Denham Harman

Oxygen Radicals and Human Disease

Toxic oxygen free radicals have been implicated as important pathologic mediators in many clinical disorders. We discuss the chemistry of oxygen radical production and the roles of iron and of various antioxidants as well as the diseases that have received active attention in oxy-radical research. Particular attention is focused on cigarette smoke oxidants, ischemia-reperfusion-induced radical production, carcinogenesis, and aging. Such research may well provide a firm foundation for therapeutic breakthroughs.

The Biologic Clock: The Mitochondria?

The author suggests that the maximal life span of a given mammalian species is largely an expression of genetic control over the rate of oxygen utilization. The latter determines the rate of accumulation of mitochondrial damage produced by free radical reactions, the rate increasing with the rate of oxygen consumption, which ultimately causes death.

Free radical theory of aging

Free radical reactions are ubiquitous in living things. Studies on the origin and evolution of life provide a reasonable explanation for the prominent presence of this unruly class of chemical reactions. These reactions have been implicated in aging. This phenomenon is the accumulation of changes responsible for the sequential alterations that accompany advancing age and the associated progressive increases in the chance of disease and death. Aging changes are attributed to the environment and disease, and to an inborn process, the aging process. The latter produces aging changes at an exponentially increasing rate with advancing age. Past improvements in general living conditions have decreased the chances for death so that they are now near limiting values in the developed countries. In these countries the intrinsic aging process is the major cause of disease and death after about age 28. The free radical theory of aging postulates that aging changes are caused by free radical reactions. The data supporting this theory indicate that average life expectancy at birth may be increased by 5 or more years, by nutritious low caloric diets supplemented with one or more free radical reaction inhibitors.

The Free Radical Theory of Aging

Free radical reactions are ubiquitous in living things. Studies on the origin and evolution of life provide a reasonable explanation for the prominent presence of this unruly class of chemical reactions. These reactions have been implicated in aging. This phenomenon is the accumulation of changes responsible for the sequential alterations that accompany advancing age and the associated progressive increases in the chance of disease and death. Aging changes are attributed to the environment and disease, and to an inborn process, the aging process. The latter produces aging changes at an exponentially increasing rate with advancing age. Past improvements in general living conditions have decreased the chances for death so that they are now near limiting values in the developed countries. In these countries the intrinsic aging process is the major cause of disease and death after about age 28. The free radical theory of aging postulates that aging changes are caused by free radical reactions. The data supporting this theory indicate that average life expectancy at birth may be increased by 5 or more years, by nutritious low caloric diets supplemented with one or more free radical reaction inhibitors.

Free radical theory of aging: an update: increasing the functional life span.

Abstract:  Aging is the progressive accumulation of diverse, deleterious changes with time that increase the chance of disease and death. The basic chemical process underlying aging was first advanced by the free radical theory of aging (FRTA) in 1954: the reaction of active free radicals, normally produced in the organisms, with cellular constituents initiates the changes associated with aging. The involvement of free radicals in aging is related to their key role in the origin and evolution of life. Aging changes are commonly attributed to development, genetic defects, the environment, disease, and an inborn aging process (IAP). The latter produces aging changes at an exponentially increasing rate with age, becoming the major risk factor for disease and death for humans after the age of 28 years in the developed countries. In them the IAP limits human average life expectancy at birth (ALE‐B)—a rough measure of the healthy life span—to about 85 years; few reach 100 years and only one is known to have lived to 122 years. In these countries, improvements in living conditions (ILC) have gradually raised ALE‐Bs to 76–79 years, 6–9 years less than the limit imposed by aging, with no change in the maximum life span (MLS). The extensive studies based on the FRTA hold promise that ALE‐B and the MLS can be extended, the ALE‐B possibly by a few years, and the MLS somewhat less.

Free radicals in aging.

SummaryAging is the progressive accumulation of changes with time that are responsible for the ever-increasing likelihood of disease and death. These irreversible changes are attributed to the aging process. This process is now the major cause of death in the developed countries. This fact is obscured by the protean nature of the contributions of this process to the events which terminate life.The aging process may be due to free radical reations. This theory is supported by: 1) studies on the origin and evolution of life; 2) the numerous studies of the effect of ionizing radiation on living systems; 3) life span experiments in which the diet was modified so as to alter endogenous free radical reaction levels; 4) the plausible explanations it provides for aging phenomena; and 5) the growing number of studies which implicate free radical reactions in the pathogenesis of specific diseases.The relationship between aging and diseases involving free radical reactions seems to be a direct one. Modulation of the normal distribution of deleterious free radical reaction-induced changes throughout the body by genetic and environmental differences between individuals results in patterns of change, in some sufficiently different from the normal aging pattern to be recognized as disease. The growing number of ‘free radical’ diseases includes the two major causes of death, cancer and atherosclerosis.It is reasonable to expect on the basis of present data that a judicious selection of diets and antioxidant supplements will increase the healthy, active life span by 5–10 or more years.

Free‐Radical Theory of Aging

Aging is the accumulation of changes that increase the risk of death. Aging changes can be attributed to development, genetic defects, the environment, disease, and an inborn process: the aging process. The latter is the major risk factor for disease and death after age 28 in the developed countries. In these countries, average life expectancies at birth (ALE-B) now range from 76 to 79 years, 6-9 years less than the limit of approximately 85 years imposed by aging. Aging changes may be caused by free radical reactions. The extensive studies based on this possibility hold promise that the ALE-B can be extended to >85 years and the maximum life span increased.

Free Radical Involvement in Aging

SummaryFree radical reactions are ubiquitous in living things. Studies on the origin and evolution of life provide a reasonable explanation for the prominent presence of this unruly class of chemical reactions. These reactions have been implicated in aging. Aging is the accumulation of changes responsible for the sequential alterations that accompany advancing age, and the associated progressive increases in the chance of disease and death. Aging changes are attributed to the environment and disease, and to an inborn process, the aging process. The latter produces aging changes at an exponentially increasing rate with advancing age. Improvements in general living conditions decrease the chance of death toward limiting values. Chances for death are now near these limits in the developed countries. Future significant increases in the average life span in the developed countries can only be achieved by slowing the rate of damage produced by the aging process. Support for the possibility that free radical reactions are responsible for the aging process now includes: i) studies on the origin of life and evolution; ii) studies on the effect of ionising radiation on living things; iii) dietary manipulations of endogenous free radical reactions; iv) the plausible explanations it provides for aging phenomena; and v) the growing numbers of studies that implicate free radical reactions in the pathogenesis of specific diseases. It is reasonable to expect on the basis of present data, that the average life expectancy at birth can be increased by 5 or more years by nutritious low caloric diets supplemented with one or more free radical reaction inhibitors.

Free radical theory of aging: Consequences of mitochondrial aging

Mitochondria may serve as biologic clocks. This paper provides plausible explanations, based on mitochondrial aging, of some aging phenomenon: a) the inverse relationship between basal metabolic rate and life span; b) the antioxidants studies thus far which increase the average life span of mice, depress body weight and fail to lengthen maximum life span; c) the association of degenerative diseases with the terminal part of the life span; d) the exponential nature of the mortality curve, and e) the beneficial effect of caloric restriction on degenerative diseases and life span. A short discussion is also presented of the effect of exercise on life span and aging of muscle mitochondria.

Free radical theory of aging: The “free radical” diseases

The free radical theory of aging postulates that free radical reactions are responsible for the progressive accumulation of changes with time associated with or responsible for the ever-increasing likelihood of disease and death that accompanies advancing age.Modulation of the normal distribution of deleterious free radical reaction-induced changes throughout the body by genetic and environmental differences between individuals results in patterns of change, in some sufficiently different from the normal aging pattern to be recognized as disease. These “free radical” diseases can be classified into three groups in which a given disorder is mainly due to: 1) genetics, 2) a combination of genetic and environmental factors, and 3) largely to environmental influences.The growing number of “free radical” diseases includes the two major causes of death, cancer and atherosclerosis. To illustrate the role of free radicals in disease a discussion is presented, of cancer, atherosclerosis, essential hypertension, senile dementia of the Alzheimer’s type, amyloidosis, and the immune deficiency of age.Dietary intervention in the “free radical” diseases can reasonably be expected to decrease the period of senescence and to increase by 5 or more years the span of healthy productive life.The free radical theory of aging postulates that free radical reactions are responsible for the progressive accumulation of changes with time associated with or responsible for the ever-increasing likelihood of disease and death that accompanies advancing age. Modulation of the normal distribution of deleterious free radical reaction-induced changes throughout the body by genetic and environmental differences between individuals results in patterns of change, in some sufficiently different from the normal aging pattern to be recognized as disease. These “free radical” diseases can be classified into three groups in which a given disorder is mainly due to: 1) genetics, 2) a combination of genetic and environmental factors, and 3) largely to environmental influences. The growing number of “free radical” diseases includes the two major causes of death, cancer and atherosclerosis. To illustrate the role of free radicals in disease a discussion is presented, of cancer, atherosclerosis, essential hypertension, senile dementia of the Alzheimer’s type, amyloidosis, and the immune deficiency of age. Dietary intervention in the “free radical” diseases can reasonably be expected to decrease the period of senescence and to increase by 5 or more years the span of healthy productive life.