Several studies have provided evidence that noncoding transposable elements in the genome may be involved in aging. Long-interspersed nuclear element-1 retrotransposons, for instance, have been linked to cellular senescence and age-related phenotypes. In a recent paper published in Cell, a team led by Guang-Hui Liu reports a link between aging and a different class of retrotransposons known as endogenous retroviruses (ERVs), which are the genomic remnants of evolutionarily ancient retroviral infections.
Although ERVs normally remain transcriptionally silent, the authors of this study found that expression of a human ERV known as HERVK was upregulated in human mesenchymal progenitor cells (hMPCs) that were either replicatively or prematurely senescent, and in hMPCs obtained from older human donors. The senescent cells expressed the viral protein Env and produced retrovirus-like particles. Artificially promoting the expression of HERVK in hMPCs promoted senescence, whereas repressing the retrotransposon had the opposite effect. The authors went on to show that HERVK expression caused the activation of the cGAS–STING innate immune response and the downstream upregulation of components of the proinflammatory senescence-associated secretory phenotype. The team also found that endogenous retroviral elements were expressed as proteins in various tissues from aged monkeys, and in the skin and serum of older human donors. Exposure of young hMPCs to serum from older individuals led to an increase in the expression of cytokines and markers of cellular senescence, and these effects could be reduced by HERVK immunodepletion. In mice, suppressing the expression of a closely related ERV improved several age-related phenotypes linked to cartilage thickness, bone density, muscle strength and memory.
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