A new theory proposes that the resurrection of endogenous retroviruses could enhance cellular senescence and amplify ageing.
The co-option between viruses and humans has significant effects on the evolution of humans. Endogenous retroviruses (ERVs), which belong to long terminal repeat retrotransposons and make up about 8% of the human genome, are a relic of ancient retroviral infection that were fixed in the genome during evolution. As a result of evolutionary pressure, the majority of human ERVs (HERVs) accumulate mutations and deletions. Additionally, host mechanisms like epigenetic regulation firmly suppress these archaic enemies.
Programmed epigenetic changes play significant roles in cellular senescence, which is an important hallmark of age-related illnesses. However, can endogenous retroviruses evade detection as the host ages? If so, will they pave the way for the cell’s or even the organism’s demise?
In a study published in Cell, researchers from the Institute of Zoology and the Beijing Institute of Genomics of the Chinese Academy of Sciences report that the youngest subfamily of ERV is awakened during ageing and proposed a new theory of programmed and contagious ageing caused by the resurrection of ERVs.
A multi-faceted intervention strategy was also developed to prevent the reactivation and transmission of ERVs in order to slow down the ageing process.
Combining multiple ageing models and technologies, the researchers discovered that epigenetic derepression (such as heterchromatin loss) activates ERV transcription, enhancing viral protein translation and causing the accumulation of viral-like particles (RVLPs) in senescent cells.
The cGAS-STING-mediated innate immune pathway is activated by the reverse transcripts of ERVs, inducing inflammatory reactions and quickening cellular senescence.
Additionally, the senescence of “infected” young cells is caused by the release of RVLPs by senescent cells, which can efficiently transmit and amplify aging signals among organs, tissues, and cells in a paracrine or humoral-mediated way.
The scientists have also created a number of effective intervention strategies to prevent the reactivation of ERVs and get rid of viral particles, including CRISPR/dCas9-mediated gene editing systems that target the regulatory components of ERVs, small molecule drugs that target reverse transcriptase, and neutralising antibodies that target viral envelope proteins, and other technologies.
To reduce tissue and organismal aging, each of these intervention methods inhibits a separate stage of the viral life cycle, such as ERV transcription, reverse transcription, and viral infection.
This study provides proof that cellular, tissue, and organismal ageing are all characterised by and driven by ageing-induced resurrection of endogenous retrovirus. These discoveries set the groundwork for the concept of planned, transmissible, and intervenable aging and offer new insights into the mechanisms behind ageing. Additionally, it creates opportunities for constructing a scientific technique for assessing ageing and creating clinical methods to treat ageing and disorders associated with age.
Overall, the resurgence of ERV may shine new light on the “Pandora’s box” of ageing, opening up a new field of study and, paradoxically, bringing new hope for the prevention and treatment of ageing-related disorders. More conundrums about the activation of ERVs during aging will need to be resolved in the future by persistent scientific research using novel methods. [APBN]
Source: Liu et al. (2023). Resurrection of endogenous retroviruses during aging reinforces senescence. Cell.