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Medical Forum / General / General / December 2004

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ACE Inhibition Is Partial "Fountain Of Youth"

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doe - 14 Dec 2004 11:29 GMT
http://www.biospace.com/news_story.cfm?StoryID=18425620&full=1

University of California, Irvine Researcher Confirms GenoMed, Inc.'s
Patent-Pending Discovery: ACE Is Major Aging Gene, ACE Inhibition Is Partial
"Fountain Of Youth"

Who loves ya.
Tom
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Sbharris[atsign]ix.netcom.com - 15 Dec 2004 01:42 GMT
> http://www.biospace.com/news_story.cfm?StoryID=18425620&full=1
>
> University of California, Irvine Researcher Confirms GenoMed, Inc.'s
> Patent-Pending Discovery: ACE Is Major Aging Gene, ACE Inhibition Is Partial
> "Fountain Of Youth"

COMMENT:

An interesting story. This company is convinced that
Angiotensin Converting Enzyme (ACE) gene alleles of various
kinds are associated with rapid aging syndromes, which could
be modulated by ACE inhibitors. Of course, what the article
doesn't tell you is that ACE inhibitor compounds have been
part of medicine for more than 20 years. These compounds
general end with the suffix "-pril", as for example
Captopril (capoten) which was the first one commercially
available.

This is all starting to get interesting, however, because
there have been suggestions for some time that ACE
inhibitors do more beneficially for people than just lower
blood pressure (their ostensible use). In fact, they are
vaguely reminiscent of the statins in being overall "tonics"
for diabetics, interfering in all kinds of diabetic angio
and arteriolar complications by mechanisms uncertain.

Recently, angiotensin II ("AII", a major regulatory peptide
which results, after two steps, from ACE action) has been
implicated in the formation of fibrous changes in the heart.
These cause the ventricular stiffness which is seen not only
in chronic hypertension, but also to some extent in normal
aging, even if people are never hypertensive. Everybody's
left ventricle and arteries lose elasticity with age.

And so do their lungs, all of which is replaced by fibrous
tissue. These changes in the lungs result in the well-known
decrease in Forced Expiratory Volume (1 sec) which is one of
the aging changes which is most robust and least susceptible
to positive modification, in longitudinal aging studies.
That is, you can always make your FEV(1) drop faster by
smoking or mistreating your lungs, but there's nothing you
can do, exercise included, to stop its normal
non-pathological age-related decline.  If ACE or AII have
anything to do with any of these changes, in normal aging
heart OR lungs, it would be a very, very exciting result.
Previously, we've had absolutely nothing to use to modify
these processes which replace youthful elastic fibers with e
lderly stiff fibrous collagen.

ACE action is part of the body's regulatory action, and ACE
inhibition, even partial inhibition, does sometimes have
unacceptable side effects. Interestingly, ACE does more than
make AII. It also helps to break down bradykinin, a major
inflammatory mediator. So if you inhibit ACE, bradykinin
goes up, and so does inflammation in some places (whether
inflammation from bradykinin or anti-inflammation from less
AII wins out, depends on the tissue). Inflammation in some
cases might be a good thing, for it increases blood flow
(for example, perhaps in heart arterioles). In some cases,
ACE inhibition causes enough new bradykinin release to cause
angioedema or at least a chronic irritative cough.

More recently, however, a number of angiotensin II blocking
drugs (ATB drugs), which directly act at the AII receptor,
have become available in medicine, and these may also end up
doing more than simply lowering blood pressure. So we have a
very, very specific way of blocking AII effects in humans,
and these drugs are already well tested, quite benign, and
long-approved pharmaceuticals (they typically end in the
suffix "-sartan" as in olmesartan = Benicar). Will either
ACE inhibitors or ATBs turn out to have anti-aging
properties? This whole area is one to watch.

SBH
Kofi - 16 Dec 2004 04:18 GMT
There are also a number of naturally occurring ACE inhibitors found in
the diet - grape seed extract, for instance.  This might account for
some of the longevity seen among red wine drinkers.
tcarter2@elp.rr.com - 16 Dec 2004 05:40 GMT
Hi Steve,
Nice review, I hadn't known about the bradykinin/cough
relationship. Perhaps the various anti-inflammatories many of us take
will help in this respect. I too wish the 20 yr record of ACE
inhibitors was a bit better. Studies generally show a mortality
reduction of 10-20%. One's first reaction to this might be that a
much smaller reduction in mortality would be expected in the general
population, but I don't see it that way for the following reasons.
While it's generally taken as gospel that hi blood pressure shortens
life span by causing heart attacks and stroke there is, in my minority
view no convincing evidence for this. Yes, there is a clear
relationship (OR's are between two and three in observational
studies), but when blood pressure (BP) is reduced by any one of four BP
drugs, there is no concurrent reduction in mortality. These drugs are
calcium channel blockers, diuretics, alpha blockers, and angiotensin
receptor blockers. The results of many trials showing this more or less
prove that either blood pressure reduction doesn't extend life, or
that side effects of all four just about exactly cancel out the
benefits. (more than cancel out in the case of alpha blockers.) Occam
says that the best guess is the former and that the apparent
relationship is due to the fact that something else is causing both hi
blood pressure and the vascular incidents. Beta blockers and ACEi do
show a mortality benefit, but if it's due to the reduction of blood
pressure what's wrong with the other four drugs?  Beta blockers
inhibit the action of adrenaline and noradrenalin this reduces stress
and may well the mechanism for the very moderate life extension by beta
blockers.
As for the ACEi, Doug has shown life extension in two
trials with drosophila, Tim has posted a sound study suggesting strong
mitochondrial benefits, and I've posted papers showing cancer, and
neurodegeneration benefits, protection from calcification thru Klotho,
an antiaging gene, and  reversal of carotid atherogenesis in a small
human intervention trial. This last is a trial with pomegranate juice
(as were Doug's experiments) which, based on skimpy evidence is by
far the best ACEi with action that not only goes beyond BP reduction,
but also beyond ACE inhibition itself, and with BP and ACE inhibition
equal to the drugs.
If ACEi cause a 10-20% reduction in mortality in heart
patients without benefiting them thru BP reduction it seems quite
possible that a similar benefit will be seen in the general population,
perhaps even better with long term use. In summary I too, believe this
issue bears watching, am  not quite as apprehensive as Steve over the
moderate life extension so far shown in short term trials of patients,
and ask the question,  is the risk/benefit ratio for drinking a glass
of pomegranate juice low enough to warrant this intervention by life
extensionists?
       
        Thomas
Sbharris[atsign]ix.netcom.com - 16 Dec 2004 22:23 GMT
Thomas:

In the very large ALLHAT study the "diuretic" antihypertensive
chlorthalidone did better at decreasing morbitity and mortality than
did the ACE drug. Things aren't as simple as you paint them.
http://www.aafp.org/afp/20040701/fpin.html

Steve
tcarter2@elp.rr.com - 17 Dec 2004 23:13 GMT
Hi Steve,
Yes, quite true and very consistent with about a half dozen
other trials comparing ACEi with other classes of blood pressure drugs.
ACEi are not used as stand alone treatments in hypertension for that
very reason, they are one of the types of drugs that don't reduce
mortality in heart patients over the 2 to 5 yrs that most trials run.
But this is niether my point nor yours, we are both discussing the
possible anti-aging aspects of ACEi. The 10 to 20% reduction in
mortality I refered to is for ACEi vs placebo as a second line
treatment, mostly with thiazides, a type of diuretic that does get
about a 10% reduction in mortality as a stand alone treatment. Some
beta blockers get about the same and ACEi along with other types get
little or none.
What you believe bears watching is the long term potential for
ACEi as an anti-aging intervention. While I agree I also intend to do a
bit more than watch while waiting for elucidation. And I intend watch
closely to see which ACEi gives the best results while supplementing
with one which I think already has displayed a satisfactory
risk/benefit ratio.

Thomas
RArmant - 18 Dec 2004 00:22 GMT
>What you believe bears watching is the long term potential for
>ACEi as an anti-aging intervention. While I agree I also intend to do a
>bit more than watch while waiting for elucidation.

>And I intend watch
>closely to see which ACEi gives the best results while supplementing
>with one which I think already has displayed a satisfactory
>risk/benefit ratio.

Which ACE inhibitor would that be?
tcarter2@elp.rr.com - 18 Dec 2004 20:59 GMT
Hi, RArmant,
Pomegranate juice, Google it in sci.life-extension for
evidence from peer reviewed journals showing it to be as good as the
prescribed drugs at BP reduction and ACE Inhibition, and AFAIK the best
treatment known to man for reducing atherosclerosis, the biggest killer
known to man.  (If a small intervention trial I posted is verified)
I will also to take this opportunity to clarify my remarks as
they were I think not very well written. Drugs that reduce blood
pressure do not in general extend life span in hypertensives at hi risk
for heart attacks. This signifies to me that hi blood pressure is not
the killer its made out to be, perhaps within reasonable limits not a
killer at all. In fact Ive posted studies showing high BP is related
to slower brain aging and extended life span in studies done on elderly
people. Some BP drugs do give a modest 10% reduction in mortality.
Logically it would seem this is due to effects other than reduction in
BP.
ACEi are not a good stand alone treatment for BP in general.
One of their protective mechanisms seems to be that they inhance the
bodies natural antioxidative defenses. This effect may not be strong
enough to give protection to heart disease patients who are already
well down the road to heart failure. For those who are more healthy,
and especially older ones, who suffer more from oxidative stress they
may well be the best when given long term. See the paper I post below
which indicates so. Note that this study ran for four years which is
one of the longer ones. Even if not true, ACEi are well known to be
life extending when given with other BP drugs. These facts indicate
that ACEi are beneficial to people with hi BP and at hi risk for heart
attacks,  are probably beneficial to normaly healthy people,  and may
be an authentic anti aging intervention.
For normal healthy people natural health products long
recognized as safe which inhibit the ACE would seem to be indicated.
They are among others. Sour milk, bonito, tea, salt, grape seed/skin
extract, and pomegranate juice which is by far the strongest and best
researched in this respect.  There is some evidence that each of these
substances is life extending.

N Engl J Med. 2003 Feb 13;348(7):583-92. Related Articles, Links
Comment in:
ACP J Club. 2003 Sep-Oct;139(2):38.
Expert Opin Pharmacother. 2003 May;4(5):825-8.
J Fam Pract. 2003 Jun;52(6):436-8.
N Engl J Med. 2003 Feb 13;348(7):639-41.
N Engl J Med. 2003 Jul 3;349(1):90-3; author reply 90-3.
N Engl J Med. 2003 Jul 3;349(1):90-3; author reply 90-3.
N Engl J Med. 2003 Jul 3;349(1):90-3; author reply 90-3.
N Engl J Med. 2003 Jul 3;349(1):90-3; author reply 90-3.
N Engl J Med. 2003 Jul 3;349(1):90-3; author reply 90-3.
A comparison of outcomes with angiotensin-converting--enzyme
inhibitors and diuretics for hypertension in the elderly.
Wing LM, Reid CM, Ryan P, Beilin LJ, Brown MA, Jennings GL, Johnston
CI, McNeil JJ, Macdonald GJ, Marley JE, Morgan TO, West MJ; Second
Australian National Blood Pressure Study Group.
School of Medicine, Flinders University, Adelaide, Australia.
BACKGROUND: Treatment of hypertension with diuretics,
beta-blockers, or both leads to improved outcomes. It has been
postulated that agents that inhibit the renin-angiotensin system confer
benefit beyond the reduction of blood pressure alone. We compared the
outcomes in older subjects with hypertension who were treated with
angiotensin-converting-enzyme (ACE) inhibitors with the outcomes in
those treated with diuretic agents. METHODS: We conducted a
prospective, randomized, open-label study with blinded assessment of
end points in 6083 subjects with hypertension who were 65 to 84 years
of age and received health care at 1594 family practices. Subjects were
followed for a median of 4.1 years, and the total numbers of
cardiovascular events in the two treatment groups were compared with
the use of multivariate proportional-hazards models. RESULTS: At base
line, the treatment groups were well matched in terms of age, sex, and
blood pressure. By the end of the study, blood pressure had decreased
to a similar extent in both groups (a decrease of 26/12 mm Hg). There
were 695 cardiovascular events or deaths from any cause in the
ACE-inhibitor group (56.1 per 1000 patient-years) and 736
cardiovascular events or deaths from any cause in the diuretic group
(59.8 per 1000 patient-years; the hazard ratio for a cardiovascular
event or death with ACE-inhibitor treatment was 0.89 [95 percent
confidence interval, 0.79 to 1.00]; P=0.05). Among male subjects, the
hazard ratio was 0.83 (95 percent confidence interval, 0.71 to 0.97;
P=0.02); among female subjects, the hazard ratio was 1.00 (95 percent
confidence interval, 0.83 to 1.21; P=0.98); the P value for the
interaction between sex and treatment-group assignment was 0.15. The
rates of nonfatal cardiovascular events and myocardial infarctions
decreased with ACE-inhibitor treatment, whereas a similar number of
strokes occurred in each group (although there were more fatal strokes
in the ACE-inhibitor group). CONCLUSIONS: Initiation of
antihypertensive treatment involving ACE inhibitors in older subjects,
particularly men, appears to lead to better outcomes than treatment
with diuretic agents, despite similar reductions of blood pressure.
Copyright 2003 Massachusetts Medical SocietyPMID: 12584366
christopher.a.dowling@gmail.com - 18 Dec 2004 01:29 GMT
Do you think there's any merit to "natural" ACE inhibitors, such as the
katuobishi oligopeptide?
Hua Kul - 17 Dec 2004 15:34 GMT
Dr. Moskowitz has been quite open to direct email exchanges if you want
to correspond.  His treatment aims at reducing tissue levels of ACE, or
blocking ACE receptors, or a combination.  He has had very good success
in helping patients recover from West Nile virus.

He currently has an application on the Genomed web site to take part in
his study for use of ACE inhibitors against influenza.  You can print
it out and take it to your doctor for "admission" to the trial.  It
might be more beneficial than a flu vaccine.

Here's a brief interview with him:
http://www.chronicfatiguesupport.com/library/showarticle.cfm/ID/5007/e/1/T/CFIDS_FM/

==================================================================

I began studying the angiotensin I-converting enzyme or "ACE" gene ten
years ago, while still in academia. My lab found that over-activity of
ACE was responsible for kidney failure due to diabetes and high blood
pressure. What was surprising was that another 150 or so diseases
seemed to be caused by too much ACE activity.

Our approach is to attack diseases at their source, so as to achieve
regression ("cure"). It just so happens that ACE appears to be at the
source of virtually all common diseases except prostate cancer. In
particular, all autoimmune diseases, such as Lupus, Rheumatoid
Arthritis, Multiple Sclerosis, and even allergies to penicillin and
sulfa drugs, start with overactivity of ACE. The logical treatment to
try, then, especially for diseases with no good treatment yet, is an
ACE inhibitor or an angiotensin II blocker (ACE makes angiotensin II).

..............................

But the symptoms of CFS and FM most resemble the flu, and suggest the
work of the monocyte/macrophage, a key player in the host's innate
immune response. Tumor necrosis factor-alpha (tnf-alpha, or cachectin)
is just one of many hormones released by activated macrophages. In
fact, most of the symptoms of the flu (muscle aches or "myalgias,"
weakness, fatigue) are due to release of hormones from macrophages.

Since activated macrophages express ACE on their surface membrane, ACE
has something to do with their activated state. The product of ACE,
angiotensin II, is probably an activating hormone, or "cytokine," for
macrophages. Blocking the macrophage with an ACE inhibitor or
angiotensin II receptor blocker ("arb") is a very gentle, benign way of
trying to tone down the inflammation. We have seen it work for several
diseases already characterized by overly exuberant inflammation or even
outright autoimmune disease.
==================================================================
--Hua Kul
Daniel Prince - 17 Dec 2004 20:56 GMT
>But the symptoms of CFS and FM most resemble the flu, and suggest the
>work of the monocyte/macrophage, a key player in the host's innate
>immune response. Tumor necrosis factor-alpha (tnf-alpha, or cachectin)
>is just one of many hormones released by activated macrophages. In
>fact, most of the symptoms of the flu (muscle aches or "myalgias,"
>weakness, fatigue) are due to release of hormones from macrophages.

Please post this entire message on alt.med.cfs.  Thank you for
posting it on sci.med and in advance for posting it on alt.med.cfs.
-
Signature

I am TERRIBLY cruel to my cat.  I tease him with a vine tendril
until he either jumps up in the air to bat at it or zooms around
in a circle until he gets too dizzy to stand up.  What is cruel about
it is that I don't do it nearly as much as he wants me to.

Hua Kul - 22 Dec 2004 05:53 GMT
> Please post this entire message on alt.med.cfs. Thank you for
> posting it on sci.med and in advance for posting it on alt.med.cfs

Daniel, I posted the topic several days ago on alt.med.cfs but it has
not yet appeared.  It's a moderated group so I don't know what else I
can do.  There have been other new topics posted since I submitted this
one.

--Hua Kul
Daniel Prince - 22 Dec 2004 07:06 GMT
>> Please post this entire message on alt.med.cfs. Thank you for
>> posting it on sci.med and in advance for posting it on alt.med.cfs
[quoted text clipped - 5 lines]
>
>--Hua Kul

May I post it for you?  I will make it clear that the original
message was from you.
Signature

I am TERRIBLY cruel to my cat.  I tease him with a vine tendril
until he either jumps up in the air to bat at it or zooms around
in a circle until he gets too dizzy to stand up.  What is cruel about
it is that I don't do it nearly as much as he wants me to.

gmp@adres.nl - 22 Dec 2004 13:27 GMT
> >> Please post this entire message on alt.med.cfs. Thank you for
> >> posting it on sci.med and in advance for posting it on alt.med.cfs
[quoted text clipped - 12 lines]
> until he either jumps up in the air to bat at it or zooms around
> in a circle until he gets too dizzy to stand up.  What is cruel about

> it is that I don't do it nearly as much as he wants me to.

Feel free to post the article under your own name if you would like, no
problem.

--Hua Kul
 
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