Inhibition of miR-141-3p Reduces Age-Related Inflammation, Improves Health
Researchers here demonstrate an approach to inhibiting miR-141-3p that leads to improved health in old mice following twelve weeks of treatment. It appears that this microRNA is involved in the at least the inflammatory signaling characteristic of old age, but potentially a range of other mechanisms as well, such as mitochondrial function, and tendency for cells to become senescent. Since every aspect of cellular biochemistry influences every other aspect, one can produce benefits in this way and still be left with an unclear understanding of exactly why the results are positive.
We previously demonstrated elevated levels of miR-141-3p with age in human and murine bone marrow environments. We have also reported that miR-141-3p inhibits the osteogenic differentiation of bone marrow stromal cells. Several other groups have shown elevated levels of miR-141-3p in age-related diseases, such as neurodegenerative disorders, and cardiovascular diseases. The current study was designed to answer the critical question whether by inhibiting miR-141-3p during aging can we improve overall health, specifically systemic and musculoskeletal health. For this study, we treated mice at 15 months of age subcutaneously twice a week for three months.
Overall health depends on oxidative and inflammatory stress levels in tissue and organs. With advanced age, pro-inflammatory cytokines tend to be higher. In our study, we found that serum pro-inflammatory cytokine levels (TNF-α, IL-1β, IFN-γ) declined in the Anti-miR-141-3p treatment. Moreover, we found decreased M1 and increased M2 macrophage in splenocytes in the treated group. This suggested that Anti-miR-141-3p treatment helps in maintaining better immune health.
Maintaining musculoskeletal health is an important contributing factor to healthy aging and longevity. We, therefore, analyzed the effects of Anti-miR-141-3p on muscle and bone microstructure. We observed muscle fiber size was increased in the mice treated with Anti-miR-141-3p compared to the vehicle-treated group. As expected, we also observed better bone microstructure in Anti-miR-141-3p treated animals. Ours is the first study to demonstrate the treatment with Anti-miR-141-3p decreases systemic inflammation and improves musculoskeletal health in aged mice.
We hypothesized that miR-141-3p induces a determinate effect on aging cells through multiple signaling pathways, specifically by promoting a pro-inflammatory environment and inducing premature senescence. Our data demonstrated that treatment of cells in vitro with miR-141-3p elevated the expression of pro-inflammatory cytokines (TNF-α, IL-1β) and senescence markers (p16, p21) and Anti-miR-141-3p reversed the effect.