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With a tissue culture version of parabiosis, we found that aged fibroblasts secrete an activity that induces aging-related polarity defects in young fibroblasts. Secretomics identified the factor as apolipoprotein D (ApoD), a circulating protein whose levels are known to rise with age. ApoD increased SUN1 levels and disrupted polarity in fibroblasts via SUN1-promoted coupling of microtubules to the nucleus. In turn, elevated SUN1 enhanced ApoD expression and secretion, forming a feedback loop that promotes acquisition of aged phenotypes. In mice, ApoD induced aging-related phenotypes in muscle. Elevated ApoD expression required coupling between SUN1, its outer nuclear membrane binding partner nesprin-2, and microtubules. Broader analysis revealed that this pathway regulates hundreds of genes. These findings define microtubule-nuclear coupling as a direct mechanotransduction pathway controlling gene expression and promoting aging-associated phenotypes.<\/jats:p>","DOI":"10.64898\/2026.09.08.750279","type":"posted-content","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T19:35:12Z","timestamp":1789068912000},"source":"Crossref","is-referenced-by-count":0,"title":["A SUN1-ApoD feedback loop promotes cellular aging via microtubule-nuclear mechanotransduction"],"prefix":"10.64898","author":[{"given":"Mengqi","family":"Chen","sequence":"first","affiliation":[{"name":"MOE Frontier Science Centre for Precision Oncology, University of Macau; Taipa, Macau, China"},{"name":"Department of Biomedical Sciences, Faculty of Medicine, University of Macau; Taipa, Macau, China"},{"name":"Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, University of Macau; Taipa, Macau, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paige C.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Columbia University; 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