Iter-4360dd15-0004-transcript
第 4 轮执行轨迹
→ call search_memory({"limit":8,"query":"4360dd15 rapamycin human trial systematic review endpoints included studies 2024"}) → call list_recent({"n":8})
→ call list_by_tag({"limit":20,"tag":"4360dd15"})
【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-4360dd15-0001-transcript", "tags": "iteration transcript", "modified": "20260424173243000", "preview": "!! 第 1 轮执行轨迹 【tool:list_recent】
{"ok": true, "items": [{"title": "Iter-4360dd15-0003-reflection", "modified": "20260424173853000", "tags": "iteration reflection"}, {"title": "NEXT_FOCUS", "modified": "20260424173853000", "tags": "pinned focus"}, {"title": "先用摘要锁定，再补全文校验", "modified": "20260424173853000", "tags": "lesson evidence human-trials retrieval"}, {"title": "Iter-4360dd15-0003-transcript", "modified": "20260424173843000", "tags": "iteration transcript"}, {"title": "Iter-4360dd15-0002-reflection", "modified": "20260424173558000", "tags": "iteration reflection"}, {"title": "先抓人类试验证据表", "modified": "20260424173558000", "tags": "lesson evidence human-trials rapamycin"}, {"title": "Iter-4360dd15-0002-transcript", "modified": "20260424173549000", "tags": "iteration transcript"}, {"title": "Rapamycin human trials: extracted endpoints and outcomes from the 2024 systematic review review pass 1", "modified": "20260424173529000", "tags": "knowledge fact experiment 4360dd15"}]}
【tool:list_by_tag】
{"ok": true, "items": [{"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 web_search({"limit":5,"query":"\"Targeting ageing with rapamycin and its derivatives in humans: a systematic review\" included studies 19 PubMed"})
→ call list_tools({})
【tool:read_note】
{"ok": true, "title": "NEXT_FOCUS", "tags": "pinned focus", "text": "!! 下轮焦点（来自 mission 4360dd15 · Iter-0003）\n\n下一轮只攻克一个最窄问题：从摘要片段和二级来源重建 rapamycin 人体试验的完整纳入列表及各试验主要终点。"}
【tool:web_search】
{"ok": true, "query": "\"Targeting ageing with rapamycin and its derivatives in humans: a systematic review\" included studies 19 PubMed", "results": []}
【tool:list_tools】
{"ok": true, "tools": [{"name": "search_memory", "description": "在 TiddlyWiki 长期记忆中按关键字搜索（支持中文空格分隔），返回标题、标签、预览。每轮迭代开始前应先调用以回忆。", "custom": false}, {"name": "read_note", "description": "读取某一条 tiddler 的完整正文。", "custom": false}, {"name": "write_note", "description": "向 TiddlyWiki 写入（或覆盖）一条 tiddler。这是 Sisyphus 的长期记忆入口——每轮至少写一条。建议标签：knowledge, experiment, reflection, plan, idea, fact, question, lesson。TiddlyWiki 标记：!! 小标题，''粗体''，斜体，其它tiddler。", "custom": false}, {"name": "list_recent", "description": "列出最近修改过的 tiddler。", "custom": false}, {"name": "list_by_tag", "description": "按标签列出相关 tiddler。", "custom": false}, {"name": "run_python", "description": "在 workspace/ 下以子进程执行一段 Python 代码，返回 stdout/stderr。用于计算、模拟、验证假设、抓取公开数据（禁止任何破坏性操作）。", "custom": false}, {"name": "read_file", "description": "读取 workspace/ 下的某个文件。", "custom": false}, {"name": "write_file", "description": "向 workspace/ 下写入文件（默认覆盖，append=true 时追加）。", "custom": false}, {"name": "list_files", "description": "列出 workspace/ 下的文件。", "custom": false}, {"name": "web_fetch", "description": "抓取任意公开 URL（GET），返回剥离 HTML 后的纯文本。适合读论文摘要、文档、博客、百科。", "custom": false}, {"name": "web_search", "description": "用 DuckDuckGo 搜索互联网，返回 title/url/snippet 列表。找入口、找链接、调研时用。", "custom": false}, {"name": "wiki_search", "description": "维基百科搜索：返回若干条目的摘要和 URL。lang 默认 en，可传 zh 等。", "custom": false}, {"name": "arxiv_search", "description": "arXiv 论文检索：标题/作者/摘要/链接。理论、数学、物理、CS、bio 类前沿论文的主入口。", "custom": false}, {"name": "pubmed_search", "descriptio
→ call pubmed_search({"limit":10,"query":"\"Targeting ageing with rapamycin and its derivatives in humans: a systematic review\""})
→ call web_search({"limit":10,"query":"\"Targeting ageing with rapamycin and its derivatives in humans\" review pdf abstract"})
→ call web_search({"limit":10,"query":"rapamycin human trials systematic review 19 studies endpoints trial list"})
【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": "\"Targeting ageing with rapamycin and its derivatives in humans\" review pdf abstract", "results": []}
【tool:web_search】
{"ok": true, "query": "rapamycin human trials systematic review 19 studies endpoints trial list", "results": [{"title": "Targeting ageing with rapamycin and its derivatives in humans: a ...", "url": "https://www.thelancet.com/journals/lanhl/article/PIIS2666-7568(23)00258-1/fulltext", "snippet": "Articles included in this systematic review met the following criteria: the mean or median age of the study cohort was 18 years or older; outcomes on ageing-related physiological changes or disease were reported; and they were interventional studies with rapamycin or its derivatives (no restriction on the method). Articles were excluded if in vitro or animal models were used; rapamycin or its ..."}, {"title": "Targeting ageing with rapamycin and its derivatives in humans: a ...", "url": "https://www.sciencedirect.com/science/article/pii/S2666756823002581", "snippet": "Articles included in this systematic review met the following criteria: the mean or median age of the study cohort was 18 years or older; outcomes on ageing-related physiological changes or disease were reported; and they were interventional studies with rapamycin or its derivatives (no restriction on the method)."}, {"title": "Blazing a trail for the clinical use of rapamycin as a geroprotecTOR", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC10643772/", "snippet": "The goal of this review is to (1) briefly showcase how mTORC1 inhibition by rapamycin and rapamycin analogs (rapalogs) can extend healthspan by maintainin
→ call web_fetch({"max_chars":12000,"url":"https://www.thelancet.com/journals/lanhl/article/PIIS2666-7568(23)00258-1/fulltext"})
→ call web_fetch({"max_chars":12000,"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10643772/"})
→ call web_search({"limit":10,"query":"site:pmc.ncbi.nlm.nih.gov rapamycin human trials table 19 systematic review Lancet Healthy Longevity"})
【tool:web_fetch】
{"ok": false, "error": "Client error '403 Forbidden' for url 'https://www.thelancet.com/journals/lanhl/article/PIIS2666-7568(23)00258-1/fulltext'\nFor more information check: https://developer.mozilla.org/en-US/docs/Web/HTTP/Status/403"}
【tool:web_fetch】
{"ok": true, "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC10643772/", "status": 200, "content_type": "text/html; charset=utf-8", "text": "Blazing a trail for the clinical use of rapamycin as a geroprotecTOR - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Official websites use .gov A .gov website belongs to an official government organization in the United States. Secure .gov websites use HTTPS A lock ( Lock Locked padlock icon ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites. Search Log in Dashboard Publications Account settings Log out Search… Search NCBI Primary site navigation Search Logged in as: Dashboard Publications Account settings Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide PERMALINK Copy As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice GeroScience . 2023 Oct 6;45(5):2769–2783. doi: 10.1007/s11357-023-00935-x Search in PMC Search in PubMed View in NLM Catalog Add to search Blazing a trail for the clinical use of rapamycin as a geroprotecTOR Adam R Konopka Adam R Konopka 1 Division of Geriatrics, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705 USA 2 William S. Middlet
【tool:web_search】
{"ok": true, "query": "site:pmc.ncbi.nlm.nih.gov rapamycin human trials table 19 systematic review Lancet Healthy Longevity", "results": [{"title": "Blazing a trail for the clinical use of rapamycin as a geroprotecTOR", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC10643772/", "snippet": "It is important to note that this is not an endorsement for or against the use of mTOR inhibitors, but rather a compendium of upcoming clinical trials leveraging the last two decades of pre-clinical data to help advance our understanding of the impact of rapamycin on human healthspan."}, {"title": "Rapamycin for longevity: the pros, the cons, and future perspectives", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC12226543/", "snippet": "Further, the long-term effects and safety of chronic mTOR inhibition in healthy humans and whether rapamycin can truly \"slow\" human aging or prevent age-related diseases without unacceptable side effects is unknown. The mTOR pathway and the function of rapamycin"}, {"title": "Influence of rapamycin on safety and healthspan metrics after one year ...", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC12074816/", "snippet": "An important gap in the clinical understanding of rapamycin for longevity is that to date, no long-term randomized controlled trials (RCT) have been conducted to explore the safety and effectiveness of low-dose, intermittent rapamycin regimens for improving multiple healthspan metrics in normative aging cohorts."}, {"title": "Evalua
→ call web_search({"limit":10,"query":"\"19 studies\" rapamycin systematic review humans trial list sirolimus everolimus RTB101"})
→ call web_search({"limit":10,"query":"\"The review included 19 studies\" rapamycin humans"})
→ call web_search({"limit":10,"query":"site:pmc.ncbi.nlm.nih.gov 19 studies rapamycin humans systematic review"})
→ call pubmed_search({"limit":10,"query":"rapamycin humans systematic review 19 studies"})
【tool:web_search】
{"ok": true, "query": "\"19 studies\" rapamycin systematic review humans trial list sirolimus everolimus RTB101", "results": []}
【tool:web_search】
{"ok": true, "query": "\"The review included 19 studies\" rapamycin humans", "results": []}
【tool:web_search】
{"ok": true, "query": "site:pmc.ncbi.nlm.nih.gov 19 studies rapamycin humans systematic review", "results": [{"title": "Rapamycin persistently improves cardiac function in aged, male and ...", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC6996961/", "snippet": "In this study, we analyzed functional and molecular outcomes from continuous and transient rapamycin treatment in aged, male and female C57BL/6 mice. In both sexes, rapamycin treatment replicated our previous results showing a significant improvement in cardiac diastolic function, and this effect was persistent for 2 months after rapamycin was ..."}, {"title": "A Randomized Control Trial to Establish the Feasibility and Safety of ...", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC5869166/", "snippet": "Inhibition of the mechanistic target of rapamycin (mTOR) pathway by rapamycin (RAPA), an FDA-approved immunosuppressive drug used as a clinical therapy to prevent solid organ allograft rejection, enhances longevity in mice. Importantly, RAPA was ..."}, {"title": "The use of rapamycin to treat vascular tumours and malformations: A ...", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC8381855/", "snippet": "Abstract Objectives To assess the safety and efficacy of rapamycin in treating children with vascular tumours and malformations. Study design We performed a retrospective review at a large tertiary care paediatric centre to assess the efficacy and safety of using rapamycin to treat vascular tumours and malformat
【tool:pubmed_search】
{"ok": true, "query": "rapamycin humans systematic review 19 studies", "results": []}
→ call web_search({"limit":10,"query":"rapamycin human studies review table clinical trial completed studies everolimus RTB101 skin influenza endothelial 19"})
→ call web_search({"limit":10,"query":"\"rapamycin\" \"influenza vaccination response\" everolimus trial healthy older adults"})
→ call web_search({"limit":10,"query":"\"rapamycin\" skin senescent cells trial Chung 2019 topical placebo"})
→ call web_search({"limit":10,"query":"\"rapamycin\" \"blood flow restricted resistance exercise\" Gundermann 2014 human trial"})
【tool:web_search】
{"ok": true, "query": "rapamycin human studies review table clinical trial completed studies everolimus RTB101 skin influenza endothelial 19", "results": [{"title": "Targeting ageing with rapamycin and its derivatives in humans: a ...", "url": "https://www.thelancet.com/journals/lanhl/article/PIIS2666-7568(23)00258-1/fulltext", "snippet": "Rapamycin and its derivatives (rapalogs) are inhibitors of mTOR, a major regulator of the ageing process. We aimed to summarise the effects of rapamycin and its derivatives on the severity of ageing-related physiological changes and disease in adults. A search across five databases yielded 18 400 unique articles, resulting in 19 included studies . Rapamycin and its derivatives improved ..."}, {"title": "Targeting ageing with rapamycin and its derivatives in humans: a ...", "url": "https://www.sciencedirect.com/science/article/pii/S2666756823002581", "snippet": "Rapamycin and its derivatives (rapalogs) are inhibitors of mTOR, a major regulator of the ageing process. We aimed to summarise the effects of rapamycin and its derivatives on the severity of ageing-related physiological changes and disease in adults. A search across five databases yielded 18 400 unique articles, resulting in 19 included studies ."}, {"title": "Blazing a trail for the clinical use of rapamycin as a geroprotecTOR", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC10643772/", "snippet": "It is important to note that this is not an endorsement for or against the use of
【tool:web_search】
{"ok": true, "query": "\"rapamycin\" \"influenza vaccination response\" everolimus trial healthy older adults", "results": []}
【tool:web_search】
{"ok": true, "query": "\"rapamycin\" skin senescent cells trial Chung 2019 topical placebo", "results": [{"title": "Topical rapamycin reduces markers of senescence and aging in human skin ...", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC6925069/", "snippet": "Methods Patient recruitment and trial design This prospective, randomized, placebo -controlled, exploratory study was conducted to test the hypothesis that a topical application of rapamycin (10 μM) would decrease the number of senescent cells in the skin and decrease markers of aging."}, {"title": "PDF Topical rapamycin reduces markers of senescence and aging in human skin ...", "url": "https://link.springer.com/content/pdf/10.1007/s11357-019-00113-y.pdf", "snippet": "This prospective, randomized, placebo -controlled, ex-ploratory study was conducted to test the hypothesis that a topical application of rapamycin (10 μM) would de-crease the number of senescent cells in the skin and decrease markers of aging."}, {"title": "Topical rapamycin reduces markers of senescence and aging in human skin ...", "url": "https://www.researchgate.net/publication/337489185_Topical_rapamycin_reduces_markers_of_senescence_and_aging_in_human_skin_an_exploratory_prospective_randomized_trial", "snippet": "To determine whether rapamycin , an FDA-approved drug targeting the mechanistic target of rapamycin (mTOR) complex, can reduce senescence and markers of aging in human skin , an exploratory, placebo ..."}, {"title": "Topical rapamycin
【tool:web_search】
{"ok": true, "query": "\"rapamycin\" \"blood flow restricted resistance exercise\" Gundermann 2014 human trial", "results": []}
→ call web_fetch({"max_chars":25000,"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10643772/"})
→ call web_search({"limit":10,"query":"site:clinicaltrials.gov rapamycin aging trial endpoints immune skin exercise everolimus trial"})
【tool:web_fetch】
{"ok": true, "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC10643772/", "status": 200, "content_type": "text/html; charset=utf-8", "text": "Blazing a trail for the clinical use of rapamycin as a geroprotecTOR - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Official websites use .gov A .gov website belongs to an official government organization in the United States. Secure .gov websites use HTTPS A lock ( Lock Locked padlock icon ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites. Search Log in Dashboard Publications Account settings Log out Search… Search NCBI Primary site navigation Search Logged in as: Dashboard Publications Account settings Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide PERMALINK Copy As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice GeroScience . 2023 Oct 6;45(5):2769–2783. doi: 10.1007/s11357-023-00935-x Search in PMC Search in PubMed View in NLM Catalog Add to search Blazing a trail for the clinical use of rapamycin as a geroprotecTOR Adam R Konopka Adam R Konopka 1 Division of Geriatrics, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705 USA 2 William S. Middlet
【tool:web_search】
{"ok": true, "query": "site:clinicaltrials.gov rapamycin aging trial endpoints immune skin exercise everolimus trial", "results": [{"title": "NCT05835999 | Everolimus Aging Study - ClinicalTrials.gov", "url": "https://clinicaltrials.gov/study/NCT05835999", "snippet": "Using a double-blinded, randomized, placebo-controlled clinical trial , the investigators will perform a battery of gold-standard and innovative techniques to test the hypothesis that daily low dose or weekly everolimus treatment will improve 4 inter-related domains of physiological aging : metabolic, cardiac, cognitive, and physical function."}, {"title": "Novel Compositions for Treating or Preventing Dermal Disorders", "url": "https://clinicaltrials.gov/study/NCT03103893", "snippet": "Systemic application of rapamycin has been a central part of immuno suppressive therapy for transplant patients in combination with other immuno suppressants. The safety record for systemic use of rapamycin is excellent and few side effects are associated with extended use."}, {"title": "PDF An open-label, multi-center everolimus roll-over protocol for patients ...", "url": "https://cdn.clinicaltrials.gov/large-docs/81/NCT01789281/Prot_000.pdf", "snippet": "Overall, everolimus + exemestane is considered to have a positive benefit-risk profile for postmenopausal women with hormone receptor-positive advanced breast cancer in combination with an aromatase inhibitor, after prior endocrine therapy; the benefits of therapy with everoli
→ 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": "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\nTargeting 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":20,"query":"\"Lee\" Hodzic Kuerec Maier rapamycin 19 studies table 1 supplementary"})
→ call web_search({"limit":20,"query":"\"Targeting ageing with rapamycin and its derivatives in humans\" supplementary table included studies"})
→ call web_search({"limit":20,"query":"\"rapamycin and its derivatives in humans\" \"Table 1\" \"19 included studies\""})
→ call web_search({"limit":20,"query":"\"Targeting ageing with rapamycin and its derivatives in humans\" pdf"})
【tool:web_search】
{"ok": true, "query": "\"Lee\" Hodzic Kuerec Maier rapamycin 19 studies table 1 supplementary", "results": [{"title": "Rapamycin: The Dimmer Switch Dilemma - Can a Transplant Drug Safely ...", "url": "https://foodmedcenter.org/rapamycin-slow-aging/", "snippet": "A systematic review published in The Lancet Healthy Longevity in 2024 by Lee , Hodzic Kuerec , and Maier examined all available human rapamycin data. A systematic review is a study of studies : researchers methodically gather every published trial on a topic, assess their quality, and synthesize the findings into an overall conclusion."}, {"title": "1922 GUY
```