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bioRxiv · 10.64898/2026.09.08.750279

A SUN1-ApoD feedback loop promotes cellular aging via microtubule-nuclear mechanotransduction

Chen, M.·Wilson, P. C.·Yang, W.·Ma, Y.·Li, Y.·Wang, X.·Bennett, R. L.·Licht, J. D.·Gundersen, G. G.·Chang, W.
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Abstract

Alterations in nuclear envelope proteins such as SUN1 and prelamin A are known hallmarks of cellular aging, but how they cause aging phenotypes beyond the expressing cells is unknown. 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.

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Chen, M., Wilson, P. C., Yang, W., Ma, Y., Li, Y., Wang, X., Bennett, R. L., Licht, J. D., Gundersen, G. G., Chang, W.. 2026-09-10. A SUN1-ApoD feedback loop promotes cellular aging via microtubule-nuclear mechanotransduction. https://doi.org/10.64898/2026.09.08.750279

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