{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T06:11:27Z","timestamp":1790143887412,"version":"4.0.1"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To investigate the healthy aging effects of Formononetin and its underlying molecular mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      SAMP8 mice were administered Formononetin (4, 8, 16\u00a0mg\/kg, po) for 5 months. Behavioral tests were performed in 9-month-old mice, followed by histopathology. 5-methylcytosine (5-mC) level in the brain were detected by immunofluorescence, aging-related protein expression was measured by Western blot. In\n                      <jats:italic>C<\/jats:italic>\n                      .\n                      <jats:italic>elegans<\/jats:italic>\n                      , the lifespan, stress resistance, and aging-related gene expressions were assessed. Mutant strains (\n                      <jats:italic>daf-16<\/jats:italic>\n                      and\n                      <jats:italic>skn-1<\/jats:italic>\n                      ) were used to verify pathway dependency.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Formononetin dose-dependently ameliorated cognitive deficits, anxiety-like behaviors, and motor decline in SAMP8 mice, attenuated neuronal damage in the hippocampal CA1, DG and cerebral cortex, reversed 5-mC level, downregulated protein expression of P53, P21, while upregulated CDK4 and Nrf2. In\n                      <jats:italic>C<\/jats:italic>\n                      .\n                      <jats:italic>elegans<\/jats:italic>\n                      , Formononetin (37.30\u00a0\u03bcmol\/L) significantly extended lifespan under normal, thermal stress, and oxidative stress conditions, improved locomotion, reduced lipofuscin accumulation, increased total SOD activity, and upregulated\n                      <jats:italic>skn-1, sir-2.1, daf-16<\/jats:italic>\n                      and\n                      <jats:italic>sod-3<\/jats:italic>\n                      mRNA. No lifespan extension was observed in daf-16 or skn-1 mutants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Formononetin effectively attenuated cognitive deficits, ameliorated neuronal damage and increased 5-mC level, possibly\n                      <jats:italic>via<\/jats:italic>\n                      regulated P53, P21, CDK4 and Nrf2 protein expression in the brain of SAMP8 mice. In\n                      <jats:italic>C. elegans<\/jats:italic>\n                      , Formononetin extended lifespan, increased stress resistance, and improved locomotion and lipofuscin accumulation, possibly\n                      <jats:italic>via<\/jats:italic>\n                      regulated expression of DAF-16 and SKN-1.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1918524","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T05:50:14Z","timestamp":1790142614000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Formononetin improved healthspan via the P53\/P21\/CDK4 pathway in SAMP8 mice and DAF-16\/SKN-1 signaling pathway in C.elegans"],"prefix":"10.3389","volume":"17","author":[{"given":"Bo","family":"Liu","sequence":"first","affiliation":[{"name":"Key Lab for Basic Pharmacology and Joint International Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Cui","sequence":"additional","affiliation":[{"name":"Key Lab for Basic Pharmacology and Joint International Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Lab for Basic Pharmacology and Joint International Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunyan","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Lab for Basic Pharmacology and Joint International Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"115811","DOI":"10.1016\/j.biopha.2023.115811","article-title":"The potential role of formononetin in cancer treatment: an updated review","volume":"168","author":"Aliya","year":"2023","journal-title":"Biomed. 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