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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.

SUBMITTER: Olivieri F

PROVIDER: S-EPMC4742121 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Publications

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

Olivieri Fabiola F Albertini Maria Cristina MC Orciani Monia M Ceka Artan A Cricca Monica M Procopio Antonio Domenico AD Bonafè Massimiliano M

Oncotarget 20151101 34

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 eve ...[more]

PMID: 26431329

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Project description:The contribution of inflammation to the pathogenesis of tendinopathy and high prevalence of re-injury is not well established, although recent evidence suggests involvement of prostaglandins. We investigated the roles of prostaglandins and inflammation-resolving mediators in naturally occurring equine tendon injury with disease stage and age. Levels of prostaglandins E(2) (PGE(2)), F(2?) (PGF(2?)), lipoxin A(4) (LXA(4)) and its receptor FPR2/ALX were analysed in extracts of normal, sub-acute and chronic injured tendons. To assess whether potential changes were associated with altered PGE(2) metabolism, microsomal prostaglandin E synthase-1 (mPGES-1), prostaglandin dehydrogenase (PGDH), COX-2 and EP(4) receptor expression were investigated. The ability of tendons to resolve inflammation was determined by assessing FPR2/ALX expression in natural injury and IL-1? stimulated tendon explants.Alterations in the profile of lipid mediators during sub-acute injury included low PGE(2) and elevated LXA(4) levels compared to normal and chronic injuries. In contrast, PGF(2?) levels remained unchanged and were three-fold lower than PGE(2). The synthetic capacity of PGE(2) as measured by the ratio of mPGES-1:PGDH was elevated in sub-acute injury, suggesting aberrations in tendon prostaglandin metabolism, whilst COX-2 and EP(4) receptor were unchanged. Paradoxically low tendon PGE(2) levels in early injury may be attributed to increased local clearance via PGDH or the class switching of lipid mediators from the prostaglandin to the lipoxin axis. PGE(2) is therefore implicated in the development of tendon inflammation and its ensuing resolution. Whilst there was no relationship between age and tendon LXA(4) levels, there was an age-associated decline in FPR2/ALX receptor expression with concurrent increased PGE(2) levels in injury. Furthermore, uninjured tendon explants from younger (<10 years) but not older horses (?10 years) treated with IL-1? responded by increasing FPR2/ALX suggesting aged individuals exhibit a reduced capacity to resolve inflammation via FPR2/ALX, which may present a potential mechanism for development of chronic tendinopathy and re-injury.

Dataset Information

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

Publications

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

Similar Datasets

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