DNA damage response (DDR) and senescence: shuttled inflamma-miRNAs on the stage of inflamm-aging

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.

Leukocyte telomere length and mortality risk in patients with type 2 diabetes

“…Although inflammation has been suggested to have a key role in T2DM development and progression, its molecular bases are still being investigated [42–44]. Inflammaging - the age-related chronic state of low grade inflammation that modulates the aging process and promotes the development and progression of age-related diseases - is mainly sustained by protracted activation of the immune system and an increased burden of senescent cells with a secretory phenotype (SASP) [45–46]. Support for the link between telomere length and systemic inflammation has recently been provided by the report that telomeric repeat-containing RNA (TERRA) is a component of extracellular inflammatory exosomes [47].…”

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

“…For example, miR-126–3p inhibits endothelial inflammation, and low levels of miR-126–3p were found in patients with CVD and diabetes 50 , whereas miR-21–5p levels are correlated negatively with CRP and fibrinogen levels, and miR-21–5p levels are higher in patients with CVD than in age-matched controls 44 . Other miRNAs, such as miR-146 and miR-155, might also have a role in inflammageing by affecting cellular senescence or modulating immune responses, although these activities might not be reflected by changes in miRNA concentration or these miRNAs might be detected only in exosomes or other structures carrying miRNAs 51 . Overall, the contribution of miRNAs to inflammageing is an active area of investigation with high translational potential.…”

Extracellular vesicles and aging

“…Moreover, it was demonstrated that the functional hypothalamic stem/ progenitor cells release exosomes into the cerebral spinal fluid that likely contribute to slowing aging through transfer of miRNAs (57). Conversely, it has been demonstrated that senescent cells release more EVs and with a different composition (58)(59)(60), likely contributing to the SASP. Taken together, these results suggest that functional stem/ progenitor cell-derived EVs are able to extend healthspan and lifespan whereas senescent cell-derived EVs could function as pro-geronic factors.…”