Retroviral Activation as a Component of Neuronal Aging
In recent years, researchers have implicated the activation of transposable elements such as retrovirus sequences in degenerative aging. Transposable elements are largely the remnants of ancient viral infections, and have the ability to copy themselves in the genome. In youth, transposable elements are effectively suppressed, but with advancing age this suppression falters. Transposable elements can then act as a form of DNA damage, as well as provoking cell dysfunction via other means, such as inflammatory signaling resulting from innate immune sensing of viral signatures, which may meaningfully contribute to harmful outcomes in aging.
The primate frontal lobe (FL) is sensitive to aging-related neurocognitive decline. However, the aging-associated molecular mechanisms remain unclear. Efforts have been made to reveal molecular events that trigger aging-related dysfunctions in FL, however intrinsic alterations in neurons in response to aging are not completely understood.
Using the neuronal aging-in-a-dish model derived from human embryonic stem cells, we genetically perturbed the expression of Lamin B1 and Lamin B2 in human neurons and pinpointed that decreased B-type lamins drive the activation of endogenous retrovirus (ERV) retrotransposons during neuronal aging, which leads to elevated senescence and inflammation. Our study demonstrated that this in vitro human neuronal model could mimic the aging-related phenotypes of neurons from primate brains and study cell-autonomous mechanisms underlying primate neuronal aging.
ERV element activation has been reported to be associated with cellular senescence. In addition, increased expression of ERV elements was found to contribute to neurodegenerative diseases, such as amyotrophic lateral sclerosis. However, the links between ERV derepression and physiological brain aging have not been established. For the first time, our study revealed that ERV retrotransposable elements are derepressed in aged human neurons, which activate cGAS signaling, exacerbating neuroinflammation, thus providing a vivid paradigm of how this cascade functions in a highly physiologically and pathologically relevant context, the aging brain.
We previously found that the inhibition of reverse transcription of the endogenous retrovirus can alleviate cartilage degeneration and aging-related inflammation. In this study, we further found that treatment with abacavir can attenuate the augmented inflammation and protein aggregates in human neurons during prolonged culture and in the neurons of FL from aged mice, indicating ERV targeting as a promising strategy to delay brain aging and extend healthspan.