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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Senotherapeutic agents targeting senescent cell (SnC) accumulation represent a promising frontier in aging research. These agents encompass senolytics that selectively eliminate accumulated SnCs and senomorphics that suppress the pathological persistence of the senescence-associated secretory phenotype (SASP). Concerns regarding off-target effects of synthetic senolytics have intensified interest in plant-derived alternatives that offer multitargeted mechanisms and favorable safety profiles. This scoping review was conducted following Joanna Briggs Institute guidelines and PRISMA-ScR, mapped preclinical evidence on plant-derived senotherapeutics published between 2015 and 2025 across PubMed, Scopus, Web of Science, Wiley Library and Google Scholar. Of 1355 identified articles, 111 studies met inclusion criteria. Most characterized compound classes included flavonoids, non-flavonoid polyphenols and stilbenes, terpenoids and alkaloids, and combination and complex plant extracts. Mechanistically, BCL-2\/BCL-XL apoptosis, PI3K\/AKT\/mTOR and p53\/p21\/p16INK4a modulation emerged as senolytic mechanisms, while NF-\u03baB-mediated SASP suppression predominated among senomorphic agents. Ginkgetin-mediated cyclic GMP-AMP-synthase\u2013stimulator of interferon genes (cGAS-STING) inhibition was identified as a mechanistically novel target within natural senotherapy. Metabolomics demonstrated dual utility in guiding compound discovery from complex plant matrices (e.g., phenolamides from Allium hookeri) and mechanistic validation by characterizing senescence-associated metabolic remodeling, including retinoic acid metabolism restoration, lipotoxic metabolites attenuation, tricarboxylic acid (TCA) cycle, and choline-betaine-TCA cascade regulation. However, challenges in pharmacokinetic optimization, methodological heterogeneity in senescence induction and biomarker panels persist. Plant-derived senotherapy characterized through metabolomics-guided pipelines provides a compelling foundation for their progression toward clinical validation and functional food applications as accessible interventions for healthy aging and age-related disease management.<\/jats:p>","DOI":"10.3390\/ijms27167181","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T13:46:16Z","timestamp":1786455976000},"page":"7181","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Plant-Derived Senotherapeutics in Cellular Senescence: A Scoping Review of Preclinical Evidence, Mechanistic Pathways, and Metabolomic-Guided Discovery"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3250-6155","authenticated-orcid":false,"given":"Nor Muhammad Hilmi","family":"Hussin","sequence":"first","affiliation":[{"name":"Centre for Healthy Ageing and Wellness (H-CARE), Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur 50300, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6892-1995","authenticated-orcid":false,"given":"Ahmed","family":"Mediani","sequence":"additional","affiliation":[{"name":"Institute of Systems Biology (INBIOSIS), Universiti Kebangsaan Malaysia, Bangi 43600, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4957-5369","authenticated-orcid":false,"given":"Normala","family":"Abd Latip","sequence":"additional","affiliation":[{"name":"Integrative Pharmacogenomics Institute (iPROMISE), Universiti Teknologi MARA (UiTM) Selangor, Puncak Alam 42300, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8466-0991","authenticated-orcid":false,"given":"Michael","family":"Fenech","sequence":"additional","affiliation":[{"name":"Health and Biomedical Innovation, UniSA Clinical and Health Sciences, University of South Australia, Adelaide 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4934-8131","authenticated-orcid":false,"given":"Rahma Micho","family":"Widyanto","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, Universitas Brawijaya, Malang 65151, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7174-7353","authenticated-orcid":false,"given":"Razinah","family":"Sharif","sequence":"additional","affiliation":[{"name":"Centre for Healthy Ageing and Wellness (H-CARE), Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur 50300, Malaysia"},{"name":"Faculty of Health Sciences, Universitas Brawijaya, Malang 65151, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.cell.2022.11.001","article-title":"Hallmarks of aging: An expanding universe","volume":"186","author":"Blasco","year":"2023","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Kudlova, N., De Sanctis, J.B., and Hajduch, M. 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