The regulation of Insulin/IGF-1 signaling by miR-142-3p associated with human longevity

Wang, X.; Jung, H. J.; Milholland, B.; Cui, J.; Tazearslan, C.; Atzmon, G.; Yang, J.; Guo, Q.; Barzilai, N.; Robbins, P. D.; Suh, Y.

doi:10.1101/2023.05.19.541542

bioRxiv · 10.1101/2023.05.19.541542

The regulation of Insulin/IGF-1 signaling by miR-142-3p associated with human longevity

Wang, X.·Jung, H. J.·Milholland, B.·Cui, J.·Tazearslan, C.·Atzmon, G.·Yang, J.·Guo, Q.·Barzilai, N.·Robbins, P. D.·Suh, Y.

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Abstract

MicroRNAs (miRNAs) have been demonstrated to modulate life span in the invertebrates C. elegans and Drosophila by targeting conserved pathways of aging, such as insulin/IGF-1 signaling (IIS). However, a role for miRNAs in modulating human longevity has not been fully explored. Here we investigated novel roles of miRNAs as a major epigenetic component of exceptional longevity in humans. By profiling the miRNAs in B-cells from Ashkenazi Jewish centenarians and 70-year-old controls without a longevity history, we found that the majority of differentially expressed miRNAs were upregulated in centenarians and predicted to modulate the IIS pathway. Notably, decreased IIS activity was found in B cells from centenarians who harbored these upregulated miRNAs. miR-142-3p, the top upregulated miRNA, was verified to dampen the IIS pathway by targeting multiple genes including GNB2, AKT1S1, RHEB and FURIN. Overexpression of miR-142-3p improved the stress resistance under genotoxicity and induced the impairment of cell cycle progression in IMR90 cells. Furthermore, mice injected with a miR-142-3p mimic showed reduced IIS signaling and improved longevity-associated phenotypes including enhanced stress resistance, improved diet/aging-induced glucose intolerance, and longevity-associated change of metabolic profile. These data suggest that miR-142-3p is involved in human longevity through regulating IIS-mediated pro-longevity effects. This study provides strong support for the use of miR-142-3p as a novel therapeutic to promote longevity or prevent aging/aging-related diseases in human.

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Wang, X., Jung, H. J., Milholland, B., Cui, J., Tazearslan, C., Atzmon, G., Yang, J., Guo, Q., Barzilai, N., Robbins, P. D., Suh, Y.. 2023-05-20. The regulation of Insulin/IGF-1 signaling by miR-142-3p associated with human longevity. https://doi.org/10.1101/2023.05.19.541542

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