Hydralazine extends C. elegans lifespan

#1

Nuclear factor (erythroid-derived 2)-like 2 and its Caenorhabditis elegans ortholog, SKN-1, are transcription factors that have a pivotal role in the oxidative stress response, cellular homeostasis, and organismal lifespan. Similar to other defense systems, the NRF2-mediated stress response is compromised in aging and neurodegenerative diseases. Here, we report that the FDA approved drug hydralazine is a bona fide activator of the NRF2/SKN-1 signaling pathway. We demonstrate that hydralazine extends healthy lifespan (~25%) in wild type and tauopathy model C. elegans at least as effectively as other anti-aging compounds, such as curcumin and metformin. We show that hydralazine-mediated lifespan extension is SKN-1 dependent, with a mechanism most likely mimicking calorie restriction. Using both in vitro and in vivo models, we go on to demonstrate that hydralazine has neuroprotective properties against endogenous and exogenous stressors. Our data suggest that hydralazine may be a viable candidate for the treatment of age-related disorders.

https://www.nature.com/articles/s41467-017-02394-3

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.

https://www.nature.com/articles/s41467-019-12425-w

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#2

And the ITP is testing it already in mice, which is good to know… Suggestions for ITP drugs to test - #98 by RapAdmin

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#3

I’ve just sponsored Hydralazine with Ora Biomedical to see if we can replicate the findings.

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#4

The strategy of repurposing FDA-approved drugs has significantly contributed to new therapy development. Hydralazine, first synthesized in the 1940s, was initially recognized as a potent vasodilator for treating hypertension. In the 1980s, hydralazine was repurposed for heart failure treatment, and, in the 2000s, found application in cancer epigenetic therapy.

Consideration of hydralazine as a possible anti-aging drug has been stimulated by data showing effects on molecular pathways associated with longevity. In C. elegans , hydralazine has been shown to extend lifespan by activating NRF2/SKN-1 signaling and by enhancing mitochondrial function via sirtuin activation

HYD was detected in each of 8 female mice (6.2 ± 1.5 ng/ml), but only 2 of 6 tested males had measurable HYD, with a detection limit of 5 ng/ml. Hydralazine (HYD) was evaluated in two independent cohorts, one of which got HYD from 6 months, and the other from 16 months of age.

We also failed to detect any lifespan benefit from NEBI, DNP, or HYD. It is possible that one or more of these agents might have led to increased lifespan using a different protocol, for example, at a different dose, starting at a different age, or with treatment restricted to some age interval, although the most plausible interpretation is that none of these agents can slow mouse aging. Both DNP and NEBI were detected in the plasma of every mouse tested in an initial pilot experiment; NEBI levels were higher in males than in females. HYD was detected in each of 8 female mice in a pilot group, but in only 2 of 6 pilot males; it is possible that a higher dose might have reached therapeutic levels more consistently in both sexes.

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#5

If you’re going to take it, I would think a bedtime dose as sedation is primary side effect.

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#6

In vitro, hydralazine did not inhibit DNMT activity. Instead, hydralazine inhibited ERK pathway signaling, thereby decreasing DNMT1 and DNMT3a mRNA expression and DNMT enzyme activity similar to mitogen-activated protein kinase kinase (MEK) inhibitors. Inhibiting T cell ERK pathway signaling with an MEK inhibitor was sufficient to induce anti–double-stranded DNA antibodies in a murine model of drug-induced lupus, similar to the effect of hydralazine.