Nuclear lamina erosion-induced resurrection of endogenous retroviruses underlies neuronal aging

The primate frontal lobe (FL) is sensitive to aging-related neurocognitive decline. However, the aging -associated molecular mechanisms remain unclear. Here, using physiologically aged non-human pri-mates (NHPs), we depicted a comprehensive landscape of FL aging with multidimensional profiling en-compassing bulk and single-nucleus transcriptomes, quantitative proteome, and DNA methylome. Conjoint analysis across these molecular and neuropathological layers underscores nuclear lamina and heterochromatin erosion, resurrection of endogenous retroviruses (ERVs), activated pro -inflamma-tory cyclic GMP-AMP synthase (cGAS) signaling, and cellular senescence in post-mitotic neurons of aged NHP and human FL. Using human embryonic stem-cell-derived neurons recapitulating cellular aging in vitro, we verified the loss of B-type lamins inducing resurrection of ERVs as an initiating event of the aging-bound cascade in post-mitotic neurons. Of significance, these aging-related cellular and molecular changes can be alleviated by abacavir, a nucleoside reverse transcriptase inhibitor, either through direct treatment of senescent human neurons in vitro or oral administration to aged mice.

Automated summary

By analyzing aged non-human primates, we uncovered the molecular and neuropathological changes in the primate frontal lobe associated with aging, including nuclear lamina and heterochromatin erosion, resurrection of endogenous retroviruses, activation of pro-inflammatory signaling, and cellular senescence. We also demonstrated that these aging-related changes can be alleviated by treatment with the nucleoside reverse transcriptase inhibitor abacavir, both in vitro and in vivo.