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PubMed1999

Genetic stability: the key to longevity?

In gerontology, there are abundant data indicating that functional cell capacity decreases with age. Clinical practice and the results of several studies have demonstrated that a high (depending on the study) percentage of people over eighty are practically 'normal' (successful aging). The hypothesis is that they are in fact in much the same position as the normal population of middle age. The reason for this may be the genetic stability of these persons. With time, the amount of damage to DNA rises and accumulates, which leads to cancer, heart problems and getting old. In genetically stable individuals, that period of accumulation is longer so they live longer. In humans, there appear to be two subgroups that age at different rates. The slower-aging group have better DNA repair systems. Genome stability plays a fundamental role in such age-related differences. The evolution of the human race would have been much slower if it had involved only genetically stable individuals. From the individual's point of view, however, it is better to have genetic stability. Regardless of the classical theory of aging, the lifespan of a species is related to metabolic rate. The apes and the humans have practically the same rate of metabolism, but humans live twice as long as apes. A similar phenomenon has been observed in other species and other tissues. Modification of DNA repair capacity plays a fundamental role in determination of the life span of a species. Genetic instability could be one of the basic reasons for senescence. The rise of chromosomal aberrations in long-lived persons is attributable to their genetic stability. They are practically in the same position as a normal population at middle age. Genetic instability is often associated with cancer and many different disorders of the immune system, which are frequent in the elderly.

Chromosome Aberrations↗
PubMed2004

Effects of Soy-derived diets on plasma and liver lipids, glucose tolerance, and longevity in normal, long-lived and short-lived mice.

We examined the effects of diets based on a low isoflavone or a high isoflavone soy protein isolates in normal, growth-hormone receptor knockout and Ames dwarf, and Prop 1 (df) mice that are hypoinsulinemic, insulin-sensitive, and exceptionally long-lived, as well as in growth hormone transgenic mice that are hyperinsulinemic, insulin-resistant, dyslipidemic, and short-lived. Soybean diets tended to normalize plasma cholesterol levels in dwarf and transgenic mice, while low isoflavone diet reduced plasma triglycerides in most of the examined genotypes. The effects of low isoflavone and high isoflavone diets on the levels of free and esterified cholesterol in the liver were strongly genotype-dependent. Fasting blood glucose levels were reduced and glucose tolerance improved by both low isoflavone and high isoflavone diets in growth hormone-transgenic mice and in their normal siblings. Glucose tolerance was also improved by high-isoflavone diet in growth hormone receptor knockout mice. Lifespan was increased by low isoflavone diet in normal mice from two of the examined stocks. High isoflavone diet increased lifespan in normal animals from one line, but reduced lifespan of normal mice from a different line. We conclude that dietary soy protein intake can improve plasma and hepatic lipid profiles, reduce fasting glucose, enhance capacity for glucose tolerance, and prolong life, but all of these effects are strongly genotype-dependent.

Animals↗
PubMed2000

Longevity of patients born with myelomeningocele.

There are limited data concerning the life expectancy for individuals born with myelomeningocele (MM), with and without hydrocephalus. To ascertain such data was our first purpose. We have selected all patients with MM in our computer database, The Patient Data Management System (PDMS/fx). Data were transferred to Excel for primary and SPSS/PC for final analysis by Kaplan-Meier life survival curves. Of the 1,054 patients with MM in the Birth Defects Clinic and the University of Washington Medical Center (UWMC) of Seattle, 505 are now over the age of 21 (391) or have died (114). Follow-up information was available since 1994 for 132, 62% of whom we have had contact within the past 2 years. The second purpose was to identify potential health factors associated with long-term outcome of patients with MM. Patient variables chosen as relevant to survival included hydrocephalus, treatment before or after 1975, and health maintenance determined by outcome for those receiving care within the last 5 years or those last seen before. Age at last appointment and reason for visit were determined in order to identify age-specific health care needs of the adult population. Survival and medical needs were obtained from the UWMC's computer database, Mindscape, and by telephone survey for adult patients not seen in the last 2 years. Death is more frequent earlier in life for those MM patients with hydrocephalus. Ordinary degenerative disorders affect MM patients earlier in life than normals. Our data extend life expectancy for patients with MM and hydrocephalus to age 40 years with some reliability for those treated from 1957 to 1974, but only 24 years for those treated with modern techniques after 1974. More data is needed to determine long-term survival.

Adolescent↗
PubMed1986

Physical activity, all-cause mortality, and longevity of college alumni.

We examined the physical activity and other life-style characteristics of 16,936 Harvard alumni, aged 35 to 74, for relations to rates of mortality from all causes and for influences on length of life. A total of 1413 alumni died during 12 to 16 years of follow-up (1962 to 1978). Exercise reported as walking, stair climbing, and sports play related inversely to total mortality, primarily to death due to cardiovascular or respiratory causes. Death rates declined steadily as energy expended on such activity increased from less than 500 to 3500 kcal per week, beyond which rates increased slightly. Rates were one quarter to one third lower among alumni expending 2000 or more kcal during exercise per week than among less active men. With or without consideration of hypertension, cigarette smoking, extremes or gains in body weight, or early parental death, alumni mortality rates were significantly lower among the physically active. Relative risks of death for individuals were highest among cigarette smokers and men with hypertension, and attributable risks in the community were highest among smokers and sedentary men. By the age of 80, the amount of additional life attributable to adequate exercise, as compared with sedentariness, was one to more than two years.

Adult↗
PubMed2003

Deletion of the p66Shc longevity gene reduces systemic and tissue oxidative stress, vascular cell apoptosis, and early atherogenesis in mice fed a high-fat diet.

Several experimental and clinical studies have shown that oxidized low-density lipoprotein and oxidation-sensitive mechanisms are central in the pathogenesis of vascular dysfunction and atherogenesis. Here, we have used p66(Shc-/-) and WT mice to investigate the effects of high-fat diet on both systemic and tissue oxidative stress and the development of early vascular lesions. To date, the p66(Shc-/-) mouse is the unique genetic model of increased resistance to oxidative stress and prolonged life span in mammals. Computer-assisted image analysis revealed that chronic 21% high-fat treatment increased the aortic cumulative early lesion area by approximately 21% in WT mice and only by 3% in p66(Shc-/-) mice. Early lesions from p66(Shc-/-) mice had less content of macrophage-derived foam cells and apoptotic vascular cells, in comparison to the WT. Furthermore, in p66(Shc-/-) mice, but not WT mice, we found a significant reduction of systemic and tissue oxidative stress (assessed by isoprostanes, plasma low-density lipoprotein oxidizability, and the formation of arterial oxidation-specific epitopes). These results support the concept that p66(Shc-/-) may play a pivotal role in controlling systemic oxidative stress and vascular diseases. Therefore, p66(Shc) might represent a molecular target for therapies against vascular diseases.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Sir2 mediates longevity in the fly through a pathway related to calorie restriction.

Calorie restriction can extend life span in a variety of species including mammals, flies, nematodes, and yeast. Despite the importance of this nearly universal effect, little is understood about the molecular mechanisms that mediate the life-span-extending effect of calorie restriction in metazoans. Sir2 is known to be involved in life span determination and calorie restriction in yeast mother cells. In nematodes increased Sir2 can extend life span, but a direct link to calorie restriction has not been demonstrated. We now report that Sir2 is directly involved in the calorie-restriction life-span-extending pathway in Drosophila. We demonstrate that an increase in Drosophila Sir2 (dSir2) extends life span, whereas a decrease in dSir2 blocks the life-span-extending effect of calorie reduction or rpd3 mutations. These data lead us to propose a genetic pathway by which calorie restriction extends life span and provides a framework for genetic and pharmacological studies of life span extension in metazoans.

Animals↗
PubMed1972

Circadian systems: longevity as a function of circadian resonance in Drosophila melanogaster.

Drosophila melanogaster, which had been reared under standard conditions (25 degrees and a 24-hr light/dark cycle involving 12 hr of light) were exposed, on the first day of adult life, to four environments (all at 25 degrees ) as follows: (i) a 24-hr day consisting of 12 hr light and 12 hr dark; (ii) a 21-hr day (10.5 hr light, 10.5 hr dark); (iii) a 27-hr day (13.5 hr light, 13.5 hr dark); and (iv) constant light. The experiment was repeated four times. In all four experiments the flies on a 24-hr day lived significantly longer than the flies in the other environments. This result, comparable to other observations on plants, indicates that eukaryotic systems as oscillators perform most effectively when they are driven close to their natural "circadian" frequency.

Adaptation, Physiological↗
PubMed1975

Evolution of human longevity and the genetic complexity governing aging rate.

Genetic complexity of processes governing the aging rate of man was estimated by determining the maximum rate lifespan has evolved along the hominid ancestral-descendant sequence. Maximum lifespan potential was found to have increased approximately 2-fold over the past 3 million years, reaching a maximum rate of increase of 14 years per 100,000 years about 100,000 years ago. It is estimated that about 0.6% of the total functional genes have received substitutions leading to one or more adaptive amino acid changes during this 100,000-year time-period. This suggests that aging is not the result of an expression of a large number of independently acting processes. Instead, primary aging processes appear to exist where only a few genetic changes are necessary to decrease uniformly the aging rate of many different physiological functions.

Aging↗
PubMed1996

Longevity and the genetic determination of collagen glycoxidation kinetics in mammalian senescence.

A fundamental question in the basic biology of aging is whether there is a universal aging process. If indeed such a process exists, one would expect that it develops at a higher rate in short- versus long-lived species. We have quantitated pentosidine, a marker of glycoxidative stress in skin collagen from eight mammalian species as a function of age. A curvilinear increase was modeled for all species, and the rate of increase correlated inversely with maximum life-span. Dietary restriction, a potent intervention associated with increased life-span, markedly inhibited glycoxidation rate in the rodent. On the assumption that collagen turnover rate is primarily influenced by the crosslinking due to glycoxidation, these results suggest that there is a progressive age-related deterioration of the process that controls the collagen glycoxidation rate. Thus, the ability to withstand damage due to glycoxidation and the Maillard reaction may be under genetic control.

Aging↗
PubMed1997

Sex-specific quantitative trait loci affecting longevity in Drosophila melanogaster.

Senescence, the decline in survivorship and fertility with increasing age, is a near-universal property of organisms. Senescence and limited lifespan are thought to arise because weak natural selection late in life allows the accumulation of mutations with deleterious late-age effects that are either neutral (the mutation accumulation hypothesis) or beneficial (the antagonistic pleiotropy hypothesis) early in life. Analyses of Drosophila spontaneous mutations, patterns of segregating variation and covariation, and lines selected for late-age fertility have implicated both classes of mutation in the evolution of aging, but neither their relative contributions nor the properties of individual loci that cause aging in nature are known. To begin to dissect the multiple genetic causes of quantitative variation in lifespan, we have conducted a genome-wide screen for quantitative trait loci (QTLs) affecting lifespan that segregate among a panel of recombinant inbred lines using a dense molecular marker map. Five autosomal QTLs were mapped by composite interval mapping and by sequential multiple marker analysis. The QTLs had large sex-specific effects on lifespan and age-specific effects on survivorship and mortality and mapped to the same regions as candidate genes with fertility, cellular aging, stress resistance and male-specific effects. Late age-of-onset QTL effects are consistent with the mutation accumulation hypothesis for the evolution of senescence, and sex-specific QTL effects suggest a novel mechanism for maintaining genetic variation for lifespan.

Animals↗
PubMed2004

DNA methyltransferase gene dDnmt2 and longevity of Drosophila.

The DNA methylation program of the fruit fly Drosophila melanogaster is carried out by the single DNA methyltransferase gene dDnmt2, the function of which is unknown before. We present evidence that intactness of the gene is required for maintenance of the normal life span of the fruit flies. In contrast, overexpression of dDnmt2 could extend Drosophila life span. The study links the Drosophila DNA methylation program with the small heatshock proteins and longevity/aging and has interesting implication on the eukaryotic DNA methylation programs in general.

Aging↗
PubMed2003

Effects of overexpression of copper-zinc and manganese superoxide dismutases, catalase, and thioredoxin reductase genes on longevity in Drosophila melanogaster.

The overexpression of antioxidative enzymes such as CuZn-superoxide dismutase (SOD), Mn-SOD, and catalase has previously been reported to extend life span in transgenic flies (Drosophila melanogaster). The purpose of this study was to determine whether life-extending effects persist if the recipient control strains of flies are relatively long-lived. Accordingly, the life spans of large numbers of replicate control and overexpressor lines were determined in two long-lived genetic backgrounds involving a combined total of >90,000 flies. Significant increases in the activities of both CuZn-SOD and catalase had no beneficial effect on survivorship in relatively long-lived y w mutant flies and were associated with slightly decreased life spans in wild type flies of the Oregon-R strain. The introduction of additional transgenes encoding Mn-SOD or thioredoxin reductase in the same genetic background also failed to cause life span extension. In conjunction with data from earlier studies, the results show that increasing the activities of these major antioxidative enzymes above wild type levels does not decrease the rate of aging in long-lived strains of Drosophila, although there may be some effect in relatively short-lived strains.

Aging↗
PubMed2000

Mediterranean diet and longevity.

Mortality statistics from the WHO database covering the period 1960 to 1990 have provided intriguing evidence that something unusual has been affecting in a beneficial way the health of the Mediterranean population. In recent papers, which evaluated the evidence accumulated over the last three decades, it was concluded that the traditional Mediterranean diet meets several important criteria for a healthy diet. Direct evidence in support of the beneficial properties of the Mediterranean diet has also become available. These data were derived from three studies, which have used a diet score, devised a priori on the basis of eight desirable key features of the traditional common diet in the Mediterranean region. The conclusion of these studies is that a diet that adheres to the principles of the traditional Mediterranean one is associated with longer survival. The Greek version of the Mediterranean diet is dominated by the consumption of olive oil and by high consumption of vegetables and fruits. Antioxidants represent a common element in these foods and an antioxidant action provides a plausible explanation for the apparent benefits. Wild edible greens frequently eaten in rural Greece in the form of salads and pies contain very high quantities of flavonoids-- considerably higher than those found in red wine or black tea. While there is no direct evidence that these antioxidants are central to the benefits of the Mediterranean Diet, indirect evidence from epidemiological data and the increasing understanding of their mechanisms of action suggest that antioxidants may play a major role.

Aged↗