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Questioning the free radical theory of aging


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#1 Ethan

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Posted 03 December 2008 - 01:04 PM


<H1 class=story>Antioxidants Are Unlikely To Prevent Aging, Study Suggests</H1>ScienceDaily (Dec. 2, 2008) — Diets and beauty products which claim to have anti-oxidant properties are unlikely to prevent aging, according to research funded by the Wellcome Trust. Researchers at the Institute of Healthy aging at UCL (University College London) say this is because a key fifty year old theory about the causes of aging is wrong.

"Superoxide" free radicals – oxygen molecules that have an imbalance of electrons to protons – are generated in the body through natural processes such as metabolism. These free radicals can cause oxidation in the body, analogous to rust when iron is exposed to oxygen. Biological systems, such as the human body, are usually able to restrict or repair this damage.

In 1956, Denham Harman proposed the theory that aging is caused by an accumulation of molecular damage caused by "oxidative stress", the action of reactive forms of oxygen, such as superoxide, on cells. This theory has dominated the field of aging research for over fifty years. But now, a study published online today in the journal Genes & Development suggests that this theory is probably incorrect and that superoxide is not a major cause of aging.

"The fact is that we don't understand much about the fundamental mechanisms of aging," says Dr David Gems from UCL. "The free radical theory of aging has filled a knowledge vacuum for over fifty years now, but it just doesn't stand up to the evidence."

Dr Gems and colleagues at the Institute of Healthy aging studied the action of key genes involved in removing superoxide from the bodies of the nematode worm C. elegans, a commonly-used model for research into aging. By manipulating these genes, they were able to control the worm's ability to "mop up" surplus superoxide and limit potential damage caused by oxidation.

Contrary to the result predicted by the free radical theory of aging, the researchers found that the lifespan of the worm was relatively unaffected by its ability to tackle the surplus superoxide. The findings, combined with similar recent findings from the University of Texas using mice, imply that this theory is incorrect.

"One of the hallmarks of aging is the accumulation of molecular damage, but what causes this damage?" says Dr Gems. "It's clear that if superoxide is involved, it only plays a small part in the story. Oxidative damage is clearly not a universal, major driver of the aging process. Other factors, such as chemical reactions involving sugars in our body, clearly play a role."

Dr Gems believes the study suggests that anti-aging products which claim to have anti-oxidant properties are unlikely to have any effect.

"A healthy, balanced diet is very important for reducing the risk of developing many diseases associated with old age, such as cancer, diabetes and osteoporosis," he says. "But there is no clear evidence that dietary antioxidants can slow or prevent aging. There is even less evidence to support the claims of most anti-aging products."

The research was welcomed by Dr Alan Schafer, Head of Molecular and Physiological Sciences at the Wellcome Trust.

"With increasing lifespan comes greater exposure and vulnerability to the aging process," comments Dr Schafer. "Research such as this points to how much we have to learn about aging, and the importance of understanding the mechanisms behind this process. This new study will encourage researchers to explore new avenues in aging research."

#2 dehook

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Posted 04 May 2009 - 03:36 PM

hi,

my interest in biochemistry and ageing theories is a recent one so my knowledge is limited, but after browsing through the posts on this forum, i am surprised to see how many people are advocating the use of antioxidants and demonizing free radicals for causing ageing. from my understanding of the scientific literature i cannot believe this to be true. for example -

* caloric restriction still remains the best method of slowing the ageing process, yet Leonard Guarente has clearly demonstrated that respiration increases during CR, therefore there will be more free radicals, not less.

* all the classical measures of oxidative stress are higher in the naked mole rat, yet they exhibit exceptional longevity with no functional declines in any system

* Removal of the worms' (Caenorhabditis elegans) reproductive systems had a dramatic effect - the worms' life span increased by 60%. There are likely many pathways associated with this increase, but remember that castration in humans has been proven to increase a significant pro-oxidant state in the body - again contrary to the free radical theory.

* oxidation is our main defence against disease. there is so much evidence that i do not know where to begin. why would we want to work against our bodies natural capacity to heal itself by ingesting antioxidants?

* antioxidant studies have been poor, very few have shown any benefit and some have even shown an increase in cancer, heart disease, etc. the one antioxidant that has shown considerable promise is vitamin c, but remember that vitamin c is also a powerful pro-oxidant and this is likely the reason for its benefits.

i could go on, but there is a lot of evidence proving that ageing seems to be linked to a decrease in cellular O2 consumption. i have never seen any evidence that our antioxidant defences fail with age, is there any?

mutations/deletions in mitochondrial dna are clearly involved in ageng, but is this really due to an increase in free radicals? inflammation seems to be a major player, and exactly why it is so damaging to our bodies could hold the key. but maybe inflammation rises precisely because our levels of O2 consumption decrease as we age, therefore the body compensates for this by increasing inflammation?

if anyone could shed some light on this i'd appreciate it, and remember that my knowledge is limited at the moment so go easy on me :)

Edited by dehook, 04 May 2009 - 03:42 PM.


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#3 VictorBjoerk

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Posted 04 May 2009 - 04:05 PM

antioxidants has never been proven to extend maximum lifespan of healthy animals. This has been repeated many times on this forum.

Free radicals are necessary for different functions in the body,the immune system needs free radicals as you said.

I suggest that you buy and read the book Ending Aging if you are interested in gerontology/extending life/understanding aging,

mutations in mitochondrial DNA is involved in aging as you mentioned, I suggest that you should read about de Grey's "reductive hotspot hypothesis"

The defective mitochondria creates a lot of free radicals which causes oxidative stress which increases the more you age, the increase in free radicals causes more damage of cellular components in the body etc...so aging is something that goes faster the longer you live. There is more difference between a 70-year-old and 80-year old than a 20-year old and a 30-year old.

Edited by VictorBjoerk, 04 May 2009 - 04:05 PM.


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#4 dehook

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Posted 04 May 2009 - 05:12 PM

The defective mitochondria creates a lot of free radicals which causes oxidative stress which increases the more you age, the increase in free radicals causes more damage of cellular components in the body etc...

don't studies show that mitochondrial DNA suffered as much or more mutagenic changes as did nuclear DNA? the free radical theory overlooks the obvious critique that even anaerobes age. everything ages, including diamonds, albeit very slowly.

so aging is something that goes faster the longer you live.

I remember reading that later in life living organisms experience a decline in the rate of aging. I have looked for studies but can't find any.

#5 Mind

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Posted 04 May 2009 - 05:27 PM

After reading many discussion here, (layman speaking here) I have also drifted away from the free-radical theory of aging as one of the root causes. Malfunctioning mitos late in life cranking out above normal free radicals can certainly cause damage (as well as other processes that produce free radicals), but trying to neutralize free radicals with aggressive use of supplements/creams/what-not does not seem like an effective strategy, only a band-aid approach.

A longer discussion about some new ideas on aging.

#6 dehook

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Posted 04 May 2009 - 11:13 PM

After reading many discussion here, (layman speaking here) I have also drifted away from the free-radical theory of again as one of the root causes. Malfunctioning mitos late in life cranking out above normal free radicals can certainly cause damage (as well as other processes that produce free radicals), but trying to neutralize free radicals with aggressive use of supplements/creams/what-not does not seem like an effective strategy, only a band-aid approach.

A longer discussion about some new ideas on aging.

I agree, more research continues to show that aging is due to specific genetic changes and not accumulated damage. Case in point, last year when Edward Tobinick administered an anti-inflammatory drug into the brains of Alzheimer's patients via injection into neck veins, and observed an almost immediate recovery of memory in his patients. Therefore the brains of alzheimer patients are likely intact and alzheimers is not an inevitable consequence of accumulated cell death, it is the inflammation that intereferes with the transmission of neurotransmitters across the gap between brain cells that impairs memory. High levels of oxygen (EMODs) and low levels of antioxidant enzymes are the normal conditions in the brain from early age through adulthood and should result in early onset of Alzheimer's disease or other neurodegenerative diseases(Huntington's, ALS and prion disorders), but it does not. Another blow to the free radical theory.

Edited by dehook, 04 May 2009 - 11:31 PM.


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#7 Mind

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Posted 04 May 2009 - 11:33 PM

I still think repairing damage is a useful approach for rejuvenation, if you consider damage & junk as well as gene mutations and epigenetic mutations as "damage". Accumulated damage/junk does cause pathology and does cause death. There are many types of junk/plaques that would be nice to get rid of and no doubt the body would run more efficiently. Still there could be more powerful genetic regulatory pathways we could tweak. We just don't have all the knowledge or tools to test it out yet.

#8 VidX

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Posted 08 May 2009 - 01:41 PM

I agree, more research continues to show that aging is due to specific genetic changes and not accumulated damage.

- I wouldn't agree, as there really aren't much of a data on that (that would prove it). Genetic changes probably ARE a major cause of decline, though I don't think it's the cause by itself. More and more I start to think about a "simple" entropy, which takes place after puberty (as the energy directed towards preservation of body goes to reproductive goals, and as many times said - selective pressure dissapears). I guess it may be tiny bits of "goes wrong" type of occurences in cellular level that accumulate (like that "misrepair" of a "Novel theory of ageing") and as errors accumulate - all the destruction fastens up. 

 Though there must be some "patterns" of what goes wrong over time, we need to find 'em out (some are pretty obvious at thjis moment.. pieces of the puzzle). It's important to find out what upregulates/downregulates during childhood and puberty and why is that so. Maybe there's a way to induce that upregulation... 



And as you mentioned - everything ages, so I doubt very very strolgly that there's some "ageing" program in genes. Much more possible would be a natural entropy and the loss of the "balance" in a system becasue of small fluctuations which add up over lifetime.

#9 dehook

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Posted 09 May 2009 - 03:22 PM

there must be some "patterns" of what goes wrong over time, we need to find 'em out (some are pretty obvious at thjis moment.. pieces of the puzzle). It's important to find out what upregulates/downregulates during childhood and puberty and why is that so. Maybe there's a way to induce that upregulation...

Yeah - what we don't have yet, thanks to the stupidity of the researchers, is a genetic profile of youth compared with an aging state.

Maybe a better way of defining ageing is "specific genetic changes that determine how well your body responds to accumulated damage". Clearly some things accumulate with age (misfolded proteins, etc) and play a major part, as those who started caloric restriction earlier in life are almost always younger on the outside (as well as inside), but those who start CR in their 50s for example can still benefit immensely but the biological clock is not turned back much. I think the importance of AGEs is overblown, at least the results from ALT-711 so far aren't anything special.

Edited by dehook, 09 May 2009 - 03:28 PM.


#10 Mind

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Posted 10 May 2009 - 02:53 PM

And as you mentioned - everything ages, so I doubt very very strolgly that there's some "ageing" program in genes. Much more possible would be a natural entropy and the loss of the "balance" in a system becasue of small fluctuations which add up over lifetime.


Not everything ages, or at least a few species of plants and animals show no known signs of aging, or at the very least they age so slowly that we cannot perceive how they age.

Ageless animals.

No signs of aging in bristlecone pine trees.

#11 VidX

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Posted 10 May 2009 - 09:05 PM

Yes, that was an overgeneralization. The genetic specifics of these ageless creatures should be one of the primary targets. 

#12 TianZi

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Posted 26 May 2009 - 03:24 AM

Yes, that was an overgeneralization. The genetic specifics of these ageless creatures should be one of the primary targets. 


This was a study using worms. Worms and people are very different.

I find more interesting the recent study published this year finding that the telomeres of human beings (not worms) were 5.2% longer in those people who regularly took a simple multivitamin versus those who didn't.

If there are many root causes of aging which are at best only tangentially linked to one another, then dealing with only one of them is unlikely to appreciably extend maximum lifespan.

#13 brokenportal

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Posted 18 May 2010 - 08:15 PM

So, where does the free radical theory of aging jive with sens? Isnt the free radical theory pretty much just one of the symptoms of the 7 sources of damage production that sens addresses?

#14 Trevor

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Posted 01 August 2010 - 07:17 PM

Mice that are genetically engineered not to produce SOD die within a few days amidst massive free radical oxidation.

http://www.nature.co...ng1295-376.html

The free radical theory may not be the end all of aging, but it is certainly a major factor.

#15 brokenportal

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Posted 01 August 2010 - 07:29 PM

Can somebody tell me what used to be considered the smoking gun for the free radical theory? I heard this recently but couldnt catch exactly what they meant the smoking gun was.

#16 aLurker

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Posted 01 August 2010 - 11:58 PM

antioxidants has never been proven to extend maximum lifespan of healthy animals. This has been repeated many times on this forum.

I'm not disputing this claim. Although I want to mention that Deprenyl can extend maximum lifespan of healthy animals and that this might be through antioxidant enzyme activities. I don't personally know of any other explanation on how Deprenyl otherwise would achieve this lifespan extension but I'm listening.

There are numerous sources on this, here is one:
(-)Deprenyl has been reported to prolong the life span of different animal species. Further, the drug effectively increases antioxidant enzyme activities such as superoxide dismutase (SOD) and catalase (CAT) in brain dopaminergic regions.

#17 Logan

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Posted 03 August 2010 - 07:23 PM

antioxidants has never been proven to extend maximum lifespan of healthy animals. This has been repeated many times on this forum.

I'm not disputing this claim. Although I want to mention that Deprenyl can extend maximum lifespan of healthy animals and that this might be through antioxidant enzyme activities. I don't personally know of any other explanation on how Deprenyl otherwise would achieve this lifespan extension but I'm listening.

There are numerous sources on this, here is one:
(-)Deprenyl has been reported to prolong the life span of different animal species. Further, the drug effectively increases antioxidant enzyme activities such as superoxide dismutase (SOD) and catalase (CAT) in brain dopaminergic regions.


One other reason may be that deprenyl inhibits that breakdown of MAO B, acting as a powerful neuroprotective agent and helping to prevent the breakdown of dopamine, the neurotransmitter that most drastically drops off with age.

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#18 aLurker

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Posted 03 August 2010 - 11:31 PM

One other reason may be that deprenyl inhibits that breakdown of MAO B, acting as a powerful neuroprotective agent and helping to prevent the breakdown of dopamine, the neurotransmitter that most drastically drops off with age.


Yes, interesting thought. You are totally correct about the effects of Deprenyl and that dopamine drops off with age. I didn't mention this because I'm personally unsure about the relationship between dopamine and the ageing process. Decreased levels of dopamine could merely be a symptom of ageing and if so just keeping the dopamine levels higher alone wouldn't increase lifespan. You could be on to something though, hard to tell if increased dopamine might play a part.




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