DHA-Accelerated Aging Hypothesis: An Update
mik...@my-deja.com
In article <au136.15458$O7.7...@news-east.usenetserver.com>,
"Fred Thomas" <fr...@stellartron.com> wrote:
> <gjon...@my-deja.com> wrote in message news:92i4ol$a8b$1...@nnrp1.deja.com...
>
> > I'm willing to sacrifice a little quality of the omega-3's... to not
> > have to deal with fish oil. Even in capsule form. :)
>
> There's also the concern that DHA is worse that ALA because it is more
> oxidizable. Read Micheal Rae's "MiFR: Flax, not Fish?" post from March 24, 2000.
This idea has been vigorously debated on the CR list; I'm more firmly
convinced of it than ever, as much more evidence is now available. A
brief summary, w/links to some key posts, is reproduced here:
The by now well-established facts which constitute essence of the
argument:
1.Across species, double bond content in the mt inner membrane (MIM) --
and esp DHA content -- is inversely correlated with max LS.
2. Within a species, double bond content in MIM increases with aging.
3. CR, the only anti-aging therapy per se (only therapy which extends max
LS), retards (2).
4. Feeding all animals yet tested longer-chain PUFA, such as DHA,
increases DHA content in MIM.
5. Specifically, in rodents, feeding fish oil both increases MIM DHA
content, AND increases the actual peroxidation of the MIM.
Inductive conclusion, from the above & a few other tidbits: eating DHA
will lead to more DHA in MIM; more DHA in MIM is in direct opposition to
a known effect of CR, and correlates with aging within and across
species. Plus, it peroxidizes the MIM; bad almost self-evidently, but
more on this below.
So don't eat DHA.
There's a broader theoretical framework involving various versions of the
mt free radical theory of aging (MiFRA), which nicely explains why all
the above might connect: more double bonds, all things being equal, makes
an acyl chain on an mt phospholipid more peroxidizable, thus
theoretically increasing ROS damage to MIM, which (per various MiFRAs) is
bad; and evidence (cited in a post below) does show that, in vivo,
animals fed DHA end up with more peroxidized MIMs.
But I'd stick to the DHA-accelerated aging (wittily & flatteringly coined
"MiRFAA" (Michael Rae's Fishoil-Accelerated Aging) theory even if MiFRA
per se were conclusively disproven, on the basis of the above.
On the specific issue of DHA-acclerated aging:
http://x71.deja.com/[ST_rn=ps]/getdoc.xp?AN=601931444&CONTEXT=
973286188.417136648&hitnum=1
http://www.egroups.com/message/crsociety/2905
The results of study in the above post are more clearly tabulated toward
the bottom of this post:
http://www.egroups.com/message/crscience/7
http://www.egroups.com/message/crscience/9
NB that I do expect the effect on intrinsic aging to be relatively minor,
& thus only of relevance to those already slowing same. The only folks
who might be in the latter category are CR practitioners. However, ALA
does appear to be the better supplement for CVD, as well:
http://www.egroups.com/message/crsociety/3070
Although these ideas have been hashed to death on the CR society, I'd
like to hear outside commentary, esp. from the esteemed Dr. de Grey.
-Michael
Sent via Deja.com
http://www.deja.com/
Winter QQ
thing?
Winter
joe record
Aubrey de Grey
Michael Rae wrote:
> Michael Rae's Fishoil-Accelerated Aging
I agree with all of that except one thing:
> 2. Within a species, double bond content in MIM increases with aging.
This is news to me. In fact, I thought that the opposite was true,
because the most unsaturated phospholipid in the MIM is cardiolipin,
whose abundance declines with age. What is your source of this info?
Aubrey de Grey
UnclJunior
>Aubrey de Grey
Given this, do you have any reccomendation on the fish vs flax issue?
Thanks.
dav...@my-deja.com
acid) which protects against mitochondrial oxidation?
Willy Wouters
In Japan, stroke is a very common cause of disability and death.
Japanese researchers tested the
possibility that docosahexaenoic acid (DHA) supplements might improve
mental functioning in patients with moderately severe dementia from
thrombotic stroke. DHA is enriched in brain tissues and plays an
important role in sensory functions. It also has electrical stabilizing
effects and is anti-thrombotic.
Twenty male and female elderly patients (average age 83) with mild to
moderate dementia due to stroke(s)
were studied. The patients were divided into two groups, one of which
received DHA, while the other
received placebo. Each day, the DHA group received 6 DHA capsules (2
capsules taken three times a day)
containing a total of 720 mg. DHA daily for a year. In the elderly with
moderately severe dementia, the DHA supplementation improved their
dementia scores (as determined by the Hasegawa's Dementia rating scale
and the Mini-Mental State Examination scale), though no discussion was
given here on what the scores mean in terms of the particular mental
functions or behaviors improved.
Terano et al, "Docosahexaenoic Acid Supplementation Improves the
Moderately Severe Dementia from
Thrombotic Cerebrovascular Diseases"
Matti Narkia
mik...@my-deja.com wrote:
>5. Specifically, in rodents, feeding fish oil both increases MIM DHA
>content, AND increases the actual peroxidation of the MIM.
>
According to
Urano S, Sato Y, Otonari T, Makabe S, Suzuki S, Ogata M, Endo T
Aging and oxidative stress in neurodegeneration.
Biofactors 1998;7(1-2):103-12
PMID: 9523034, UI: 98183635
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9523034&dopt=Abstract
"In a measurement of fatty acid content in the membranes, the content of
docosahexaenoic acid (DHA, C22:6) decreased significantly during aging and
by hyperoxia. These results suggest that free radicals derived from oxygen
may attack nerve terminals and peroxidize the membrane, resulting in the
deterioration of function of brain synapse, and that susceptibility of
synapse to oxidative stress was significantly increased with age."
Doesn't therefore seem sensible to supplement DHA in old age to restore DHA to
the "youthful levels" ? :-) The abstract continues:
"Vitamin E content in the synaptic plasma membranes decreased with age. When
rats were subjected to oxidative stress, the content was lower in each age
than in normal rat membranes. An intraperitoneal administration of vitamin E
prior to stress reduced these abnormalities. It is obvious that vitamin E
contributes to the protection against nerve terminal dysfunction caused by
oxidative stress."
>Inductive conclusion, from the above & a few other tidbits: eating DHA
>will lead to more DHA in MIM; more DHA in MIM is in direct opposition to
>a known effect of CR, and correlates with aging within and across
>species. Plus, it peroxidizes the MIM; bad almost self-evidently, but
>more on this below.
>
Have you taken into consideration that DHA may also induce effects which
counteract peroxidation? The abstract
Hossain MS, Hashimoto M, Gamoh S, Masumura S
Antioxidative effects of docosahexaenoic acid in the cerebrum versus cerebellum
and brainstem of aged hypercholesterolemic rats.
J Neurochem 1999 Mar;72(3):1133-8
PMID: 10037485, UI: 99155089
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10037485&dopt=Abstract
concludes:
"We suggest that DHA plays an important role in inducing an antioxidative
defense against active oxygen by enhancing the cerebral activities of CAT,
GPx, and GSH."
Reaching very old age may not be satisfying if one loses a large part of his
cognitive function. The abstract
Kalmijn S, Feskens EJ, Launer LJ, Kromhout D.
Polyunsaturated fatty acids, antioxidants, and cognitive function in very old
men.
Am J Epidemiol 1997 Jan 1;145(1):33-41.
http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=8982020&form=6&db=m&Dopt=b
concludes:
"This study raises the possibility that high linoleic acid intake is
positively associated with cognitive impairment and high fish consumption
inversely associated with cognitive impairment."
Reaching a very old age may not be a blessing if one is troubled with a chronic
disease. It may not be even possibble if one gets a life-threatening disease
and cannot survive it. The abstract
Horrocks LA, Yeo YK.
Health benefits of docosahexaenoic acid.
Pharmacol Res. 1999 Sep;40(3):211-25. Review.
PMID: 10479465; UI: 99410600
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10479465&dopt=Abstract
suggests that DHA may help in this.
>So don't eat DHA.
>
So eat your DHA, but don't overdo it, perhaps take some antioxidants with it,
such as vitamin E, alpha lipoic acid and coenzyme Q10 :-).
--
Matti Narkia
mik...@my-deja.com
In article <566n5tc83daje0p4h...@4ax.com>,
Matti Narkia <mn...@iname.com> wrote:
> Mon, 08 Jan 2001 02:28:41 GMT in article <93b8kj$imr$1...@nnrp1.deja.com>
> mik...@my-deja.com wrote:
>
> >5. Specifically, in rodents, feeding fish oil both increases MIM DHA
> >content, AND increases the actual peroxidation of the MIM.
> >
> Have you taken into consideration that DHA may also induce effects
which
> counteract peroxidation? The abstract
>
> Hossain MS, Hashimoto M, Gamoh S, Masumura S
> Antioxidative effects of docosahexaenoic acid in the cerebrum versus
cerebellum
> and brainstem of aged hypercholesterolemic rats.
> J Neurochem 1999 Mar;72(3):1133-8
> PMID: 10037485, UI: 99155089
>
> concludes:
>
> "We suggest that DHA plays an important role in inducing an
antioxidative
> defense against active oxygen by enhancing the cerebral activities
of CAT,
Similarly, dav...@my-deja.com wrote:
> Why not simply take a supplement along with the DHA (such as lipoic
> acid) which protects against mitochondrial oxidation?
>
The problem with both of these (which is discussed in the cited posts
& threads) is that none of these antioxidants are known to reduce
peroxidation of MIM. Lipoate may, conceivably, but we have no direct,
on-site evidence; CAT (& GSH, vit E, ctSOD, & even largely mnSOD) are
not effective MIM antioxidants. The effects on cellular membranes (where
a-tocopherol, eg, is quite effective against peroxidation) are
thus distinct from those on MIM. This may explain the fact that most
endogenous AO's levels are either not correlated, or INVERSELY
correlated, w/species max LS, & that CR's effects on AOs are so wildly
variant by AO & tissue.
This underlies the whole point of the various MiFRAs: it allows a
theoretician to still say that ROS (LECs) are actually involved in
aging, despite the consistent failure of dietary AOs to affect max LS, &
despite the aforementioned non-relation betwixt endogenous AOs & LS.
See Aubrey's smashing paper:
de Grey (2000), "The non-correlation between maximum lifespan and
antioxidant enzyme levels among homeotherms: implications for retarding
human aging." J. Anti-Aging Med. 3(1):25-36.
> According to
>
> Urano S, Sato Y, Otonari T, Makabe S, Suzuki S, Ogata M, Endo T
> Aging and oxidative stress in neurodegeneration.
> Biofactors 1998;7(1-2):103-12
> PMID: 9523034, UI: 98183635
>
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&lis
t_uids=9523034&dopt=Abstract
>
> "In a measurement of fatty acid content in the membranes, the
content of
> docosahexaenoic acid (DHA, C22:6) decreased significantly during
aging and
> by hyperoxia. These results suggest that free radicals derived from
oxygen
> may attack nerve terminals and peroxidize the membrane, resulting
in the
> deterioration of function of brain synapse, and that susceptibility
of
> synapse to oxidative stress was significantly increased with age."
>
> Doesn't therefore seem sensible to supplement DHA in old age to
restore DHA to
> the "youthful levels" ? :-)
It would -- if it didn't accelerate the global aging process. If you're
in a short-term crisis, like a premature infant, this might make sense;
but for those of us taking the long view, brain DHA levels can be
maintained with adequate n3 intake from ALA.
http://x74.deja.com/[ST_rn=ps]/getdoc.xp?AN=601931444.2&CONTEXT=97914168
0.1056374813&hitnum=1
The abstract continues:
> >Inductive conclusion, from the above & a few other tidbits: eating
DHA
> >will lead to more DHA in MIM; more DHA in MIM is in direct opposition
to
> >a known effect of CR, and correlates with aging within and across
> >species. Plus, it peroxidizes the MIM; bad almost self-evidently, but
> >more on this below.
> >
> GPx, and GSH."
>
> Reaching very old age may not be satisfying if one loses a large part
of his
> cognitive function. The abstract
>
> Kalmijn S, Feskens EJ, Launer LJ, Kromhout D.
> Polyunsaturated fatty acids, antioxidants, and cognitive function in
very old
> men.
> Am J Epidemiol 1997 Jan 1;145(1):33-41.
>
> concludes:
>
> "This study raises the possibility that high linoleic acid intake
is
> positively associated with cognitive impairment and high fish
consumption
> inversely associated with cognitive impairment."
So? Don't take in a lot of LA, either.
Nelson J. Navarro
<mik...@my-deja.com> wrote in message news:93i0hi$u25$1...@nnrp1.deja.com...
> All:
>
> In article <566n5tc83daje0p4h...@4ax.com>,
> Matti Narkia <mn...@iname.com> wrote:
> > Mon, 08 Jan 2001 02:28:41 GMT in article <93b8kj$imr$1...@nnrp1.deja.com>
> > mik...@my-deja.com wrote:
> >
<snip>
> > Why not simply take a supplement along with the DHA (such as lipoic
> > acid) which protects against mitochondrial oxidation?
> >
> The problem with both of these (which is discussed in the cited posts
> & threads) is that none of these antioxidants are known to reduce
> peroxidation of MIM. Lipoate may, conceivably, but we have no direct,
> on-site evidence; CAT (& GSH, vit E, ctSOD, & even largely mnSOD) are
> not effective MIM antioxidants. The effects on cellular membranes (where
> a-tocopherol, eg, is quite effective against peroxidation) are
> thus distinct from those on MIM. This may explain the fact that most
> endogenous AO's levels are either not correlated, or INVERSELY
> correlated, w/species max LS, & that CR's effects on AOs are so wildly
> variant by AO & tissue.
>
> This underlies the whole point of the various MiFRAs: it allows a
> theoretician to still say that ROS (LECs) are actually involved in
> aging, despite the consistent failure of dietary AOs to affect max LS, &
> despite the aforementioned non-relation betwixt endogenous AOs & LS.
This is why I can't wait to see what happens with the mitochondrial specific
antioxidants being developed by Murphy et al.
If they ever get around to doing some lifespan tests with them, that is.
Their latest creation, a ubiquinone derivative seems particularly exciting.
The full text paper is here: http://www.jbc.org/cgi/reprint/M009093200v1
J Biol Chem 2000 Nov 22; [epub ahead of print] Related Articles, Books,
LinkOut
Selective targeting of a redox-active ubiquinone to mitochondria within
cells: antioxidant and antiapoptotic properties.
Kelso GF, Porteous CM, Coulter CV, Hughes G, Porteous WK, Ledgerwood EC,
Smith RA, Murphy MP
Biochemistry, University of Otago, Dunedin.
[Record supplied by publisher]
With the recognition of the central role of mitochondria in apoptosis there
is a need to develop specific tools to manipulate mitochondrial function
within cells. Here we report on the development of a novel antioxidant that
selectively blocks mitochondrial oxidative damage, enabling the roles of
mitochondrial oxidative stress in different types of cell death to be
inferred. This antioxidant, named mitoQ, is a ubiquinone derivative targeted
to mitochondria by covalent attachment to a lipophilic triphenylphosphonium
cation through an aliphatic carbon chain. Due to the large mitochondrial
membrane potential, the cation was accumulated within mitochondria inside
cells, where the ubiquinone moiety inserted into the lipid bilayer and was
reduced by the respiratory chain. The ubiquinol derivative thus formed was
an effective antioxidant that prevented lipid peroxidation and protected
mitochondria from oxidative damage. After detoxifying a reactive oxygen
species the ubiquinol moiety was regenerated by the respiratory chain
enabling its antioxidant activity to be recycled. In cell culture studies,
the mitochondrially-localized antioxidant protected mammalian cells from
hydrogen peroxide-induced apoptosis, but not from apoptosis induced by
staurosporine or tumor necrosis factor-a. This was compared to untargeted
ubiquinone analogs which were ineffective in preventing apoptosis. These
results suggest that mitochondrial oxidative stress may be a critical step
in apoptosis induced by hydrogen peroxide, but not for apoptosis induced by
staurosporine or tumor necrosis factor-a. We have shown that selectively
manipulating mitochondrial antioxidant status with targeted and recyclable
antioxidants is a feasible approach to investigate the role of mitochondrial
oxidative damage in apoptotic cell death. This approach will have further
applications in investigating mitochondrial dysfunction in a range of
experimental models.
PMID: 11092892
<snip>
Regards,
Nelson
mik...@my-deja.com
First, before Aubrey beats me over the head, I should note that in my
post on this thread earlier today I should have said that the problem I
was citing was, specifically, the lack of effective AOs in the mt
intermembrane space.
In article <93dgt0$2fj$1...@pegasus.csx.cam.ac.uk>,
ag...@mole.bio.cam.ac.uk (Aubrey de Grey) wrote:
>
> Michael Rae wrote:
>
> > Michael Rae's Fishoil-Accelerated Aging
>
> I agree with all of that
Good Lord!
except one thing:
Drats.
>
> > 2. Within a species, double bond content in MIM increases with aging.
>
> This is news to me. In fact, I thought that the opposite was true,
> because the most unsaturated phospholipid in the MIM is cardiolipin,
> whose abundance declines with age. What is your source of this info?
I was very surprised by this comment, as we've discussed some of the
studies I'm about to cite before, & the others are what one would expect
from these. What these papers found was that the content of longer-chain
PUFA in the acyl chains of assorted PL in TOTAL mt membrane preparations
increase with age, displacing shorter-chain PUFA.
Until now, I guess I've just unconsciously assumed that this extended to
MIM specifically, esp as the cardiolipin acyl side chains evidently
retain the same composition (4) or become more desaturated (5) w/age,
and, according to (1), even the LEVEL of CL is not in fact reduced by
age, either (& tho' (4) says it goes down, (5) says it goes UP).
I can see that I've overstepped the data -- but by how much? Would the
contrary assertion not require that mt OUTER membranes quite remarkably
increase LCPUFA in order to "average out" a reduction in MIM? What would
cause this differential effect?
And I take it that you'd agree that the practical implications remain
intact even were my (unconscious) assumption on this specific point
untenable?
-Michael
1: Gerontology 1993;39(1):7-18
Modulation of membrane phospholipid fatty acid composition by age and
food restriction.
Laganiere S, Yu BP
...the major phospholipid classes, phosphatidylcholine (PC),
phosphatidylethanolamine (PE), phosphatidylinositol and cardiolipin did
not vary significantly with age or diet.
The fatty acid composition of the phospholipids was determined in PC and
PE ...
in ad libitum (AL) fed rats: membrane levels of long-chain
polyunsaturated fatty acids, 22:4 and 22:5, increased progressively,
while membrane linoleic acid (18:2) decreased steadily with age. Levels
of 18:2 fell by approximately 40%, and 22:5 content almost doubled making
the peroxidizability index increase with age.
In addition, levels of 16:1 and 18:1 decreased significantly with age,
indicating a possible change in delta 9-desaturase activity coefficient.
Food restriction resulted in a significant increase in levels of
essential fatty acids while attenuating levels of 22:4, 22:5, 22:6 and
peroxidizability.
We concluded that the membrane-stabilizing action of long-term calorie
restriction relates to the selective modification of membrane long-chain
polyunsaturated fatty acids during aging.
PMID: 8440492, UI: 93178990
Lipids 1997 May;32(5):497-506
Effect of docosahexaenoic acid on mouse mitochondrial membrane
properties.
Stillwell W, Jenski LJ, Crump FT, Ehringer W
... mitochondrial docosahexaenoic acid (DHA) levels were increased by
either dietary manipulation or by fusing the mitochondria with
phospholipid vesicles made from ... (18:0/22:6 PC).... Mitochondria were
isolated from young (5-mon) and old (24-mon) mice which were maintained
on either a diet rich in saturated fats (hydrogenated coconut oil) or
rich in n-3 polyunsaturated fats (menhaden oil). ... lipid composition,
phospholipid area/molecule and extent of lipid peroxidation were also
determined.
[20:4 went up with age in all groups in PC, in HCO PE but down in MO PE,
and down in HCO CL while up in MO CL; 20:5 was unmeasured in HCO, but was
elevated in all MO *with age* (not just by the fact of their diet); DHA
went down with age in all PC and CL, but up in PE. As HCO can't affect
fatty acyl type directly, because PL always have 1 SAFA & 1 unSAFA, the
trend here appears to be increasing PUFA with age except in case of
direct intervention].
Decreases in RCI for the menhaden oil diet-modified mitochondria
paralleled those in which DHA levels were enhanced by fusion with
phospholipid vesicles. RCI reductions are attributed to DHA-induced
increases in H+ movement, producing diminished mitochondrial membrane
potentials. One purpose of this project was to determine if the
deleterious effects of aging on mitochondrial bioenergetic function could
be reversed by addition of n-3 fatty acids. The experiments reported here
indicate that incorporation of long-chain polyunsaturated n-3 fatty acids
into mitochondrial membranes does not appear likely to reverse the
effects of age on mitochondrial function.
PMID: 9168456, UI: 97311741
3: Biochem Biophys Res Commun 1987 Jun 30;145(3):1185-91
Anti-lipoperoxidation action of food restriction.
Laganiere S, Yu BP
... Restricting calories modified membrane fatty acid composition by
increasing linoleic acid and decreasing docosapentaenoic acid
content in both membranes. The significance of the fatty acid
modification was discussed in terms of anti-lipoperoxidation and membrane
fluidity.
[This paper also found less DHA in CR than AL (3.45 vs. 3.02%), & tho'
the results were not significant in this regard, there were only 4-5
rats/group].
PMID: 3606601, UI: 87270688
4. Paradies G, Ruggiero FM, Petrosillo G, Gadaleta MN, Quagliariello E.
The effect of aging and acetyl-L-carnitine on the function and on the
lipid composition of rat heart mitochondria.
Ann N Y Acad Sci. 1994 Jun 30;717:233-43. No abstract available.
PMID: 8030840; UI: 94303892
5: Mech Ageing Dev 1984 Mar;24(3):343-51
Lipid changes with aging in cardiac mitochondrial membranes.
Lewin MB, Timiras PS
Mitochondrial membranes were isolated from the myocardium of young (4-
month-old) and aged (33-month-old) male Long-Evans rats and compared in
terms of cholesterol content and phospholipid and fatty acid composition.
In aged rats, as compared to young, the major observations include:
markedly higher cholesterol content; increased percentage of ...
cardiolipin; ... increase in the longer chain (20:0, 24:0) fatty acids in
cardiolipin; decreased unsaturation index for most phospholipids [??] but
increased for cardiolipin...
PMID: 6717095, UI: 84190062
Randall Parker
Any idea whether this paper is available on-line somewhere? Sounds
intriguing as all get out.
On Wed, 10 Jan 2001 15:53:29 GMT esteemed mik...@my-deja.com did'st hold
forth thusly:
Randall Parker
On Tue, 09 Jan 2001 16:42:25 -0600 esteemed Willy Wouters did'st hold
forth thusly:
Randall Parker
something damaging it before coming into contact with an antioxidant.
This is just a limit of 3-D space. You can't have antioxidant molecules
everywhere. There are other things that need to be in those places.
On Tue, 09 Jan 2001 15:51:21 GMT esteemed dav...@my-deja.com did'st hold
forth thusly:
UnclJunior
>forth thusly:
>> Why not simply take a supplement along with the DHA (such as lipoic
>> acid) which protects against mitochondrial oxidation?
From: Randall Parker
>You can't really. Most free radicals get generated and knock into
>something damaging it before coming into contact with an antioxidant.
>This is just a limit of 3-D space. You can't have antioxidant molecules
>everywhere. There are other things that need to be in those places.
Randall, is true of free radicals in general or primarily in the mitochondria?
I've always understood antioxidant's to be like fishing with slightly too big
of a net - some get through. However, as you describe it it the unusuall free
radical that gets "matched up." Given this, and the fact the most free
radicals are generated be food, why is the reduced free radicals generated by
CR so minimized as one of the benefits of CR?
dav...@my-deja.com
Randall Parker <rgpa...@west.net> wrote:
> You can't really. Most free radicals get generated and knock into
> something damaging it before coming into contact with an antioxidant.
> This is just a limit of 3-D space. You can't have antioxidant
molecules
> everywhere. There are other things that need to be in those places.
????
Nevertheless, increasing the concentration of an antioxidant in a given
medium will (in general) help to alleviate increased oxidative stress
in that medium (provided that antioxidant is directly or indirectly
active against the type of reactive species present).
Michael, that's interesting that apparently it isn't known yet if
lipoic acid protects against MIM oxidation. Sounds like a good
potential in vitro experiment for me to do (if it's practical).
--
David B. Sprouse
Dept of Human Nutrition
Virginia Tech
mik...@my-deja.com
In article <20010111154517...@ng-cn1.aol.com>,
Are you asking:
"Why does CR reduce mtROS?"
If so: the truth is, no one knows. It is NOT, as you SEEM to think, a
simple matter of less e- being crammed thru' a given mt: specific
metabolic rate is NOT lowered by CR. Rather, CR somehow leads each mt in
the organism to process the same number of e- more "cleanly." How it does
this is a mystery.
An explanation by Aubrey, in the context of his MiFRA (read the book!),
is linked here, along wiht my ATTEMPT at a more accessible, more
"unpacked" interpretation & related speculation:
http://www.egroups.com/message/crscience/4
or
"Why does the reduction of mtROS generation by CR get so little
emphasis?"
In which case: some, like Weindruch, put a LOT of emphasis on it, from a
theoretica POV. See his Sci Am article, or this recent review, which is
CR-heavy:
Sohal RS, Weindruch R.
Oxidative stress, caloric restriction, and aging.
Science. 1996 Jul 5;273(5271):59-63. Review.
PMID: 8658196; UI: 96275589
& see this recent breakthru':
Zainal TA, Oberley TD, Allison DB, Szweda LI, Weindruch R.
Caloric restriction of rhesus monkeys lowers oxidative damage in skeletal
muscle.
FASEB J. 2000 Sep;14(12):1825-36.
[MEDLINE record in process]
PMID: 10973932; UI: 20432070
As noted above: ditto for Aubrey.
But, the point of practicing CR is not to reduce mtROS; the point is to
slow aging. If CR slows aging by reducing mtROS, then good; if CR did NOT
reduce mtROS, but still slowed aging, I wouldn't give a damn about
reducing mtROS, as mtROS would ipso facto be shown not to be a major
mechanism of aging (at least in lab-bred rodents & primates under lab
conditions -- see recent doubts on relevance of these models under
"Immortal Mice" thread).
To look at it another way: the fact that CR reduces mtROS supports the
contention that mtROS are important to aging. To say "practice CR BECAUSE
it lowers mtROS" is rather to put the horse before the cart. Rather,
practice CR because it slows aging, by an unknown mechanism, but very
plausibly by lowering mtROS.
-Michael
Randall Parker
> From: Randall Parker
> >You can't really. Most free radicals get generated and knock into
> >something damaging it before coming into contact with an antioxidant.
> >This is just a limit of 3-D space. You can't have antioxidant molecules
> >everywhere. There are other things that need to be in those places.
>
> Randall, is true of free radicals in general or primarily in the mitochondria?
True in general. Its unfortunate. The problem is that most free radicals
are going to slam into something before hitting something that can
neutralize them. Potentially one way to deal with this is to generate
less free radicals. That is what the CR practitioners may be doing that
is helping them. I'll leave Michael Rae's comments to address that.
Of course, gene therapy to repair the damage would be ideal. No matter
what you try to do to reduce the rate of damage it is likely that the
damage will still accumulate at a rate that will kill us within a century
or two if not sooner (depending on individual genes, environment, etc).
This isn't an argument against taking vitamins. Its really an argument
for the idea that their benefits are fairly limited.
> I've always understood antioxidant's to be like fishing with slightly too big
> of a net - some get through. However, as you describe it it the unusuall free
> radical that gets "matched up." Given this, and the fact the most free
> radicals are generated be food,
I wouldn't say most are. However, this brings up an important point: The
most promising place for utilising antioxidants to reduce the rate of
aging is in the gut. If we can neutralize free radicals _before_ they are
absorbed into the bloodstream then aging could be measureably slowed.
The gut is promising because there are large areas where stuff being
digested exists and our own cells are not there. The ratio of other stuff
to cells is very high there. So we ought to be able to neutralize some of
those free radicals before they come into contact with our cells.
You'll note that Aubrey posted about this in his discussion of the
"Ursini Effect" as to why wine reduces the risk of heart disease.
> why is the reduced free radicals generated by
> CR so minimized as one of the benefits of CR?
I'm let Michael Rae's answer to that stand. I have nothing more to add.
Randall Parker
forth thusly:
> > This is just a limit of 3-D space. You can't have antioxidant
> molecules
> > everywhere. There are other things that need to be in those places.
>
> ????
Example: A cholesterol blob in the bloodstream can have a free radical in
it. That free radical can react with an alpha tocopherol. But then the
alpha tocopherol will not quickly enough get out the the surface of that
blob (surely there's a more technical name for the blob that escapes me
at the moment <g>) to be recycled by ascorbic acid. So the alpha
tocopherol molecules can't handle as many free radicals as they need to.
> Nevertheless, increasing the concentration of an antioxidant in a given
> medium will (in general) help to alleviate increased oxidative stress
> in that medium (provided that antioxidant is directly or indirectly
> active against the type of reactive species present).
And yet most (all?) antioxidants have their concentrations in the body
closely regulated within ranges. The reason is that evolution selected
the trade-off based in part on the idea that locations taken up by
antioxidants are locations not available for food, muscle, etc.
Randall Parker
Very cool paper. Thanks for posting the abstract.
I just made sure Aubrey noticed this. So maybe he'll come and comment on
it.
On Thu, 11 Jan 2001 01:35:39 GMT esteemed Nelson J. Navarro did'st hold
forth thusly:
> This is why I can't wait to see what happens with the mitochondrial specific
dav...@my-deja.com
Randall Parker <rgpa...@west.net> wrote:
> And yet most (all?) antioxidants have their concentrations in the
body
> closely regulated within ranges.
Are you referring to antioxidant enzymes, non-enzymatic antioxidants,
or both? With regard to antioxidant enzymes, that's certainly true
since their expression is under genetic control and appears to vary
based on the level of oxidative stress and/or other factors. But
exogenously-administered non-enzymatic antioxidants (e.g. lipoic acid),
especially when given at pharmacological doses? Do you have evidence
for this? If this is even partly true, than it's certainly something
that I need to know.
> The reason is that evolution selected
> the trade-off based in part on the idea that locations taken up by
> antioxidants are locations not available for food, muscle, etc.
I'm not sure that I'm clear on your meaning here, but are you trying to
say that antioxidants tend not to be found in sites such as the GI
tract or muscle, where large amounts of free radicals are generated?
That may be true in general, but with regard to supplementation, it
still depends on the pharmocokinetic properties of each specific
antioxidant. Some (e.g. melatonin) are able to get into tissues very
easily and reach virtually all parts of the cell, whereas others may
remain confined mostly to the blood stream or specific tissues.
Factors such as molecular weight, lipid solubility, pKa,
presence/absence of specific transporters, etc contribute to this.
Lipoic acid, for instance, is taken up into oxidative slow-twitch
muscle fibers much more readily than into glycolytic fast-twitch
fibers. Large doses of vitamin C (above the 250 or so mg per day that
can be absorbed) are theorized to still be of benefit due to free
radical-scavenging in the GI tract.
David
Randall Parker
forth thusly:
> > And yet most (all?) antioxidants have their concentrations in the
> body
> > closely regulated within ranges.
>
> Are you referring to antioxidant enzymes, non-enzymatic antioxidants,
> or both?
Both.
> With regard to antioxidant enzymes, that's certainly true
> since their expression is under genetic control and appears to vary
> based on the level of oxidative stress and/or other factors. But
> exogenously-administered non-enzymatic antioxidants (e.g. lipoic acid),
> especially when given at pharmacological doses?
Yes, of course.
>Do you have evidence
> for this? If this is even partly true, than it's certainly something
> that I need to know.
Aubrey de Grey has made a couple of posts on revelant points. I'm digging
and digging at the moment trying to find the right ones (I need to switch
to a news reader that has a better search facility where it is possible
to scope the search for keywords only for a particular From person).
This is an excerpt from a post that Aubrey made on Apr 4, 2000:
I'm not sure. I agree with you that the level of C needed to counteract
the pro-oxidant effect of extracellular (especially LDL) E will probably
not rise linearly with the amount of E, such that there is a level of E
which is simply bad however much C you take (because it's hard to get the
extracellular C concentration higher than about 120uM, since absorption
efficiency and dehydroascorbate recycling get less efficient at high diet
levels -- I heard this at a recent meeting, sorry I don't have citations
to hand). This may translate into a maximum achievable level of E within
the cell, which may be lower than what could effectively be balanced by
intracellular C if the extracellular problem didn't exist.
>
> > The reason is that evolution selected
> > the trade-off based in part on the idea that locations taken up by
> > antioxidants are locations not available for food, muscle, etc.
>
> I'm not sure that I'm clear on your meaning here, but are you trying to
> say that antioxidants tend not to be found in sites such as the GI
> tract or muscle, where large amounts of free radicals are generated?
Do some simple math. Imagine you had a 50 kg body and somehow you could
get 5 grams of vitamin C into it. Well, only one ten thousandth of the
your body would be ascorbic acid. A free radical that was generated would
have pretty slim odds of bumping into the ascorbic acid before bumping
into something else.
Analogy: Various subatomic particles have such short half-lives that you
can not store them to use them for some purpose. They don't stick around
long enough. Well, free radicals have longer half lives than subatomic
particles but their half-lives are still very short in many cases.
Ah, after much searching here is an excerpt from another post of Aubrey's
on May 12 2000:
I'm with you all the way on (a) - though as time goes by it seems to feel
simpler - but I may be able to reassure you on (b) and (c). Regarding
(b), the major source of amplification of the problem is in branching of
peroxidation reactions within LDL particles. There is only one defence
mechanism which can protect cells against this, namely the refusal of
the standard LDL receptor to bind an LDL particle that is too oxidised.
This is a start, but the problem is that a particle which is not quite
that oxidised will continue peroxidation (including branching) after it
gets taken up, and the oxidised cholesterol in the centre of the particle
must be sequestered extremely carefully if it is not to propagate those
chain reactions even further into other regions of the cell, i.e. some
of the time it will get out and cause the cell real problems.
Regarding (c), this was the single biggest doubt I had about RHH at first
but I no longer think it is problematic. The answer comes from Stocker's
discovery (which is actually pretty intuitive in hindsight but onetheless
took a while to gain wide acceptance) of tocopherol-mediated eroxidation.
I touch only briefly on this in the book (section 10.4); maybe I should
have given it more air-time. Basically the problem is that the size of
an LDL particle gives a surface-to-volume ratio that precludes adequate
exchange of electrons between vitamin E and vitamin C.
> That may be true in general, but with regard to supplementation, it
> still depends on the pharmocokinetic properties of each specific
> antioxidant. Some (e.g. melatonin) are able to get into tissues very
> easily and reach virtually all parts of the cell, whereas others may
> remain confined mostly to the blood stream or specific tissues.
The bulk of all antioxidants are not getting into the mitochondria.
Maybe someone more knowledgeable on this point will jump in with some
more particulars.
> Factors such as molecular weight, lipid solubility, pKa,
> presence/absence of specific transporters, etc contribute to this.
> Lipoic acid, for instance, is taken up into oxidative slow-twitch
> muscle fibers much more readily than into glycolytic fast-twitch
> fibers. Large doses of vitamin C (above the 250 or so mg per day that
> can be absorbed) are theorized to still be of benefit due to free
> radical-scavenging in the GI tract.
I agree that high doses of vits might be beneficial in the GI tract. That
may well be where they provide the bulk of their benefit in fact.
dav...@my-deja.com
Randall Parker <rgpa...@west.net> wrote:
> On Fri, 12 Jan 2001 20:52:25 GMT esteemed dav...@my-deja.com did'st
hold
> forth thusly:
> > > And yet most (all?) antioxidants have their concentrations in the
> > body
> > > closely regulated within ranges.
> >
> > Are you referring to antioxidant enzymes, non-enzymatic
antioxidants,
> > or both?
>
> Both.
>
> > With regard to antioxidant enzymes, that's certainly true
> > since their expression is under genetic control and appears to vary
> > based on the level of oxidative stress and/or other factors. But
> > exogenously-administered non-enzymatic antioxidants (e.g. lipoic
acid),
> > especially when given at pharmacological doses?
>
> Yes, of course.
> >Do you have evidence
> > for this?
>
>
> the pro-oxidant effect of extracellular (especially LDL) E will
probably
> not rise linearly with the amount of E, such that there is a level of
E
> which is simply bad however much C you take (because it's hard to get
the
> extracellular C concentration higher than about 120uM, since
absorption
> efficiency and dehydroascorbate recycling get less efficient at high
diet
> levels -- I heard this at a recent meeting, sorry I don't have
citations
> to hand). This may translate into a maximum achievable level of E
within
> the cell, which may be lower than what could effectively be balanced
by
> intracellular C if the extracellular problem didn't exist.
Aubrey was referring specifically to vitamins C and E. Even so, his
point seems to be that there is a limit to how much reduced vitamin E
and C can exist within a cell and (in your other quote) that vitamin C
is not in close enough proximity to regenerate vitamin E within an LDL
particle, not that vitamin E is insignificant overall as an antioxidant.
In any event, this has nothing to do with the pharmacokinetics of alpha-
lipoic acid. Like I said, different antioxidants have different
properties. Especially considering the fact the dihydrolipoic acid has
the ability to boost the entire so-called "antioxidant network" by
regenerating vitamin C, ubiquinol, and glutathione from their oxidized
forms. Furthermore, dihydrolipoic acid is itself regenerated using
cellular reducing equivalents (such as NADH) that are derived from
glycolysis and the TCA, so it's not a "one-shot" antioxidant like C and
E are.
> >
> > > The reason is that evolution selected
> > > the trade-off based in part on the idea that locations taken up by
> > > antioxidants are locations not available for food, muscle, etc.
> >
> > I'm not sure that I'm clear on your meaning here, but are you
trying to
> > say that antioxidants tend not to be found in sites such as the GI
> > tract or muscle, where large amounts of free radicals are generated?
>
> Do some simple math. Imagine you had a 50 kg body and somehow you
could
> get 5 grams of vitamin C into it. Well, only one ten thousandth of
the
> your body would be ascorbic acid. A free radical that was generated
would
> have pretty slim odds of bumping into the ascorbic acid before
bumping
> into something else.
That is an oversimplified view of the situation. Do a Pub Med search
and see for yourself the huge array of studies showing that various
supplemental antioxidants can cause a reduction in oxidative stress.
Certainly there are limits to how much supplements can do (though
again, it greatly varies depending on the particular compound), and it
may well be that reducing the amount of pro-oxidants formed in the
first place is a more effective method than trying to quench them
afterwards. However, exogenous antioxidants can have quite a
significant effect. Regards,
-David
UnclJunior
>From: mik...@my-deja.com
snip
>> From: Randall Parker
>> >You can't really. Most free radicals get generated and knock into
>> >something damaging it before coming into contact with an antioxidant.
snip
> unclj...@aol.com (UnclJunior) wrote:
>> Randall, is true of free radicals in general or primarily >>in the
mitochondria?
>> I've always understood antioxidant's to be like fishing >>with slightly too
big
>> of a net - some get through. However, as you >>describe it it the unusuall
free
>> radical that gets "matched up." Given this, and the >>fact the most free
>> radicals are generated be food, why is the reduced >>free radicals generated
by
>> CR so minimized as one of the benefits of CR?
>Are you asking:
>"Why does CR reduce mtROS?"
No, but maybe that's what I should have been asking.
>If so: the truth is, no one knows. It is NOT, as >you SEEM to think, a simple
matter of less e- >being crammed thru' a given mt: specific
>metabolic rate is NOT lowered by CR.
That is was my ASSumption.
>Rather, CR somehow leads each mt in
>the organism to process the same number of >e- more "cleanly." How it does
>this is a mystery.
It would seem to me that even if CR didn't get an organism to burn e more
cleanly - less e would still mean less "mess." A Linclon driven 10 miles a day
will generate less pollutants that a Honda Civic driven 100. (Or did I just
make your argument instead of mine?)
>An explanation by Aubrey, in the context of >his MiFRA (read the book!),
I intend to. However, even getting through Barry Sears anti-aging zone, I feel
like one Jane Goodall's chimps trying speak with signs.
>is linked here, along wiht my ATTEMPT at a >more accessible, more
>"unpacked" interpretation & >related speculation:
>
>http://www.egroups.com/message/crscience/4
>
>or
>
>"Why does the reduction of mtROS generation >by CR get so little emphasis?"
>In which case: some, like Weindruch, put a LOT of emphasis on it, from a
>theoretica POV. See his Sci Am article, or this recent review, which is
>CR-heavy:
>
>Sohal RS, Weindruch R.
>Oxidative stress, caloric restriction, and aging.
>Science. 1996 Jul 5;273(5271):59-63. Review.
>PMID: 8658196; UI: 96275589
>
>& see this recent breakthru':
>
>Zainal TA, Oberley TD, Allison DB, Szweda LI, Weindruch R.
>Caloric restriction of rhesus monkeys lowers oxidative damage in skeletal
>muscle.
>FASEB J. 2000 Sep;14(12):1825-36.
>[MEDLINE record in process]
>PMID: 10973932; UI: 20432070
>
>As noted above: ditto for Aubrey.
>But, the point of practicing CR is not to reduce >mtROS; the point is to slow
aging. If CR slows >aging by reducing mtROS, then good; if CR >did NOT
>reduce mtROS, but still slowed aging, I >wouldn't give a damn about
>reducing mtROS,
Of course.
> as mtROS would ipso facto .be shown not to >be a major mechanism of aging (at
Randall Parker
forth thusly:
> Aubrey was referring specifically to vitamins C and E. Even so, his
> point seems to be that there is a limit to how much reduced vitamin E
> and C can exist within a cell and (in your other quote) that vitamin C
> is not in close enough proximity to regenerate vitamin E within an LDL
> particle, not that vitamin E is insignificant overall as an antioxidant.
The body regulates C concentrations. It probably does the same with alpha
lipoic acid.
> In any event, this has nothing to do with the pharmacokinetics of alpha-
> lipoic acid.
Well, does the body regulate the concentration of alpha lipoic acid?
>Like I said, different antioxidants have different
> properties. Especially considering the fact the dihydrolipoic acid has
> the ability to boost the entire so-called "antioxidant network" by
> regenerating vitamin C, ubiquinol, and glutathione from their oxidized
> forms. Furthermore, dihydrolipoic acid is itself regenerated using
> cellular reducing equivalents (such as NADH) that are derived from
> glycolysis and the TCA, so it's not a "one-shot" antioxidant like C and
> E are.
Yes, alpha lipoic acid is wonderful. I've been to
http://packer.berkeley.edu and read all about it. But does the body limit
its max concentration? Are there parts of the cell where it doesn't go? I
suspect the answer to both questions is yes.
dav...@my-deja.com
Randall Parker <rgpa...@west.net> wrote:
> Yes, alpha lipoic acid is wonderful. I've been to
> http://packer.berkeley.edu and read all about it. But does the body
limit
> its max concentration? Are there parts of the cell where it doesn't
go? I
> suspect the answer to both questions is yes.
Naturally there's going to be a maximum physiological concentration
that be reached for any given substance in any given cell or
compartment, and therefore as you say, its antioxidant effects will
reach a limit; nevertheless, that limit doesn't prevent it from
significantly inhibiting oxidative stress. LA can theoretically reach
both lipid and aqueous cell compartments, but in practice it has a
greater concentration in aqueous compartments after exogenous
administration. I don't believe it's known yet whether or not LA can
get into the mitochondria or into the nucleus....theoretically it can,
but that hasn't been demonstrated to my knowledge. If anyone knows
better, please let us know!!
Aubrey de Grey
Nelson Navarro wrote:
> > <mik...@my-deja.com> wrote in message news:93i0hi$u25$1...@nnrp1.deja.com...
> >
> > This underlies the whole point of the various MiFRAs: it allows a
> > theoretician to still say that ROS (LECs) are actually involved in
> > aging, despite the consistent failure of dietary AOs to affect max LS, &
> > despite the aforementioned non-relation betwixt endogenous AOs & LS.
>
> This is why I can't wait to see what happens with the mitochondrial specific
> antioxidants being developed by Murphy et al.
> If they ever get around to doing some lifespan tests with them, that is.
>
> Their latest creation, a ubiquinone derivative seems particularly exciting.
>
> The full text paper is here: http://www.jbc.org/cgi/reprint/M009093200v1
Personally I will be surprised if mitochondrially-targeted ubiquinol is as
useful as mitochondrially-targeted tocopherol, because I don't think there
is an argument that the partitioning of Q is problematic as it is for vit.
E (Stocker's work, see elsewhere in this thread). But sure, let's do the
experiment.
Aubrey de Grey
Aubrey de Grey
Michael Rae wrote:
> > This is news to me. In fact, I thought that the opposite was true,
> > because the most unsaturated phospholipid in the MIM is cardiolipin,
> > whose abundance declines with age. What is your source of this info?
>
> I was very surprised by this comment, as we've discussed some of the
> studies I'm about to cite before, & the others are what one would expect
> from these. What these papers found was that the content of longer-chain
> PUFA in the acyl chains of assorted PL in TOTAL mt membrane preparations
> increase with age, displacing shorter-chain PUFA.
Sorry, I zoned out here -- you're quite right, these studies showed a
substantial rise in membrane unsaturation with age. I didn't know the
Lewin/Timiras study, which is contrary to everything more recent that
I've seen (such as Hagen's work) and you cite; I must have a look at it
to see if I can figure out where the discrepancy lies. If there isn't
anything obvious that merits ignoring the Lewin/Timiras study, we must
conclude that heart and liver do opposite things with age, which would
take some explaining.
> And I take it that you'd agree that the practical implications remain
> intact even were my (unconscious) assumption on this specific point
> untenable?
Absolutely.
Aubrey de Grey
Aubrey de Grey
Randall Parker wrote:
I'm afraid not -- but I can send reprints, of course.
Aubrey de Grey
Aubrey de Grey
Randall Parker wrote:
> The problem is that most free radicals
> are going to slam into something before hitting something that can
> neutralize them.
and elsewhere:
> Do some simple math. Imagine you had a 50 kg body and somehow you could
> get 5 grams of vitamin C into it. Well, only one ten thousandth of the
> your body would be ascorbic acid. A free radical that was generated would
> have pretty slim odds of bumping into the ascorbic acid before bumping
> into something else.
Certainly not most, but still an irreducible (for the reasons you give)
fraction. The reason it's not most is that most reactions happen only a
tiny proportion of the time that the reagents collide. Your maths works
if the radical is hydroxyl, which reacts a high proportion of the time
with essentially any macromolecule, but it doesn't work for other species.
So, a very small proportion of our body is superoxide dismutase (SOD), but
superoxide reacts really fast with SOD, whereas it hardly reacts at all
with the stuff we're mainly made of. The main reactions that can make
hydroxyl radical in vivo are superoxide-dependent. So if we could mop
up all the superoxide, we're done, even with small amount of the right
SOD or SOD-like things. (There is the problem that superoxide may also
have important signalling roles, so we may not WANT to mop it up quite
so assiduously, but that's another story.)
> Potentially one way to deal with this is to generate
> less free radicals. That is what the CR practitioners may be doing that
> is helping them.
Yes.
> > I've always understood antioxidant's to be like fishing with slightly
> > too big of a net - some get through. However, as you describe it it
> > the unusual free radical that gets "matched up." Given this, and the
> > fact the most free radicals are generated be food,
>
> I wouldn't say most are. However, this brings up an important point: The
> most promising place for utilising antioxidants to reduce the rate of
> aging is in the gut. If we can neutralize free radicals _before_ they are
> absorbed into the bloodstream then aging could be measureably slowed.
This is a bit inexact. What the "Ursini effect" (and by the way, note
that that is not a term you will find in the literature) is is the
reduced absorption of lipid hydroperoxides from the gut. Hydroperoxides
are not free radicals. But they are very easily oxidisable (they react
easily with free radicals), and in particular they can mediate the
amplification (branching) of free radical chain reactions by reacting
with transition metals.
Aubrey de Grey
Aubrey de Grey
Randall Parker wrote:
> This is an excerpt from a post that Aubrey made on Apr 4, 2000:
>
> > I'm not sure. I agree with you that the level of C needed to counteract
> > the pro-oxidant effect of extracellular (especially LDL) E will probably
> > not rise linearly with the amount of E, such that there is a level of E
> > which is simply bad however much C you take (because it's hard to get the
> > extracellular C concentration higher than about 120uM, since absorption
> > efficiency and dehydroascorbate recycling get less efficient at high diet
> > levels -- I heard this at a recent meeting, sorry I don't have citations
> > to hand). This may translate into a maximum achievable level of E within
> > the cell, which may be lower than what could effectively be balanced by
> > intracellular C if the extracellular problem didn't exist.
to which David Sprouse wrote:
> Aubrey was referring specifically to vitamins C and E. Even so, his
> point seems to be that there is a limit to how much reduced vitamin E
> and C can exist within a cell and (in your other quote) that vitamin C
> is not in close enough proximity to regenerate vitamin E within an LDL
> particle, not that vitamin E is insignificant overall as an antioxidant.
Sort of. I'm saying that the ideal partitioning of E between the inside
and outside of cells (in terms of antioxidant potential) may not be
achievable: we could only reach the ideal inside by having a damaging
amount outside.
> In any event, this has nothing to do with the pharmacokinetics of alpha-
> lipoic acid. Like I said, different antioxidants have different
> properties. Especially considering the fact the dihydrolipoic acid has
> the ability to boost the entire so-called "antioxidant network" by
> regenerating vitamin C, ubiquinol, and glutathione from their oxidized
> forms. Furthermore, dihydrolipoic acid is itself regenerated using
> cellular reducing equivalents (such as NADH) that are derived from
> glycolysis and the TCA, so it's not a "one-shot" antioxidant like C and
> E are.
No -- C and E are regenerated too. E mainly by C and C mainly by various
enzymes that get the electrons from NAD(P)H.
> > That may be true in general, but with regard to supplementation, it
> > still depends on the pharmocokinetic properties of each specific
> > antioxidant. Some (e.g. melatonin) are able to get into tissues very
> > easily and reach virtually all parts of the cell, whereas others may
> > remain confined mostly to the blood stream or specific tissues.
>
> The bulk of all antioxidants are not getting into the mitochondria.
Or, even if they get into mitochondria, they aren't getting to the spots
within mitochondria where the damage is being done. But David is right
that different antioxidants do different things -- if something could
do everything, we wouldn't need the rest. Both partitioning and
intrinsic reactivity come into that variety.
Aubrey de Grey
dav...@my-deja.com
>>Furthermore, dihydrolipoic acid is itself regenerated using
>>cellular reducing equivalents (such as NADH) that are derived from
>>glycolysis and the TCA, so it's not a "one-shot" antioxidant like C
and
>> E are.
>No -- C and E are regenerated too. E mainly by C and C mainly by
>various enzymes that get the electrons from NAD(P)H.
A momentary lapse of reason on my part, there. I was trying to make a
point that DHLA is regenerated more easily than C or E due to the
abundance of cellular reducing equivalents, but now that I think about
it, I'm not even sure that's true since the limiting factor should be
the density/proximity of DHLA-regenerating enzymes, right? Is there an
advantage inherent in the fact that DHLA lies relatively high up on
the "antioxidant hierarchy" (i.e. its ability to directly reduce
ubiquinone, oxidized glutathione, and oxidized C)? Thanks for your
replies, Dr. de Grey!
-David
Aubrey de Grey
David Sprouse wrote:
> I was trying to make a
> point that DHLA is regenerated more easily than C or E due to the
> abundance of cellular reducing equivalents, but now that I think about
> it, I'm not even sure that's true since the limiting factor should be
> the density/proximity of DHLA-regenerating enzymes, right?
Right (and that of the reducing equivalents themselves, and the Km and
Vmax of the enzymes).
> Is there an
> advantage inherent in the fact that DHLA lies relatively high up on
> the "antioxidant hierarchy" (i.e. its ability to directly reduce
> ubiquinone, oxidized glutathione, and oxidized C)?
Not really. What matters is the rate at which electrons can get from
any reservoir (reduced antioxidant or other reducing equivalent) to the
sink that needs them (free radical or oxidised antioxidant), and that's
a highly complex (in fact, just about intractable) function of the whole
antioxidant network.
Aubrey de Grey
timo...@my-deja.com
dav...@my-deja.com wrote:
> Why not simply take a supplement along with the
DHA (such as lipoic
> acid) which protects against mitochondrial
oxidation?
>
I'm new to this forum so if I've missed
something excuse me. I think olive oil is a
better alternative to supplementing with fish oils
as its protects mtDNA , reduces lipid
peroxidation, stabilizes membrane ubiquinone
levels, and seems to do much that fish oils may
do and also contains some natural antioxidants.
Barja and Herrero have done fascinating work in
regards to interspecies MLSP's, though their main
focus is on the mitochondrial theory of aging.
I've listed a few samples's of their abstracts
regarding membrane peroxidizability in regards to
MLSP.
J Gerontol A:Biol Sci Med Sci 2000 Jun;55
(6):B286-91
Low fatty acid unsaturation:a mechanism for
lowered lipoperoxidative modification of tissue
proteins in mammalian species with long life
spans.
Pamplona R, et al
J Lipid Res 1998 Oct,39(10)1989-94
Mitochondrial membrane peroxidizability index is
inversely related to maximum lifespan in mammals.
Pamplona R, et al
Mech Ageing Dev 1999 Jan 15;100(3)283-06
A low degree of fatty acid unsaturation leads to
lower lipid peroxidation and lipoxidation-derived
protein modification in heart mitochondria of the
longevous pigeon than in the short-lived rat.
Pamplona R, et al
The full abstracts and related abstracts by the
authors can be found on medline, also abstracts
concerning olive oil and ubiquinone etc.
Tim
Tom Matthews
> But, the point of practicing CR is not to reduce mtROS; the point is to
> slow aging. If CR slows aging by reducing mtROS, then good; if CR did NOT
> reduce mtROS, but still slowed aging, I wouldn't give a damn about
> reducing mtROS, as mtROS would ipso facto be shown not to be a major
> mechanism of aging
This is not a logical conclusion. Reducing mtROS might not be the
*current* limiting factor to life-extension (just as I don't think
telomere length is) but it might still be important to any attempt to
extend lifespan even further than CR does. We must never forget that CR
and a 20-30% increase in lifespan is merely the beginning! What we are
after is a truly unbounded lifespan.
--Tom
Tom Matthews
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Tom Matthews
> However, this brings up an important point: The
> most promising place for utilising antioxidants to reduce the rate of
> aging is in the gut. If we can neutralize free radicals _before_ they are
> absorbed into the bloodstream then aging could be measureably slowed.
I don't think that free radicals are absorbed from the gut to any
extent. Any that are generated in the gut would be neutralized by
processes in the intestinal lining cells after perhaps damaging those
cells. However, the intestinal lining is constantly sloughing off
perhaps partly for this reason.
What *does* happen and is a good reason for having copious amounts of
antioxidants in your gut (a good reason why vitamins should be taken
*with* meals), is that fats and chlesterol are oxidized, proteins are
glycated and AGEs formed, etc. *Then* these harmful species of chemicals
are absorbed. I think that some of them are capable of spawning free
radicals inside the body even they themselves are not free radicals.
> The gut is promising because there are large areas where stuff being
> digested exists and our own cells are not there. The ratio of other stuff
> to cells is very high there. So we ought to be able to neutralize some of
> those free radicals before they come into contact with our cells.
>
> You'll note that Aubrey posted about this in his discussion of the
> "Ursini Effect" as to why wine reduces the risk of heart disease.
That is correct, but I think that you slightly misunderstood it, and I
know of no proof yet for Aubrey's reasonably conjectured mechanism.
Tom Matthews
>
> All:
>
> In article <566n5tc83daje0p4h...@4ax.com>,
> Matti Narkia <mn...@iname.com> wrote:
> > According to
> >
> > Urano S, Sato Y, Otonari T, Makabe S, Suzuki S, Ogata M, Endo T
> > Aging and oxidative stress in neurodegeneration.
> > Biofactors 1998;7(1-2):103-12
> > PMID: 9523034, UI: 98183635
> >
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&lis
> t_uids=9523034&dopt=Abstract
> >
> > "In a measurement of fatty acid content in the membranes, the
> content of
> > docosahexaenoic acid (DHA, C22:6) decreased significantly during
> aging and
> > by hyperoxia. These results suggest that free radicals derived from
> oxygen
> > may attack nerve terminals and peroxidize the membrane, resulting
> in the
> > deterioration of function of brain synapse, and that susceptibility
> of
> > synapse to oxidative stress was significantly increased with age."
> >
> > Doesn't therefore seem sensible to supplement DHA in old age to
> restore DHA to
> > the "youthful levels" ? :-)
>
> It would -- if it didn't accelerate the global aging process. If you're
> in a short-term crisis, like a premature infant, this might make sense;
> but for those of us taking the long view, brain DHA levels can be
> maintained with adequate n3 intake from ALA.
Michael, I don't agree with your logic here. For someone who is older
and is fighting against all the factor which cause brain atrophy and
senility of one kind or another, getting DHA into the brain is highly
important. It is just as important as DHA is to the developing brain of
a baby (and not merely premature - see many studies).
Furthermore, I reject the above logic that states take ALA to generate
DHA in the brain!! It is well proven that the amount of DHA produced
from ALA is miniscule, and, in addition, by your logic why would not
this same generation of DHA from ALA cause DHA to be increased in MIM?
You cannot have it both ways as you seem to be trying to do.
There are many, many papers which verify the age-old wisdom that fish is
excellent brain food.
Finally, there is such a large interconvertability between the highly
beneficial EPA (also produced from ALA before DHA is, in any case) which
is the largest omega-3 component of fish oils, that a true reduction of
body DHA would also require a reduction of EPA as well. This would have
large negative effects on a number of other age-related disorders such
as arthritis, heart disease and once more, brain decline.
Once again this may be a case of: If you are under 40 do not supplement
with fish oil, but if you are over 60 it is likely wise to do so.
Dwight Ringdahl
>This is not a logical conclusion. Reducing mtROS might not be the
>*current* limiting factor to life-extension (just as I don't think
>telomere length is) but it might still be important to any attempt to
>extend lifespan even further than CR does. We must never forget that CR
>and a 20-30% increase in lifespan is merely the beginning! What we are
>after is a truly unbounded lifespan.
Pardon, new to the group, what is CR? I know about DHA.
So who has the secret to longer, younger life? When buying these products,
is there a vast difference in quality? If so which brand is best to buy?
Thanks
--
Dwight Ringdahl
WebUseNet Corp.
Formally UseNetServer.Com
Tom Matthews
>
> >This is not a logical conclusion. Reducing mtROS might not be the
> >*current* limiting factor to life-extension (just as I don't think
> >telomere length is) but it might still be important to any attempt to
> >extend lifespan even further than CR does. We must never forget that CR
> >and a 20-30% increase in lifespan is merely the beginning! What we are
> >after is a truly unbounded lifespan.
>
> Pardon, new to the group, what is CR? I know about DHA.
CR stands for caloric restriction which is the method of increasing
maximum lifespan which has been tested most rigorously on the most
species.
> So who has the secret to longer, younger life?
There is no proven formula for a given individual. That is why we are
all still discussing the subject instead of merely practicing the
"answer" and getting on with the rest of our lives.
> When buying these products,
> is there a vast difference in quality? If so which brand is best to buy?
These are not objectively answerable questions without an enormous
amount of research which no one is willing to do. As a purchaser, you
have to do your own investigation to decide these questions for
yourself. Generally, the answer is different for each individual because
the weights of their values and priorities is different.