MicroRNA‐570 is a novel regulator of cellular senescence and inflammaging

Abstract

Diseases of accelerated aging often occur together (multimorbidity), and their prevalence is increasing, with high societal and health care costs. Chronic obstructive pulmonary disease (COPD) is one such condition, in which one half of patients exhibit ≥4 age-related diseases. Diseases of accelerated aging share common molecular pathways, which lead to the detrimental accumulation of senescent cells. These senescent cells no longer divide but release multiple inflammatory proteins, known as the senescence-associated secretory phenotype, which may perpetuate and speed disease. Here, we show that inhibiting miR-570-3p, which is increased in COPD cells, reverses cellular senescence by restoring the antiaging molecule sirtuin-1. MiR-570-3p is induced by oxidative stress in airway epithelial cells through p38 MAP kinase-c-Jun signaling and drives senescence by inhibiting sirtuin-1. Inhibition of elevated miR-570-3p in COPD small airway epithelial cells, using an antagomir, restores sirtuin-1 and suppresses markers of cellular senescence (p16, p21, and p27), thereby restoring cellular growth by allowing progression through the cell cycle. MiR-570-3p inhibition also suppresses the senescence-associated secretory phenotype (matrix metalloproteinases-2/9, C-X-C motif chemokine ligand 8, IL-1β, and IL-6). Collectively, these data suggest that inhibiting miR-570-3p rejuvenates cells via restoration of sirtuin-1, reducing many of the abnormalities associated with cellular senescence.-Baker, J. R., Vuppusetty, C., Colley, T., Hassibi, S., Fenwick, P. S., Donnelly, L. E., Ito, K., Barnes, P. J. MicroRNA-570 is a novel regulator of cellular senescence and inflammaging.

Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases

“…It is unrealistic to achieve reversal of normal aging, but may be more likely to fine tune the pathways that result in premature senescence. However, the reversal of senescence (rejuvenation) in small airway epithelial cells of COPD patients by specific antagomirs suggests that some reversal of senescence might be possible in the future (60,69).…”

“…Targeting miRNAs, such as miR-34a and miR-570, may be a future therapeutic strategy for treating and preventing cellular senescence as this has rejuvenates senescent airway epithelial cells in COPD patients (60,69). Delivery of miRNA mimics or antagomirs via extracellular vesicles and nanoparticles might be a novel way to deliver these therapies (90).…”

The emerging role of cellular senescence in renal diseases

“…It has been shown that SIRT1 can inhibit cellular senescence of endothelial cells. 38 On the contrary, increased expression and activity of SIRT1 prevent cells from entering into the state of senescence by inhibiting p53 activity.…”

“…37 Furthermore, it has been shown that inhibition of miR-570-3p in small airway epithelial cells from COPD patients restores SIRT1 expression, leading to SIRT1-dependent inhibition of senescence markers and cellular rejuvenation. 38…”

Virus-Induced Asthma Exacerbations: SIRT1 Targeted Approach

“…MAPK signaling and PI3K signaling were thought to be the possible pathways involved in this response [112,113]. It was reported that SIRT1 was inhibited by p38 MAPK and PI3K signaling via micro-RNA (miRNA) 34-a and miRNA570 expression, if the airway epithelial cells were subjected to oxidative stress [114,115]. The possible mechanisms by which SIRT1 regulates allergic airway inflammation through ILC2, such as cellular apoptosis and lipid metabolic pathways, as well as the presence of miRNAs, require further investigation.…”