The Contribution of Retroviral Transposable Elements to Aging

A growing body of academic work is focused on the activity of transposable elements in degenerative aging, and some of these projects may produce approaches to therapy based on suppressing this activity. Transposable elements are DNA sequences capable of copying themselves within the genome, thought to be the result of ancient viral infections, but which contribute to evolution by providing a ready path to mutational change. Transposable elements are suppressed in youth, but with age the regulation of gene expression becomes more ragged, and transposable elements exhibit ever greater activity. This is supposed by many researchers to contribute to degenerative aging in much the same way as other stochastic mutational damage, though proving this is ever a challenge, and also via provoking chronic innate immune responses to what might look like viral activity.

There are several categories of transposable element, one of which, the retroviruses, is the topic of today's open access paper. The researchers assess the evidence for one particular pathway to be responsible for ensuring that retrovirus activation in older individuals produces an inflammatory response. As more researchers engage with the question of the role of transposable elements in aging, we'll see more research directed at potential target mechanisms that might be used to suppress transposable element activity in later life. Suppressing transposable element activity is the right way forward to determine just how much damage is being caused by this age-related failure to control the replication of transposable elements, to determine just how much of an influence this process has on degenerative aging. In matters relating to aging, fixing a given mechanism is really the only way to assess the degree to which that specific mechanism is hurting us all.

Endogenous Retroviruses (ERVs): Does RLR (RIG-I-Like Receptors)-MAVS Pathway Directly Control Senescence and Aging as a Consequence of ERV De-Repression?

Transposable elements (TE) make up about 46% of the human genome. They consist in repetitive sequences which are capable to or potentially capable to actively or passively insert copies of themselves elsewhere in the genome. TE are classified in Class I TEs, if they are RNA retrotransposons that require reverse transcriptase activity for transposition, and Class II TEs, or DNA transposons, that require transposase enzyme for their mobilization. LINE (long interspersed nuclear elements) and SINE (short interspersed nuclear elements) are the most studied and abundant class I TEs. The third family of Class I TEs consists of long terminal repeat (LTR) retroelements, known as HERVs (human endogenous retroviruses). HERV are residues of viral infections from the past that have remained in the human genome and occupy about 8% of it.

Bi-directional transcription of hERVs is a common feature of autoimmunity, neurodegeneration, and cancer. Higher rates of cancer incidence, neurodegeneration, and autoimmunity but a lower prevalence of autoimmune diseases characterize elderly people. Although the re-expression of hERVs is commonly observed in different cellular models of senescence as a result of the loss of their epigenetic transcriptional silencing, the hERVs modulation during aging is more complex, with a peak of activation in the sixties and a decline in the nineties. What is clearly accepted, instead, is the impact of the re-activation of dormant hERV on the maintenance of stemness and tissue self-renewing properties.

An innate cellular immunity system, based on the RLR-MAVS circuit, controls the degradation of double-stranded DNAs arising from the transcription of hERV elements, similarly to what happens for the accumulation of cytoplasmic DNA leading to the activation of cGAS/STING pathway. While agonists and inhibitors of the cGAS-STING pathway are considered promising immunomodulatory molecules, the effect of the RLR-MAVS pathway on innate immunity is still largely based on correlations and not on causality. Here we review the most recent evidence regarding the activation of MDA5-RIG1-MAVS pathway as a result of hERV de-repression during aging, immunosenescence, cancer, and autoimmunity. We will also deal with the epigenetic mechanisms controlling hERV repression and with the strategies that can be adopted to modulate hERV expression in a therapeutic perspective. Finally, we will discuss if the RLR-MAVS signalling pathway actively modulates physiological and pathological conditions or if it is passively activated by them.

Comments

would seem a rejuvenated immune system would take care of multiple problems, i.e. suppress transposable element activity, remove harmful gut microbes, remove senescent cells

Posted by: erasmus at July 6th, 2022 6:15 AM
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