Reactivation of senescence-associated endogenous retroviruses by ATF3 drives interferon signaling in aging.

Jian Mao, Qian Zhang, Yang Zhuang, Yinyu Zhang, Linmeng Li, Juan Pan, Lu Xu, Yuxuan Ding, Miao Wang, Yu-Sheng Cong

Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Zhejiang Key Laboratory of Medical Epigenetics, Hangzhou Normal University School of Basic Medical Sciences, Hangzhou, China. [email protected] Laboratory of Aging and Cancer Biology of Zhejiang Province, Zhejiang Key Laboratory of Medical Epigenetics, Hangzhou Normal University School of Basic Medical Sciences, Hangzhou, China. [email protected]. · pubmed

Paper

Abstract

Reactivation of endogenous retroviruses (ERVs) has been proposed to be involved in aging. However, the mechanism of reactivation and contribution to aging and age-associated diseases is largely unexplored. In this study, we identified a subclass of ERVs reactivated in senescent cells (termed senescence-associated ERVs (SA-ERVs)). These SA-ERVs can be bidirectional transcriptionally activated by activating transcription factor 3 (ATF3) to generate double-stranded RNAs (dsRNAs), which activate the RIG-I/MDA5-MAVS signaling pathway and trigger a type I interferon (IFN-I) response in senescent fibroblasts. Consistently, we found a concerted increased expression of ATF3 and SA-ERVs and enhanced IFN-I response in several tissues of healthy aged individuals and patients with Hutchinson-Gilford progeria syndrome. Moreover, we observed an accumulation of dsRNAs derived from SA-ERVs and higher levels of IFNβ in blood of aged individuals. Together, these results reveal a previously unknown mechanism for reactivation of SA-ERVs by ATF3 and illustrate SA-ERVs as an important component and hallmark of aging.

The following analysis is generated by AI and may contain errors. It is separate from the authors’ abstract and is not peer review.

Research summary

The paper explores the reactivation of senescence-associated endogenous retroviruses (SA-ERVs) and their role in driving interferon signaling in aging, which is directly related to the mechanisms of aging and age-associated diseases. This research contributes to understanding the biological processes underlying aging, making it relevant to longevity research. However, while it presents solid findings, the impact is limited as it primarily identifies a mechanism without providing direct interventions or solutions to aging, thus rating it as a solid but not groundbreaking contribution.

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