NEUROVASCULAR MEDICINE - Pursuing Cellular Longevity for Healthy Aging Part 1 ppsx

NEUROVASCULAR MEDICINE

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Neurovascular Medicine

Pursuing Cellular Longevity

for Healthy Aging

Kenneth Maiese, MD

Division of Cellular and Molecular

Cerebral Ischemia

Departments of Neurology and Anatomy &

Cell Biology

Barbara Ann Karmanos Cancer Institute

Center for Molecular Medicine and Genetics

Institute of Environmental Health Sciences

Wayne State University School of Medicine

Detroit, MI

1

2009

3

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Library of Congress Cataloging-in-Publication Data

Neurovascular medicine: pursuing cellular longevity for

healthy aging / [edited by] Kenneth Maiese.

p. ; cm.

Includes bibliographical references and index.

ISBN 978-0-19-532669-7

1. Pathology, Cellular. 2. Pathology, Molecular. 3. Nervous system—Degeneration.

4. Infl ammation—Mediators. I. Maiese, Kenneth, 1958- [DNLM: 1. Nervous System Physiology.

2. Aging—physiology. 3. Cell Physiology. 4. Neurodegenerative

Diseases—prevention & control. 5. Neurons—physiology. WL 102 N5122 2008]

RB113.N48 2008

616.07—dc22 2008006253

9 8 7 6 5 4 3 2 1

Printed in China

on acid-free paper

Preface

It is estimated that more than 500 million individuals

suffer from nervous and vascular system disorders in

the world. These disorders can comprise both acute

and chronic degenerative diseases that involve hyper￾tension, cardiac insuffi ciency, stroke, traumatic brain

injury, presenile dementia, Alzheimer’s disease, and

Parkinson’s disease. In regards to metabolic disor￾ders such as diabetes mellitus, diabetes itself is pre￾sent in more than 165 million individuals worldwide,

and by the year 2030, it is predicted that more than

360 million individuals will be affected by diabe￾tes mellitus. Of potentially greater concern is the

incidence of undiagnosed diabetes that consists of

impaired glucose tolerance and fl uctuations in serum

glucose levels that can increase the risk for acute and

long-term complications in the vascular and cardiac

systems.

Considering the signifi cant risks that can be pre￾sented to the nervous and vascular systems, it is sur￾prising to learn that organs such as the brain are

highly susceptible to loss of cellular function and have

only limited capacity to avert cellular injury. A vari￾ety of observations support this premise. For example,

the brain possesses the highest oxygen metabolic rate

of any organ in the body, consuming 20% of the total

amount of oxygen in the body and enhancing the

possibility for the aberrant generation of free radi￾cals. In addition, the brain is composed of signifi -

cant amounts of unsaturated fats that can readily

serve as a source of oxygen free radicals to result in

oxidative stress. Although a number of mechanisms

can account for the loss of neuronal and vascular

cells, the generation of cellular oxidative stress rep￾resents a signifi cant component for the onset of

pathological complications. Initial work in this fi eld

by early pioneers observed that increased metabolic

rates could be detrimental to animals in an elevated

oxygen environment. More current studies outline

potential aging mechanisms and accumulated toxic

effects for an organism that are tied to oxidative

stress. The effects of oxidative stress are linked to the

generation of oxygen free radical species in excessive

or uncontrolled amounts during the reduction of

oxygen. These oxygen free radicals are usually pro￾duced at low levels during normal physiological condi￾tions and are scavenged by a number of endogenous

antioxidant systems such as superoxide dismutase;

glutathione peroxidase; and small molecule sub￾stances such as vitamins C, E, D3, and B3.

Yet, the brain and vascular system may suffer from

an inadequate defense system against oxidative stress

despite the increased risk factors for the generation of

elevated levels of free radicals in the brain. Catalase

activity in the brain, an endogenous antioxidant, has

been reported to exist at levels markedly below those

in the other organs of the body, sometimes approach￾ing catalase levels as low as 10% in other organs such

as the liver. Free radical species that are not scavenged

can ultimately lead to cellular injury and programmed

cell death, also known as apoptosis. Interestingly, it

has recently been shown that genes involved in the

apoptotic process are replicated early during pro￾cesses that involve cell replication and transcription,

suggesting a much broader role for these genes than

originally anticipated. Apoptotically induced oxida￾tive stress can contribute to a variety of disease states,

such as diabetes, cardiac insuffi ciency, Alzheimer’s

disease, trauma, and stroke and lead to the impair￾ment or death of neuronal and vascular endothelial

cells.

It is clear that disorders of the nervous and vascu￾lar systems continue to burden the planet’s population

not only with increasing morbidity and mortality but

also with a signifi cant fi nancial drain through increas￾ing medical care costs coupled to a progressive loss in

economic productivity. With the varied nature of dis￾eases that can develop and the multiple cellular path￾ways that must function together to lead to a specifi c

disease pathology, one may predict that the complex￾ity that occurs inside a cell will also defi ne the varied

relationships that can result among different cells that

involve neuronal, vascular, and glial cells. For example,

v