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

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.