A Role for Transposable Elements in Cellular Senescence
Transposable elements are largely the remnants of ancient viral infections, DNA sequences capable of copying themselves within the genome via a number of different mechanisms. Transposable elements are suppressed in youth, but this suppression breaks down with age, and the resulting disruptive activity may provide a meaningful contribution to degenerative aging. Separately, researchers are finding that transposable elements are active in senescent cells, and contribute to some of the behaviors that make lingering senescent cells harmful in aged tissues, as noted in this paper.
Silent long-interspersed element-1 (LINE1) retrotransposons, belonging to non-long terminal repeat (non-LTR) retrotransposons, can be activated during senescence, triggering the innate immune response that is responsible for part of the senescence-associated phenotypes. A different class of retroelements, endogenous retroviruses (ERVs), belonging to LTR retrotransposons are a relic of ancient retroviral infection, fixed in the genome during evolution, comprising about 8% of the human genome. As a result of evolutionary pressure, most human ERVs (HERVs) accumulate mutations and deletions that prevent their replication and transposition function. However, some evolutionarily young subfamilies of HERV proviruses, such as the recently integrated HERVK human mouse mammary tumor virus like-2 (HML-2) subgroup, maintain open reading frames encoding proteins required for viral particle formation.
Except at specific stages of embryogenesis when DNA is hypomethylated and under certain pathological conditions such as cancer, HERVs are transcriptionally silenced by host surveillance mechanisms such as epigenetic regulation in post-embryonic developmental stages. Notably, whether ERVs can escape host surveillance during aging and, if so, what effects they may exert on cellular and organismal aging are still poorly investigated.
In this study, using cross-species models and multiple techniques, we revealed an uncharacterized role of endogenous retrovirus resurrection as a biomarker and driver for aging. Specifically, we identified endogenous retrovirus expression associated with cellular and tissue aging and that the accumulation of HERVK retrovirus-like particles (RVLPs) mediates the aging-promoting effects in recipient cells. These HERVK RVLPs constitute a transmissible message to elicit senescence phenotypes in young cells, which can be blocked by neutralizing antibodies. We can thus inhibit endogenous retrovirus-mediated pro-senescence effects to alleviate cellular senescence and tissue degeneration in vivo, suggesting possibilities for developing therapeutic strategies to treat aging-related disorders.