20 replies to this topic

[Michael]

All:

Cross-posting this from the Methuselah Foundation Forums, to stop people from hearing about this elsewhere and running out to take a black-market, potentially fatal drug ...

Calorie restriction is the most effective non-genetic intervention to enhance life span known to date. A major research interest has been the development of therapeutic strategies capable of promoting the beneficial results of this dietary regimen.

In this sense, we propose that compounds that decrease the efficiency of energy conversion, such as mitochondrial uncouplers, can be caloric restriction mimetics.

Treatment of mice with low doses of the protonophore 2,4-dinitrophenol promotes enhanced tissue respiratory rates, improved serological glucose, triglyceride and insulin levels, decrease of reactive oxygen species levels and tissue DNA and protein oxidation, as well as reduced body weight [and occasionally kills people from thermogenic fever -MR].

Importantly, dinitrophenol-treated animals also presented enhanced longevity. [Importantly, this is nonsense -- see below -MR]

Our results demonstrate that mild mitochondrial uncoupling is a highly effective in vivo antioxidant strategy, and describe the first therapeutic intervention capable of effectively reproducing the physiological, metabolic and life span effects of caloric restriction in healthy mammals. (1)

Well, first, lots of other therapeutic interventions have reproduced some of the physiological and metabolic effects of CR; the question is whether a given agent reproduces the important ones (the ones responsible for retarding the aging process). Unfortunately, we still don't know quite what those effects are ...

On the longevity claim: this is just 'the usual nonsense': ALL the animals were short-lived, and those that got DNP lived a little longer, but still not nearly as long as a normal, healthy, well-husbanded, non-genetically-messed-up mouse (which will on av'g live ~900 days) (2). In this study, "Median longevity in the control group was 722 days, versus 771 days in the DNP group, while mean lifespan was 718.8 days in the control and 769.7 days in the treated group. Although the change in life span promoted by DNP was not large, it is statistically significant (p = 0.038). " . And there was no extension of maximum LS at all, even compared to the short-lived controls; extension of max LS is the very essence of the CR life extension effect, which is exactly what marks it as the sole genuine anti-aging intervention validated in mammals to date)

The human analogy would be a study in which you took a bunch of people , put half of them on a dangerous drug for their entire lives, and at the end of the study the average control lived just 67 years (rather than 82, you'd expect from a random sample of the USA) -- but look! People taking the drug lived to be 70! It's a miracle anti-aging drug!!

What happened? I note that "Food intake was also equal in both groups (Fig. 1c), while DNP-treated animals presented significantly lower body mass (Fig. 1d)"; I'm going to GUESS that they just let the mice eat themselves into obesity, and DNP partially corrected for the ensuing metabolic mayhem.

The conclusion is not that DNP is an anti-aging drug; the conclusion is tht DNP can help some sick mice, and these folks need to learn to take better care of them.

-Michael

1. Caldeira da Silva CC, Cerqueira FM, Barbosa LF, Medeiros MH, Kowaltowski AJ.
Mild Mitochondrial Uncoupling in Mice Affects Energy Metabolism, Redox Balance and Longevity.
Aging Cell. 2008 May 23. [Epub ahead of print]
PMID: 18505478

2. Miller RA, Harper JM, Dysko RC, Durkee SJ, Austad SN.
Longer life spans and delayed maturation in wild-derived mice.
Exp Biol Med (Maywood). 2002 Jul;227(7):500-8.
PMID: 12094015

[Sasuke]

2,4-DNP is being used for longevity these days? I was surprised enough that it is being marketed as a fat burner.

I also recommend staying away from 2,4-dinitrophenol. Some additional info on it:

• It was first noticed in France prior to World War I when it was being used in arms manufacturing. I'm not sure how, but at some point they decided to ingest it and "recognized that it stimulated cellular metabolism".
• It was tested as a fat burner in the early 1900s, but discontinued usage due to health concerns, such as the rapid formation of cataracts (that part I saw on the 2,4-dintrophenol wikipedia article).
• Peter Mitchell used 2,4-DNP to confirm his theory on the way ATP is generated (via proton motive force driving ATPase), winning the nobel prize. He used 2,4-DNP to "decouple" the proton gradient between the mitochondrial matrix and inner membrane, which halted the production of ATP. The energy from metabolism that was no longer powering the proton motive force was released as heat.
• Some animals use decouplers similar to 2,4-DNP to increase body temperature.
• 2,4-DNP and similar decouplers were made into highly effective pesticides.

I guess that shows the difference in how some people think Some people see something that disrupts the vital oxidative-phosphorylation ATP producing process as a way to kill living things, others see it as a fat burner, or a way to increase lonvevity...

I'm not sure why 2,4-DNP led to rapid cataract formation, since I don't know much about that process. I do take it as a clear warning sign, along with its use as a pesticide. I am wary that it will cause to long term damage, and unfortunately, possibly damage that will be hard to directly attribute to 2,4-DNP.

Since the decoupling is interfering with a vitally important function, and doing so in a unspecific way throughout the body, any damage that it causes is probably not going to be predicable, in general. I find this somewhat analogous to a fever. A fever also leads to the disruption of vitally important functions in an unspecific way (having your bodies enzymes be out of their functional temperature ranges). As a result, there are not highly specific results for some fevers; fevers of the same temperature will produce a very wide range of results: from something that is unnoticed a day later, to death!

Based on the observations of human use of decouplers, it probably is not that drastic, or we would have found out by now. The wikipedia article says that death by increased temperature will occur before any death by ATP deprivation.

Given that some people on this site seem to be into so-called nootropic substances that increase ATP levels in the brain, the ATP reduction from decouplers is a huge reason to stay away.

Here is a paper on the history of 2,4-DNP: Dinitrophenol and bioenergetics: a historical perspective, by John Parascandola.

Edited by Sasuke, 01 June 2008 - 08:24 PM.

[inawe]

This thread is about the new paper with the abstract at PMID: 18505478. It describes work done in order to understand on what pathways Calory Restriction (CR) manages to attain health benefits. Most of us are familiar with how by claiming a connection between resveratrol and CR Sinclair and his Sirtris gang managed to make millions of dollars. Resveratrol acts on several pathways but it's hard to argue that it is a CR mimetic.

When I saw the abstract of PMID:18505478 by a Brazilian group I searched for the complete paper. Contrary to what some critics say, the paper doesn't recommend the human use of DNA. The authors search for a route to the development of true CR mimetics.

From the paper: "In all, preventing mitochondrial generation of ROS by uncoupling may be a far more effective antioxidant strategy than attempting to remove these species by supplementing antioxidants. Indeed, although antioxidant supplementation effectively decreases oxidative stress under pathological conditions and/or dietary limitations, there is little evidence of any effectiveness under physiological conditions (Møller & Loft, 2006, Hwang & Bowen, 2007). On the other hand, we show here that in vivo uncoupling (Fig 2c-e), similarly to caloric restriction (Sohal & Weindruch, 1996, Merry, 2004), has a marked effect preventing physiological oxidative modifications to proteins and DNA. Our results thus demonstrate that chronic systemic mitochondrial uncoupling is a highly effective antioxidant strategy. In addition to improving redox state, DNP treatment presented a positive effect on energy metabolism. Animals presented lower glucose and insulin levels, and significantly reduced serum triglycerides (Fig. 3).

These changes are most probably a result of the decreased efficiency of energy conversion, leading to higher catabolic fluxes. Interestingly, similar effects are observed in animals submitted to caloric restriction, which exhibit mitochondria with higher proton leaks (Lambert & Merry, 2004). The reasons for this effect are not easily understood, since uncoupling further hampers energy metabolism in animals with limited access to calories. It is possible that the resulting increase in metabolic rates compensates for the decrease in efficiency (Nisoli et al., 2005, Guarente, 2008). Indeed, the occurrence of mitochondrial biogenesis under these conditions may help compensate for the decrease in efficiency of ATP production by enhancing the number of functional respiratory chains (Lambert et al., 2004; Nisoli et al., 2005). Irrespective of the reason for this uncoupling, it involves hormonal signalling, since infusion of insulin into calorie-restricted animals reverses uncoupling (Lambert & Merry, 2004). Lower insulin levels in calorie restricted animals may induce nitric oxide synthase (Nisoli et al., 2005) and increase uncoupling protein expression (Nisoli et al., 2003). Interestingly, nitric oxide increases promoted by caloric restriction also promote mitochondrial biogenesis (Nisoli et al., 2005). In all, literature data strongly support the concept that calorie restriction is accompanied by insulin and nitric-oxide signalled enhancement in respiratory rates. Overall, our results indicate that increased respiration and oxidative phosphorylation inefficiency are central modulators of the beneficial effects of calorie restriction, since the mitochondrial uncoupler DNP acts as a highly effective calorie restriction mimetic."

Edited by Michael, 02 October 2012 - 12:37 AM.

[niner]

I found this on Wikipedia, in their reference desk archive.

DNP was definitely used as a diet pill. I was just not sure if it was still on the market. Some more research shows that it was banned by the FDA in 1938. Quotes from the following paper Obesity Part 2:Pharmacotherapy by David E Oeser, Pharm.D. are as follows:
"Dinitrophenol (2,4-DNP) was introduced in 1933 for the treatment of obesity and soon found its way into numerous “anti-fat” patent medicines (Tainter et al. 1933). Dintrophenols induce weight loss by uncoupling oxidative phosphorylation, thereby markedly increasing the metabolic rate and body temperature. However, the use of these compounds was abandoned in 1937 because of reports of severe intoxications and deaths. Dinitrophenol is used currently as a wood preservative and insecticide. Tainter ML, Stockton AB, Cutting WC. Use of dinitrophenol in obesity and related conditions JAMA 1933;101:1472-5. "

DNP is structurally similar to dinitrochlorobenzene, which will cause immunosensitization like the poison ivy toxin. Even if DNP did this just a little bit, that would be a plausible explanation for the fevers, intoxications, and deaths. It doesn't sound like something that you would want to ingest. It's also very likely to be explosive...

[inawe]

"unlike any other part of the cell, mitochondria have their own DNA (mtDNA), separate from the nucleus. Being at the site of cellular respiration, the mtDNA is vulnerable to its reactive by-products. Worse yet, the mitochondria's capacity for repairing DNA damage is much more limited than that of the nucleus. Thus we need a different system to combat the inevitable accumulation of such mutations." Does this sound familiar? Yeah, it's from SENS.org.

Being the power plants of the cells, more ROS are generated in the mitochondria than in other parts. And "the mitochondria's capacity for repairing DNA damage is much more limited than that of the nucleus" (de Grey). So what's the solution? Give de Grey 100 million dollars a year for 10 years to see if he can figure out how to locate mtDNA in the nucleos (good luck). Others meanwhile are studying alternatives. Like what happens if the mitochondria power generation is disrupted and the cell is forced to produce energy elsewhere. Then, the mitochondria are less stressed by ROS and can last longer. DNP is the easiest uncoupler to use in mice right now but there are others. What about the toxicity? From the paper: "Here, we used doses 10-100 times lower than those used therapeutically in the past, and over 1000 times lower than the lethal dose for mice."

As for the results: "In addition to improving redox state, DNP treatment presented a positive effect on energy metabolism. Animals presented lower glucose and insulin levels, and significantly reduced serum triglycerides".

Aren't the authors of this paper aware of the problems with DNP? Of course they are: "Although the notoriety and toxicity of DNP still precludes its direct clinical use, we believe modifications of DNP, use of uncouplers with very controlled and mild effects (Lou et al., 2007) or the use of drugs targeting natural mitochondrial mild uncoupling pathways, including uncoupling proteins (Nègre-Salvayre et al., 1997, Ricquier & Bouillaud, 2000) and ATP-sensitive K+ channels (Kowaltowski et al., 2001, Ferranti et al., 2003), will prove useful in controlling redox state, triglyceride levels, glycemia, insulinemia and life span."

Edited by Michael, 02 October 2012 - 12:45 AM.

[edward]

I first read about DNP in Muscle Media 2000 in the 90's (a very interesting liberal publication, that coincidentally introduced me to the Life Extension Foundation, Nootropics and eventually Life Extension in general) when I was a in highschool. It was being used as a hardcore thermogenic fat burner that through mitochondrial uncoupling effectively wasted energy, raising the body temperature measurably. One had to be very careful not to take to much and basically cook yourself. Sounded way to extreme for me and the biological mechanism to my uneducated mind at the time seemed a little scary and well rough on the body. I am surprised to see it being discussed here, but I can see the logic behind low doses.

[mike250]

ah yes DNP, the god of all weight loss drugs. But....the free radicals generated and the mechanism by which it works makes it a bad deal IMO--and I have done it a fair amount once upon a time. Anything that shunts the ATP process is just bad mojo even though it is only done short term and the normal ATP cycle continues once the drug is fully metabolized.

That being said, there really isn't a good reason to use it unless you are an

A) competitive bodybuilder
B) have to get lean REALLY quick.

[treonsverdery]

I heard about dinitrophenol from an old book; I think this is a thrilling molecule

first: I read a reputable reference to a study where dietary nitrite ion (no2) reduced cardiac ischemia harm near 40 pt The nitro groups of dinitrophenol are different but think

second: this is a tiny molecule, just attaching a Se associated group could keep it on the body side of the blood brain barrier reducing cognitive risk; se has various advantages

third: any medication that shunts across the atp cycle has deep implication with cryopreservation; atp shunting to my thinking resembles hibernation at the organ level

fourth: dmso penetrates; dinitrophenol with sulfoxide moiety might also creating a spot reducer hint: beauty grail

[treonsverdery]

here is an item describing dinitrophenol as a potential therapeutic agent against Alzheimer's disease

Cyclic AMP enhancers and Abeta oligomerization blockers as potential therapeutic agents in Alzheimer's disease.De Felice FG, Wasilewska-Sampaio AP, Barbosa AC, Gomes FC, Klein WL, Ferreira ST.
Instituto de Bioquímica Médica, Programa de Bioquímica e Biofísica Celular, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil. felice@bioqmed.ufrj.br

One of the earliest manifestations of Alzheimer's disease (AD) is the characteristic inability of affected individuals to form new memories. Memory impairment appears to significantly predate the death of nerve cells, implying that neuronal dysfunction is responsible for the pathophysiology of early stage AD. Mounting evidence now indicates that soluble oligomers of the amyloid-beta peptide (Abeta) are the main neurotoxins that lead to early neuronal dysfunction and memory deficits in AD. Cyclic AMP (cAMP) is a central component of intracellular signaling pathways that regulate a wide range of biological functions, including memory. Among other actions, cAMP triggers the phosphorylation and activation of the cAMP responsive element binding protein (CREB), a transcription factor that regulates the expression of genes that are important for long-term memory. Here, we discuss recent evidence suggesting that cAMP enhancing compounds may find applications as neurocognitive enhancers in AD and in other neurological disorders, as well as possible roles of cAMP in the regulation of neuronal regeneration. In particular, we review recent results showing that low concentrations of 2,4-dinitrophenol (DNP) upregulate neuronal cAMP and tau levels, promote neurite outgrowth and neuronal differentiation and block the oligomerization and neurotoxicity of Abeta. Possible implications of these findings in the development of novel therapeutic approaches in AD are discussed.

I think that swimmers or bodysurfers might like a version of this that is crafted to be cardio beneficial as well as cognitive beneficial; pleasant ocean swimming with greater latitude thermoregulation

[unbreakable]

I think Dinitrophenol-2,4 is a pretty dangerous drug. It has killed a lot of Bodybuilders (its' very easy to overdose because of the long half
-life / duration of action and the narrow "therapeutic window"). For people who speak German:

http://www.team-andr...dybuilding.html
http://www.focus.de/...aid_133170.html

Taking Dinitrophenol in medium doses would not kill somebody in the short term, but it would drastically increase oxidative stress IMHO.

Edited by unbreakable, 12 June 2008 - 11:13 AM.

[mike250]

I used 100-200mg of that stuff.

[unbreakable]

That's a pretty "safe" dose for short time use, bodybuilders take more (up to 800mg or in worst case a dosage that induces multi organ failure, which has high mortality rates even in ICU). But also low doses used for longer periods of time could be dangerous because of accumulation.

If somebody wants to loose weight, then he should eat healthy and exercise ;-). If it must be drugs, then keep in mind that the FDA approved meds orlistat, silbutramine and rimonabant only give modest, but still significant results.

Wikipedia:

In order to circumvent the number of feedback mechanisms that prevent most monotherapies from producing sustained large amounts of weight loss, it has been hypothesized that combinations of drugs may be more effective by targeting multiple pathways and possibly inhibiting feedback pathways that work to cause a plateau in weight loss. This was evidenced by the success of the combination of phentermine and fenfluramine or dexfenfluramine, popularly referred to phen-fen, in producing significant weight loss but fenfluramine and dexfenfluramine were pulled from the market due to safety fears regarding a potential link to heart valve damage. The damage was found to be a result of activity of fenfluramine and dexfenfluramine at the 5-HT2B serotonin receptor in heart valves. Newer combinations of SSRIs and phentermine, known as phenpro, have been used with equal efficiency as fenphen with no known heart valve damage due to lack of activity at this particular serotonin receptor due to SSRIs. There has been a recent resurgence in combination therapy clinical development with the development of 3 combinations: Qnexa (topiramate + phentermine), Excalia (bupropion + zonisamide) and Contrave (bupropion + naltrexone).[

[edward]

Michael,

Do you have the full text of that article if so could you post it in the members section, I put in a request for it here:
http://www.imminst.o...nce-t22585.html

Caldeira da Silva CC, Cerqueira FM, Barbosa LF, Medeiros MH, Kowaltowski AJ.
Mild Mitochondrial Uncoupling in Mice Affects Energy Metabolism, Redox Balance and Longevity.
Aging Cell. 2008 May 23. [Epub ahead of print]
PMID: 18505478
http://dx.doi.org/10...26.2008.00407.x

Edited by edward, 14 June 2008 - 06:26 AM.

[gn1tmac]

DNP= DO NOT PARTICIPATE ****VERY BAD STUFF!****


it messes with a whole slew of liver microsomal and mito cytochrome P450s thru PXR and CAR nuclear receptors - the primary steroid and xenobiotic drug metabolism activators. But worse, it effects RXR and FXR, the retinoid and bile acid nuclear receptors. It causes problems with a certain P450 compound that is necessary for bile production and the safety mechanism (sulfonation and glucaration) that keeps bile acids from being exceptionally corrosive and damaging to liver and gallbladder. DNP is chauffered out of the body by binding to glutathione. Its sucks it out of liver and it activates drug detox mechanisms once glutathione is depleted you are left with ROS causing all sorts of damage and possibly forming DNA adducts The p450 cytochrome system is in the mitochondria, and where ATP is formed, as well as where the majority of drug detoxification occurs. This system is interrupted under DNP as you disrupt the electron transport chain... ATP is not produced, and the production of GSH is distrupted

DNP is a nuclear receptor regulator.

DNP and nuclear receptors: how you short circuit BA buffering
http://toxsci.oxford...t/full/67/2/182

Fuck up of bile acid release: how you are self propagating BA
secretion by turning on FXR

Oxysterol 22®-hydroxycholesterol induces the expression of the bile salt export pump through nuclear receptor farsenoid X receptor but not liver X receptor. Deng R, Yang D, Yang J, Yan B. J Pharmacol Exp Ther. 2006 Apr;317(1):317-25.

Oxysterols are intermediates in the synthesis of bile acids and steroid hormones from cholesterol and function as ligands for liver X receptor (LXR). Bile salt export pump (BSEP) is responsible for canalicular secretion of bile acids and is tightly regulated by its substrates bile acids through nuclear receptor farnesoid X receptor (FXR). In a microarray study using human hepatocytes, BSEP was markedly induced not only by chenodeoxycholic acid (CDCA) but also by oxysterol 22®-hydroxycholesterol [22®-OHC].
We hypothesized that the expression of BSEP was induced by oxysterols through activation of LXR. To test the hypothesis, human primary hepatocytes or hepatoma cells were treated with 22®-OHC, and expression of BSEP was determined. The level of BSEP mRNA was increased as much as 5-fold upon oxysterol induction. In contrast to our hypothesis, the oxysterol-induced up-regulation of BSEP is mediated through FXR but not LXR. BSEP promoter activity was markedly induced by 22®-OHC in the presence of FXR but not LXRs. Mutation of the FXR element IR1 in the BSEP promoter significantly reduced its ability to respond to oxysterol induction. To determine whether 22®-OHC and CDCA bind to similar structural features of FXR, site-directed mutagenesis was performed in the FXR ligand binding domain. Mutation of residues R331 and I352 abolished activation mediated by CDCA and 22®-OHC. In contrast, substitution of residues L340 and R351 differentiated CDCA- and 22®-OHC-mediated activation. In conclusion, oxysterol 22®-OHC functions as an FXR ligand to induce BSEP expression and differs in the binding with FXR from CDCA.

Nuclear receptors and their inteactions - dietary considerations Nuclear Receptors and Lipid Physiology: Opening the X-Files

http://www.sciencema...t/294/5548/1866

Edited by Michael, 02 October 2012 - 12:47 AM.

[krillin]

Confirmation that uncoupling doesn't slow aging.

Cell Metab. 2007 Dec;6(6):497-505.
Respiratory uncoupling in skeletal muscle delays death and diminishes age-related disease.
Gates AC, Bernal-Mizrachi C, Chinault SL, Feng C, Schneider JG, Coleman T, Malone JP, Townsend RR, Chakravarthy MV, Semenkovich CF.
Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.

Age-related disease, not aging per se, causes most morbidity in older humans. Here we report that skeletal muscle respiratory uncoupling due to UCP1 expression diminishes age-related disease in three mouse models. In a longevity study, median survival was increased in UCP mice (animals with skeletal muscle-specific UCP1 expression), and lymphoma was detected less frequently in UCP female mice. In apoE null mice, a vascular disease model, diet-induced atherosclerosis was decreased in UCP animals. In agouti yellow mice, a genetic obesity model, diabetes and hypertension were reversed by induction of UCP1 in skeletal muscle. Uncoupled mice had decreased adiposity, increased temperature and metabolic rate, elevated muscle SIRT and AMP kinase, and serum characterized by increased adiponectin and decreased IGF-1 and fibrinogen. Accelerating metabolism in skeletal muscle does not appear to impact aging but may delay age-related disease.

PMID: 18054318

[inawe]

Aubrey de Grey doesn't think Calorie Restriction (CR) will do much in extending human life. I humbly agree with that. On the other hand,
more than a few researchers keep banging on the CR drum. They get grants from proposals to find CR mimetics.
Nobody knows for sure how CR does whatever it's suppose to do. One of the hypothesis relies
in partial decoupling (or uncoupling). That's the reason for the recent papers dealing with this issue.
As for the PMID:18054318 paper the title states: "Respiratory uncoupling in skeletal muscle delays death and diminishes age-related disease". Why would anybody prefer
to emphasize "Accelerating metabolism in skeletal muscle does not appear to impact aging but may delay age-related disease" instead?
How are we supposed to understand this? Aging through disease leads to death. If uncoupling delays disease but not death, what do the mice
die from? Boredom? Or are some cats around?

[krillin]

As for the PMID:18054318 paper the title states: "Respiratory uncoupling in skeletal muscle delays death and diminishes age-related disease". Why would anybody prefer
to emphasize "Accelerating metabolism in skeletal muscle does not appear to impact aging but may delay age-related disease" instead?
How are we supposed to understand this? Aging through disease leads to death. If uncoupling delays disease but not death, what do the mice
die from? Boredom? Or are some cats around?

You already know the answer to this and are just trolling, but I'll answer anyway. We already have loads of things with better risk profiles than DNP that square the longevity curve. (Increase mean but not maximum lifespan.) The only thing that will excite us is something that shifts the curve to the right. (Increases both mean and maximum lifespan.)

[inawe]

As for the PMID:18054318 paper the title states: "Respiratory uncoupling in skeletal muscle delays death and diminishes age-related disease". Why would anybody prefer
to emphasize "Accelerating metabolism in skeletal muscle does not appear to impact aging but may delay age-related disease" instead?
How are we supposed to understand this? Aging through disease leads to death. If uncoupling delays disease but not death, what do the mice
die from? Boredom? Or are some cats around?

You already know the answer to this and are just trolling, but I'll answer anyway. We already have loads of things with better risk profiles than DNP that square the longevity curve. (Increase mean but not maximum lifespan.) The only thing that will excite us is something that shifts the curve to the right. (Increases both mean and maximum lifespan.)

Wow! "trolling". Is that the best you could come up with?
This thread started as a critic by Michael of a paper, the purpose of which he didn't understand. It's obvious you didn't understand it either.
Once again, in the paper being criticized, the researchers described how they used 2,4-dinitrophenol in mice to see if that can replicate some CR effects. They didn't recommend it's use by humans.
As for the for considering something that "square the longevity curve", many people would accept it until something better comes along. Except for somebody who already is obviously square.
As usual go ahead and have the last word.

[krillin]

Wow! "trolling". Is that the best you could come up with?
This thread started as a critic by Michael of a paper, the purpose of which he didn't understand. It's obvious you didn't understand it either.
Once again, in the paper being criticized, the researchers described how they used 2,4-dinitrophenol in mice to see if that can replicate some CR effects. They didn't recommend it's use by humans.
As for the for considering something that "square the longevity curve", many people would accept it until something better comes along. Except for somebody who already is obviously square.
As usual go ahead and have the last word.

You were trolling. You clearly understand the concept of curve-squaring, but in that post you were pretending not to.

Michael’s understanding of the paper’s purpose was spot-on. Look at this part of the abstract

Our results demonstrate that mild mitochondrial uncoupling is a highly effective in vivo antioxidant strategy, and describe the first therapeutic intervention capable of effectively reproducing the physiological, metabolic and life span effects of caloric restriction in healthy mammals.

Note how they said "the physiological, metabolic and life span effects" and not "some of the effects". For that to be true, maximum lifespan would have to have been increased. It wasn't. They're just a bunch of con men trying to fool people into thinking that they discovered a CR mimetic.

[edDe]

Hi All,

I've just read an interesting article on Ouroboros :

http://ouroboros.wor...ie-restriction/

Which references the abstract :

http://www3.intersci...750652/abstract

Has anyone access to the article, and can summarize the highlights ? The
study looks interesting. But is it just another study with a badly looked after,
short-lived strain of mice ?

The article claims that DNP might be another possible CR mimetic (though it looks
like risky stuff to take). It seems that DNP is taken by body builders (I've never
heard of it - but I'm not a body builder - I'm a CR-er ). Has anyone run across
this supplement?

Thanks,

edDe.

[edward]

There is a big thread on this, its kind of hard to find so many haven't seen it I guess

http://www.imminst.o...p;hl=uncoupling

Michael did a pretty complete job showing how this was not a true life extension effect but rather a curve squaring effect. Short lived mice lived longer because some of the things that made them short lived were overcome by DNP.

Basically this could translate into humans using DNP or other uncoupling agents to prevent some of the diseases of aging (in particular metabolic syndrome, obesity, diabetes type II related) thus allowing "short lived humans" to live a normal lifespan, but not allow normal or long lived humans to live any longer.

Still as I think Niner mentioned many people need a little curve squaring... But DNP will never be available for open use as overdose is very easy and of course fatal, you basically cook yourself. Now.... sane low dosage long term on the other hand, well I'm not going to touch this one any further....

edit: horrendous speling n' gramur issues, couldn't ignore.

edit: was going to change this because I thought I posted in the wrong place but nope the threads were merged

Edited by edward, 02 November 2008 - 05:07 AM.