMC review Table 1: completed human rapamycin / rapalog trials\n\nI re-read the accessible PMC review [[Blazing a trail for the clinical use of rapamycin as a geroprotecTOR]] (GeroScience 2023; PMCID PMC10643772) and extracted its completed-trial table.\n\n!! What this source actually contains\nThe table lists ''8 completed human studies'' and gives each study’s primary endpoint.\n\n!! Extracted trial list\n| Study | Agent | Population | Primary endpoint |\n|---|---|---|---|\n| Krebs et al. 2007 | rapamycin | 11 men, 28 ± 1 y | Increase in peripheral insulin sensitivity during insulin clamp plus amino acid infusion |\n| Drummond et al. 2009 | rapamycin | 15 men, 29 ± 2 y | Difference in post-resistance-exercise mixed-muscle protein synthesis rates |\n| Gunderman 2014 | rapamycin | 16 men, 26 ± 1 y | Difference in post-blood-flow-restricted resistance-exercise mixed-muscle protein synthesis rates |\n| Mannick et al. 2014 | everolimus | 218 adults ≥65 y | Improvement in influenza vaccination response |\n| Mannick et al. 2018 | everolimus / BEZ235 | 264 adults ≥65 y | Improvement in influenza vaccination response |\n| Kraig et al. 2018 | rapamycin | 25 healthy adults 70–95 y | Immunological response |\n| Chung et al. 2019 | topical rapamycin | 36 adults with aging skin >40 y | Decreased p16-positive senescent cells in skin |\n| Mannick et al. 20
【tool:read_note】
{"ok": true, "title": "Rapamycin human trials: extracted endpoints and outcomes from the 2024 systematic review review pass 1", "tags": "knowledge fact experiment 4360dd15", "text": "!! Rapamycin human trial evidence from a 2024 systematic review\nThis round I narrowed the long-longevity question to a single mechanism: //rapamycin / mTOR//.\n\n!! Source\n[[Targeting ageing with rapamycin and its derivatives in humans: a systematic review]] (Lee, Hodzic Kuerec, Maier), //Lancet Healthy Longevity// 2024; 5(2):e152-e162. The VU repository page includes the abstract and full bibliographic metadata.\n\n!! Extracted human trial snapshot\nThe review reports: 18,400 unique records screened, 19 included studies. Benefits were seen mainly in immune, cardiovascular, and integumentary systems; no significant effects in endocrine, muscular, or neurological systems.\n\n| Study | Population | Agent | Dose / schedule | Design | Primary endpoint | Result |\n|---|---|---|---|---|---|---|\n| Krebs et al. 2007 | 11 men, 28 +/- 1 y | rapamycin | 6 mg single dose | randomized, double-blind, placebo-controlled, crossover | peripheral insulin sensitivity during insulin clamp + amino acid infusion | met |\n| Drummond et al. 2009 | 15 men, 29 +/- 2 y | rapamycin | 12 mg single dose 2 h before resistance exercise | acute exercise +/- rapamycin | post-exercise mixed-muscle protein synthesis | met |\n| Gunderman 2014 | 16 men, 26 +/- 1 y | rapamycin | 16 mg single dose 1 h before blood-flow-restricted re
→ call web_search({"limit":8,"query":"\"Targeting ageing with rapamycin and its derivatives in humans: a systematic review\" references rapamycin trial"})
→ call pubmed_search({"limit":5,"query":"\"Targeting ageing with rapamycin and its derivatives in humans: a systematic review\""})
→ call web_search({"limit":8,"query":"site:pmc.ncbi.nlm.nih.gov rapamycin human trial primary endpoint review table 19 studies"})
【tool:web_search】
{"ok": true, "query": "\"Targeting ageing with rapamycin and its derivatives in humans: a systematic review\" references rapamycin trial", "results": []}
【tool:pubmed_search】
{"ok": true, "query": "\"Targeting ageing with rapamycin and its derivatives in humans: a systematic review\"", "results": [{"pmid": "38310895", "title": "Targeting ageing with rapamycin and its derivatives in humans: a systematic review.", "source": "Lancet Healthy Longev", "pubdate": "2024 Feb", "authors": ["Lee DJW", "Hodzic Kuerec A", "Maier AB"], "url": "https://pubmed.ncbi.nlm.nih.gov/38310895/"}, {"pmid": "28504837", "title": "Immunotherapy for metastatic renal cell carcinoma.", "source": "Cochrane Database Syst Rev", "pubdate": "2017 May 15", "authors": ["Unverzagt S", "Moldenhauer I", "Nothacker M", "Roßmeißl D", "Hadjinicolaou AV", "Peinemann F", "Greco F", "Seliger B"], "url": "https://pubmed.ncbi.nlm.nih.gov/28504837/"}]}
【tool:web_search】
{"ok": true, "query": "site:pmc.ncbi.nlm.nih.gov rapamycin human trial primary endpoint review table 19 studies", "results": []}
→ call web_search({"limit":10,"query":"\"Targeting ageing with rapamycin and its derivatives in humans\" full text pdf"})
→ call web_search({"limit":10,"query":"\"38310895\" rapamycin ageing humans pdf"})
→ call web_search({"limit":10,"query":"\"Lancet Healthy Longevity\" rapamycin humans systematic review references"})
【tool:web_search】
{"ok": true, "query": "\"Targeting ageing with rapamycin and its derivatives in humans\" full text pdf", "results": []}
【tool:web_search】
{"ok": true, "query": "\"38310895\" rapamycin ageing humans pdf", "results": []}
【tool:web_search】
{"ok": true, "query": "\"Lancet Healthy Longevity\" rapamycin humans systematic review references", "results": []}
→ call pubmed_search({"limit":5,"query":"Krebs rapamycin insulin sensitivity amino acid infusion"})
→ call pubmed_search({"limit":5,"query":"Drummond rapamycin protein synthesis resistance exercise"})
→ call pubmed_search({"limit":5,"query":"Gunderman rapamycin blood-flow-restricted resistance exercise"})
→ call pubmed_search({"limit":5,"query":"Kraig rapamycin immunological response older adults"})
→ call pubmed_search({"limit":5,"query":"Chung topical rapamycin aging skin p16 senescent cells"})
【tool:pubmed_search】
{"ok": true, "query": "Krebs rapamycin insulin sensitivity amino acid infusion", "results": [{"pmid": "29369529", "title": "Diabetes and branched-chain amino acids: What is the link?", "source": "J Diabetes", "pubdate": "2018 May", "authors": ["Bloomgarden Z"], "url": "https://pubmed.ncbi.nlm.nih.gov/29369529/"}, {"pmid": "17709744", "title": "Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistance.", "source": "Proc Natl Acad Sci U S A", "pubdate": "2007 Aug 28", "authors": ["Tremblay F", "Brûlé S", "Hee Um S", "Li Y", "Masuda K", "Roden M", "Sun XJ", "Krebs M"], "url": "https://pubmed.ncbi.nlm.nih.gov/17709744/"}, {"pmid": "17329620", "title": "The Mammalian target of rapamycin pathway regulates nutrient-sensitive glucose uptake in man.", "source": "Diabetes", "pubdate": "2007 Jun", "authors": ["Krebs M", "Brunmair B", "Brehm A", "Artwohl M", "Szendroedi J", "Nowotny P", "Roth E", "Fürnsinn C"], "url": "https://pubmed.ncbi.nlm.nih.gov/17329620/"}, {"pmid": "16123357", "title": "Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability.", "source": "Diabetes", "pubdate": "2005 Sep", "authors": ["Tremblay F", "Krebs M", "Dombrowski L", "Brehm A", "Bernroider E", "Roth E", "Nowotny P", "Waldhäusl W"], "url": "https://pubmed.ncbi.nlm.nih.gov/16123357/"}]}
【tool:pubmed_search】
{"ok": true, "query": "Drummond rapamycin protein synthesis resistance exercise", "results": [{"pmid": "27780819", "title": "Light-load resistance exercise increases muscle protein synthesis and hypertrophy signaling in elderly men.", "source": "Am J Physiol Endocrinol Metab", "pubdate": "2017 Apr 1", "authors": ["Agergaard J", "Bülow J", "Jensen JK", "Reitelseder S", "Drummond MJ", "Schjerling P", "Scheike T", "Serena A"], "url": "https://pubmed.ncbi.nlm.nih.gov/27780819/"}, {"pmid": "25735236", "title": "Effect of age on basal muscle protein synthesis and mTORC1 signaling in a large cohort of young and older men and women.", "source": "Exp Gerontol", "pubdate": "2015 May", "authors": ["Markofski MM", "Dickinson JM", "Drummond MJ", "Fry CS", "Fujita S", "Gundermann DM", "Glynn EL", "Jennings K"], "url": "https://pubmed.ncbi.nlm.nih.gov/25735236/"}, {"pmid": "25332468", "title": "Leucine-enriched amino acid ingestion after resistance exercise prolongs myofibrillar protein synthesis and amino acid transporter expression in older men.", "source": "J Nutr", "pubdate": "2014 Nov", "authors": ["Dickinson JM", "Gundermann DM", "Walker DK", "Reidy PT", "Borack MS", "Drummond MJ", "Arora M", "Volpi E"], "url": "https://pubmed.ncbi.nlm.nih.gov/25332468/"}, {"pmid": "23343671", "title": "Protein blend ingestion following resistance exercise promotes human muscle protein synthesis.", "source": "J Nutr", "pubdate": "2013 Apr", "authors": ["Reidy PT", "Walker DK", "Dickinson JM", "Gunderm
【tool:pubmed_search】
{"ok": true, "query": "Gunderman rapamycin blood-flow-restricted resistance exercise", "results": []}
【tool:pubmed_search】
{"ok": true, "query": "Kraig rapamycin immunological response older adults", "results": []}
【tool:pubmed_search】
{"ok": true, "query": "Chung topical rapamycin aging skin p16 senescent cells", "results": []}
→ call pubmed_search({"limit":10,"query":"\"rapamycin does not affect post-absorptive protein metabolism in human skeletal muscle\""})
→ call pubmed_search({"limit":10,"query":"\"The mammalian target of rapamycin pathway regulates nutrient-sensitive glucose uptake in man\""})
→ call pubmed_search({"limit":10,"query":"rapamycin human skeletal muscle metabolism trial"})
→ call web_search({"limit":10,"query":"\"rapamycin does not affect post-absorptive protein metabolism in human skeletal muscle\" abstract"})
【tool:pubmed_search】
{"ok": true, "query": "\"rapamycin does not affect post-absorptive protein metabolism in human skeletal muscle\"", "results": [{"pmid": "42030040", "title": "The Mechanism Underlying the Abnormal Expression of α-Synuclein in the Cortical Lesions of Patients With FCD Type IIb and TSC.", "source": "CNS Neurosci Ther", "pubdate": "2026 Apr", "authors": ["Zhang L", "Song JP", "Huang J", "Liang P", "Yang H", "Zhang CQ", "Shen KF"], "url": "https://pubmed.ncbi.nlm.nih.gov/42030040/"}, {"pmid": "42027897", "title": "Neutral impact of mTOR inhibitors on cardiovascular outcomes after kidney transplantation.", "source": "Clin Kidney J", "pubdate": "2026 Apr", "authors": ["Domingo-Pinent E", "Cacho J", "Cassia M", "Torres V", "Vergara H", "Herceda A", "Juarez P", "Gonzalez-Rojas Á"], "url": "https://pubmed.ncbi.nlm.nih.gov/42027897/"}, {"pmid": "42027728", "title": "Soy Protein Concentrate Dietary Substitution and Bacillus coagulans Supplementation Influence the Growth Performance, Digestive Enzyme Activity, Antioxidant Capacity, Gene Expression, and Gut Microbiota of Hybrid Grouper (Epinephelus fuscoguttatus♀ × Epinephelus lanceolatus♂).", "source": "Aquac Nutr", "pubdate": "2026", "authors": ["Yuan Y", "Zhang Z", "Sun D", "Liu Q", "Wang L", "Chen Y"], "url": "https://pubmed.ncbi.nlm.nih.gov/42027728/"}, {"pmid": "42025690", "title": "Clinical outcomes of Sirolimus coated balloons for the treatment of coronary disease. The Metal-Free registry.", "source": "Can J Cardiol", "pubdate": "2
【tool:pubmed_search】
{"ok": true, "query": "\"The mammalian target of rapamycin pathway regulates nutrient-sensitive glucose uptake in man\"", "results": [{"pmid": "17329620", "title": "The Mammalian target of rapamycin pathway regulates nutrient-sensitive glucose uptake in man.", "source": "Diabetes", "pubdate": "2007 Jun", "authors": ["Krebs M", "Brunmair B", "Brehm A", "Artwohl M", "Szendroedi J", "Nowotny P", "Roth E", "Fürnsinn C"], "url": "https://pubmed.ncbi.nlm.nih.gov/17329620/"}]}
【tool:pubmed_search】
{"ok": true, "query": "rapamycin human skeletal muscle metabolism trial", "results": [{"pmid": "41356921", "title": "The Role of Mammalian Target of Rapamycin (mTOR) and Adenosine Monophosphate-Activated Protein Kinase (AMPK) Signaling in Skeletal Muscle Hypertrophy: A Literature Review With Implications for Health and Disease.", "source": "Cureus", "pubdate": "2025 Nov", "authors": ["Jeong SY"], "url": "https://pubmed.ncbi.nlm.nih.gov/41356921/"}, {"pmid": "41321015", "title": "Dileucine-supplemented essential amino acids support whole-body anabolism after resistance exercise and serum-stimulated cell-based anabolism.", "source": "J Int Soc Sports Nutr", "pubdate": "2025 Dec 31", "authors": ["Aguilera JA", "Tinline-Goodfellow CT", "Lees MJ", "Kortebi I", "West DWD", "Abou Sawan S", "Sharma M", "Bashir R"], "url": "https://pubmed.ncbi.nlm.nih.gov/41321015/"}, {"pmid": "41166543", "title": "Glucagon-like peptide-1 receptor agonists and muscle health: potential role in sarcopenia prevention and treatment.", "source": "Eur J Endocrinol", "pubdate": "2025 Oct 30", "authors": ["González-Luis A", "Llinares-Arvelo V", "Martínez-Alberto CE", "Hernández-Carballo C", "Mora-Fernández C", "Navarro-González JF", "Donate-Correa J"], "url": "https://pubmed.ncbi.nlm.nih.gov/41166543/"}, {"pmid": "40722197", "title": "Human umbilical cord-derived mesenchymal stromal cell exosomes ameliorate aging-associated skeletal muscle atrophy and dysfunction in SAMP10 mice.", "source": "Stem Cell Res The
【tool:web_search】
{"ok": true, "query": "\"rapamycin does not affect post-absorptive protein metabolism in human skeletal muscle\" abstract", "results": []}
→ call web_fetch({"max_chars":5000,"url":"https://pubmed.ncbi.nlm.nih.gov/22959478/"})
→ call web_fetch({"max_chars":5000,"url":"https://pubmed.ncbi.nlm.nih.gov/17329620/"})
→ call web_fetch({"max_chars":5000,"url":"https://pubmed.ncbi.nlm.nih.gov/37897143/"})
【tool:web_fetch】
{"ok": false, "error": "Client error '403 Forbidden' for url 'https://pubmed.ncbi.nlm.nih.gov/22959478/'\nFor more information check: https://developer.mozilla.org/en-US/docs/Web/HTTP/Status/403"}
【tool:web_fetch】
{"ok": false, "error": "Client error '403 Forbidden' for url 'https://pubmed.ncbi.nlm.nih.gov/17329620/'\nFor more information check: https://developer.mozilla.org/en-US/docs/Web/HTTP/Status/403"}
【tool:web_fetch】
{"ok": false, "error": "Client error '403 Forbidden' for url 'https://pubmed.ncbi.nlm.nih.gov/37897143/'\nFor more information check: https://developer.mozilla.org/en-US/docs/Web/HTTP/Status/403"}
→ call search_memory({"limit":10,"query":"4360dd15 mTOR inhibition energy homeostasis sex-specific body weight loss humans rapamycin"})
【tool:search_memory】
{"ok": true, "results": [{"title": "Iter-4360dd15-0003-transcript", "tags": "iteration transcript", "modified": "20260424173843000", "preview": "!! 第 3 轮执行轨迹
→ call search_memory({\\\"limit\\\":10,\\\"query\\\":\\\"4360dd15 rapamycin senolytics NEXT_F"}, {"title": "Iter-4360dd15-0004-transcript", "tags": "iteration transcript", "modified": "20260424174235000", "preview": "!! 第 4 轮执行轨迹 → call search_memory({\"limit\":10,\"query\":\"4360dd15 rapamycin senolytics NEXT_FOCUS human trial review\"}) → call list_recent({\"n\":8}) → call list_by_tag({\"limit\":20,\"tag\":\"4360dd15\"}) 【tool:search_me → call search_memory({"limit":8,"query":"4360dd15 NCT04488601 rapamycin weekly healthy older adults primary endpoint"})
【tool:search_memory】
{"ok": true, "results": [{"title": "Iter-4360dd15-0003-transcript", "tags": "iteration transcript", "modified": "20260424173843000", "preview": "!! 第 3 轮执行轨迹
→ call search_memory({\\\"limit\\\":10,\\\"query\\\":\\\"4360dd15 rapamycin senolytics NEXT_F"}, {"title": "Iter-4360dd15-0002-transcript", "tags": "iteration transcript", "modified": "20260424173549000", "preview": "!! 第 2 轮执行轨迹 → ca"}, {"title": "Iter-4360dd15-0004-transcript", "tags": "iteration transcript", "modified": "20260424174235000", "preview": "!! 第 4 轮执行轨迹 → call web_search({"limit":8,"query":"\"Mammalian target of rapamycin inhibition impacts energy homeostasis and induces sex-specific body weight loss in humans\" abstract"})
→ call web_search({"limit":8,"query":"\"Mammalian target of rapamycin inhibition impacts energy homeostasis and induces sex-specific body weight loss in humans\""})
→ call web_search({"limit":8,"query":"\"37997143\" rapamycin body weight loss humans"})
【tool:web_search】
{"ok": true, "query": "\"Mammalian target of rapamycin inhibition impacts energy homeostasis and induces sex-specific body weight loss in humans\" abstract", "results": []}
【tool:web_search】
{"ok": true, "query": "\"Mammalian target of rapamycin inhibition impacts energy homeostasis and induces sex-specific body weight loss in humans\"", "results": []}
【tool:web_search】
{"ok": true, "query": "\"37997143\" rapamycin body weight loss humans", "results": []}
→ call web_search({"limit":10,"query":"\"Mammalian target of rapamycin inhibition impacts energy homeostasis and induces sex-specific body weight loss in humans\" abstract pdf"})
→ call web_search({"limit":10,"query":"\"sex-specific body weight loss in humans\" mTOR inhibition abstract"})
→ call web_search({"limit":10,"query":"site:pmc.ncbi.nlm.nih.gov \"Mammalian target of rapamycin inhibition impacts energy homeostasis\""})
【tool:web_search】
{"ok": true, "query": "\"Mammalian target of rapamycin inhibition impacts energy homeostasis and induces sex-specific body weight loss in humans\" abstract pdf", "results": []}
【tool:web_search】
{"ok": true, "query": "\"sex-specific body weight loss in humans\" mTOR inhibition abstract", "results": []}
【tool:web_search】
{"ok": true, "query": "site:pmc.ncbi.nlm.nih.gov \"Mammalian target of rapamycin inhibition impacts energy homeostasis\"", "results": []}
→ call web_search({"limit":10,"query":"37897143 J Cachexia Sarcopenia Muscle mTOR inhibition energy homeostasis humans"})
→ call web_search({"limit":10,"query":"Mannaa Pfennigwerth Fielitz Gollasch Boschmann mTOR inhibition energy homeostasis humans"})
→ call web_search({"limit":10,"query":"\"J Cachexia Sarcopenia Muscle\" mTOR inhibition humans body weight loss"})
【tool:web_search】
{"ok": true, "query": "37897143 J Cachexia Sarcopenia Muscle mTOR inhibition energy homeostasis humans", "results": [{"title": "Journal of Cachexia, Sarcopenia and Muscle - Wiley Online Library", "url": "https://onlinelibrary.wiley.com/journal/1353921906009", "snippet": "The Journal of Cachexia , Sarcopenia and
```