Cell senescence is a major contributor to ageing. It is characterized by the senescence-associated secretory phenotype (SASP) — secretion of specific cytokines and other factors — which induces chronic inflammation. Retrotransposons can be transcriptionally activated concurrently with the SASP and during ageing. Liu et al. now show that reactivation of specific endogenous retroviruses promotes senescence and ageing.

During evolution, endogenous retroviruses accumulate mutations that prevent their propagation. However, some evolutionarily young (that is, recently integrated into the genome) human endogenous retrovirus (HERV) families, such as HERV-K (HML2), maintained their open reading frames and can express their proteins, thereby allowing them to propagate.

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The authors found that, in human mesenchymal progenitor cells (hMPCs) that have undergone replicative senescence (rs-hMPCs), or in prematurely senescent hMPCs (ps-hMPCs) that recapitulate the phenotypes of premature ageing disorders, HERV-K genomic regions exhibited transcription-promoting features, including DNA hypomethylation. Accordingly, the cells expressed HERV-K mRNA and proteins, and accumulated retrovirus-like particles (RVLPs). By contrast, RVLPs were very rare in early-passage (‘young’) wild-type hMPCs. Furthermore, HERV-K expression was considerably higher in primary hMPCs derived from older individuals than in hMPCs from younger persons.

To assess the causality between HERV-K expression and cell senescence, young wild-type hMPCs were either treated with a DNA methyltransferase inhibitor (5-AZA) — to mimic ageing-associated DNA hypomethylation — or subjected to CRISPR-mediated transcriptional activation of HERV-K proviruses. Both treatments induced senescence, and the 5-AZA effect was abrogated by HERV-K knockdown, suggesting that senescence is at least partially mediated by HERV-K activation. In line with this result, HERV-K knockdown or transcriptional inactivation in ps-hMPCs alleviated their premature senescence.

The HERV-K polymerase has reverse transcriptase activity and thus can produce DNA from HERV-K RNA. Indeed, an increased level of HERV-K DNA was observed in the cytoplasm of senescent hMPCs, which was accompanied by marked enrichment of cGAS (a sensor of cytoplasmic DNA) on the HERV-K DNA. This enrichment, with the induction of the SASP and inflammation, resulted in activation of the cGAS–STING innate immunity pathway. Senescent hMPCs treated with the reverse-transcriptase inhibitor abacavir had diminished HERV-K DNA content and SASP, whereas HERV-K activation in young wild-type hMPCs augmented the SASP and the innate immunity response. Therefore, increased HERV-K expression drives cell senescence by inducing the cGAS–STING pathway.

Previous studies indicated that HERV-K RVLPs are released into cell-culture medium and taken up by other cells. Likewise, HERV-K RVLPs were detected budding from and outside of senescent hMPCs. Importantly, young wild-type hMPCs cultured with RVLPs collected from medium of ps- or rs-hMPCs underwent accelerated senescence. Immunodepletion of the HERV-K envelope protein from the culture medium before treatment resulted in lower HERV-K abundance in young hMPCs and reduced cell senescence. Furthermore, analysis of tissue samples obtained from young and old humans found that expression of the HERV-K envelope protein was markedly increased with age, and application of serum from old individuals to primary hMPCs increased HERV-K cellular abundance, accelerated cell senescence and elicited an inflammatory response. Thus, extracellular HERV-K RVLPs can transmit ageing signals to young cells.

Finally, levels of the envelope protein of mouse mammary tumour virus (MMTV), which is closely related to HERV-K, were found to be higher in tissues of aged mice than of young mice, concomitantly with the activation of innate immunity and inflammation in these tissues. Furthermore, in aged mice, MMTV was substantially upregulated in the articular cartilage; intra-articular repression of MMTV alleviated ageing of the tissue, and abacavir treatment reduced cartilage degeneration. MMTV repression in mice also improved the condition and function of joints of aged mice, and abacavir treatment improved their overall physical condition and short-term memory.

“… increased HERV-K expression drives cell senescence”

In summary, endogenous retroviruses can promote cell senescence and tissue ageing, and are potential drug targets to increase human healthspan. The study also raises the possibility that viral contagion has a role in ageing.