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Small animal live longer when ROS is stopped

ros redox

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#1 Kalliste

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Posted 15 March 2015 - 06:25 PM


This is interesting with re to mitochondrial antioxidans with broad functionality:

AbstractSend to:

J Gerontol A Biol Sci Med Sci. 2014 Sep 4. pii: glu160. [Epub ahead of print]

Redox-Based Flagging of the Global Network of Oxidative Stress Greatly Promotes Longevity.

Canistro D1, Boccia C2, Falconi R2, Bonamassa B3, Valgimigli L4, Vivarelli F5, Soleti A5, Genova ML6, Lenaz G6, Sapone A5, Zaccanti F2, Abdel-Rahman SZ7, Paolini M5.

Author information

Abstract

Despite more than 50 years of investigations into the free radical theory, the direct role of oxidative stress (OS) in aging and age-related diseases remains unproven. Little progress in identifying antioxidant drugs promoting longevity has been made, likely due to selectivity toward one or few radical species, variable efficacy in vivo, inherent pro-oxidant behavior of such drugs, or lack of synergism with metabolic redox homeostasis. Silencing the wide range of reactive free radicals has a great impact on OS-linked outcomes and age-related disorders. Here we show that an innovative, redox-active, multi-radical-scavenger catalytic drug delays the age-associated decline in physiological processes and markedly prolongs the mean lifespan of the adult freshwater annelids Aeolosoma viride by 170%. This unprecedented extension is associated with a decreased OS status. Consistently, treatment of annelids increases their natural resistance to oxygen-derived damage without affecting mitochondrial respiration or reproductive activity. Conversely, the superoxide dismutase (SOD)-mimetic EUK 134 that we selected as a positive control led to an increase in lifespan of ~50%, the same increase previously observed in nematodes. Our results show that reduction of the global network of OS has a profound impact on aging, prompting the development of a possible redox-based therapeutic intervention to counteract the progression of aging.

© The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

KEYWORDS:

Longevity; Oxidative stress

PMID: 25190068 [PubMed - as supplied by publisher]

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#2 corb

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Posted 15 March 2015 - 07:18 PM

That's almost triple lifespan. Wow.

It's in a worm but it's still pretty impressive.
If they can translate even a quarter of this into humans, it'd still be incredible news.

 



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#3 pone11

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Posted 15 March 2015 - 07:56 PM

The text "Here we show that an innovative, redox-active, multi-radical-scavenger catalytic drug...." sounds like a line from marketing literature, not a study.   Very strange description to see in a scientific abstract.

 

Can you post a link to full text, and what was the actual substance being studied?



#4 niner

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Posted 15 March 2015 - 08:22 PM

Cool article.  I wonder why we missed it for so long?  It's in worms, so maybe that's it.  They got a large life extension with a compound that consists of two mostly-hydrophobic nitroxide spin traps esterified to a 10-carbon diacid.  It's a little bit like c60oo, in that you have a catalytic antioxidant linked to a long hydrophobic chain.
 
Here is the part I found interesting:
 

Concentrations both below and slightly
above this optimum concentration showed shorter exten-
sions, whereas 10-time higher concentrations caused
toxicity and drastically reduced lifespan, compared to con-
trols.


What if this were the case with C60oo? No one has done dose-ranging experiments looking for an optimal dose. If you're megadosing, it might be worth getting a redox stress panel.



#5 corb

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Posted 15 March 2015 - 08:25 PM

The text "Here we show that an innovative, redox-active, multi-radical-scavenger catalytic drug...." sounds like a line from marketing literature

 

edit: Whoops my mistake.
I guess that's just how they write for that magazine.


Edited by corb, 15 March 2015 - 08:30 PM.


#6 niner

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Posted 15 March 2015 - 08:31 PM

Why can't I attach a pdf to a post?  Is this a new feature?  I got the full text from the usual friendly neighborhood heroes of citizen science / masters of copyright violation, and didn't want to post a link.  Trying to fly under the radar.


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#7 corb

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Posted 15 March 2015 - 08:41 PM

Why can't I attach a pdf to a post?  Is this a new feature?  I got the full text from the usual friendly neighborhood heroes of citizen science / masters of copyright violation, and didn't want to post a link.  Trying to fly under the radar.

 

Can't you upload it to something like docdroid, then just post the direct link?



#8 pone11

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Posted 15 March 2015 - 10:12 PM

I think posting a link is probably the most straightforward thing since we only used a search engine to find it:

http://biomedgeronto...na.glu160.short

 

I only find the antioxidant IAC referenced as an antioxidant one other place in the literature:

http://www.ncbi.nlm....les/PMC2915424/

 

Can anyone tell us if IAC is available commercially, and is it over the counter?



#9 pone11

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Posted 15 March 2015 - 10:54 PM

Some interesting parts from the study:

 

"Unlike conventional antioxidants, IAC has an additional action: upon quenching ROS, it becomes super-activated, turning from a hydroxylamine to a nitroxide—an even more potent and catalytic antioxidant.  Hence, its antioxidant behavior is modulated by redox homeostasis."

 

As @niner points out, the dose response is extremely dramatic.  See Table 1 in the study.   I am really shocked that the antioxidant would have such a narrow range of benefit, and it does make you wonder about whether C60 will be shown to have a similar dose response.   It's very scary that people here are taking megadoses of C60.   This study result is cautionary.   It's fantastic that the researcher was thoughtful enough to test at so many concentrations.   I'm surprised they didn't try combining IAC and the other substance used in controls to see if there were synergies.

 

"To further validate our hypothesis, we also measured whether exposure of annelids to IAC affects mitochondrial respiration (ie, energy supply). The growth of zooids in the presence of 1.25 µM IAC did not show any significant effect on the rate of cyanide-sensitive oxygen consumption as compared to untreated zooids (9.24 vs 8.95 pmoles O2 · s¢ · 10¢ animals, respectively; Figure 2A). The marked life-span extension produced by the multi-radical scavenger in A viride could be due to its ability to counteract overall oxidative stress while not causing an impairment of oxidative phosphorylation, differently from caloric restriction mimetic agents (30), including some antioxidants (31)."

 


Edited by pone11, 15 March 2015 - 10:56 PM.


#10 Kalliste

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Posted 16 March 2015 - 05:39 AM

The idea that you need to target all the radical species to get a change is alluring. That is usually the kind of multifactorial logic that biological mess responds well to. Of course my mind was brought to C60 but I didn't want to post in that forum.

 

I have been searching for SOD-mimetics and other similar terms. One that stood out at me was a substance called EUK-<insert number here>.

 

http://www.ncbi.nlm....pubmed/18569084

 

 

EUK-189, a salen-manganese complex and superoxide dismutase/catalase mimetic, was administered subcutaneously (sc; 30 or 70 mg/kg) to mice at - 24, - 1, +1, or +6 h relative to whole-body cobalt-60 gamma irradiation (LD(90/30) dose), and survival was monitored for 30 days. Cell counts and cytokines in circulation were measured in sublethally irradiated mice treated with EUK-189. EUK-189 (70 mg/kg, - 24 h) enhanced 30-day survival with a dose reduction factor (DRF) of 1.15 (p = 0.047, 95% confidence limits: 1.053, 1.244). LD(50/30)s were 7.96 and 9.13 Gy for saline- and EUK-189-treated groups, respectively. Drug treatment was associated with elevations in numbers of total white blood cells, eosinophils, lymphocytes, and platelets in irradiated mice, compared to vehicle-injected, irradiated controls. EUK-189 did not stimulate production of any cytokine or chemokine tested.

 


Edited by Cosmicalstorm, 16 March 2015 - 05:42 AM.


#11 Kalliste

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Posted 16 March 2015 - 05:43 AM

Another one:

 

 

Significant In Vivo Anti-Inflammatory Activity of Pytren4Q-Mn a Superoxide Dismutase 2 (SOD2) Mimetic Scorpiand-Like Mn (II) Complex.
Abstract
BACKGROUND:

The clinical use of purified SOD enzymes has strong limitations due to their large molecular size, high production cost and immunogenicity. These limitations could be compensated by using instead synthetic SOD mimetic compounds of low molecular weight.

BACKGROUND/METHODOLOGY:

We have recently reported that two SOD mimetic compounds, the MnII complexes of the polyamines Pytren2Q and Pytren4Q, displayed high antioxidant activity in bacteria and yeast. Since frequently molecules with antioxidant properties or free-radical scavengers also have anti-inflammatory properties we have assessed the anti-inflammatory potential of Pytren2Q and Pytren4Q MnII complexes, in cultured macrophages and in a murine model of inflammation, by measuring the degree of protection they could provide against the cellular injury produced by lipopolisacharide, a bacterial endotoxin.

PRINCIPAL FINDINGS:

In this report we show that the MnII complex of Pytren4Q but not that of Pytren2Q effectively protected human cultured THP-1 macrophages and whole mice from the inflammatory effects produced by LPS. These results obtained with two molecules that are isomers highlight the importance of gathering experimental data from animal models of disease in assessing the potential of candidate molecules.

CONCLUSION/SIGNIFICANCE:

The effective anti-inflammatory activity of the MnII complex of Pytren4Q in addition to its low toxicity, water solubility and ease of production would suggest it is worth taking into consideration for future pharmacological studies.

http://www.ncbi.nlm....pubmed/25742129



#12 pone11

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Posted 16 March 2015 - 06:33 AM

Another one:

 

 

Significant In Vivo Anti-Inflammatory Activity of Pytren4Q-Mn a Superoxide Dismutase 2 (SOD2) Mimetic Scorpiand-Like Mn (II) Complex.
Abstract
BACKGROUND:

The clinical use of purified SOD enzymes has strong limitations due to their large molecular size, high production cost and immunogenicity. These limitations could be compensated by using instead synthetic SOD mimetic compounds of low molecular weight.

BACKGROUND/METHODOLOGY:

We have recently reported that two SOD mimetic compounds, the MnII complexes of the polyamines Pytren2Q and Pytren4Q, displayed high antioxidant activity in bacteria and yeast. Since frequently molecules with antioxidant properties or free-radical scavengers also have anti-inflammatory properties we have assessed the anti-inflammatory potential of Pytren2Q and Pytren4Q MnII complexes, in cultured macrophages and in a murine model of inflammation, by measuring the degree of protection they could provide against the cellular injury produced by lipopolisacharide, a bacterial endotoxin.

PRINCIPAL FINDINGS:

In this report we show that the MnII complex of Pytren4Q but not that of Pytren2Q effectively protected human cultured THP-1 macrophages and whole mice from the inflammatory effects produced by LPS. These results obtained with two molecules that are isomers highlight the importance of gathering experimental data from animal models of disease in assessing the potential of candidate molecules.

CONCLUSION/SIGNIFICANCE:

The effective anti-inflammatory activity of the MnII complex of Pytren4Q in addition to its low toxicity, water solubility and ease of production would suggest it is worth taking into consideration for future pharmacological studies.

http://www.ncbi.nlm....pubmed/25742129

 

Antioxidants and SOD mimetics have such a poor track record that I think people should demand studies that show significant life extension before they bother taking these.  It's not enough to show significant antioxidant activity.   

 

Probably this thread should be steered back to talking about IAC, which is the antioxidant you originally posted about.



#13 pone11

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Posted 18 March 2015 - 10:00 AM

I contacted the researcher on the originally posted study, and she confirmed that their group is the only one studying IAC.

 

I asked if they would study this in mice, and she said they are waiting on funding.   Wow, that doesn't surprise me because:

http://www.longecity...e-7#entry719305



#14 Kalliste

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Posted 18 March 2015 - 10:47 AM

Tell her to contact the Chinese government and suggest this as a prophylactic agent for pollution related health problems :)

 

 

Abstract

The objectives of this study were to determine whether differences in the size and composition of coarse (2.5-10 micro m), fine (< 2.5 microm), and ultrafine (< 0.1 microm) particulate matter (PM) are related to their uptake in macrophages and epithelial cells and their ability to induce oxidative stress. The premise for this study is the increasing awareness that various PM components induce pulmonary inflammation through the generation of oxidative stress. Coarse, fine, and ultrafine particles (UFPs) were collected by ambient particle concentrators in the Los Angeles basin in California and used to study their chemical composition in parallel with assays for generation of reactive oxygen species (ROS) and ability to induce oxidative stress in macrophages and epithelial cells. UFPs were most potent toward inducing cellular heme oxygenase-1 (HO-1) expression and depleting intracellular glutathione. HO-1 expression, a sensitive marker for oxidative stress, is directly correlated with the high organic carbon and polycyclic aromatic hydrocarbon (PAH) content of UFPs. The dithiothreitol (DTT) assay, a quantitative measure of in vitro ROS formation, was correlated with PAH content and HO-1 expression. UFPs also had the highest ROS activity in the DTT assay. Because the small size of UFPs allows better tissue penetration, we used electron microscopy to study subcellular localization. UFPs and, to a lesser extent, fine particles, localize in mitochondria, where they induce major structural damage. This may contribute to oxidative stress. Our studies demonstrate that the increased biological potency of UFPs is related to the content of redox cycling organic chemicals and their ability to damage mitochondria.

 



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#15 Brainbox

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Posted 01 April 2015 - 01:15 AM

 

This is very interesting indeed.It kind of sheds some light on controversial results with antioxidant activity wrt. LE..

 

But I have some basic questions.

 

170% lifespan increase wrt. the laboratory controls is dramatic indeed. But how is the lab control group related to a real-life 'control group'? Diet-wise or lifespan-wise? Is it known how long these worms live in a normal natural habitat?

 

Wrt. extrapolating this result to humans, which is to premature to think about anyway, raises some fundamental questions regarding dosing and delivery methods of such a substance. Given the very narrow effective concentration bandwidth, would it even be possible to realize the required concentration throughout all the important area's of the human body with one single intake dose? Or to put this backwards, wouldn't this require an enormously complicated or localized delivery system to assure correct concentration in all the relevant body area's? E.g. a hypothetical simple oral intake for an optimal brain concentration would overwhelm the digestive tract with the stuff resulting in a very healthy brain with no box.

 

From a pure technical perspective this all is very interesting, but for humans probably diversity in antioxidant activity is key.

 

?

 

Corrected typo's


Edited by Brainbox, 01 April 2015 - 01:20 AM.






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