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Iter-4360dd15-0002-transcript

iteration transcript

修改：20260424173549000

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_memory】
{"ok": true, "results": [{"title": "Iter-4360dd15-0001-transcript", "tags": "iteration transcript", "modified": "20260424173243000", "preview": "!! 第 1 轮执行轨迹
→ call search_memory({\"limit\":10,\"query\":\"4360dd15 长生不老 immortality 抗衰老 目标\"}) → call list_recent({\"n\":10}) → call list_tools({}) 【tool:search_memory】 {\"ok\": true, \"results\": [{\"title\": \"GOAL\", \"tags\": \"goal pinned\", \"modified\": \"20260424172208000\", \"preview\": \"目标：找到让人类长生不老的方法 Mission ID：4360dd15 起始时间：2026-04-25T01:22:08 !! 使用说明 这是 Sisyphus 的北极星。永远围绕这个目标展开。 其它 mis"}, {"title": "Human longevity interventions evidence maturity matrix 2026-04-25", "tags": "knowledge fact experiment 4360dd15", "modified": "20260424173237000", "preview": "!! 人类长寿干预的证据成熟度矩阵（初版） 本轮子任务：把“如何让人类长生不老”压缩成一个可比较的系统问题：哪些干预已经进入人类临床证据层，哪些仍主要停留在机制层。 !! 结论（按当前公开检索证据） # ''rapamycin / mTOR''：最高成熟度之一。 ## 证据 - ClinicalTrials.gov 的随机、双盲、安慰剂对照试验：NCT04488601（间歇性 rapamycin，每周给药） - Lancet Healthy Longevity 综述：检索 5 个数据库后纳入 19 项研究，报告其可改善健康相关生理参数（免疫、心血管、皮肤等） - Cell Metabolism 2023 综述把 TORC1 inhibitors 列为已进入临床测试的抗衰老药物之一 # ''senolytics''：最高成熟度之一。 ## 证据 - ClinicalTrials"}, {"title": "Iter-0005-transcript", "tags": "iteration transcript", "modified": "20260424171817000", "preview": "!! 第 5 轮执行轨迹 
   → call search_memory({\"limit\":8,\"query\":\"NEXT_FOCUS prime 100 模6 状态 转移 表 质数 间隔\"})    → call list_recent({\"n\":8})  【tool:search_memory】 {\"ok\": true, \"results\": [{\"title\": \"Iter-0002-transcript\", \"tags\":
【tool:list_recent】
{"ok": true, "items": [{"title": "Iter-4360dd15-0001-reflection", "modified": "20260424173249000", "tags": "iteration reflection"}, {"title": "NEXT_FOCUS", "modified": "20260424173249000", "tags": "pinned focus"}, {"title": "先选一条机制再读人类证据", "modified": "20260424173249000", "tags": "lesson evidence focus geroscience"}, {"title": "Iter-4360dd15-0001-transcript", "modified": "20260424173243000", "tags": "iteration transcript"}, {"title": "Human longevity interventions evidence maturity matrix 2026-04-25", "modified": "20260424173237000", "tags": "knowledge fact experiment 4360dd15"}, {"title": "GOAL", "modified": "20260424172208000", "tags": "goal pinned"}, {"title": "NEXT_FOCUS-archived-legacy-20260425-012208", "modified": "20260424172208000", "tags": "archive focus"}, {"title": "Iter-0005-reflection", "modified": "20260424171825000", "tags": "iteration reflection"}]}
【tool:list_by_tag】
{"ok": true, "items": [{"title": "Human longevity interventions evidence maturity matrix 2026-04-25", "modified": "20260424173237000"}]}
  → call web_search({"limit":5,"query":"rapamycin review human trials healthy aging randomized placebo controlled Lancet Healthy Longevity"})
  → call pubmed_search({"limit":5,"query":"rapamycin review human trials healthy aging randomized placebo controlled"})
【tool:web_search】
{"ok": true, "query": "rapamycin review human trials healthy aging randomized placebo controlled Lancet Healthy Longevity", "results": [{"title": "Targeting ageing with rapamycin and its derivatives in ... - The Lancet", "url": "https://www.thelancet.com/journals/lanhl/article/PIIS2666-7568(23)00258-1/fulltext", "snippet": "A search across five databases yielded 18 400 unique articles, resulting in 19 included studies. Rapamycin and its derivatives improved physiological parameters associated with ageing in the immune, cardiovascular, and integumentary systems of healthy individuals or individuals with ageing-related diseases."}, {"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 improved physiological parameters associated with ageing in the immune, cardiovascular, and integumentary systems of healthy individuals or individuals with ageing-related diseases. Overall, no significant effects on the endocrine, muscular, or neurological systems were found."}, {"title": "PEARL lands: decoding rapamycin's first human longevity trial", "url": "https://therelaymag.com/pearl-lands-decoding-rapamycins-first-human-longevity-trial", "snippet": "On April 4, 2025, the PEARL trial published the first randomized , double blind, placebo controlled readout of intermittent low dose rapamycin in healthy older adults. The paper matters for a s
【tool:pubmed_search】
{"ok": true, "query": "rapamycin review human trials healthy aging randomized placebo controlled", "results": []}
  → call web_fetch({"max_chars":12000,"url":"https://www.thelancet.com/journals/lanhl/article/PIIS2666-7568(23)00258-1/fulltext"})
  → call web_search({"limit":8,"query":"site:pubmed.ncbi.nlm.nih.gov rapamycin humans trial review 19 studies mTOR aging"})
【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_search】
{"ok": true, "query": "site:pubmed.ncbi.nlm.nih.gov rapamycin humans trial review 19 studies mTOR aging", "results": [{"title": "Blazing a trail for the clinical use of rapamycin as a ... - PubMed", "url": "https://pubmed.ncbi.nlm.nih.gov/37801202/", "snippet": "Results from these early phase studies will help guide the design of phase 3 clinical trials to determine whether rapamycin can be used safely to inhibit mTORC1 for the treatment and prevention of age-related diseases in humans ."}, {"title": "Rapamycin and Alzheimer's disease: Time for a clinical trial?", "url": "https://pubmed.ncbi.nlm.nih.gov/30674654/", "snippet": "The drug rapamycin has beneficial effects in a number of animal models of neurodegeneration and aging including mouse models of Alzheimer's disease. Despite its compelling preclinical record, no clinical trials have tested rapamycin or other mTOR inhibitors in patients with Alzheimer's disease. We a …"}, {"title": "Towards disease-oriented dosing of rapamycin for longevity: does aging ...", "url": "https://pubmed.ncbi.nlm.nih.gov/37477535/", "snippet": "Rapamycin is a prophylactic anti- aging drug that decelerates early development of age-related diseases. I further discuss hyperfunction theory of quasi-programmed diseases, which challenges the need for the traditional concept of aging itself."}, {"title": "The effect of rapamycin and its analogues on age-related ...", "url": "https://pubmed.ncbi.nlm.nih.gov/35861940/", "snippet": "Abstra
  → call web_search({"limit":10,"query":"rapamycin humans review 19 studies physiological parameters immune cardiovascular integumentary PMC"})
  → call web_search({"limit":10,"query":"site:pmc.ncbi.nlm.nih.gov rapamycin humans review 19 studies integrated systematic review"})
【tool:web_search】
{"ok": true, "query": "rapamycin humans review 19 studies physiological parameters immune cardiovascular integumentary PMC", "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": "A search across five databases yielded 18 400 unique articles, resulting in 19 included studies . Rapamycin and its derivatives improved physiological parameters associated with ageing in the immune , cardiovascular , and integumentary systems of healthy individuals or individuals with ageing-related diseases."}, {"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 improved physiological parameters associated with ageing in the immune , cardiovascular , and integumentary systems of healthy individuals or individuals with ageing-related diseases. Overall, no significant effects on the endocrine, muscular, or neurological systems were found."}, {"title": "Blazing a trail for the clinical use of rapamycin as a geroprotecTOR - PMC", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC10643772/", "snippet": "Results from these early phase studies will help guide the design of phase 3 clinical trials to determine whether rapamycin can be used safely to inhibit mTORC1 for the treatment and prevention of age-related diseas
【tool:web_search】
{"ok": true, "query": "site:pmc.ncbi.nlm.nih.gov rapamycin humans review 19 studies integrated systematic review", "results": [{"title": "Rapamycin for longevity: the pros, the cons, and future perspectives", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC12226543/", "snippet": "A systematic review evaluated the effects of rapamycin and its derivatives on aging-related physiological changes and diseases and found improvements in the immune, cardiovascular, and integumentary systems but not in the endocrine, muscular, or neurological systems (Lee et al., 2024)."}, {"title": "Influence of rapamycin on safety and healthspan metrics after one year ...", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC12074816/", "snippet": "Notable among these is rapamycin , which is widely used for its purported longevity and healthspan benefits within the pro-longevity community [8]. While evidence supports a role for rapamycin in improving life- and health-spans in preclinical studies [9], little data exists on its clinical efficacy in normative aging humans ."}, {"title": "Rapamycin for longevity: opinion article - PMC", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC6814615/", "snippet": "Rapamycin -induced SPD is a relatively rare side effect and probably can be avoided by administering the drug intermittently or at lower doses, and if SPD does occur, it can be reversed by discontinuation of the drug. In some studies in transplant patients, rapamycin (sirolimus) and everolimus did not 
  → call web_search({"limit":10,"query":"\"Targeting ageing with rapamycin and its derivatives in humans\" trial endpoints included studies"})
  → call web_search({"limit":10,"query":"\"Targeting ageing with rapamycin and its derivatives in humans\" PDF"})
  → call pubmed_search({"limit":10,"query":"\"Targeting ageing with rapamycin and its derivatives in humans\""})
【tool:web_search】
{"ok": true, "query": "\"Targeting ageing with rapamycin and its derivatives in humans\" trial endpoints included studies", "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": "A search across five databases yielded 18 400 unique articles, resulting in 19 included studies . Rapamycin and its derivatives improved physiological parameters associated with ageing in the immune, cardiovascular, and integumentary systems of healthy individuals or individuals with ageing-related diseases."}, {"title": "PDF Targeting ageing with rapamycin and its derivatives in humans: a ...", "url": "https://www.thelancet.com/pdfs/journals/lanhl/PIIS2666-7568(23)00258-1.pdf", "snippet": "A search across five databases yielded 18 400 unique articles, resulting in 19 included studies . Rapamycin and i
【tool:web_search】
{"ok": true, "query": "\"Targeting ageing with rapamycin and its derivatives in humans\" PDF", "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. Rapamycin and its derivatives improved ..."}, {"title": "PDF Targeting ageing with rapamycin and its derivatives in humans: a ...", "url": "https://www.thelancet.com/pdfs/journals/lanhl/PIIS2666-7568(23)00258-1.pdf", "snippet": "Deborah J W Lee*, Ajla Hodzic Kuerec*, Andrea B Maier Rapamyc
【tool:pubmed_search】
{"ok": true, "query": "\"Targeting ageing with rapamycin and its derivatives in humans\"", "results": [{"pmid": "41996004", "title": "Lactate-driven pyrimidine synthesis promotes ferroptosis resistance in hepatocellular carcinoma.", "source": "Mol Biomed", "pubdate": "2026 Apr 17", "authors": ["Park MJ", "Lee S", "Kim DH", "Kim MK", "Jang BK", "Yoon G", "Park M", "Jeong GH"], "url": "https://pubmed.ncbi.nlm.nih.gov/41996004/"}, {"pmid": "41929967", "title": "The Cheung Glutamatergic Regimen as a candidate for primary and secondary prevention of Alzheimer's disease onset.", "source": "J Alzheimers Dis Rep", "pubdate": "2026 Jan-Dec", "authors": ["Cheung N"], "url": "https://pubmed.ncbi.nlm.nih.gov/41929967/"}, {"pmid": "41909987", "title": "Sirolimus and Mimetics: Modulator Sine Qua Non for Cardiac Xenotransplantation?", "source": "FASEB J", "pubdate": "2026 Apr 15", "authors": ["Uzoigwe CE"], "url": "https://pubmed.ncbi.nlm.nih.gov/41909987/"}, {"pmid": "41787128", "title": "Metabolic regulation by tanycyte-derived extracellular vesicles through insulin precursor-mediated neuronal recognition and mTORC component delivery.", "source": "Nat Metab", "pubdate": "2026 Mar", "authors": ["Choi Y", "Kim MW", "Go G", "Cai D"], "url": "https://pubmed.ncbi.nlm.nih.gov/41787128/"}, {"pmid": "41484271", "title": "Curcumin attenuates PM2.5-triggered pulmonary senescence via the mTOR/S6K1 signaling pathway.", "source": "Biogerontology", "pubdate": "2026 Jan 3", "authors": ["Liu K", "Shi M",
  → call web_fetch({"max_chars":12000,"url":"https://europepmc.org/article/MED/38310895"})
  → call web_fetch({"max_chars":12000,"url":"https://research.vu.nl/en/publications/targeting-ageing-with-rapamycin-and-its-derivatives-in-humans-a-s"})
【tool:web_fetch】
{"ok": true, "url": "https://europepmc.org/article/MED/38310895", "status": 200, "content_type": "text/html;charset=UTF-8", "text": "Europe PMC Europe PMC 1 Sign in | Create an account https://orcid.org https://plus.europepmc.org Europe PMC Menu About About Europe PMC Preprints in Europe PMC Funders Become a funder Governance Roadmap Outreach Tools Tools overview Article status monitor Grant finder External links service RSS feeds About SciLite annotations Annotations submission service Developers Developer resources Articles RESTful API Grants RESTful API API case studies SOAP web service Annotations API OAI service Bulk downloads Developers Forum Support User guide Search syntax guide Contact us Contact us Helpdesk Feedback Twitter Blog Tech blog Developer Forum Europe PMC plus NOTICE: The ORCID Claiming tool has been temporarily disabled, because of technical issues. Please check back in later.", "truncated": false}
【tool:web_fetch】
{"ok": true, "url": "https://research.vu.nl/en/publications/targeting-ageing-with-rapamycin-and-its-derivatives-in-humans-a-s/", "status": 200, "content_type": "text/html;charset=UTF-8", "text": "Targeting ageing with rapamycin and its derivatives in humans: a systematic review - Vrije Universiteit Amsterdam Skip to main navigation Skip to search Skip to main content Vrije Universiteit Amsterdam Home Help & FAQ Link opens in a new tab Search content at Vrije Universiteit Amsterdam Home Profiles Research units Research output Courses Projects Datasets / Software Activities Prizes / Grants Press / Media Targeting ageing with rapamycin and its derivatives in humans: a systematic review Deborah J W Lee , Ajla Hodzic Kuerec , Andrea B Maier Prevention and Rehabilitation AMS - Ageing & Vitality APH - Aging & Later Life APH - Global Health Research output : Contribution to Journal › Review article › Academic › peer-review Overview Fingerprint Abstract 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 physiological parameters associated with ageing in the immune, cardiovascular, and integumentary systems of healthy individuals or individuals with agein
  → call web_search({"limit":10,"query":"ClinicalTrials.gov NCT04488601 rapamycin endpoints randomized placebo healthy older adults"})
  → call web_search({"limit":10,"query":"\"Effect of Low-Dose Rapamycin on Senescence Markers and Physical Performance\" endpoints results elderly cardiac rehabilitation"})
  → call web_search({"limit":10,"query":"rapamycin human trial immune cardiovascular skin endpoints review included studies"})
【tool:web_search】
{"ok": true, "query": "ClinicalTrials.gov NCT04488601 rapamycin endpoints randomized placebo healthy older adults", "results": [{"title": "Study Details | NCT04488601 - ClinicalTrials.gov", "url": "https://clinicaltrials.gov/study/NCT04488601", "snippet": "Details for study NCT04488601 , | ClinicalTrials.gov A randomized , double-blind, placebo -controlled trial assessing the effects of low and high doses of intermittent Rapamycin on a weekly schedule. The researchers aim to establish a long-term safety profile, determine the long-term efficacy of Rapamycin in reducing clinical aging measures, and biochemical and physiological endpoints associated ."}, {"title": "Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity ...", "url": "https://ctv.veeva.com/study/participatory-evaluation-of-aging-with-rapamycin-for-longevity-study", "snippet": "A randomized , double-blind, placebo -controlled trial assessing the effects of low and high doses of intermittent Rapamycin on a weekly schedule. The researchers aim to establish a long-term safety profile, determine the long-term efficacy of Rapamycin in reducing clinical aging measures, and biochemical and physiological endpoints associated with declining health and aging in healthy older adult"}, {"title": "Rapamycin in Aging - Clinical Trials Registry - ICH GCP", "url": "https://ichgcp.net/clinical-trials-registry/NCT04488601", "snippet": "A randomized , double-blind, placebo -controlled trial assessing the effects of low
【tool:web_search】
{"ok": true, "query": "\"Effect of Low-Dose Rapamycin on Senescence Markers and Physical Performance\" endpoints results elderly cardiac rehabilitation", "results": []}
【tool:web_search】
{"ok": true, "query": "rapamycin human trial immune cardiovascular skin endpoints review included studies", "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": "A search across five databases yielded 18 400 unique articles, resulting in 19 included studies . Rapamycin and its derivatives improved physiological parameters associated with ageing in the immune , cardiovascular , and integumentary systems of healthy individuals or individuals with ageing-related diseases."}, {"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 maintaining, improving, or restoring select indices of physiological function in pre-clinical and some human studies (Table 1); (2) discuss potential risks and key knowledge gaps regarding the clinical ..."}, {"title": "Targeting the biology of aging with mTOR inhibitors - Nature", "url": "https://www.nature.com/articles/s43587-023-00416-y", "snippet": "Here, we review the effects of rapamycin on the longevity and survival of both wild-type mice and mouse models of human diseases."}, {"title": "Targeting ageing with rapamycin and its derivatives in humans: a ...", "url": "
  → call web_fetch({"max_chars":14000,"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10643772/"})
  → call web_fetch({"max_chars":14000,"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12074816/"})
【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_fetch】
{"ok": true, "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC12074816/", "status": 200, "content_type": "text/html; charset=utf-8", "text": "Influence of rapamycin on safety and healthspan metrics after one year: PEARL trial results - 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 Publicati