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kofi

Posted: Mon Jan 12, 2004 1:41 am

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http://www.sciencedaily.com/releases/2004/01/040105071356.htm

Source:
University Of California, Los Angeles

Date:
2004-01-05
Neuroscientists Pinpoint Midlife Crisis In Brain Circuitry As Key To
Brain Aging And Onset Of Alzheimer's Later In Life

A novel model of human brain aging developed by a UCLA neuroscientist
identifies midlife breakdown of myelin, a fatty insulation coating the
brain's internal wiring, as a possible key to the onset of Alzheimer's
disease later in life.

Detailed in the January edition of the peer-reviewed journal
Neurobiology of Aging, the model presents opportunities to explore how
lifestyle changes, hormone replacement therapy, higher education or
treatment with common medications in middle age might help brains remain
healthy longer.

"This model embraces the human brain as a high-speed Internet rather
than a computer. The quality of the Internet's connections is the key to
its speed, fidelity and overall capability," said Dr. George Bartzokis,
the author and visiting professor of neurology at UCLA's David Geffen
School of Medicine. He also is director of the UCLA Memory Disorders and
Alzheimer's Disease Clinic and Clinical Core director of the UCLA
Alzheimer's Disease Research Center.

"Close analysis of brain tissue and MRIs clearly shows that the brain's
wiring develops until middle age and then begins to decline as the
breakdown of myelin triggers a destructive domino affect. Our time at
the peak is short indeed," Bartzokis said. "The challenge for science
and medicine is to figure out how to extend the brain's peak performance
so that our minds function as long as our bodies."

The journal also published six commentaries on the model written by
investigators from around the world, as well as a response by Bartzokis.
The response expands on his findings to discuss the role myelin plays in
overall brain function as well as its dysfunction in many other
neuropsychiatric disorders that occur over the human lifespan.

Myelin is a sheet of lipid, or fat, with very high cholesterol content ‹
the highest of any brain tissue. The high cholesterol content allows
myelin to wrap tightly around axons, speeding messages through the brain
by insulating these neural "wire" connections.

As the brain continues to develop in adulthood and as myelin is produced
in greater and greater quantities, cholesterol levels in the brain grow
and eventually promote the production of a toxic protein that attacks
the brain. The protein attacks myelin, disrupts message transfer through
the axons and eventually leads to the brain/mind-destroying plaques and
tangles visible years later in the cortex of Alzheimer's patients.

Bartzokis' analysis of magnetic resonance images and post-mortem tissue
data suggests that genetic factors coupled with the brain's own
developmental process of increasing cholesterol and iron levels in
middle age help degrade the myelin. The papers describe how complex
connections that take the longest to develop and allow humans to think
at their highest level are among the first to deteriorate as the brain's
myelin breaks down in reverse order of development.

"The body was designed to myelinate through the natural lifespan.
Medical advances, however, have expanded the lifespan well beyond the
brain's natural capacity to operate in a healthy, efficient manner,"
Bartzokis said. "The process of adult brain development and becoming
'wiser' has this downside that evolution could not anticipate."

This new model of brain development and degeneration suggests that the
best time to address the inevitability of myelin breakdown is when it
begins, in middle age. By the time the effects of Alzheimer's disease
become apparent in a patient's 60s, 70s or 80s, it may be too late to
reverse the course of the disease.

Preventive therapies worth investigating include cholesterol- and
iron-lowering medications, anti-inflammatory medications, diet and
exercise programs and possibly hormone replacement therapy designed to
prevent menopause rather than simply ease the symptoms. In addition,
education or other activities designed to keep the mind active may
stimulate the production of myelin. Finally, there may be ways to
address genetic and environmental factors that accelerate the
degeneration process.

Commentaries accompanying the paper were written by Drs. Francine M.
Benes, Harvard Medical School; Heiko Braak and Kelly Del Tredici,
Frankfurt/Main, Germany; James R. Connor, Penn State University College
of Medicine, M.S. Hershey Medical Center; Terry L. Jernigan, University
of California, San Diego; Mark Noble, University of Rochester Medical
Center; and Gregory T. Whitman, and Carl W. Cotman, University of
California, Irvine.

The UCLA Department of Neurology encompasses 260 teachers, researchers
and clinicians, and 245 staff personnel involved in more than a dozen
research, clinical and teaching programs. These programs cover brain
mapping and neuroimaging, movement disorders, Alzheimer's disease,
multiple sclerosis, neurogenetics, nerve and muscle disorders, epilepsy,
neuro-oncology, neurotology, neuropsychology, headaches and migraines,
neurorehabilitation, and neurovascular disorders. The department ranks
No. 1 among its peers nationwide in National Institutes of Health
funding, with $23.4 million in active research grants.

The Alzheimer Disease Research Center (ADRC) at UCLA, directed by Dr.
Jeffrey L. Cummings, was established in 1991 by a grant from the
National Institute on Aging. Together with grants from the Alzheimer's
Disease Research Center of California and the Sidell-Kagam Foundation,
the center provides a mechanism for integrating, coordinating and
supporting new and ongoing research by established investigators in
Alzheimer's disease and aging. The Memory Disorders and Alzheimer's
Disease Clinic of the ADRC is an evaluation clinic for individuals over
the age of 45 who are experiencing mild but gradually progressing
cognitive or memory declines that are not related to other brain
diseases such as strokes, tumors, infection, metabolic abnormalities,
psychiatric disease or trauma.

Editor's Note: The original news release can be found here.
------------------------------------------------------------------------

This story has been adapted from a news release issued by University Of
California, Los Angeles.

‹‹‹‹‹‹‹   Copyright © 1995-2003 ScienceDaily Magazine   |   Contact:
editor@sciencedaily.com   ‹‹‹‹‹‹‹

Thomas Carter

Posted: Mon Jan 12, 2004 2:11 pm

Guest

Hi Kofi,
This ties in well with recent information on Alzheimer's vs Statins.

Thomas

Pharmacopsychiatry. 2003 Sep;36 Suppl 2:S113-9.

Brain cholesterol, statins and Alzheimer's Disease.

Kirsch C, Eckert GP, Koudinov AR, Muller WE.

Department of Pharmacology, Biocenter Niederursel, University of Frankfurt,
Frankfurt/M, Germany.

Growing evidence suggests that cellular cholesterol homeostasis is causally
involved in different steps leading to pathological events in the brain of
Alzheimer's Disease (AD) patients. It was previously demonstrated that the
processing of the amyloid beta-peptide precursor protein (APP) is modulated by
pronounced alterations in cellular cholesterol levels using statins or
cholesterol extracting agents. However, a cholesterol-rich diet was found to
enhance amyloid beta-peptide (Abeta) burden in the brain of transgenic mice
without clearly affecting total brain cholesterol levels. Recent retrospective
epidemiological studies have reported that the use of statins potentially
suppresses the development of AD. Although some HMG-CoA reductase inhibitors
seem to influence the central cholesterol pool in vivo, the above
epidemiological findings are probably not linked to statin-induced changes in
brain membrane cholesterol levels per se since not all statins active in
preventing AD enter the central nervous system (CNS). Recently, we reported that
different statins, regardless of their brain availability, induce alterations in
cellular cholesterol distribution in the brain. Such pleiotropic,
cholesterol-synthesis independent statin effects might be indirect and are
possibly mediated at the blood-brain barrier (BBB) via nitric oxide (NO) or
apolipoprotein E (ApoE).

PMID: 14574624

kofi

Posted: Tue Jan 13, 2004 12:21 am

Guest

Thanks. It might have to do with the relationship between NAD/NADH and
HDL/eNOS I've been posting about today. Increasing HDL - which statins
do - probably decreases LDL-driven inflammation and renders nitric oxide
generation more efficient in the brain. I would guess HDL has mild
life-extending effects. Astilbin is a natural statin like red yeast
rice - although I have no idea where to purchase it from. Estrogen
stimulates HDL levels and probably arginine would help too. There are a
few polyphenols which raise HDL, I think. Any gene that shifted
production from LDL to HDL would probably be good.

Thomas Carter

Posted: Tue Jan 13, 2004 3:12 pm

Guest

kofi <kofi@anon.un> wrote in message news:<kofi-C24AA2.23222712012004@news03.east.earthlink.net>...

Quote:

Hi Kofi,
Yes, at least mild life extending benefits, I would say.
Exercise raises it. There are drugs in the works that might do it.

Thomas

J Am Geriatr Soc 2001 Jan;49(1):76-9

Offspring of centenarians have a favorable lipid profile.
Barzilai N, Gabriely I, Gabriely M, Iankowitz N, Sorkin JD.
Department of Medicine, Albert Einstein College of Medicine, Bronx,
New York 10461, USA.
OBJECTIVES: It is well recognized that a favorable lipid profile
provides protection from atherosclerotic cardiovascular disease.
Because the major cause of nontraumatic death in the western world is
considered to be due to cardiovascular disease, centenarians (defined
here as subjects over 95 years of age) are believed to possess
"atherosclerotic protective" factors. However, it is impossible to
study comparatively the lipid profile in centenarians because of lack
of controls. Assuming that certain genes responsible for encoding the
lipid phenotype may be inherited, we studied the lipid profile
characteristics of offspring of centenarians and compared them with
control groups. DESIGN: Prospective cohort study. SETTING: The study
was part of the Longevity Genes Project at Albert Einstein College of
Medicine. PARTICIPANTS: Ashkenazi Jewish centenarians (n = 27, 98.4
+/- 10.4 years) and their offspring (n = 33, 67.4 +/- 1.4 years). The
Ashkenazi Jewish offsprings' spouses, who were not related by blood to
the centenarians or their offspring, were used as a control group (n =
26, 68.4 +/- 1.2 years). MEASUREMENTS: The lipoprotein profile of the
offspring was compared with the above control group and to a larger
control group (age and gender matched) from the National Health and
Nutrition Examination Survey (NHANES) III study (without the sample
weights, n = 394, 60 to 69 years). RESULTS: Female offspring of
centenarians had significantly higher plasma levels of high density
lipoprotein-cholesterol (HDL-C) levels compared with controls (70.2
+/- 3.1 vs 59.0 +/- 4.1 mg/dl, P = .029). Male offspring of
centenarians had higher plasma levels of HDL-C levels (56.2 +/- 7.1 vs
44.3 +/- 3.4 mg/dl, P = 0.130) and significantly lower LDL-cholesterol
(LDL-C) levels (95.0 +/- 6.0 vs 127.0 +/- 8.0 mg/dl, P = .009)
compared with controls. CONCLUSION: Offspring of centenarians have a
favorable lipid profile compared with controls. These data support the
notion that a certain phenotypic lipid profile may be transmitted in
families and suggest that a favorable lipid profile may play a role in
longevity.
PMID: 11207846
In the study, Thomas Perls, M.D., director of the New England
Centenarian Study in Boston, John Wilmoth, Ph.D., of the University of
California, Berkeley, and other researchers analyzed data collected
from 444 families that had at least one member living to age 100 or
older. According to the analysis, sisters of centenarians had about
one-half the risk of dying at any given age compared to the national
average. Brothers of centenarians had similarly low mortality rates,
except during the teenage years and young adulthood. These decreased
mortality rates greatly enhanced the odds that siblings of
centenarians would become centenarians themselves. Compared to the
general population, brothers of centenarians were 17 times more likely
to achieve age 100, and sisters were at least eight times more likely
to reach this age.

J Am Geriatr Soc 1997 Dec;45(12):1504-9

Preserved antilipolytic insulin action is associated with a less
atherogenic plasma lipid profile in healthy centenarians.
Paolisso G, Gambardella A, Ammendola S, Tagliamonte MR, Rizzo MR,
Capurso A, Varricchio M.
Department of Geriatric Medicine and Metabolic Diseases, II University
of Naples, Italy.
OBJECTIVE: Recent studies have demonstrated that centenarians have a
preserved glucose tolerance and insulin action and a more favorable
body composition and fat distribution than aged subjects. The strong
relationship among glucose tolerance, insulin action, plasma lipid
concentration, and lipoprotein metabolism would lead to the hypothesis
that healthy centenarians may also have a less atherogenic profile
than aged subjects less than 100 years old. DESIGN: Investigation of
the relationship between insulin action and lipid metabolism in
healthy centenarians. PARTICIPANTS: Fifty-six subjects were
categorized into three groups: Adults (< or = 50 years old; n = 20);
Aged (> or = 75 years old; n = 22); Centenarians (> or = 100 years
old; n = 14). The latter represented a select group of individuals
free of major age-related diseases. MEASUREMENTS: Anthropometric
measurements were made in all subjects, fasting blood samples were
drawn for metabolite determinations, and an euglycemic glucose clamp
was performed. RESULTS: Compared with aged subjects, healthy
centenarians appeared to have a less atherogenic plasma lipid profile.
Fasting plasma LDL cholesterol (2.4 +/- 0.6 vs 3.7 +/- .6 mmol/L P <
..010) was significantly higher in aged subjects than in centenarians,
whereas fasting plasma HDL cholesterol (1.0 +/- 0.4 vs 1.7 +/- .4
mmol/L P < .005) had an opposite trend. In centenarians,
insulin-mediated glucose uptake was greater (34.6 +/- 0.5 vs 23.3 +/-
..05 mumol/Kg FFM x min P < .010) than in aged subjects and correlated
with fasting plasma triglycerides, FFA, LDL, and HDL cholesterol, Apo
B, and Apo A1 concentrations. Finally, insulin infusion suppressed
plasma FFA concentration in similar ways in adults and centenarians.
CONCLUSION: Our study demonstrates that centenarians have a less
atherogenic plasma lipid and lipoprotein profile than aged subjects.
PMID: 9400562
Supersized cholesterol carriers key to long life?
Researchers say genetic variation necessary for longevity
Tuesday, October 14, 2003 Posted: 4:03 PM EDT (2003 GMT)
CHICAGO, Illinois (AP) -- One reason some people live into their 90s
and beyond may be a genetic variation that makes the cholesterol
particles in their blood really big.
"Supersize it" is not usually associated with good health, but
evidence increasingly is showing that bigger is indeed better when it
comes to the lipoprotein particles that carry cholesterol through the
bloodstream.
Smaller particles, it is believed, can more easily embed themselves in
the blood vessel walls, contributing to the fatty buildups that lead
to heart attacks and strokes.
A study in Wednesday's Journal of the American Medical Association
suggests that the tendency to have large cholesterol particles can be
inborn.
The study, led by Dr. Nir Barzilai, director of the Institute for
Aging Research at Albert Einstein College of Medicine, found that
people in their late 90s and beyond are more likely to have a gene
variation that causes large particles of both HDL cholesterol -- the
good variety -- and LDL cholesterol, the bad kind.
"We basically think the size is necessary for longevity," Barzilai
said.
The results are intriguing and support the notion that "exceptional
longevity may depend, at least in part, on inheriting 'good' genes,"
said Anna McCormick of the National Institute on Aging, which helped
fund the study.
Nevertheless, while genes probably determine particle size, recent
research has suggested that exercise can enlarge the particles.
Doctors do not routinely test for HDL and LDL particle size, but a few
companies offer such tests commercially. If the findings are
confirmed, they could lead to wider testing. Moreover, research is
already under way on a cholesterol-lowering drug that also makes the
particles bigger.
And Dr. Ronald M. Krauss, director of atherosclerosis research at
Children's Hospital Oakland Research Institute, said the findings
suggest that large HDL and LDL particles may protect against all sorts
of life-shortening ailments, not just heart disease.
The study involved 213 people of Ashkenazi, or Eastern European,
Jewish descent, ages 95 to 107, along with 216 of their children. The
researchers also used a comparison group made up of 258 of the
children's spouses and neighbors.
The gene variation was found in nearly 25 percent of the old people
but in just 8.6 percent of the younger comparison group, a threefold
difference. The related children were twice as likely to have the
mutation as the comparison group.
The Ashkenazi group and their children also had greater levels of HDL
cholesterol in their blood and substantially larger HDL and LDL
particles than the comparison subjects.
J Am Geriatr Soc 2001 Jan;49(1):76-9

Offspring of centenarians have a favorable lipid profile.
Barzilai N, Gabriely I, Gabriely M, Iankowitz N, Sorkin JD.
Department of Medicine, Albert Einstein College of Medicine, Bronx,
New York 10461, USA.
OBJECTIVES: It is well recognized that a favorable lipid profile
provides protection from atherosclerotic cardiovascular disease.
Because the major cause of nontraumatic death in the western world is
considered to be due to cardiovascular disease, centenarians (defined
here as subjects over 95 years of age) are believed to possess
"atherosclerotic protective" factors. However, it is impossible to
study comparatively the lipid profile in centenarians because of lack
of controls. Assuming that certain genes responsible for encoding the
lipid phenotype may be inherited, we studied the lipid profile
characteristics of offspring of centenarians and compared them with
control groups. DESIGN: Prospective cohort study. SETTING: The study
was part of the Longevity Genes Project at Albert Einstein College of
Medicine. PARTICIPANTS: Ashkenazi Jewish centenarians (n = 27, 98.4
+/- 10.4 years) and their offspring (n = 33, 67.4 +/- 1.4 years). The
Ashkenazi Jewish offsprings' spouses, who were not related by blood to
the centenarians or their offspring, were used as a control group (n =
26, 68.4 +/- 1.2 years). MEASUREMENTS: The lipoprotein profile of the
offspring was compared with the above control group and to a larger
control group (age and gender matched) from the National Health and
Nutrition Examination Survey (NHANES) III study (without the sample
weights, n = 394, 60 to 69 years). RESULTS: Female offspring of
centenarians had significantly higher plasma levels of high density
lipoprotein-cholesterol (HDL-C) levels compared with controls (70.2
+/- 3.1 vs 59.0 +/- 4.1 mg/dl, P = .029). Male offspring of
centenarians had higher plasma levels of HDL-C levels (56.2 +/- 7.1 vs
44.3 +/- 3.4 mg/dl, P = 0.130) and significantly lower LDL-cholesterol
(LDL-C) levels (95.0 +/- 6.0 vs 127.0 +/- 8.0 mg/dl, P = .009)
compared with controls. CONCLUSION: Offspring of centenarians have a
favorable lipid profile compared with controls. These data support the
notion that a certain phenotypic lipid profile may be transmitted in
families and suggest that a favorable lipid profile may play a role in
longevity.
PMID: 11207846

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