Free radicals and aging

Brian Rowley browley at UNIXG.UBC.CA
Wed Jul 10 16:36:59 EST 1996

According to Richard Cutler, antioxidant supplementation can suppress 
production of endogenous antioxidant enzymes like SOD, etc. Darned 
homeostatic response. The ideal is to find antioxidants that increase the 
body's NET mop-up of extraneous free radicals; i.e., ones that mop up 
deleterious free radicals better than they suppress endogenous free radicals.

I've heard that different antioxidants act in different compartments
(glutatione in water soluble environments, vitamin E in fat soluble
environments). If a particular antioxidant is limited to certain
compartments of the body but not others, the obvious suggestion is to use
a combination of antioxidants. However, evident is required before this
can be justified. A good experiment would be to do an experiment with
different groups of mice: group 1 is given placebo, group 2 is given
antioxidant A, group 3 is given antioxidant B and group 4 is given
antioxidant A and antioxidant B. It would be interesting if there was
synergy among different antioxidants with regards to longevity benefits. 

The other thing to think about is that rodents have a greatly inferior
antioxidant system to humans. Our blood is almost saturated with uric acid
(sometimes it crystalizes in the joints to cause gout). We also do not
produce our own vitamin C, unlike most rodents. It turns out that uric
acid is a greatly superior antioxidant to vitamin C, or so I've heard.
Vitamin C, in really high doses, actually increases free radicals, so I
have also heard. So we humans perhaps traded vitamin C for uric acid
somewhere along the way for that particular antioxidant niche, giving us
greater longevity. And humans produce more SOD per gram of tissue when
corrected for metabolic rate. What I'm trying to say is that just because
antioxidants increase life expectancy of rodents by 30% does not
necessarily imply that they will do the same for people. We have such a
good system already, there is less to improve on. Something to consider
anyway :->

  On 10 Jul 1996 EdKrug at wrote:

> Hello David Cassarino
>      In answer to your question, presented below, threre are three points I
> want to bring up for consideration.
>      1.  Free radical scavangers may reduce but they do not eliminate totally
> free radicals residing outside of tightly coupled reactions.  In a lab here
> at the Univ. of  Colorado Health Sciences Center has been measuring in vitro
> free radical damage as evidenced in the accumulation of lipofuscin-like
> material.  He has been able to reduce the rate of accumulation by no more
> than about 30% with all the interventions permitted in vitro.  Applying this
> concept to the whole organism it becomes relavant to ask "What percentage of
> the free radical damage is prevented by antioxidants?"   
>      2.  Point one above is too simplistic in that even single cell organisms
> consist of many compartments from which free radicals can be generated and in
> which damage can accumulate.  Additionally, the different free radical
> scavangers do not necessarly distribute uniformly throughout the whole
> organism.  The cataloging of all the sources of free radicals and there
> relative contribution to the total burden needs to be achieved, first in the
> steady state and then the acute conditions with elevated free radical
> generation, such as exhaustive exercise.    As an aside, would the levels of
> antioxidants adequate in steady state life still be adequate in conditions of
> elevated free radical generation?   I am afraid that there is much yet to be
> done before we even know if the whole question has been asked, let alone
> answered.
>      3.  Free radicals are undoubtedly important but, in the evolution of
> increasingly complex organisms the systems which limited life span in one
> system may not have been abandoned or resolved as that organism evolved into
> a different species.  Since Nature is the ultimate concervative it is
> probable that some of the limitations of life span in earlier species are
> still active in later ones.  Add to that the new threats to life span faced
> by the later species and you have a many layer problem.  Consequently the I
> suggest that we are not looking at an "either/or" situation but an "and"
> situation.  We have:
>       -accumulation of free radical damage
>       -loss of cell numbers due to reaching their Hayflick number or
> teleomere depletion
>       -accumulation of simple wear and tear with "not just like new" type
> repair
>       -completion of the growth clock with a subsequent decline in growth
> hormones and thymus activity
>       -completion of the reproductive clock with concomitant loss of
> reproductive hormones
>        -steady and episotic accumulation of nonenzymatic glycosylation of
>  multiple targets
>        -gross abuse of the organism with poor choices in present time such as
> excesses in food, alcohol, fat, smoking and more
>       -irreversable "hits" taken from just living, such as intake of heavy
> metals, chlorinated organic compounds, uv irridation and probably more.
>      That is to say that achieving a fruit fly with ten times normal life
> span should provide information useful for humans, humans have additional
> life span limiting circumstances not faced by the fruit fly.  
>      All that said, I contend that the fact that antioxidants can extend mean
> life span indicates that they are part of picture.  As the free radical
> component of senesence gets resolved the mist will lift and the remaining
> factors will be seen more clearly.  I anticipate that this process will have
> to be repeated a number of times.
>      I hope this helps.
> "The Devil (or GOD) is in the details"
> "Life is what happens while we are getting ready"
> Edward C. Krug, Ph.D.                           
> Dept. of Infectious Diseases          
> Univ. of Colorado Health Sciences Center
> Denver, Colorado
> <snip> 
> ""I have been reading a bit on the putative role of free radicals
> in aging, and I'm wondering what others think about the
> proposal that free radicals and oxidative damage are a
> significant cause of aging?""
> ""Although it is clear that these factors are involved in such
> pathologies as ischemic heart injury, autoimmune diseases, and
> neurodegenerative diseases, it is not certain if they just
> contribute to aging or are actually causative.""
> ""I think it's very interesting that in calorie-restricted
> animals, the levels of free radical scavenging enzymes like SOD
> and GPX are elevated, and that mice clones overexpressing SOD
> have prolonged life spans.  The theory is that these enzymes,
> and others like GSH-RD and catalase are protecting the organism
> from oxidative damage to DNA, prots, lipids, etc., which
> normally => aging and cell death.  
> Arguing against the free radicals/aging theory are experiments
> showing only an increased mean but not MAXIMUM life span in
> animals fed antioxidants like Vits A, C, E, Se, etc.""
> ""I would really be interested in hearing others' opinions on
> this topic.""
> ""David S. Cassarino              "The mind is not a vessel to be filled
> MSTP, Neuroscience 2nd Year          but a fire to be kindled."
> UVA School of Medicine                   -Plutarch
> dsc9w at  ""

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