Living in an oxygenated environment has required the evolution of effective cellular strategies to detect and detoxify metabolites of molecular oxygen known as reactive oxygen species. Here we review evidence that the appropriate and inappropriate production of oxidants, together with the ability of organisms to respond to oxidative stress, is intricately connected to ageing and life span.

Oxidants, oxidative stress and the biology of ageing.

https://www.cell.com/cell/pdf/S0092-8674(05)00109-1.pdf

Mitochondria, Oxidants, and Aging

Beckman, Kenneth B., and Bruce N. Ames. The Free Radical Theory of Aging Matures. Physiol. Rev. 78: 547–581, 1998. — The free radical theory of aging, conceived in 1956, has turned 40 and is rapidl...

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The Free Radical Theory of Aging Matures

Life is the interplay between structure and energy, yet the role of energy deficiency in human disease has been poorly explored by modern medicine. Since the mitochondria use oxidative phosphorylation (OXPHOS) to convert dietary calories into usable energy, generating reactive oxygen species (ROS) as a toxic by-product, I hypothesize that mitochondrial dysfunction plays a central role in a wide range of age-related disorders and various forms of cancer. Because mitochondrial DNA (mtDNA) is present in thousands of copies per cell and encodes essential genes for energy production, I propose that the delayed-onset and progressive course of the agerelated diseases results from the accumulation of somatic mutations in the mtDNAs of post-mitotic tissues. The tissue-specific manifestations of these diseases may result from the varying energetic roles and needs of the different tissues. The variation in the individual and regional predisposition to degenerative diseases and cancer may result from the interaction of modern dietary caloric intake and ancient mitochondrial genetic polymorphisms. Therefore the mitochondria provide a direct link between our environment and our genes and the mtDNA variants that permitted our forbears to energetically adapt to their ancestral homes are influencing our health today.

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A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine

Ribosomal DNA (rDNA) sequences have been aligned and compared in a number of living organisms, and this approach has provided a wealth of information about phylogenetic relationships. Studies of rDNA sequences have been used to infer phylogenetic history across a very broad spectrum, from studies among the basal lineages of life to relationships among closely related species and populations. The reasons for the systematic versatility of rDNA include the numerous rates of evolution among different regions of rDNA (both among and within genes), the presence of many copies of most rDNA sequences per genome, and the pattern of concerted evolution that occurs among repeated copies. These features facilitate the analysis of rDNA by direct RNA sequencing, DNA sequencing (either by cloning or amplification), and restriction enzyme methodologies. Constraints imposed by secondary structure of rRNA and concerted evolution need to be considered in phylogenetic analyses, but these constraints do not appear to impede seriously the usefulness of rDNA. An analysis of aligned sequences of the four nuclear and two mitochondrial rRNA genes identified regions of these genes that are likely to be useful to address phylogenetic problems over a wide range of levels of divergence. In general, the small subunit nuclear sequences appear to be best for elucidating Precambrian divergences, the large subunit nuclear sequences for Paleozoic and Mesozoic divergences, and the organellar sequences of both subunits for Cenozoic divergences. Primer sequences were designed for use in amplifying the entire nuclear rDNA array in 15 sections by use of the polymerase chain reaction; these "universal" primers complement previously described primers for the mitochondrial rRNA genes. Pairs of primers can be selected in conjunction with the analysis of divergence of the rRNA genes to address systematic problems throughout the hierarchy of life.

Ribosomal DNA: molecular evolution and phylogenetic inference.

Much attention has focused on the aetiology of oxidative damagein cellular and organismal ageing1,2,3,4. Especially toxic arethe reactive oxygen byproducts of respiration and other biological processes5. A mev-1 (kn1 ) mutant of Caenorhabditis elegans has been found to be hypersensitive to raised oxygen concentrations6,7. Unlike the wild type, its lifespan decreases dramatically as oxygen concentrations are increased from 1 to 60% (ref. 7). Strains bearing this mutation accumulate markers of ageing (such as fluorescent materials and protein carbonyls) faster than the wild type8,9. We show here that mev-1 encodes a subunit of the enzyme succinate dehydrogenase cytochrome b , which is a component of complex II of the mitochondrial electron transport chain. We found that the ability of complex II to catalyse electron transport from succinate to ubiquinone is compromised in mev-1 animals. This may cause an indirect increase in superoxide levels, which in turn leads to oxygen hypersensitivity and premature ageing. Our results indicate that mev-1 governs the rate of ageing by modulating the cellular response to oxidative stress.

A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes

A methyl violagen (paraquat)-sensitive mutant, mev-1 (LG III), in Caenorhabditis elegans was about 4 times more sensitive to methyl viologen than the wild type. This mutant was also hypersensitive to oxygen. The brood size was about 1 4 that of the wild type. The average life span was determined to be 9.3 days as compared to 14.3 days for the wild type. The activity of superoxide dismutase (SOD), a scavenging enzyme for superoxide anion, was about half the wild-type level. We suggest that oxygen radicals may be involved in the normal aging mechanism in C. elegans.

A methyl viologen-sensitive mutant of the nematode Caenorhabditis elegans

The effects of atmospheric oxygen on the life span and aging rate of the nematode Caenorhabditis elegans were examined. The mean and maximum life spans of both the wild type and mev-1(kn1) mutant, whose cytoplasmic superoxide dismutase activity level is about half of the wild type, were increased and decreased under low and high concentrations of oxygen, respectively. The Gompertz component, a parameter of aging rate, of the wild type was smaller under 1% oxygen than under 2% or more oxygen. Further, the Gompertz component of the mutant increased with an increase in oxygen concentration. These effects of oxygen on the perturbation of life span and aging rate were more pronounced in the mev-1(kn1) mutant than in the wild type. The oxygen-dependent perturbation of life span and aging rate seems to be enhanced by a genetic defect of the mutant in antioxidant defense. A 1% oxygen exposure at the early phase of life span was ineffective for life span extension in the mutant, suggesting that the effect of oxygen concentrations on life span is not secondary to the effects of development and maturation. These results show that changes in oxygen concentration perturb aging rate, and hence oxygen is involved in the specification of life span of the nematode.

Oxygen-Dependent Perturbation of Life Span and Aging Rate in the Nematode

Rapid accumulation of fluorescent material with aging in an oxygen-sensitive mutant mev-1 of Caenorhabditis elegans.

A biological dosimetry system for measuring solar UV-B light was established using bacteriophage T1 with E. coli Bs-1 as the host cell. Also a new physical UV-B dosimeter was developed which can specifically detect the UV spectral region related to inactivation of phage T1. Phage T1 is very stable in liquid suspension and it has adequate sensitivity to measure the intensity of solar UV-B. In addition, the survival of phage T1 responded linearly to UV fluences when plotted semi-logarithmic ally. Thus T1 seemed to have characteristic features making it suitable material as a biological dosimeter for sunlight. Outdoor experiments throughout one year showed that the mean amount of solar UV light in summer was about 6 fold larger than that in winter at Isehara (139.5 degrees E, 35.5 degrees N), Japan. A novel physical dosimeter which responds faithfully to UV-B light under atmospheric conditions on the ground was developed as well. The spectral response was very close to that of biological materials. Readings of this UV-B dosimeter could be converted into the efficiency of sunlight upon biological materials. This instrument is compact; it can also be used as an erythemal dosimeter.

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Kenshi Suzuki

Papers

A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes

A methyl viologen-sensitive mutant of the nematode Caenorhabditis elegans

Oxygen-Dependent Perturbation of Life Span and Aging Rate in the Nematode

Rapid accumulation of fluorescent material with aging in an oxygen-sensitive mutant mev-1 of Caenorhabditis elegans.

Biological and physical dosimeters for monitoring solar UV-B light.