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Hydralazine targets cAMP-dependent protein kinase leading to sirtuin1/5 activation and lifespan extension in C. elegans
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Hydralazine targets cAMP-dependent protein kinase leading to sirtuin1/5 activation and lifespan extension in C. elegans
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Journal Article
Hydralazine targets cAMP-dependent protein kinase leading to sirtuin1/5 activation and lifespan extension in C. elegans
2019
Overview
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.
Hydralazine is a drug used in the treatment of heart failure and cancer, and it has recently been shown to promote lifespan in
C. elegans
. Here, the authors elucidate the mechanism of action of hydralazine, and show that it targets PKA to promote mitochondrial function via Sirtuin1/5.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/31
/ 64/11
/ 82/1
/ 82/58
/ Aging
/ Animals
/ Caenorhabditis elegans - drug effects
/ Caenorhabditis elegans - genetics
/ Caenorhabditis elegans - growth & development
/ Caenorhabditis elegans - metabolism
/ Caenorhabditis elegans Proteins - genetics
/ Caenorhabditis elegans Proteins - metabolism
/ Cyclic AMP-Dependent Protein Kinases - genetics
/ Cyclic AMP-Dependent Protein Kinases - metabolism
/ Female
/ Humanities and Social Sciences
/ Humans
/ Hydralazine - administration & dosage
/ Kinases
/ Male
/ Proteins
/ Science
/ Worms
/ Yeast
