Hydralazine targets cAMP-dependent protein kinase leading to sirtuin1/5 activation and lifespan extension in C. elegans

Esmaeil Dehghan (), Mohammad Goodarzi, Bahar Saremi, Rueyling Lin and Hamid Mirzaei ()
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Esmaeil Dehghan: UT Southwestern Medical Center
Mohammad Goodarzi: UT Southwestern Medical Center
Bahar Saremi: University of Texas at Arlington and University of Texas Southwestern Medical Center Joint Biomedical Engineering Program
Rueyling Lin: UT Southwestern Medical Center
Hamid Mirzaei: UT Southwestern Medical Center

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract Therapeutic activation of mitochondrial function has been suggested as an effective strategy to combat aging. Hydralazine is an FDA-approved drug used in the treatment of hypertension, heart failure and cancer. Hydralazine has been recently shown to promote lifespan in C. elegans, rotifer and yeast through a mechanism which has remained elusive. Here we report cAMP-dependent protein kinase (PKA) as the direct target of hydralazine. Using in vitro and in vivo models, we demonstrate a mechanism in which binding and stabilization of a catalytic subunit of PKA by hydralazine lead to improved mitochondrial function and metabolic homeostasis via the SIRT1/SIRT5 axis, which underlies hydralazine’s prolongevity and stress resistance benefits. Hydralazine also protects mitochondrial metabolism and function resulting in restoration of health and lifespan in C. elegans under high glucose and other stress conditions. Our data also provide new insights into the mechanism(s) that explain various other known beneficial effects of hydralazine.

Date: 2019
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DOI: 10.1038/s41467-019-12425-w

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