Peroxide-producing potential of tissues: inverse correlation with longevity of mammalian species.

Peroxidation reactions may cause many of the dysfunctions associated with aging. Accordingly, the 30-fold differences in aging rate among the mammalian species could be determined in part by peroxidation defense processes. This possibility was tested by measuring the spontaneous autoxidation of aerobically incubated brain and kidney tissue homogenates of 24 different mammalian species as a function of their maximum lifespan potential. Results show a statistically significant inverse correlation between both the rate of autoxidation and the amount of peroxidizable substrate with maximum lifespan potential. Kinetic analysis of the data indicates that the amount of peroxidizable substrate was the major factor determining the rate of autoxidation. For human tissues, antioxidants also appear to contribute to their unusually low sensitivity to peroxidation. These results support the hypothesis that aging may be caused in part by oxygen radicals initiating peroxidation reactions and that peroxidation defense processes are involved in governing the longevity of mammalian species.     

The nature and mechanism of superoxide production by the electron transport chain: Its relevance to aging

Most biogerontologists agree that oxygen (and nitrogen) free radicals play a major role in the process of aging. The evidence strongly suggests that the electron transport chain, located in the inner mitochondrial membrane, is the major source of reactive oxygen species in animal cells. It has been reported that there exists an inverse correlation between the rate of superoxide/hydrogen peroxide production by mitochondria and the maximum longevity of mammalian species. However, no correlation or most frequently an inverse correlation exists between the amount of antioxidant enzymes and maximum longevity. Although overexpression of the antioxidant enzymes SOD1 and CAT (as well as SOD1 alone) have been successful at extending maximum lifespan in Drosophila, this has not been the case in mice. Several labs have overexpressed SOD1 and failed to see a positive effect on longevity. An explanation for this failure is that there is some level of superoxide damage that is not preventable by SOD, such as that initiated by the hydroperoxyl radical inside the lipid bilayer, and that accumulation of this damage is responsible for aging. I therefore suggest an alternative approach to testing the free radical theory of aging in mammals. Instead of trying to increase the amount of antioxidant enzymes, I suggest using molecular biology/transgenics to decrease the rate of superoxide production, which in the context of the free radical theory of aging would be expected to increase longevity. This paper aims to summarize what is known about the nature and mechanisms of superoxide production and what genes are involved in controlling the rate of superoxide production.     

Superoxide dismutase: correlation with life-span and specific metabolic rate in primate species.

Much evidence now suggests that superoxide dismutase (superoxide:superoxide oxidoreductase, EC 1.15.1.1) may be a major intracellular protective enzyme against oxygen toxicity by catalyzing the removal of the superoxide radical. We examined the possible role this enzyme may have in determining the life-span of primate species. Superoxide dismutase specific activity levels were measured in cytoplasmic fractions of liver, brain, and heart of 2 rodent and 12 primate species. These species had maximum life-span potentials ranging from 3.5 to 95 years. Liver, brain, and heart had similar specific activity levels for a given species, but the levels for different species varied over 2-fold, with man having the highest level. No general correlation was found in the levels with life-span. However, the ratio of superoxide dismutase specific activity to specific metabolic rate of the tissue or of the whole adult organism was found to increase with increasing maximum lifespan potential for all the species. This correlation suggests that longer-lived species have a higher degree of protection against by-products of oxygen metabolism.     

Serum uric acid: Correlation with behavioral,metabolic, age,and lifespan parameters among inbred mice

Uric acid represents a major antioxidant in the serum of most mammalian species. A positive correlation of serum concentrations with lifespan potential among mammalian species implicates uric acid as a longevity determinant. Moreover, other data suggest that uric acid may be a neurostimulant which might affect locomotor activity. To assess whether uric acid is related to differences in lifespan and locomotor activity among inbred mice, serum uric acid concentrations were determined in seven genotypes and correlated with individual and strain differences in lifespan, metabolic rate, lifespan energy potential, body weight, and locomotor activity. Marked genotype differences in some parameters were observed; however, the analysis yielded only a modest non-significant positive correlation between serum uric acid and lifespan, which was lowered even further when differences in metabolic activity were considered. A negative correlation between serum uric acid and locomotor activity was observed both among genotypes and within one strain, C57BL/6J. When age differences (4–28 mo) in serum uric acid were examined within the C57BL/6J strain, an age-related increase (75%) was found. This observation contrasted with the age-related decrease in locomotor activity within this strain. Thus, for these seven mouse genotypes, the hypothesized positive correlations between serum uric acid and lifespan or locomotor activity were not observed. Mr. Reynolds is the recipient of the Second Annual Walter Nicolai Prize in Biomedical Gerontology. He is a student in the Dental School of the University of Maryland, Baltimore. This prize was made possible by the Glenn Foundation for Medical Research.     

The oxidative stress theory of aging: embattled or invincible? Insights from non-traditional model organisms

Reactive oxygen species (ROS), inevitable byproducts of aerobic metabolism, are known to cause oxidative damage to cells and molecules. This, in turn, is widely accepted as a pivotal determinant of both lifespan and health span. While studies in a wide range of species support the role of ROS in many age-related diseases, its role in aging per se is questioned. Comparative data from a wide range of endotherms offer equivocal support for this theory, with many exceptions and inconclusive findings as to whether or not oxidative stress is either a correlate or a determinant of maximum species lifespan. Available data do not support the premise that metabolic rate and in vivo ROS production are determinants of lifespan, or that superior antioxidant defense contributes to species longevity. Rather, published studies often show either a negative associate or lack of correlation with species longevity. Furthermore, many long-living species such as birds, bats and mole-rats exhibit high levels of oxidative damage even at young ages. Similarly genetic manipulations altering expression of key antioxidants do not necessarily show an impact on lifespan, even though oxidative damage levels may be affected. While it is possible that these multiple exceptions to straightforward predictions of the free radical theory of aging all reflect species-specific, “private” mechanisms of aging, the preponderance of contrary data nevertheless present a challenge to this august theory. Therefore, contrary to accepted dogma, the role of oxidative stress as a determinant of longevity is still open to question.     

Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis.

During primate evolution, a major factor in lengthening life-span and decreasing age-specific cancer rates may have been improved protective mechanisms against oxygen radicals. We propose that one of these protective systems is plasma uric acid, the level of which increased markedly during primate evolution as a consequence of a series of mutations. Uric acid is a powerful antioxidant and is a scavenger of singlet oxygen and radicals. We show that, at physiological concentrations, urate reduces the oxo-heme oxidant formed by peroxide reaction with hemoglobin, protects erythrocyte ghosts against lipid peroxidation, and protects erythrocytes from peroxidative damage leading to lysis. Urate is about as effective an antioxidant as ascorbate in these experiments. Urate is much more easily oxidized than deoxynucleosides by singlet oxygen and is destroyed by hydroxyl radicals at a comparable rate. The plasma urate levels in humans (about 300 microM) is considerably higher than the ascorbate level, making it one of the major antioxidants in humans. Previous work on urate reported in the literature supports our experiments and interpretations, although the findings were not discussed in a physiological context.     

Enhanced protein repair and recycling are not correlated with longevity in 15 vertebrate endotherm species

Previous studies have shown that longevity is associated with enhanced cellular stress resistance. This observation supports the disposable soma theory of aging, which suggests that the investment made in cellular maintenance will be proportional to selective pressures to extend lifespan. Maintenance of protein homeostasis is a critical component of cellular maintenance and stress resistance. To test the hypothesis that enhanced protein repair and recycling activities underlie longevity, we measured the activities of the 20S/26S proteasome and two protein repair enzymes in liver, heart and brain tissues of 15 different mammalian and avian species with maximum lifespans (MLSP) ranging from 3 to 30 years. The data set included Snell dwarf mice, in which lifespan is increased by ∼50% compared to their normal littermates. None of these activities in any of the three tissues correlated positively with MLSP. In liver, 20S/26S proteasome and thioredoxin reductase (TrxR) activities correlated negatively with body mass. In brain tissue, TrxR was also negatively correlated with body mass. Glutaredoxin (Grx) activity in brain was negatively correlated with MLSP and this correlation remained after residual analysis to remove the effects of body mass, but was lost when the data were analysed using Felsenstein’s independent contrasts. Snell dwarf mice had marginally lower 20S proteasome, TrxR and Grx activities than normal controls in brain, but not heart tissue. Thus, increased longevity is not associated with increased protein repair or proteasomal degradation capacities in vertebrate endotherms.     

Coevolution of exceptional longevity, exceptionally high metabolic rates, and mitochondrial DNA-coded proteins in mammals

Mammals' longevity is inversely related to mass-specific basal metabolic rate because the generation of reactive oxygen species constrains lifespan. Longevity increases with body mass because the latter is inversely related to mass-specific basal metabolic rates. In placental mammals the longevity residuals from the power laws that describe longevity as a function of mass-specific basal metabolic rates, or body mass, are positively correlated with the relative rates of evolution of cytochrome b, a generator of reactive oxygen species. Therefore, longevity is more accurately described as a function of both mass-specific basal metabolic rate and the relative rate of cytochrome b evolution. The longevity residuals from the power law that describe longevity as a function of body mass are positively correlated with the relative rate of evolution of most other mtDNA-coded proteins. In taxa with very high rate of cytochrome b evolution exceptional longevity is associated with an increase, rather than the predicted decrease, of basal metabolic rates. These finding are compatible with the hypothesis that, in placental mammals, the accelerated evolution of mtDNA-coded proteins, allowed the extension of lifespan by selecting mutations that reduce the generation of reactive oxygen species, mostly by increasing internal proton leak, that accelerates mitochondrial electron transport.     

Evidence for a relationship between longevity of mammalian species and a lens growth parameter

The lens growth was studied in a number of curves representing 16 mammalian species. Emphasis was placed on determining the length of the lens development stage. All the lens curves studied went through a growth crisis: It is a period of apparent growth slowing down, lasting linear during the resting lifespan (adult stage). The growth crisis occurred at a length that was characteristic for the species and was shown to be directly correlated with the species maximum lifespan potential. These results may indicate the prevalence of a common functional basis regulating the lens growth and thus operating in the longevity of mammalian species.