Reversine Increases Cell Plasticity, and Appears to Allow Some Cell Types to Escape Senescence

If I'm understanding the results presented here correctly, the reversine small molecule enables senescent cells to return to a more normal state of function, including replication, at least in muscle cells examined in cell culture. The researchers believe it is triggering some of the same reprogramming pathways as the Yamanaka factors, perhaps by inducing expression of Oct4, but are not yet certain as to what is going on under the hood. Is it a good idea to take senescent cells in the body and return them to normal function? That is a good question, and has been raised for other approaches to senescence reversal. At least some senescent cells are senescent for a good reason, being damaged in ways that may lead to cancer, and all senescent cells undergo significant DNA damage in the process of becoming senescent. Reversal of senescence, versus just destroying senescent cells, sounds a lot like a cancer waiting to happen.

Skeletal muscle has a remarkable capacity to regenerate by activation of myogenic progenitor cells; however, both the number of these progenitors and their regenerative capacity decline with aging and cellular senescence. Metabolic changes such as impaired glycolysis, insulin sensitivity, and mitochondrial respiration are affected by senescence contributing to loss of the myoblast capacity to differentiate. Aging is also associated with impaired autophagy, which is essential to maintain satellite cell stemness and mitochondrial turn over.

Several studies found that the small molecule 2,6-disubstituted purine, reversine, increased cellular plasticity as demonstrated by increased differentiation potential of progenitor cells toward the neuroectodermal lineage; dedifferentiation of C2C12 myoblasts to a progenitor-like state; as well as dedifferentiation of sheep fibroblasts into multipotent progenitor cells, possibly via expression of the pluripotent factor, Oct4. Other studies reported that reversine may have anticancer properties. Indeed, reversine is an Aurora B protein kinase inhibitor, causing failure in mitotic chromosome segregation, cytokinesis, and cell proliferation.

Based on these results, we hypothesized that reversine might ameliorate the hallmarks of cellular senescence in human myoblasts. We discovered that short-term treatment of fully senescent myoblasts with reversine could restore insulin resistance, enhance glucose metabolism and oxidative phosphorylation, likely via reactivation of autophagy, ultimately restoring the differentiation ability of myoblasts to form myofibers. Our results suggest that reversine may have the potential to be used as a novel, antiaging treatment.



For what it's worth, the Wikipedia citation suggests that: "[Reversine] also has the potential to selectively induce cell death in cancer cells." A win-win perhaps? Too early to tell.

Posted by: Jim Coli at January 27th, 2023 8:18 AM
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