Understanding the Process of Aging: The Roles of Mitochondria: Free Radicals, and Antioxidants

384 Pages·1999·1.17 MB·English

by  Lester Packer

Page i
Understanding the Process of Aging
The Roles of Mitochondria, Free Radials, and Antioxidants
edited by
Enrique Cadenas
University of Southern California School of Pharmacy
Los Angeles, California
Lester Packer
University of California
Berkeley, California
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ISBN: 0-8247-1723-6
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Series Introduction
Oxygen is a dangerous friend. Overwhelming evidence indicates that oxidative stress can lead to cell and tissue injury.
However, the same free radicals that are generated during oxidative stress are produced during normal metabolism and
thus are involved in both human health and disease.
Free radicals are molecules with an odd number of electrons. The odd, or
unpaired, electron is highly reactive as it seeks to pair with another free
electron.
Free radicals are generated during oxidative metabolism and energy
production in the body.
Free radicals are involved in:
Enzyme-catalyzed reactions
Electron transport in mitochondria
Signal transduction and gene expression
Activation of nuclear transcription factors
Oxidative damage to molecules, cells, and tissues
Antimicrobicidal action of neutrophils and macrophages
Aging and disease
Normal metabolism is dependent upon oxygen, a free radical. Through evolution, oxygen was chosen as the terminal
electron acceptor for respiration. The two unpaired electrons of oxygen spin in the same direction; thus, oxygen is a
biradical, but is not a very dangerous free radical. Other oxygen-derived free radical species, such as superoxide or
hydroxyl radicals, formed during metabolism or by ionizing radiation are stronger oxidants and are therefore more
dangerous.
In addition to research on the biological effects of these reactive oxygen species, research on reactive nitrogen species
has been gathering momentum. NO, or nitrogen monoxide (nitric oxide), is a free radical generated by NO synthase
(NOS). This enzyme modulates physiological responses such as vasodilation or signaling in the brain. However,
during inflammation, synthesis of NOS
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(iNOS) is induced. This iNOS can result in the overproduction of NO, causing damage. More worrisome, however,
excess NO can react with superoxide to produce the very toxic product peroxynitrite. Oxidation of lipids, proteins, and
DNA can result, thereby increasing the likelihood of tissue injury.
Both reactive oxygen and nitrogen species are involved in normal cell regulation in which oxidants and redox status
are important in signal transduction. Oxidative stress is increasingly seen as a major upstream component in the
signaling cascade involved in inflammatory responses, stimulating adhesion molecule and chemotractant production.
Hydrogen peroxide, which breaks down to produce hydroxyl radicals, can also activate NFKB, a transcription factor
involved in stimulating inflammatory responses. Excess production of these reactive species is toxic, exerting
cytostatic effects, causing membrane damage, and activating pathways of cell death (apoptosis and/or necrosis).
Virtually all diseases thus far examined involve free radicals. In most cases, free radicals are secondary to the disease
process, but in some instances free radicals are causal. Thus, there is a delicate balance between oxidants and
antioxidants in health and disease. Their proper balance is essential for ensuring healthy aging.
The term oxidative stress indicates that the antioxidant status of cells and tissues is altered by exposure to oxidants.
The redox status is thus dependent upon the degree to which a cell's components are in the oxidized state. In general,
the reducing environment inside cells helps to prevent oxidative damage. In this reducing environment, disulfide bonds
(S—S) do not spontaneously form because sulfhydryl groups kept in the reduced state (SH) prevent protein
misfolding or aggregation. This reducing environment is maintained by oxidative metabolism and by the action of
antioxidant enzymes and substances, such as glutathione, thioredoxin, vitamins E and C, and enzymes such as
superoxide dismutase (SOD), catalase, and the selenium-dependent glutathione and thioredoxin hydroperoxidases,
which serve to remove reaction oxygen species.
Changes in the redox status and depletion of antioxidants occur during oxidative stress. The thiol redox status is a
useful index of oxidative stress mainly because metabolism and NADPH-dependent enzymes maintain cell glutathione
(GSH) almost completely in its reduced state. Oxidized glutathione (glutathione disulfide, GSSG) accumulates under
conditions of oxidant exposure, and this changes the ratio of oxidized to reduced glutathione; and increased ratio
indicates oxidative stress. Many tissues contain large amounts of glutathione 2-4 mM in erythrocytes or neural tissues
and up to 8 mM in hepatic tissues. Reactive oxygen and nitrogen species can directly react with glutathione to lower
the levels of this substance, the cell's primary preventative antioxidant.
Current hypotheses favor the idea that lowering oxidative stress can have a clinical benefit. Free radicals can be
overproduced or the natural antioxidant system defenses weakened, first resulting in oxidative stress, and then leading
to
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oxidative injury and disease. Examples of this process include heart disease and cancer. Oxidation of human low-
density lipoproteins is considered the first step in the progression and eventual development of atherosclerosis, leading
to cardiovascular disease. Oxidative DNA damage initiates carcinogenesis.
Compelling support for the involvement of free radicals in disease development comes from epidemiological studies
showing that an enhanced antioxidant status is associated with reduced risk of several diseases. Vitamin E and
prevention of cardiovascular disease is a notable example. Elevated antioxidant status is also associated with
decreased incidence of cataracts and cancer, and some recent reports have suggested an inverse correlation between
antioxidant status and occurrence of rheumatoid arthritis and diabetes mellitus. Indeed, the number of indications in
which antioxidants may be useful in the prevention and/or the treatment of disease is increasing.
Oxidative stress, rather than being the primary cause of disease, is more often a secondary complication in many
disorders. Oxidative stress diseases include inflammatory bowel disease, retinal ischemia, cardiovascular disease and
restenosis, AIDS, ARDS, and neurodegenerative diseases such as stroke, Parkinson's disease, and Alzheimer's
disease. Such indications may prove amenable to antioxidant treatment because there is a clear involvement of
oxidative injury in these disorders.
In this new series of books, the importance of oxidative stress in diseases associated with organ systems of the body
will be highlighted by exploring the scientific evidence and the medical applications of this knowledge. The series will
also highlight the major natural antioxidant enzymes and antioxidant substances such as vitamins F, A, and C,
flavonoids, polyphenols, carotenoids, lipoic acid, and other nutrients present in food and beverages.
Oxidative stress is an underlying factor in health and disease. More and more evidence is accumulating that a proper
balance between oxidants and antioxidants is involved in maintaining health and longevity, and that altering this
balance in favor of oxidants may result in pathological responses causing functional disorders and disease. This series
is intended for researchers in the basic biomedical sciences and clinicians. The potential for healthy aging and disease
prevention necessitates gaining further knowledge about how oxidants and antioxidants affect biological systems.
Since the beginning of the twentieth century, the human lifespan has undergone dramatic decreases in mortality and
the result has been to shift the human survival curve versus chronological age to the right, considerably increasing
average lifespan. The main factors leading to this dramatic improvement have been better hygiene, better nutrition,
and medical advances especially in decreasing infectious diseases. Further improvements in human lifespan now will
depend more critically upon intrinsic factors, a balance between metabolism and genetic factors, and environmental
influences. Oxidants and antioxidants must be main-
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tained in a delicate balance in order to reduce degenerative diseases of aging. In 1984, Dehnam Harman, who
originated the free radical theory on aging, stated "Very few individuals, if any, reach their potential maximum
lifespan; they die instead prematurely of a wide variety of diseases—the vast majority being from free radical
diseases." The truth of this statement seems more evident in these days in that cell signaling and gene expression have
been found to exhibit steps sensitive to oxidants, redox changes, and antioxidants. Hence, including this volume,
Understanding the Process of Aging: The Roles of Mitochondria, Free Radicals, and Antioxidants seems appropriate.
LESTER PACKER
ENRIQUE CADENAS
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Preface
The idea that free radicals may play a causal role in the aging process by producing cumulative oxidative damage was
advanced in 1956 by Denham Harman. With time, the free radical theory of aging has incorporated other ideas, such
as the concept of imbalance between pro- and antioxidants as the basis for oxidative molecular damage, thus evolving
into the oxidative stress hypothesis of aging. Early on, Harman also suggested that the mitochondrion was particularly
vulnerable to oxidative stress, a concept redefined by Miquel and his colleagues in the 1980s, who proposed that
senescence was a by-product of free radical attack on the mitochondrial genome of postmitotic cells.
Mitochondria have a prominent place in the oxidative stress hypothesis of aging for several reasons.
1. These organelles are the most abundant and important subcellular site of oxyradical production in mammalian
organs and the rate of oxidant generation increases with age.
2. Mitochondrial DNA is in close proximity to the sites of oxyradical generation and is not protected by histones;
consequently, oxidatively modified bases in mitochondrial DNA are more prevalent than in nuclear DNA.
3. Mitochondria are susceptible to accruing informational errors through oxidative damage to their DNA (and RNAs),
which encodes about 10% of the respiratory chain proteins.
4. Mitochondrial dysfunction elicited by oxyradicals has profound effects for the cell: this dysfunction can be
amplified into cellular death by triggering apoptotic pathways.
Thus the mitochondrial DNA hypothesis of aging incorporates most of the basic developments since the original free
radical hypothesis was formulated over 40 years ago.
This book is devoted largely to this current view of aging, to the role of mitochondria in cellular aging, apoptosis, and
neurodegeneration, and to the eval-
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uation of mutations of mitochondrial DNA in human aging and age-related diseases. Chapters on mitochondrial
production of oxygen-centered radicals, its pathophysiological regulation by nitric oxide, and implications for
mitochondrial function provide an unprecedented insight into the mechanistic basis underlying the cellular alterations
inherent in the aging process.
Each chapter summarizes the current knowledge in the field, provides an assessment of the role of mitochondria in
aging and age-related diseases, and poses new questions pertaining to this intense and fascinating area of research.
LESTER PACKER
ENRIQUE CADENAS
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Contents
Series Introduction iii
(Lester Packer and Enrique Cadenas)
Preface vii
Contributors xi
1. The Mitochondrial Production of Oxygen Radicals and Cellular 1
Aging
Alberto Boveris, Lidia E. Costa, And Enrique Cadenas
2. Walking a Tightrope: The Balance Between Mitochondrial 17
Generation and Scavenging of Superoxide Anion
David M. Guidot And Joe M. Mccord
3. The Biochemistry of Nitric Oxide and Peroxynitrite: Implications for 39
Mitochondrial Function
Rakesh P. Patel, Trudy Cornwell, And Victor M. Darley-Usmar
4. Oxygen-Dependent Regulation of Biological Functions by Nitric 57
Oxide
Kozo Utsumi, Yoshiki Takehara, Yoko Inai, Munehisa Yabuki, Tomoko
Kanno, Manabu Nishikawa, Eisuke F. Sato, and Masayasu Inoue
5. Production of Reactive Oxygen Species in Mitochondria and Age- 73
Associated Pathophysiology: A Reality Check
Henry Jay Forman And Angelo Azzi
6. Functional Roles of Ubiquinone 95
Jeffery R. Schultz And Catherine Freitag Clarke
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