Abstract
A major issue in aging research is how cellular phenomena affect aging at the systemic level. Emerging evidence suggests that DNA damage response (DDR) signaling is a key mechanism linking DNA damage accumulation, cell senescence, and organism aging. DDR activation in senescent cells promotes acquisition of a proinflammatory secretory phenotype (SASP), which in turn elicits DDR and SASP activation in neighboring cells, thereby creating a proinflammatory environment extending at the local and eventually the systemic level. DDR activation is triggered by genomic lesions as well as emerging bacterial and viral metagenomes. Therefore, the buildup of cells with an activated DDR probably fuels inflamm-aging and predisposes to the development of the major age-related diseases (ARDs). Micro (mi)-RNAs - non-coding RNAs involved in gene expression modulation - are released locally and systemically by a variety of shuttles (exosomes, lipoproteins, proteins) that likely affect the efficiency of their biological effects. Here we suggest that some miRNAs, previously found to be associated with inflammation and senescence - miR-146, miR-155, and miR-21 - play a central role in the interplay among DDR, cell senescence and inflamm-aging. The identification of the functions of shuttled senescence-associated miRNAs is expected to shed light on the aging process and on how to delay ARD development.
Highlights
The DNA damage response (DDR) is an evolutionarily conserved signaling cascade, activated by DNA damage, which directs cell fate toward DNA repair, senescence, or apoptosis [1]
It is reasonable to hypothesize that the age-related increase in the burden of cells with DDR/senescence-associated secretory phenotype (SASP) activation links cell senescence and inflamm-aging, and that non-coding RNA, mainly microRNAs, play a key role in the diffusion of DDR/SASP signaling to surrounding nondamaged cells during human aging, suggesting that the identification of new DDR/SASP signaling components may lead to develop novel therapeutic interventions against age-related diseases (ARDs)
It is conceivable that miRNAs released by DDR/SASP-activating cells signal to non-senescent cells, spreading and increasing inflamm-aging
Summary
The DNA damage response (DDR) is an evolutionarily conserved signaling cascade, activated by DNA damage, which directs cell fate toward DNA repair, senescence, or apoptosis [1]. All these data suggest that chronic miR-146a overexpression could curb inflammation in aseptic conditions, as in accumulation of senescent cells in tissues, whereas in presence of bacterial or viral infection its upregulation may favor pathogen survival, contributing to the immunodeficiency (immunosenescence) associated with aging.
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