{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T07:00:06Z","timestamp":1790146806977,"version":"4.0.1"},"reference-count":62,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T00:00:00Z","timestamp":1763596800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-AR053237"],"award-info":[{"award-number":["R01-AR053237"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32-AR065971"],"award-info":[{"award-number":["T32-AR065971"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30-AR083854"],"award-info":[{"award-number":["P30-AR083854"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01-AG062413"],"award-info":[{"award-number":["P01-AG062413"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-AG086085"],"award-info":[{"award-number":["R01-AG086085"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-DK128552"],"award-info":[{"award-number":["R01-DK128552"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Veterans Administration","award":["I01-BX001478"],"award-info":[{"award-number":["I01-BX001478"]}]},{"name":"Veterans Administration","award":["IK6-BX003782"],"award-info":[{"award-number":["IK6-BX003782"]}]},{"name":"Veterans Administration","award":["I01-RX003714"],"award-info":[{"award-number":["I01-RX003714"]}]},{"name":"Hevolution","award":["HR-GRO-23-1199144-8"],"award-info":[{"award-number":["HR-GRO-23-1199144-8"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Aging plays a major role in the development of numerous chronic diseases, one of which is a marked decline in skeletal health. Beyond diminishing bone mass and strength, mammals of advanced age experience a decline in skeletal mechanotransduction\u2014that is, the ability of the skeleton to respond adaptively to mechanical perturbation. One possibility for the loss of mechanotransduction in bone with aging is an age-associated increase in the population density of senescent cells\u2014those cells that have undergone irreversible cell cycle arrest, resistance to apoptosis, and production of a modified secretome (the SASP) that has damaging effects to nearby healthy (non-senescent) cells. We investigated whether the presence of senescent cells might drive some of the diminished mechanical response observed in aged bone, by testing the hypothesis that the clearance of senescent cells via intermittent senolytic treatment promotes mechanical responsiveness in an aged skeleton. C57BL\/6 mice aged 6 months and 22 months were treated weekly with the senolytic cocktail Dasatinib and Quercetin (D + Q) for 1 month, then subjected to low level in vivo mechanical loading of the ulna for 1 week. The 6-month-old mice exhibited a doubling of load-induced ulnar periosteal bone formation when treated with D + Q, compared to vehicle-treated mice, but the periosteal response to loading was not significantly altered by D + Q in the aged (22-month) mice. We further probed the efficacy of D + Q in mechanotransduction by switching to an endocortical model\u2014the axial tibia loading system. Here, the 22-month-old mice had nearly double the load-induced endocortical bone formation compared to vehicle-treated mice. We further assayed the cortical bone gene expression profile in loaded and control tibias from treatment-na\u00efve 6-month and 22-month mice, to determine whether there is significant overlap between mechanically induced signaling genes and SASP genes. We found significant load-induced changes among several SASP genes, suggesting that inhibition of the SASP (i.e., senomorphics) might interfere with mechanical signaling from otherwise healthy cells. In summary, clearance of senescent cells via intermittent D + Q treatment is effective at improving endocortical mechanical responsiveness in the aged skeleton, which is commonly diminished throughout the course of aging.<\/jats:p>","DOI":"10.3390\/ijms262211233","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T15:00:17Z","timestamp":1763650817000},"page":"11233","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Senolytic Treatment Improves Responsiveness to Mechanical Loading in the Skeleton of Aged Mice"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6334-3532","authenticated-orcid":false,"given":"Connor J.","family":"Cunningham","sequence":"first","affiliation":[{"name":"Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7593-9184","authenticated-orcid":false,"given":"Hui Jean","family":"Kok","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua N.","family":"Farr","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2936-4372","authenticated-orcid":false,"given":"Sundeep","family":"Khosla","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander G.","family":"Robling","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA"},{"name":"Richard L. 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