{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T07:09:28Z","timestamp":1769065768547,"version":"3.49.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2022,8,2]],"date-time":"2022-08-02T00:00:00Z","timestamp":1659398400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100017062","name":"Johns Hopkins Hospital","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100017062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,2,24]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Aging and age-related diseases represent a compelling therapeutic goal for senolytics and drugs targeting inflammatory or metabolic pathways. We compared MyMD-1, a synthetic derivative of the alkaloid myosmine capable of suppressing TNF-\u03b1 production, to rapamycin, the best characterized drug endowed with antiaging properties. In vivo, a longitudinal cohort of 54 C57BL\/6 mice, 19-month-old at the start, was randomized to receive MyMD-1, high-dose (126 ppm) rapamycin, or low-dose (14 ppm) rapamycin plus metformin. Each treatment arm included 18 mice (10 females and 8 males) and was followed for 16 months or until death. Life span was significantly longer in MyMD-1 than rapamycin (p = .019 vs high-dose and .01 vs low-dose) in a Cox survival model that accounted for sex and serum levels of IL-6, TNF-\u03b1, and IL-17A. MyMD-1 also improved several health span characteristics, resulting in milder body weight loss, greater muscle strength, and slower progression to frailty. In vitro, MyMD-1 and rapamycin were compared using a panel of 12 human primary cell systems (BioMAP Diversity PLUS), where a total of 148 biomarkers were measured. MyMD-1 possessed antiproliferative, anti-inflammatory, and antifibrotic properties. Many were shared with rapamycin, but MyMD-1 was more active in the inhibition of proinflammatory and profibrotic biomarkers. Overall, MyMD-1 emerges as a new compound that, even when begun at an advanced age, induces beneficial effects on health and life span by modulating inflammation and tissue remodeling.<\/jats:p>","DOI":"10.1093\/gerona\/glac142","type":"journal-article","created":{"date-parts":[[2022,8,2]],"date-time":"2022-08-02T01:49:03Z","timestamp":1659404943000},"page":"227-235","source":"Crossref","is-referenced-by-count":10,"title":["MyMD-1 Improves Health Span and Prolongs Life Span in Old Mice: A Noninferiority Study to Rapamycin"],"prefix":"10.1093","volume":"78","author":[{"given":"Elena","family":"Sabini","sequence":"first","affiliation":[{"name":"Johns Hopkins Hospital, School of Medicine, Department of Pathology , Baltimore, Maryland , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alison","family":"O\u2019Mahony","sequence":"additional","affiliation":[{"name":"Eurofins Discovery, Phenotypic Services , St. Charles, Missouri , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6768-6308","authenticated-orcid":false,"given":"Patrizio","family":"Caturegli","sequence":"additional","affiliation":[{"name":"Johns Hopkins Hospital, School of Medicine, Department of Pathology , Baltimore, Maryland , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,8,2]]},"reference":[{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"e006413","DOI":"10.1136\/bmjopen-2014-006413","article-title":"Risk of developing multimorbidity across all ages in an historical cohort study: differences by sex and ethnicity","volume":"5","author":"St Sauver","year":"2015","journal-title":"BMJ Open"},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1016\/S0140-6736(12)62167-9","article-title":"Frailty in elderly people","volume":"381","author":"Clegg","year":"2013","journal-title":"Lancet"},{"key":"2023022410170021200_","first-page":"1","article-title":"Deaths: final data for 2017","volume":"68","author":"Kochanek","year":"2019","journal-title":"Natl Vital Stat Rep."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1111\/joim.13141","article-title":"Senolytic drugs: from discovery to translation","volume":"288","author":"Kirkland","year":"2020","journal-title":"J Intern Med."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1038\/s41587-020-00750-1","article-title":"Send in the senolytics","volume":"38","author":"Dolgin","year":"2020","journal-title":"Nat Biotechnol."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/j.cell.2019.10.005","article-title":"Cellular senescence: defining a path forward","volume":"179","author":"Gorgoulis","year":"2019","journal-title":"Cell"},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/s41574-018-0059-4","article-title":"Inflammaging: a new immune-metabolic viewpoint for age-related diseases","volume":"14","author":"Franceschi","year":"2018","journal-title":"Nat Rev Endocrinol."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The hallmarks of aging","volume":"153","author":"L\u00f3pez-Ot\u00edn","year":"2013","journal-title":"Cell"},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"165612","DOI":"10.1016\/j.bbadis.2019.165612","article-title":"Current nutritional and pharmacological anti-aging interventions","volume":"1866","author":"Ros","year":"2020","journal-title":"Biochim Biophys Acta Mol Basis Dis."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s43587-020-00006-2","article-title":"Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and lifespan in mice","volume":"1","author":"Richardson","year":"2021","journal-title":"Nat Aging"},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.cmet.2017.11.002","article-title":"NAD(+) intermediates: the biology and therapeutic potential of NMN and NR","volume":"27","author":"Yoshino","year":"2018","journal-title":"Cell Metab."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.ebiom.2016.11.038","article-title":"NIA interventions testing program: investigating putative aging intervention agents in a genetically heterogeneous mouse model","volume":"21","author":"Nadon","year":"2017","journal-title":"EBioMedicine"},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1111\/acel.12496","article-title":"Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an \u03b1-glucosidase inhibitor or a Nrf2-inducer","volume":"15","author":"Strong","year":"2016","journal-title":"Aging Cell."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.16351","article-title":"Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice","volume":"5","author":"Bitto","year":"2016","journal-title":"Elife"},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.3390\/ijms16011008","article-title":"Elucidating mechanisms of toxicity using phenotypic data from primary human cell systems\u2015a chemical biology approach for thrombosis-related side effects","volume":"16","author":"Berg","year":"2015","journal-title":"Int J Mol Sci."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1016\/j.oraloncology.2011.08.009","article-title":"Clinical presentation and management of mTOR inhibitor-associated stomatitis","volume":"47","author":"de Oliveira","year":"2011","journal-title":"Oral Oncol."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1126\/science.1215135","article-title":"Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity","volume":"335","author":"Lamming","year":"2012","journal-title":"Science"},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1007\/s00441-016-2511-x","article-title":"Mechanisms of lung aging","volume":"367","author":"Brandenberger","year":"2017","journal-title":"Cell Tissue Res."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"419","DOI":"10.14336\/AD.2018.0601","article-title":"The role of pathological aging in cardiac and pulmonary fibrosis","volume":"10","author":"Murtha","year":"2019","journal-title":"Aging Dis"},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"3380","DOI":"10.1021\/ac400077e","article-title":"Application of GC-MS\/MS for the analysis of tobacco alkaloids in cigarette filler and various tobacco species","volume":"85","author":"Lisko","year":"2013","journal-title":"Anal Chem."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.4049\/jimmunol.1801238","article-title":"MYMD-1, a novel immunometabolic regulator, ameliorates autoimmune thyroiditis via suppression of Th1 responses and TNF-\u03b1 release","volume":"202","author":"Di Dalmazi","year":"2019","journal-title":"J Immunol."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"577115","DOI":"10.1016\/j.jneuroim.2019.577115","article-title":"MYMD-1, a novel alkaloid compound, ameliorates the course of experimental autoimmune encephalomyelitis","volume":"339","author":"Glenn","year":"2020","journal-title":"J Neuroimmunol."},{"key":"2023022410170021200_","volume-title":"The Mouse in Biomedical Research","author":"Fox","year":"2007","edition":"2"},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"e83988","DOI":"10.1371\/journal.pone.0083988","article-title":"Mice fed rapamycin have an increase in lifespan associated with major changes in the liver transcriptome","volume":"9","author":"Fok","year":"2014","journal-title":"PLoS One."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1093\/gerona\/glx009","article-title":"A comparison of two mouse frailty assessment tools","volume":"72","author":"Kane","year":"2017","journal-title":"J Gerontol A Biol Sci Med Sci."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1016\/j.chembiol.2017.06.003","article-title":"Mechanisms of skin toxicity associated with metabotropic glutamate receptor 5 negative allosteric modulators","volume":"24","author":"Shah","year":"2017","journal-title":"Cell Chem Biol"},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"27","DOI":"10.4103\/0976-0105.177703","article-title":"A simple practice guide for dose conversion between animals and human","volume":"7","author":"Nair","year":"2016","journal-title":"J Basic Clin Pharm"},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"e261","DOI":"10.1038\/nutd.2017.6","article-title":"The role of sex and body weight on the metabolic effects of high-fat diet in C57BL\/6N mice","volume":"7","author":"Ingvorsen","year":"2017","journal-title":"Nutr Diabetes"},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1177\/1941738113502296","article-title":"Muscle changes in aging: understanding sarcopenia","volume":"6","author":"Siparsky","year":"2014","journal-title":"Sports Health"},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1007\/s00198-017-3980-9","article-title":"Nutrition and physical activity in the prevention and treatment of sarcopenia: systematic review","volume":"28","author":"Beaudart","year":"2017","journal-title":"Osteoporos Int."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1001\/jama.2010.1923","article-title":"Gait speed and survival in older adults","volume":"305","author":"Studenski","year":"2011","journal-title":"JAMA"},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1007\/s10522-009-9260-0","article-title":"Delayed but excellent myogenic stem cell response of regenerating geriatric skeletal muscles in mice","volume":"11","author":"Shavlakadze","year":"2010","journal-title":"Biogerontology"},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"10425","DOI":"10.1038\/s41598-019-46929-8","article-title":"Metabolomic analysis of skeletal muscle in aged mice","volume":"9","author":"Uchitomi","year":"2019","journal-title":"Sci Rep."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"e12954","DOI":"10.1111\/acel.12954","article-title":"Effects of IGF-1 isoforms on muscle growth and sarcopenia","volume":"18","author":"Ascenzi","year":"2019","journal-title":"Aging Cell."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"287","DOI":"10.3389\/fphys.2019.00287","article-title":"Exercise-induced myokines with therapeutic potential for muscle wasting","volume":"10","author":"Piccirillo","year":"2019","journal-title":"Front Physiol."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"5559","DOI":"10.1113\/jphysiol.2009.179515","article-title":"The diseasome of physical inactivity\u2015and the role of myokines in muscle\u2015fat cross talk","volume":"587","author":"Pedersen","year":"2009","journal-title":"J Physiol."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"e465","DOI":"10.1371\/journal.pone.0000465","article-title":"Resistance exercise reverses aging in human skeletal muscle","volume":"2","author":"Melov","year":"2007","journal-title":"PLoS One."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"M146","DOI":"10.1093\/gerona\/56.3.M146","article-title":"Frailty in older adults: evidence for a phenotype","volume":"56","author":"Fried","year":"2001","journal-title":"J Gerontol A Biol Sci Med Sci."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"43068","DOI":"10.1038\/srep43068","article-title":"A frailty index based on deficit accumulation quantifies mortality risk in humans and in mice","volume":"7","author":"Rockwood","year":"2017","journal-title":"Sci Rep."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1093\/gerona\/glt188","article-title":"Clinically relevant frailty index for mice","volume":"69","author":"Liu","year":"2014","journal-title":"J Gerontol A Biol Sci Med Sci."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1111\/acel.12194","article-title":"Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction","volume":"13","author":"Miller","year":"2014","journal-title":"Aging Cell."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1152\/physrev.00020.2018","article-title":"Cellular senescence: aging, cancer, and injury","volume":"99","author":"Calcinotto","year":"2019","journal-title":"Physiol Rev."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1146\/annurev-physiol-021119-034610","article-title":"Aging and lung disease","volume":"82","author":"Cho","year":"2020","journal-title":"Annu Rev Physiol."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S0889-8561(02)00056-5","article-title":"Age-related inflammatory cytokines and disease","volume":"23","author":"Br\u00fc\u00fcnsgaard","year":"2003","journal-title":"Immunol Allergy Clin North Am."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1097\/00062752-200105000-00001","article-title":"Aging and proinflammatory cytokines","volume":"8","author":"Bruunsgaard","year":"2001","journal-title":"Curr Opin Hematol."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"221","DOI":"10.2174\/138161208783413248","article-title":"Endothelial cell aging and apoptosis in prevention and disease: E-selectin expression and modulation as a model","volume":"14","author":"Vannini","year":"2008","journal-title":"Curr Pharm Des."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.arr.2019.04.001","article-title":"LncRNA: shedding light on mechanisms and opportunities in fibrosis and aging","volume":"52","author":"Yang","year":"2019","journal-title":"Ageing Res Rev."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.bbadis.2016.11.006","article-title":"The role of \u03b1-smooth muscle actin in fibroblast-mediated matrix contraction and remodeling","volume":"1863","author":"Shinde","year":"2017","journal-title":"Biochim Biophys Acta Mol Basis Dis."},{"key":"2023022410170021200_","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1002\/jcp.22783","article-title":"PAI-1 in tissue fibrosis","volume":"227","author":"Ghosh","year":"2012","journal-title":"J Cell Physiol."}],"container-title":["The Journals of Gerontology: Series A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/biomedgerontology\/advance-article-pdf\/doi\/10.1093\/gerona\/glac142\/45685349\/glac142.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/biomedgerontology\/article-pdf\/78\/2\/227\/49327131\/glac142.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/biomedgerontology\/article-pdf\/78\/2\/227\/49327131\/glac142.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,25]],"date-time":"2023-11-25T06:42:22Z","timestamp":1700894542000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/biomedgerontology\/article\/78\/2\/227\/6653122"}},"subtitle":[],"editor":[{"given":"Rozalyn M","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2022,8,2]]},"references-count":49,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,8,2]]},"published-print":{"date-parts":[[2023,2,24]]}},"URL":"https:\/\/doi.org\/10.1093\/gerona\/glac142","relation":{},"ISSN":["1079-5006","1758-535X"],"issn-type":[{"value":"1079-5006","type":"print"},{"value":"1758-535X","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,2,1]]},"published":{"date-parts":[[2022,8,2]]}}}