Functional role of miR-34a in diabetes and frailty

Emerging evidence has shown that microRNAs (miRNAs) play critical role in the pathogenesis of several disorders. In the present minireview, we focus our attention on the functional role of a specific miRNA, namely miR-34a, in the pathophysiology of frailty and diabetes mellitus. Based on the current literature, we speculate that this miRNA may serve as a potential biomarker of frailty in diabetic older adults. Additionally, its actions on oxidative stress might represent a druggable target to obtain new potentials treatments.


Role of miR-34a in frailty and aging
The pathophysiology of frailty includes chronic inflammation, which is prevailing in aging ("inflammaging"), oxidative stress with or without mitochondrial dysfunction, insulin resistance, loss of anabolic hormones, and reduced tolerance to physical exercise with a reduction in muscle strength (Bandeen-Roche et al., 2015;Cruz-Jentoft and Sayer, 2019;Rusanova et al., 2019).
Frailty onset is due to the failure of multiple organs and/or systems and many pathologic conditions have been associated with frailty (Walston et al., 2008;Afilalo et al., 2014;Mone and Pansini, 2020;Mone et al., 2021a;Waite et al., 2021;Mone et al., 2022e). In 2001, Fried et al. (2001) developed the five criteria now routinely used to diagnose frailty. Equally important, the frailty index is another tool to diagnose and manage frailty (Rockwood et al., 2005;Searle et al., 2008).
In 2011, Khanna et al. (2011) observed an age-dependent decreased expression of miR-34a in the brain of calorierestricted mice, mirrored by an increase in Bcl-2 expression, and a reduced expression of pro-apoptosis genes such as Bax. The authors concluded that this miRNA was involved in the neuronal survival in long-lived calorierestricted fed mice.
A subsequent investigation by Zheng and collaborators evidenced the involvement of miR-34a in cellular senescence via MAPK: the authors detected its overexpression in sarcopenia, suggesting a role of this miRNA in the aging process of the skeletal muscle (Zheng et al., 2018). Similarly, miR-34a expression was significantly up-regulated in the hearts of aged mice lacking Calstabin 2, the stabilizing protein of the cardiac isoform of Ryanodine Receptor (Yuan et al., 2014). Another investigation revealed that an increased expression of miR-34a in older rats correlates with a concomitant decrease in the brain of the anti-aging target protein SIRT1 (Hu et al., 2017).
Notably, a clinical paper indicated miR-34a as a biomarker of aging/frailty in oncogeriatric populations (Dalmasso et al., 2018). In line with these observations, a very recent paper evidenced that miR-34 regulates protein translation and protein turnover in the aging brain of Drosophila (Srinivasan et al., 2022).

FIGURE 1
Functional role of miR-34 in frailty, aging, and diabetes.

Conclusion
Herein, we summarized the investigations linking miR-34a and frailty. Furthermore, miR-34 may be linked to diabetes and endothelial dysfunction. Based on the provided evidence, we speculate that this miRNA may serve as a potential biomarker of frailty in diabetic older adults. Additionally, its actions on oxidative stress might represents a druggable target in order to develop new potentials therapeutic options.

Author contributions
Study concept and design: PM and GS. Drafting of the manuscript: PM, AP, and GS. Critical revision of the manuscript for important intellectual content: SJ, FV, UK, and GS. Administrative, technical, or material support: PM, AdD, and AP. Study supervision: PM and GS.

Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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