Role of free radicals in aging and disease.
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Aging↗
Biomedical subjects
D Harman
Publications and source records attributed to D Harman.
Free radical theory of aging: history.
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. These changes can be attributed to disease, environment, and the inborn aging process. The aging process is now the major risk factor for disease and death after about age 28. The free radical theory of aging arose in 1954 from a consideration of aging phenomenon from the premise that a single common process, modifiable by genetic and environmental factors, was responsible for the aging and death of all living things. The theory postulates that aging is caused by free radical reactions, i.e., these reactions may be involved in production of the aging changes associated with the environment, disease and the intrinsic aging process. The origination of the theory and its application to the problem of increasing the functional life span are discussed. Support for the free radical theory of aging has increased progressively and now includes: 1) studies on the origin of life and evolution, 2) studies on the effect of ionizing radiation on living things, 3) dietary manipulations of endogenous free radical reactions, 4) the plausible explanations it provides for aging phenomena, and 5) the growing numbers of studies that implicate free radical reactions in the pathogenesis of specific diseases. The rapidly growing number of scientists involved in studies on the role of free radical reactions in biological systems should assure future significant increases in the healthy, useful, life span of man.
Aging↗
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.
Aging↗
The aging process: major risk factor for disease and death.
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. Average life expectancies at birth in the developed countries are now approaching plateau values as the aging changes associated with the environment and disease near irreducible levels. The inborn aging process is now the major risk factor for disease and death after around age 28 in the developed countries and limits average life expectancy at birth to approximately 85 years. Future significant increases in average life expectancy--a rough measure of the healthy, productive life-span, i.e., the functional life-span--in these countries will be achieved only by slowing the rate of production of aging changes by the aging process. Many theories have been advanced to account for the aging process. The free radical theory of aging is discussed briefly. The importance attached to increasing the functional life-span dictates that aging hypotheses be explored for practical means of achieving this goal while work continues toward a consensus on the cause(s) of the aging process. Efforts to further increase the functional life-span by conventional measures are now almost futile, whereas those directed toward slowing the aging process are just beginning. These new efforts show promise.
Aging↗
Active fixation leads--long-term threshold reduction using a drug-infused ceramic collar.
Previous investigators, including our group, have reported the threshold reduction benefits of steroid-releasing leads. To date, all published literature has been for the passive fixation versions. The application of steroids should also enhance the performance of active fixation leads. We have developed and tested an atrial and a ventricular Accufix lead with a dexamethasone acetate-releasing, porous ceramic collar (DA DEC). A long-term sheep study has shown a significant reduction in thresholds (THR) when compared to standard Accufix leads without the collar (ACC) for atrial (ATR) and ventricular (VENT) versions (bipolar THR [0.5 msec] at 24 weeks: VENT DA DEC = 0.51 +/- 0.07, VENT ACC = 1.49 +/- 1.03; ATR DA DEC = 1.31 +/- 1.14, ATR ACC = 2.99 +/- 1.31). All other parameters tested, including pacing and sensing impedance as well as polarization overpotential, were similar for the two groups. The Accufix DEC leads therefore have excellent potential for low energy stimulation.
Aluminum Oxide↗
Differences in the pathological changes in dogs' hearts after defibrillation with extrapericardial paddles and implanted defibrillator electrodes.
A comparison was made between the pathological changes in the myocardium of eight dogs, each receiving about 90 joules of energy in a series of defibrillation discharges, delivered either between paddles placed against the pericardium (3 dogs) or between implanted Telectronics 040-105 defibrillation patch electrodes (5 dogs). The changes in the myocardium were most pronounced where the paddles had been applied to the pericardium. There was transmural damage beneath the left and right paddle positions and in the surrounding tissues. Extensive subepicardial and subendocardial myocyte damage was obvious histologically in the right ventricle of one of the patch dogs and in all of the paddle dogs. The percentage of damaged myocardial mass, both right ventricular and total involvement, was higher in the three paddle dogs compared with the five patch dogs. There was septal damage in the heart of one paddle dog. Necrosis of the right ventricular wall was observed in three of the patch dogs and in all the three paddle dogs. Scattered necrotic myocytes and some patches of mild necrosis up to 1-mm deep were observed in the left ventricle of the patch dogs (severity score 1-3). The necrosis was more extensive in the paddle dogs, ranging from mild necrosis less than 1-mm deep to marked necrosis incorporating half-to-whole ventricular wall thickness (severity score 3-5).
Animals↗
In vivo elution rate of drug eluting ceramic leads with a reduced dose of dexamethasone sodium phosphate.
We have evaluated the in vivo elution rate and the threshold voltage performance of a new lead incorporating a controlled delivery device based on a porous ceramic collar. The drug, dexamethasone sodium phosphate (DSP less than 0.2 mg), was contained within the pores of a ceramic collar that was positioned externally and adjacent to a 4 mm2 Pt/Ir coated electrode. Thirty-three leads comprising a porous ceramic drug eluting collar (DEC) were implanted in the right ventricle of 12 sheep. In vivo elution was determined by analyzing the drug remaining in the collar after 1, 3, 11, and 28 days. Voltage thresholds were measured at implant and then weekly for 28 days on three sheep. Results were compared to leads with identical electrodes but with silicone DEC (DSP less than 0.5 mg). The in vivo elution rate of the ceramic DEC leads was fast with approximately 50% of the drug content on the first day. Although the drug content and elution rates were different for the ceramic and silicone DEC leads, the threshold performance of the leads was similar. For ceramic and silicone DEC leads, threshold voltages at implant and at 4 weeks were 0.29 +/- 0.09 compared to 0.37 +/- 0.08 and 0.42 +/- 0.08 compared to 0.44 +/- 0.13, respectively. The results show that a relatively rapid release of a reduced dose of DSP from a DEC is still effective in reducing threshold peaking.
Animals↗
Lipofuscin and ceroid formation: the cellular recycling system.
Lipofuscin, age pigment, is a dark pigment with a strong autofluorescence seen with increasing frequency with advancing age in the cytoplasm of postmitotic cells. By bright-field light microscopy lipofuscin appears as irregular yellow to brown granules ranging in size from 1-2 nm in diameter. The fluorescent spectra of lipofuscin in situ generally show excitation maxima at about 360 nm and a yellowish emission maxima at 540-650 nm. Ultrastructurally the granules, localized in residual body-type lysosomes, are extremely heterogeneous and vary from one cell type to another, and frequently within a single cell. The pigment granules usually contain numerous liquid droplets embedded in an electron-dense matrix. The granules stain positively for neutral lipids but are not soluble in polar or non-polar lipid solvents. Lipofuscin contains about 50 percent by weight of proteinaceous substances, a lesser fraction of lipid-like material, and probably less than one percent by weight fluorophore(s); it is enriched in metals such as Al, Cu, and Fe, and in dolichols. Free radical reactions and the proteolytic system are implicated in lipopigment formation. Thus the rate of lipopigment formation is increased by vitamin E deficiency and by increased intake of polyunsaturated fatty acids as well as by protease inhibitors such as leupeptin. Free radical reactions and proteolysis are involved in the continual turnover of cellular components. Cellular damage from free radical reactions, and others such as hydrolysis, has been present since the beginning of life. The evolution of more complex cells necessitated development of defenses - DNA repair processes, antioxidants, etc. - against damaging reactions as well as the removal and replacement of altered parts, and of those no longer needed by the cells. Proteins "marked" for disposal by oxidation damage, or other means such as conjugation with ubiquitin, are apparently rendered more hydrophobic so that they are "recognized" for degradation by the lysosomes and the proteinases and peptidases of the cytosol and mitochondria. Oxidatively altered lipids are removed by enzymes such as phospholipase A2. The products of the degradation processes are reused by the cells. Normally the recycling of damaged components works extremely well. There may be some slow slippage with advancing age as the rate of free radical damage increases while protease activity decreases. As a result a gradually increasing fraction of lysosomal "food" may be converted to non-digestible forms, lipofuscin, before it can be broken down to reusable components. Ceroid is apparently formed when the disposal system is "overloaded" or impaired.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Free radicals in aging.
Aging 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 reactions. 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.
Aging↗
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.
Aging↗
The interrelationship between intraocular pressure and Honan Intraocular Pressure Reducer pressure.
The relationship between the pressure applied to the enucleated human eye using the Honan Intraocular Pressure Reducer (HIPR) and the peak intraocular pressure as a function of initial intraocular pressure has been examined. The peak intraocular pressure is linearly related to the applied HIPR pressure whether the latter is 30, 50, or 75 mm Hg. The slopes relating peak intraocular pressure to initial intraocular pressure at different HIPR settings are parallel. Use of the HIPR at settings greater than 30 mm Hg and an initial IOP of greater than 30 mm Hg could compromise ocular vascular perfusion.
Humans↗
Self-regulation of hemispheric asymmetry.
This study was performed to determine if individuals could demonstrate self-regulation of average EEG power of one hemisphere in comparison to the other. Temporal EEG was recorded from 8 males and 6 females. After a practice session, the subjects were instructed to increase or decrease the practice session, the subjects were instructed to increase or decrease the ratio of left to right temporal EEG. The subjects were given on-line feedback in the form of a graph presented via a computer display screen. The study demonstrated a significant ability of the subjects to change differentially the hemispheric power ratios upon instruction.
Adult↗
Free radical theory of aging: effect of age, sex and dietary precursors on rat-brain docosahexanoic acid.
Increasing the peroxidizability of dietary fat has an adverse effect on the function of the central nervous system (CNS) in the rat. This effect may be influenced by the level of docosahexanoic acid, a highly unsaturated fatty acid, selectively concentrated in the phospholipids of brain membranes. This study was aimed at determining the influence of age, sex, and the nature of a dietary lipid supplement - linolenic acid (18:3w3), docosahexanoic acid (22:6w3), or the same amount of 22:6w3 in the form of menhaden oil triglycerides - on the rate of increase in the percentage of 22:6w3 in the whole-brain fatty acids of rats between the ages of 1 and 12 months. The dietary lipid supplements were reflected in linear increases in the brain 22:6w3 of female rats throughout the study. Between 6 and 12 months of age, the rate of incorporation of dietary 22:6w3 and its precursors into the brain 22:6w3 of male rats dropped. At 12 months it was about half that for females in the case of 22:6w3 and menhaden oil, and about zero for 18:3w3. It is suggested that dietary 22:6w3 and its precursors may modify CNS function by altering membrane function and peroxidizability through changes in the concentration of 22:6w3 in membrane phospholipids.
Age Factors↗
Free radical theory of aging: effect of free-radical-reaction inhibitors on the immune response.
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Aging↗
The clinical gerontologist.
A major objective now and in the future should be that of maximizing health and well-being during our essentially fixed span of life. It is proposed that this objective be delegated to a new field of medicine, perhaps to be known as clinical gerontology--a combination of preventive medicine and geriatrics.
Forecasting↗
Free radical theory of aging: inhibition of amyloidosis in mice by antioxidants; possible mechanism.
The antioxidants, alpha-tocopherol acetate and a quinolone derivative (Santoquin), inhibited the development of amyloidosis when added to the diet of casein-injected C3HeB/FeJ male mice. Santoquin, and to a lesser extent butylated hydroxytoluene (BHT), also depressed the appearance of a plasma protein fraction in these mice; the effect of alpha-tocopherol was not determined. Consideration of the current knowledge of amyloid, in the light of these antioxidant studies, prompted the following hypothesis. Amyloidosis is largely the result of an enhanced rate of oxidative degradation of a connective-tissue glycoprotein(s) coupled with oxidative/enzymatic changes in the plasma, both of the tissue-derived substances and of immunoglobulins, to form the amyloid fibril protein subunits (AL and AA) which subsequently aggreagate to form the amyloid fibrils.
Aging↗
Free radical theory of aging: effect of dietary fat on central nervous system function.
Free radical reactions have been implicated in aging. A rise in the level of random free radical reactions in a biologic system might have a greater effect on the central nervous system (CNS) than elsewhere, partly because of the presence of glial cells and the unique connections between neurons. To evaluate this possibility, some animal experiments were conducted. The initial experiment involved old male Sprague-Dawley rats fed (since shortly after weaning) with semisynthetic diets characterized by fat differing in amount or degree of unsaturation. The number of errors made in a Hebb-Williams maze was determined and found to be higher as the amount or degree of unsaturation of the fat was increased. Likewise rats aged 6 and 9 months, fed semisynthetic diets containing 20 percent by weight of lard, oleinate, or safflower oil +alpha-tocopherol performed significantly better in a discrimination learning situation (Skinner box) than did rats fed a diet containing 20 percent by weight of safflower oil. The diets employed in these studies did not have a significant effect on the mortality rates. These results are compatible with the possibility that enhancing the level of lipid peroxidation has an adverse effect on the CNS, out of proportion to the effect on the body as a whole, as measured by the mortality rate.
Aging↗