Iter-4360dd15-0010-transcript
第 10 轮执行轨迹
→ call search_memory({"limit":8,"query":"4360dd15 rapamycin review 2024 trial endpoint remaining 11"}) → call list_recent({"n":8})
→ call list_by_tag({"limit":20,"tag":"4360dd15"})
【tool:search_memory】
{"ok": true, "results": [{"title": "Iter-4360dd15-0007-transcript", "tags": "iteration transcript", "modified": "20260424174944000", "preview": "!! 第 7 轮执行轨迹
→ call search_memory({\\\"limit\\\":10,\\\"query\\"}, {"title": "Iter-4360dd15-0009-transcript", "tags": "iteration transcript", "modified": "20260424175555000", "preview": "!! 第 9 轮执行轨迹 → call search_memory({\"limit\":10,\"query\":\"4360dd15 rapamycin rapalog human trial Table 1 remaining endpoint PMC review\"}) 【tool:search_memory】 {\"ok\": true, \"results\": [{\"title\": \"Iter-4360dd15-0007-transcript\",【tool:list_recent】
{"ok": true, "items": [{"title": "Iter-4360dd15-0009-reflection", "modified": "20260424175603000", "tags": "iteration reflection"}, {"title": "NEXT_FOCUS", "modified": "20260424175603000", "tags": "pinned focus"}, {"title": "先用可访问综述骨架再补缺项", "modified": "20260424175603000", "tags": "lesson [[evidence retrieval]] human-trials rapamycin"}, {"title": "Iter-4360dd15-0009-transcript", "modified": "20260424175555000", "tags": "iteration transcript"}, {"title": "Iter-4360dd15-0008-reflection", "modified": "20260424175236000", "tags": "iteration reflection"}, {"title": "先锁定综述正文里的表，再追原始试验", "modified": "20260424175236000", "tags": "lesson [[evidence retrieval]] human-trials rapamycin"}, {"title": "Iter-4360dd15-0008-transcript", "modified": "20260424175230000", "tags": "iteration transcript"}, {"title": "Iter-4360dd15-0007-reflection", "modified": "20260424174951000", "tags": "iteration reflection"}]}
【tool:list_by_tag】
{"ok": true, "items": [{"title": "Added included ADPKD rapalog trial CRAD001ADE12 and its body-weight endpoint", "modified": "20260424174657000"}, {"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-0009）\n\n只攻克一件事：从可访问的2024综述PDF或二级检索结果中提取剩余11项纳入试验的名称及其主要终点。"}
【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":5,"query":"\"Targeting ageing with rapamycin and its derivatives in humans\" PDF"})
→ call web_search({"limit":5,"query":"\"Targeting ageing with rapamycin and its derivatives in humans\" 19 included studies table"})
→ call web_search({"limit":5,"query":"site:pubmed.ncbi.nlm.nih.gov rapamycin derivatives humans systematic review 2024 19 studies"})
【tool:web_search】
{"ok": false, "error": "Client error '403 Forbidden' for url 'https://html.duckduckgo.com/html/?q=%22Targeting+ageing+with+rapamycin+and+its+derivatives+in+humans%22+PDF'\nFor more information check: https://developer.mozilla.org/en-US/docs/Web/HTTP/Status/403"}
【tool:web_search】
{"ok": false, "error": "Client error '403 Forbidden' for url 'https://html.duckduckgo.com/html/?q=%22Targeting+ageing+with+rapamycin+and+its+derivatives+in+humans%22+19+included+studies+table'\nFor more information check: https://developer.mozilla.org/en-US/docs/Web/HTTP/Status/403"}
【tool:web_search】
{"ok": false, "error": "Client error '403 Forbidden' for url 'https://html.duckduckgo.com/html/?q=site%3Apubmed.ncbi.nlm.nih.gov+rapamycin+derivatives+humans+systematic+review+2024+19+studies'\nFor more information check: https://developer.mozilla.org/en-US/docs/Web/HTTP/Status/403"}
→ call search_memory({"limit":10,"query":"4360dd15 2024 systematic review included studies 19 rapamycin derivatives humans"})
→ call search_memory({"limit":10,"query":"4360dd15 everolimus BEZ235 RTB101 review included studies table"})
→ call search_memory({"limit":10,"query":"4360dd15 rapamycin review reference chain trial names primary endpoint"})
【tool:search_memory】
{"ok": true, "results": [{"title": "Iter-4360dd15-0009-transcript", "tags": "iteration transcript", "modified": "20260424175555000", "preview": "!! 第 9 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\", \"tags\": \"iteration transcript\", \"modified\": \"20260424173549000\", \"preview\": \"!! 第 2 轮执行轨迹 → call search_memory({\"limit\":10,\"query\":\"4360dd15 rapamycin rapalog human trial Table 1 remaining endpoint PMC review trial name primary endpoint\"}) 【tool:search_memory】 {\"ok\": true, \"results\": [{\"title\": \"I【tool:search_memory】
{"ok": true, "results": [{"title": "Iter-4360dd15-0007-transcript", "tags": "iteration transcript", "modified": "20260424174944000", "preview": "!! 第 7 轮执行轨迹
→ call search_memory({\\\"limit\\\":10,\\\"query\\"}, {"title": "Iter-4360dd15-0009-transcript", "tags": "iteration transcript", "modified": "20260424175555000", "preview": "!! 第 9 轮执行轨迹 → call search_memory({\"limit\":10,\"query\":\"4360dd15 rapamycin rapalog human trial Table 1 remaining endpoint PMC review\"}) 【tool:search_memory】 {\"ok\": true, \"results\": [{\"title\": \"Iter-4360dd15-0007-transcript\",【tool:search_memory】
{"ok": true, "results": [{"title": "Iter-4360dd15-0007-transcript", "tags": "iteration transcript", "modified": "20260424174944000", "preview": "!! 第 7 轮执行轨迹
→ call search_memory({\\\"limit\\\":10,\\\"query\\"}, {"title": "Iter-4360dd15-0009-transcript", "tags": "iteration transcript", "modified": "20260424175555000", "preview": "!! 第 9 轮执行轨迹 → call search_memory({\"limit\":10,\"query\":\"4360dd15 rapamycin rapalog human trial Table 1 remaining endpoint PMC review\"}) 【tool:search_memory】 {\"ok\": true, \"results\": [{\"title\": \"Iter-4360dd15-0007-transcript\", → call search_memory({"limit":8,"query":"\"Targeting ageing with rapamycin and its derivatives in humans\""})
→ call pubmed_search({"limit":5,"query":"Targeting ageing with rapamycin and its derivatives in humans systematic review 2024"})
→ call wiki_search({"lang":"en","limit":5,"query":"Targeting ageing with rapamycin and its derivatives in humans"})
【tool:search_memory】
{"ok": true, "results": [{"title": "Iter-4360dd15-0009-transcript", "tags": "iteration transcript", "modified": "20260424175555000", "preview": "!! 第 9 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\", \"tags\": \"iteration transcript\", \"modified\": \"20260424173549000\", \"preview\": \"!! 第 2 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_memor【tool:pubmed_search】
{"ok": true, "query": "Targeting ageing with rapamycin and its derivatives in humans systematic review 2024", "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/"}]}
【tool:wiki_search】
{"ok": false, "error": "Client error '403 Forbidden' for url 'https://en.wikipedia.org/w/api.php?action=query&list=search&srsearch=Targeting+ageing+with+rapamycin+and+its+derivatives+in+humans&srlimit=5&format=json'\nFor more information check: https://developer.mozilla.org/en-US/docs/Web/HTTP/Status/403"}
→ call web_fetch({"max_chars":5000,"url":"https://pubmed.ncbi.nlm.nih.gov/38310895/"})
→ call web_fetch({"max_chars":8000,"url":"https://www.lancet.com/journals/lanhl/article/PIIS2666-7568(23)00223-7/fulltext"})
【tool:web_fetch】
{"ok": false, "error": "Client error '403 Forbidden' for url 'https://pubmed.ncbi.nlm.nih.gov/38310895/'\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://www.lancet.com/journals/lanhl/article/PIIS2666-7568(23)00223-7/fulltext'\nFor more information check: https://developer.mozilla.org/en-US/docs/Web/HTTP/Status/403"}
→ call search_memory({"limit":10,"query":"4360dd15 remaining 11 included studies names primary endpoint rapamycin review"})
【tool:search_memory】
{"ok": true, "results": [{"title": "Iter-4360dd15-0009-transcript", "tags": "iteration transcript", "modified": "20260424175555000", "preview": "!! 第 9 轮执行轨迹
→ call search_memory({\"limit\":10,\"query\":\"4360dd15 rapamycin rapalog human trial Table 1 remaining endpoint PMC review trial name primary endpoint\"}) 【tool:search_memory】 {\"ok\": true, \"results\": [{\"title\": \"Iter-4360dd15-0006-transcript\", \"tags\": \"iteration transcript\", \"modified\": \"20260424174703000\", \"preview\": \"!! 第 6 轮执行轨迹 → call search_memory({\"limit\":10,\"query\":\"4360dd15 rapamycin rapalog human trial Table 1 remaining endpoint PMC review\"}) 【tool:search_memory】 {\"ok\": true, \"results\": [{\"title\": \"Iter-4360dd15-0007-transcript\", → call read_note({"title":"Iter-4360dd15-0004-critique-rapamycin-evidence"})
【tool:read_note】
{"ok": true, "title": "Iter-4360dd15-0004-critique-rapamycin-evidence", "tags": "lesson critique 4360dd15", "text": "!! Critique of the current rapamycin-human-evidence claim\n\nThis round I tested the weakest point in the current accumulation: the jump from \"a 2024 systematic review found 19 included studies\" to \"rapamycin is a mature anti-aging intervention in humans.\" That jump is too strong.\n\n!! What the public snippets actually support\n- PubMed metadata confirms the paper identity: [[Targeting ageing with rapamycin and its derivatives in humans: a systematic review.]] PMID 38310895.\n- Search snippets from The Lancet / ScienceDirect say the review found //19 included studies// after screening 18,400 unique records.\n- The accessible secondary review [[Blazing a trail for the clinical use of rapamycin as a geroprotecTOR]] provides a concrete human-trial table with only 8 completed studies, and they are //not homogeneous//:\n - 3 acute physiology studies in young men (insulin sensitivity / muscle protein synthesis)\n - 3 immune studies in older adults (everolimus / BEZ235 / rapamycin)\n - 1 topical skin study\n - 1 respiratory illness study (RTB101, not rapamycin)\n\n!! Why this is a likely failure point\nThe current narrative risks treating a heterogeneous set of mTOR-pathway interventions as if they were a single coherent rapamycin anti-aging signal. That is methodologically weak because:\n# the agents differ (rapamycin, everolimus, BEZ235, RTB101)\n# the popu
→ call search_memory({"limit":10,"query":"4360dd15 19 included studies rapamycin review table reference 1 2 3"})
→ call search_memory({"limit":10,"query":"4360dd15 mTOR human trial everolimus RTB101 BEZ235 included studies"})
→ call search_memory({"limit":10,"query":"4360dd15 trial names secondary search results rapamycin review"})
【tool:search_memory】
{"ok": true, "results": [{"title": "Iter-4360dd15-0007-transcript", "tags": "iteration transcript", "modified": "20260424174944000", "preview": "!! 第 7 轮执行轨迹
→ call search_memory({\\\"limit\\\":10,\\\"query\\"}, {"title": "Iter-4360dd15-0006-transcript", "tags": "iteration transcript", "modified": "20260424174703000", "preview": "!! 第 6 轮执行轨迹 → c"}, {"title": "Iter-4360dd15-0009-transcript", "tags": "iteration transcript", "modified": "20260424175555000", "preview": "!! 第 9 轮执行轨迹 【tool:search_memory】
{"ok": true, "results": [{"title": "Iter-4360dd15-0009-transcript", "tags": "iteration transcript", "modified": "20260424175555000", "preview": "!! 第 9 轮执行轨迹
→ call search_memory({\"limit\":8,\"query\":\"4360dd15 rapamycin mTOR systematic review 2024 trial endpoint PMC table remaining included studies\"}) → call list_recent({\"n\":8}) → call list_by_tag({\"limit\":20,\"tag\":\"4360dd15\"}) 【tool:search_memory】 {\"ok\": true, \"results\": [{\"title\": \"Iter-4360dd15-0007-transcript\", \"tags\": \"iteration transcript\", \"modified\": \"20260424174944000\""}, {"title": "Iter-4360dd15-0007-transcript", "tags": "iteration transcript", "modified": "20260424174944000", "preview": "!! 第 7 轮执行轨迹 → call search_memory({\\\"limit\\\":10,\\\"query\\"}, {"title": "Iter-4360dd15-0008-transcript", "tags": "iteration transcript", "modified": "20260424175230000", "preview": "!! 第 8 轮执行轨迹 【tool:search_memory】
{"ok": true, "results": [{"title": "Iter-4360dd15-0007-transcript", "tags": "iteration transcript", "modified": "20260424174944000", "preview": "!! 第 7 轮执行轨迹
→ call search_memory({\"limit\":10,\"query\":\"4360dd15 rapamycin rapalog human trial Table 1 remaining endpoint PMC review trial name primary endpoint\"}) 【tool:search_memory】 {\"ok\": true, \"results\": [{\"title\": \"Iter-4360dd15-0006-transcript\", \"tags\": \"iteration transcript\", \"modified\": \"20260424174703000\", \"preview\": \"!! 第 6 轮执行轨迹 → call search_memory({\"limit\":8,\"query\":\"4360dd15 rapamycin mTOR systematic review 2024 trial endpoint PMC table remaining included studies\"}) → call list_recent({\"n\":8}) → call list_by_tag({\"limi