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

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.

Quercetin Attenuates Trauma-Induced Heterotopic Ossification by Tuning Immune Cell Infiltration and Related Inflammatory Insult

“…Sirtuin 1 (SIRT1) is a conserved nicotinamide adenosine dinucleotide (NAD)-dependent mammalian protein deacetylase with diverse biological functions. SIRT1 is generally delineated to perform functions in aging, metabolism and the cell cycle (18)(19)(20). In recent years, an increasing number of researchers have also reported that SIRT1 can coordinate inflammatory signaling and be viewed as a seminal target for immune microenvironment modulation.…”

Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure

“… 172–174 Hydralazine up-regulates both AMPK and SIRT1, and thus, prolongs longevity in model organisms. 175 Digitalis glycosides induce autophagy (potentially by activating AMPK), 176 but they also activate Akt, which may limit the positive inotropic effect of these drugs. 177–180 The effect of cardiac resynchronization to effect reverse remodelling is accompanied by activation of autophagic flux and improvement in mitochondrial function.…”

Sirtuins, Mitochondria and the Melatonergic Pathway in Alzheimer&rsquo;s Disease<strong> </strong>

“…There is some evidence to indicate that SIRT5 may compensate the loss of SIRT3 in mitochondria in sepsis models [39], suggesting impacts on mitochondria modulation of immune responses. Anti-ageing type effects driven by SIRT1 and nuclear factor erythroid 2-related factor (Nrf)2 in C. Elegans involve SIRT5 activation [40], paralleling the effects of SIRT1 in the deacetylation and activation of mitochondria-located SIRT3. The suppression of SIRT5 attenuates mitochondrial ATP production, as well as promoting AMP-activated protein kinase (AMPK) activation when under energy stress [41].…”