30 replies to this topic

[Phoebus]

 

We have been looking for ways to turn the splicing factors back on. In our new work, we showed that by treating old cells with a chemical that releases small amounts of hydrogen sulphide, we were able to increase levels of some splicing factors, and to rejuvenate old human cells.

 

Hydrogen sulphide is a molecule that is found naturally in our bodies and has been shown to improve several features of age-related disease in animals. But it can be toxic in large amounts, so we needed to find a way to deliver it directly to the part of the cell where it is needed.

 

By using a “molecular postcode” we have been able to deliver the molecule directly to the mitochondria, the structures that produce energy in cells, where we think it acts, allowing us to use tiny doses, which are less likely to cause side effects.

 

We are hopeful that in using molecular tools such as this, we will be able to eventually remove senescent cells in living people, which may allow us to target multiple age-related diseases at once. This is some way in the future yet, but it’s an exciting start.

 

https://www.universa...rsed-in-the-lab

[Phoebus]

been reading about hydrogen sulfide lately and it has quite a few health benefits 

 

does anyone know if there is a way to increase the body's levels of hydrogen sulfide? 

 

would taking MSM help for instance? 

 

 

"H2S has been gaining increasing attention as an important endogenous signaling molecule because of its significant effects on the cardiovascular and nervous systems," the team writes. The evidence is mounting, they note, that hydrogen sulfide slows aging by inhibiting free-radical reactions, by activating SIRT1, an enzyme believed to be a regulator of lifespan, and probably through its interactions with a gene, klotho, which appears to have its own market basket of anti-aging activity.

 

Hydrogen sulfide is produced within the human body, and has a variety of important physiological effects. For example, it relaxes the vascular endothelium and smooth muscle cells, which is important to maintaining clean arteries as one ages, says first author Zhi-Sheng Jiang, of the University of South China, Hunan. It functions as an antioxidant. And it inhibits expression of pro-inflammatory factors, all of which "imply an important role in aging and age-associated diseases," according to the paper. For example, mice lacking CSE, the gene for an enzyme involved in producing H2S, manifest extensive, premature arteriosclerosis, an inevitable consequence of aging, says Jiang.

 

https://www.scienced...30129121945.htm

[Phoebus]

 

 

http://www.ncbi.nlm....pubmed/23176571

Hydrogen Sulfide Protects Against Cellular Senescence via S-Sulfhydration of Keap1 and Activation of Nrf2.

Yang G, Zhao K, Ju Y, Mani S, Cao Q, Puukila S, Khaper N, Wu L, Wang R.

Cardiovascular and Metabolic Research Unit, Lakehead University , Ontario, Canada .

Abstract Aims: H2S, a third member of gasotransmitter family along with nitric oxide and carbon monoxide, exerts a wide range of cellular and molecular actions in our body. Cystathionine gamma-lyase (CSE) is a major H2S-generating enzyme in our body. Aging at the cellular level, known as cellular senescence, can result from increases in oxidative stress. The aim of this study was to investigate how H2S attenuates oxidative stress and delays cellular senescence. Results: Here we showed that mouse embryonic fibroblasts isolated from CSE knockout mice (CSE KO-MEFs) display increased oxidative stress and accelerated cellular senescence in comparison with MEFs from wild-type mice (WT-MEFs). The protein expression of p53 and p21 was significantly increased in KO-MEFs, and knockdown of p53 or p21 reversed CSE deficiency-induced senescence. Incubation of the cells with NaHS (a H2S donor) significantly increased the glutathione (GSH) level and rescued KO-MEFs from senescence. Nrf2 is a master regulator of the antioxidant response, and Keap1 acts as a negative regulator of Nrf2. NaHS S-sulfhydrated Keap1 at cysteine-151, induced Nrf2 dissociation from Keap1, enhanced Nrf2 nuclear translocation, and stimulated mRNA expression of Nrf2-targeted downstream genes, such as glutamate-cysteine ligase and GSH reductase. Innovation: These results provide a mechanistic insight into how H2S signaling mediates cellular senescence induced by oxidative stressConclusion: H2S protects against cellular aging via S-sulfhydration of Keap1 and Nrf2 activation in association with oxidative stress. Antioxid. Redox Signal. 18, 1906-1919.

so h2s mediates cellular senescence 

 

one way of increasing H2S may be ingesting cysteine 

 

 

Nat Commun. 2013;4:1366. doi: 10.1038/ncomms2371.

A novel pathway for the production of hydrogen sulfide from D-cysteine in mammalian cells.

Shibuya N1, Koike S, Tanaka M, Ishigami-Yuasa M, Kimura Y, Ogasawara Y, Fukui K, Nagahara N, Kimura H.

Author information

 

Abstract

In eukaryotes, hydrogen sulphide acts as a signalling molecule and cytoprotectant. Hydrogen sulphide is known to be produced from L-cysteine by cystathionine β-synthase, cystathionine γ-lyase and 3-mercaptopyruvate sulfurtransferase coupled with cysteine aminotransferase. Here we report an additional biosynthetic pathway for the production of hydrogen sulphide from D-cysteine involving 3-mercaptopyruvate sulfurtransferase and D-amino acid oxidase. Unlike the L-cysteine pathway, this D-cysteine-dependent pathway operates predominantly in the cerebellum and the kidney. Our study reveals that administration of D-cysteine protects primary cultures of cerebellar neurons from oxidative stress induced by hydrogen peroxide and attenuates ischaemia-reperfusion injury in the kidney more than L-cysteine. This study presents a novel pathway of hydrogen sulphide production and provides a new therapeutic approach to deliver hydrogen sulphide to specific tissues.

 

[Rocket]

Interesting, considering it is poisonous. I believe its used in many suicides each year.

[Phoebus]

Interesting, considering it is poisonous. I believe its used in many suicides each year.

 

 

in large amounts yes, but in small amounts AND in the correct biological location its quite useful 

[Adaptogen]

Hydrogen sulfide mediates the vasoactivity of garlic

 

[Phoebus]

Hydrogen sulfide mediates the vasoactivity of garlic

 

 

very interesting!

 

 

 

Here we show that human RBCs convert garlic-derived organic polysulfides into hydrogen sulfide (H2S), an endogenous cardioprotective vascular cell signaling molecule. 

 

I wonder if garlic supplements would work for this 

[XenMan]

A few threads on this subject at the moment, here is one:

 

https://www.longecit...-aging-therapy/

[Acetylnordopatoninol]

https://www.ncbi.nlm...pubmed/21296648

 

The garlic constituent diallyl trisulfide increases the lifespan of C. elegans via skn-1 activation.

 

Powolny AA¹, Singh SV, Melov S, Hubbard A, Fisher AL.

 

Abstract

 

Medicinal benefits of Allium vegetables, such as garlic, have been noted throughout recorded history, including protection against cancer and cardiovascular disease. We now demonstrate that garlic constituent diallyl trisulfide (DATS) increases longevity of Caenorhabditis elegans by affecting the skn-1 pathway. Treatment of worms with 5-10 μM DATS increased worm mean lifespan even when treatment is started during young adulthood. To explore the mechanisms involved in the DATS-mediated increase in longevity, we treated daf-2, daf-16, and eat-2 mutants and found that DATS increased the lifespan of daf-2 and daf-16 mutants, but not the eat-2 mutants. Microarray experiments demonstrated that a number of genes regulated by oxidative stress and the skn-1 transcription factor were also changed by DATS treatment. Consistently, DATS treatment leads to the induction of the skn-1 target gene gst-4, and this induction was dependent on skn-1. We also found that the effects of DATS on worm lifespan depend on skn-1 activity in both in the intestine and ASI neurons. Together our data suggest that DATS is able to increase worm lifespan by enhancing the function of the pro-longevity transcription factor skn-1.

 

 

if it's good enough for C. elegans, it's good enough for me.

Edited by Acetylnordopatoninol, 13 August 2018 - 10:01 PM.

[HighDesertWizard]

2017 - Acetylcholine Activates Cystathionine γ-Lyase Production of H2S in Aortic Endothelial Cells

 

Hydrogen sulfide (H2S) is the most recently described endothelium-derived vasodilator. In the endothelium, H2S is predominantly produced by cystathionine ©-lyase (CSE). We and others have previously shown CSE inhibition diminishes acetylcholine (ACh)-induced dilation in aortic ring segments. However, ACh regulation of CSE is not well-defined. The goal of this study was to identify endogenous regulators of CSE in aortic endothelial cells. Previous reports show that [Ca2+] regulates CSE activity. However, previous studies were conducted using 1–2 mM [Ca2+] and purified CSE. Because normal intracellular [Ca2+] is 100 nM to 3 μM and activity of purified enzymes may not reflect in vivo activity, it is necessary to verify regulation of endogenous CSE with physiological [Ca2+]. Thus, we hypothesized that ACh-induced increases in intracellular [Ca2+] elevates CSE production of H2S. Rat aortic endothelial cells (passage 5–6) were loaded with the H2S fluorescence indicator, sulfide fluor-7 acetoxymethylester (SF7-AM, 10 μM), exposed to either ACh (10 μM), a Ca2+ionophore (ionomycin, 100 nM) or an H2S donor (NaHS, 10 μM). Some cells were pretreated for 30 minutes with the CSE inhibitor, β-cyanoalanine (BCA, 100 μM) and changes in fluorescence recorded (Figure). These findings show that ACh increases CSE production of H2S but this activation may not be Ca2+ dependent since BCA did not reduce ionomycin-induced H2S production. Future studies will investigate Ach-induced Ca2+ signaling, ionomycin regulation of other H2S generating enzymes and Ca2+-independent Ach signaling to further delineate endogenous regulators of CSE activity.

[Phoebus]

. These findings show that ACh increases CSE production of H2S

 

 

awesome, so supplements like Alpha-GPC and phosphatidylserine should in theory raise H2S levels via ACh. 

[Nate-2004]

awesome, so supplements like Alpha-GPC and phosphatidylserine should in theory raise H2S levels via ACh. 

 

Many things raise H2S levels, allicin from aged garlic supps, sulforaphane (broccoli metabolite), possibly more.

[Phoebus]

Many things raise H2S levels, allicin from aged garlic supps, sulforaphane (broccoli metabolite), possibly more.

 

right, the question is, is any of that H2S actually getting into the mito? thats the key sounds like 

[Kalliste]

I have the best supplement experience of all with mitochondrially target antioxidants so this would make sense.

[ryukenden]

Many things raise H2S levels, allicin from aged garlic supps, sulforaphane (broccoli metabolite), possibly more.

Thanks. I have been taking Allicin & garlic supplements for past few months without knowing this.

https://www.hollanda...2000mg-60035859

[Phoebus]

I have the best supplement experience of all with mitochondrially target antioxidants so this would make sense.

 

 

which specific supplements are you referring to? 

[orion22]

this mind sound stupid but can combine something with hydrogen water that comes from hydrogen generator to get the h2s where you want it 

[Kalliste]

which specific supplements are you referring to? 

 

Forum search for MitoQ. It's a bit expensive but it does wonders for me. Waiting with high expectation for SkQ1

[XenMan]

Forum search for MitoQ. It's a bit expensive but it does wonders for me. Waiting with high expectation for SkQ1

 

I would personally stop taking it.

 

The targeted anti‐oxidant MitoQ causes mitochondrial swelling and depolarization in kidney tissue

Esther M. Gottwald et al

 

“MitoQ is an anti‐oxidant that accumulates selectively into mitochondria at very high concentration, including in the kidney in vivo, … we have now shown that MitoQ causes acute mitochondrial swelling and depolarization in PT cells …. These findings suggest that caution should be exercised before using this compound in renal patients.”

 

“In striking contrast to scant reports of toxicity, numerous studies have reported beneficial effects for MitoQ, and we believe there are several potential explanations for this apparent discrepancy. First, many studies have relied on methodologies other than live imaging, and have naturally focused predominantly on alterations in ROS levels, so may have missed off‐target effects on mitochondrial morphology and energization.”

 

“In summary, we have found that MitoQ can cause significant mitochondrial toxicity in kidney tissue independent of anti‐oxidant activity, and in the absence of a decrease in OCR. These surprising findings underline the point that drugs can have unexpected side‐effects independent of their intended mechanism of action, and provide further evidence that live imaging can play an important role in comprehensively phenotyping how mitochondria respond to pharmacological interventions.”

[HighDesertWizard]

2017 - Acetylcholine Activates Cystathionine γ-Lyase Production of H2S in Aortic Endothelial Cells
 
Hydrogen sulfide (H2S) is the most recently described endothelium-derived vasodilator. In the endothelium, H2S is predominantly produced by cystathionine ©-lyase (CSE). We and others have previously shown CSE inhibition diminishes acetylcholine (ACh)-induced dilation in aortic ring segments. However, ACh regulation of CSE is not well-defined. The goal of this study was to identify endogenous regulators of CSE in aortic endothelial cells. Previous reports show that [Ca2+] regulates CSE activity. However, previous studies were conducted using 1–2 mM [Ca2+] and purified CSE. Because normal intracellular [Ca2+] is 100 nM to 3 μM and activity of purified enzymes may not reflect in vivo activity, it is necessary to verify regulation of endogenous CSE with physiological [Ca2+]. Thus, we hypothesized that ACh-induced increases in intracellular [Ca2+] elevates CSE production of H2S. Rat aortic endothelial cells (passage 5–6) were loaded with the H2S fluorescence indicator, sulfide fluor-7 acetoxymethylester (SF7-AM, 10 μM), exposed to either ACh (10 μM), a Ca2+ionophore (ionomycin, 100 nM) or an H2S donor (NaHS, 10 μM). Some cells were pretreated for 30 minutes with the CSE inhibitor, β-cyanoalanine (BCA, 100 μM) and changes in fluorescence recorded (Figure). These findings show that ACh increases CSE production of H2S but this activation may not be Ca2+ dependent since BCA did not reduce ionomycin-induced H2S production. Future studies will investigate Ach-induced Ca2+ signaling, ionomycin regulation of other H2S generating enzymes and Ca2+-independent Ach signaling to further delineate endogenous regulators of CSE activity.

 
 

right, the question is, is any of that H2S actually getting into the mito? thats the key sounds like

 
Instead of fixating on getting H2S into the mito, I suggest focusing on The Emergent Biological Mechanism of Action Evolution, itself, managed to establish in the mito and is implicated in healthy longevity...
 
And, yes, it implicates, both, Acetylcholine and The Inflammatory Reflex...
 

 

--------
 
From...
 
a7 nicotinic acetylcholine receptor signaling inhibits inflammasome activation by preventing mitochondrial DNA release
 

Essential Neuroscience in Immunology

Edited by HighDesertWizard, 18 August 2018 - 02:03 AM.

[Phoebus]

 
 

 
Instead of fixating on getting H2S into the mito, I suggest focusing on The Emergent Biological Mechanism of Action Evolution, itself, managed to establish in the mito and is implicated in healthy longevity...
 
And, yes, it implicates, both, Acetylcholine and The Inflammatory Reflex...
 

 

--------
 
From...
 
a7 nicotinic acetylcholine receptor signaling inhibits inflammasome activation by preventing mitochondrial DNA release
 

Essential Neuroscience in Immunology

 

 

okay...? 

 

what exactly does "focusing on The Emergent Biological Mechanism of Action Evolution" mean? What does that entail? 

 

its vague to me 

[Kalliste]

I would personally stop taking it.

 

The targeted anti‐oxidant MitoQ causes mitochondrial swelling and depolarization in kidney tissue

Esther M. Gottwald et al

 

“MitoQ is an anti‐oxidant that accumulates selectively into mitochondria at very high concentration, including in the kidney in vivo, … we have now shown that MitoQ causes acute mitochondrial swelling and depolarization in PT cells …. These findings suggest that caution should be exercised before using this compound in renal patients.”

 

“In striking contrast to scant reports of toxicity, numerous studies have reported beneficial effects for MitoQ, and we believe there are several potential explanations for this apparent discrepancy. First, many studies have relied on methodologies other than live imaging, and have naturally focused predominantly on alterations in ROS levels, so may have missed off‐target effects on mitochondrial morphology and energization.”

 

“In summary, we have found that MitoQ can cause significant mitochondrial toxicity in kidney tissue independent of anti‐oxidant activity, and in the absence of a decrease in OCR. These surprising findings underline the point that drugs can have unexpected side‐effects independent of their intended mechanism of action, and provide further evidence that live imaging can play an important role in comprehensively phenotyping how mitochondria respond to pharmacological interventions.”

 

 

Greg McPherson gave a fairly Confident reply to that in the MitoQ thread. Tldr MitoQ is protective for kidneys in vivo and in organ storage studies. That was a poor study you refer to.

 

Btw That goes along well with my own feeling of improved kidney function when on MitoQ.

[XenMan]

That was a poor study you refer to.

 

If you think you know better than the authors, and you trust the CEO of the company selling the product to be honest and transparent, more power to you.

 

I'm not sure how improved kidney function feels, but if you have had renal issues and it has improved, shouldn't professional help be sought as well?

 

You have opportunities presented in all parts of life where you can learn, or you can take all your decisions personally and commit to something even when there are genuine concerns raised that contradict them.

 

I hope I'm wrong and there are no health issues from MitoQ for anyone.

[Kalliste]

If you think you know better than the authors, and you trust the CEO of the company selling the product to be honest and transparent, more power to you.

 

I'm not sure how improved kidney function feels, but if you have had renal issues and it has improved, shouldn't professional help be sought as well?

 

You have opportunities presented in all parts of life where you can learn, or you can take all your decisions personally and commit to something even when there are genuine concerns raised that contradict them.

 

I hope I'm wrong and there are no health issues from MitoQ for anyone.

 

I write a diary about my bodily functions. No aspect of them were degraded by MitoQ. Aspects degraded by other products like Curcumin (loss of erotic desires) Rhodiola (felt sick with more than one supplement brand) Coffee (good in some quantity but fucks me up above certain dosage) so lets say I'm not religious about supplements.

Also I do fasting for up to 80 hours which brings more clarity and function than administration of Mitochondrially target antioxidants.

 

I'm not religious about MitoQ, it is expensive and I feel it gives me more (at least noticeable) improvement when cycled. I do believe it might be trouble to administer it every day, everything is probably a problem when administered every day at large dosage. Nature is all about cycles IMHO.

 

Feel the function improve in the sense of wellness when urinating, more appetite for salt, overall feeling of wellness in all stomach region.

 

I'm more worried about mito-antioxidants disrupting Neural Stem Cell pool and such problems.

[eighthman]

Is there any rationale for drinking water with hydrogen sulfide in it?  Because my well water has it and I've become used to its taste, anyway.

[MikeDC]

Too much H2S will kill you. The best way to increase H2S is to take Taurine. Taurine by itself is a very important nutrient. It could also increase H2S effectively. Both Taurine and H2S levels go down with age.

[Rocket]

I've read that taurine declines with age in the eyes of mice. Don't know that it influences h2s. . .

[HighDesertWizard]

2017 - Acetylcholine Activates Cystathionine γ-Lyase Production of H2S in Aortic Endothelial Cells

 

Hydrogen sulfide (H2S) is the most recently described endothelium-derived vasodilator. In the endothelium, H2S is predominantly produced by cystathionine ©-lyase (CSE). We and others have previously shown CSE inhibition diminishes acetylcholine (ACh)-induced dilation in aortic ring segments. However, ACh regulation of CSE is not well-defined. The goal of this study was to identify endogenous regulators of CSE in aortic endothelial cells. Previous reports show that [Ca2+] regulates CSE activity. However, previous studies were conducted using 1–2 mM [Ca2+] and purified CSE. Because normal intracellular [Ca2+] is 100 nM to 3 μM and activity of purified enzymes may not reflect in vivo activity, it is necessary to verify regulation of endogenous CSE with physiological [Ca2+]. Thus, we hypothesized that ACh-induced increases in intracellular [Ca2+] elevates CSE production of H2S. Rat aortic endothelial cells (passage 5–6) were loaded with the H2S fluorescence indicator, sulfide fluor-7 acetoxymethylester (SF7-AM, 10 μM), exposed to either ACh (10 μM), a Ca2+ionophore (ionomycin, 100 nM) or an H2S donor (NaHS, 10 μM). Some cells were pretreated for 30 minutes with the CSE inhibitor, β-cyanoalanine (BCA, 100 μM) and changes in fluorescence recorded (Figure). These findings show that ACh increases CSE production of H2S but this activation may not be Ca2+ dependent since BCA did not reduce ionomycin-induced H2S production. Future studies will investigate Ach-induced Ca2+ signaling, ionomycin regulation of other H2S generating enzymes and Ca2+-independent Ach signaling to further delineate endogenous regulators of CSE activity.

 

 

 
 

 
Instead of fixating on getting H2S into the mito, I suggest focusing on The Emergent Biological Mechanism of Action Evolution, itself, managed to establish in the mito and is implicated in healthy longevity...
 
And, yes, it implicates, both, Acetylcholine and The Inflammatory Reflex...
 

 

--------
 
From...
 
a7 nicotinic acetylcholine receptor signaling inhibits inflammasome activation by preventing mitochondrial DNA release
 

Essential Neuroscience in Immunology

 

 

Too much H2S will kill you. The best way to increase H2S is to take Taurine. Taurine by itself is a very important nutrient. It could also increase H2S effectively. Both Taurine and H2S levels go down with age.

 

 

I've read that taurine declines with age in the eyes of mice. Don't know that it influences h2s. . .

 

The influence of taurine on acetylcholine content and synthesis in rat brain

 

Oh my... I wonder what happens if acetylcholine is increased in humans? Is there a study about it?

Effects of galantamine in a 2-year, randomized, placebo-controlled study in Alzheimer’s disease

They stopped the study after two years because of the statistical variance in the number of elderly dying who were not taking Galantamine, an acetylcholinesterase inhibitor.

 

I suggest... If you focus on learning about the implicated biological mechanism of action (The Inflammatory Reflex) and not on every tom, dick, and harry supplement that triggers the mechanism, you might increase your own survival probability odds.

 

Just sayin'

 

 

[Nate-2004]

I take galantamine regularly at night because one of my gene variants puts me at risk for diminished acetylcholine, plus I love the dreams.

[ta5]

Cell Chem Biol. 2018 Apr 19;25(4):447-459.e4. 

N-Acetyl Cysteine Functions as a Fast-Acting Antioxidant by Triggering Intracellular H2S and Sulfane Sulfur Production.

Ezeriņa D1, Takano Y2, Hanaoka K2, Urano Y2, Dick TP3.

The cysteine prodrug N-acetyl cysteine (NAC) is widely used as a pharmacological antioxidant and cytoprotectant. It has been reported to lower endogenous oxidant levels and to protect cells against a wide range of pro-oxidative insults. As NAC itself is a poor scavenger of oxidants, the molecular mechanisms behind the antioxidative effects of NAC have remained uncertain. Here we show that NAC-derived cysteine is desulfurated to generate hydrogen sulfide, which in turn is oxidized to sulfane sulfur species, predominantly within mitochondria. We provide evidence suggesting the possibility that sulfane sulfur species produced by 3-mercaptopyruvate sulfurtransferase and sulfide:quinone oxidoreductase are the actual mediators of the immediate antioxidative and cytoprotective effects provided by NAC.

PMID: 29429900

 

 

This is a comment on the above study:

 

Cell Chem Biol. 2018 Apr 19;25(4):353-355.

S Marks the Spot: Linking the Antioxidant Activity of N-Acetyl Cysteine to H2S and Sulfane Sulfur Species.

Cerda MM1, Pluth MD2.

N-Acetyl cysteine (NAC) is commonly used as an antioxidant and cytoprotectant, yet a broadly applicable mechanism of these activities has remained elusive. In this issue of Cell Chemical Biology, Ezeriņa et al. (2018) report an alternative mechanism for NAC cytoprotection and antioxidant activity by demonstrating that NAC treatment increases sulfane sulfur production via intermediate H2S generation.

PMID: 29677486

 

There's also this thread: 

Optimizing mitochondrial H2S for TFAM (and NMN/NAD+/SIRT-1)