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PubMed2005

[Biological aspects of longevity and ageing].

Despite very different life expectancies, a 2-year-old mouse, a 12-year-old dog, a 32-year-old chimpanzee or an 80-year-old man will share many common deficits such as a reduction in tissue elasticity, immunological responses, muscular strength, sensory perceptions, reflexes, as well as memory losses and increase of age-associated diseases (osteoporosis, osteoarthritis, type II diabetes, cardiovascular diseases, cataract and macular degeneration, neurodegenerative diseases, to name only a few...). With the increase of life expectancy in human species, ageing has become a major concern for the society, both at the human and financial level. The main challenge for biologists studying ageing is to understand how the multiple effects quoted above, so easily identifiable in various species, are nonetheless so coordinate among individuals of a given species. The acquisition of this fundamental knowledge will be essential to reach the ultimate goal of healthy ageing for human populations. At the present time, three types of recent developments on ageing research can be distinguished: 1) A consensus on evolutionist theory of ageing is developing. This theory is based on the fact that long-lived species usually arise from protected ecological niches. It implies that phenotypes which are expressed late in "aged survivors" are beyond natural selection. So, alleles underlying this late expression being adaptive or not ("good" or "bad"), contribute only slightly to the pool of genes of the following generation. 2) Study of laboratory models like the nematode C. elegans or fly D. melanogaster have enabled the observation that single-gene invalidation can increase lifespan. Interestingly, some of these changes seem to imply a common process through insulin/IGF-1 (insulin like growth factor-I) orthologue, energy metabolism and growth implicated hormones, as well as protection against free radicals. 3) In the mouse, several genes mutation increase lifespan and are associated with a decrease in growth hormone (GH) secretion as well as its main effector IGF-1. The study of such transgenic mutants, in parallel with the well-known effect of the caloric restriction on ageing, open several tracks which should allow determining common mechanisms which regulate the mammalian lifespan.

Aged↗
PubMed2000

Targeted neuronal gene expression and longevity in Drosophila.

Earlier studies from this laboratory have shown that in the insect, Drosophila melanogaster, the motorneuron is an important cellular nexus between the metabolism of reactive oxygen species (ROS) and adult lifespan. This was demonstrated by experiments in which expression of CuZn SOD (SOD1) specifically in motorneurons was shown to extend the mean and maximum adult lifespans to 140% of normal, and to rescue the majority of deliterious phenotypes displayed by SOD1-null mutants. We have interpreted these results to mean either that the lifespan of the organism is normally limited by the functional lifespan of this post-mitotic cell type, or that ROS metabolism in motorneurons affects organismic lifespan via a systemic, perhaps neuroendocrine, signaling mechanism. We have now extended these studies to ask: (i) whether expression of catalase (CAT) or of the mitochondrially-localized Mn SOD (SOD2) in motorneurons, either singly or in combination with SOD1, have similar effects on lifespan; (ii) if expression of SOD2 can rescue SOD1-null mutant phenotypes; and (iii) if ROS metabolism in cell types other than motorneurons has significant impact on aging and lifespan determination.

Aging↗
PubMed2000

Demography of longevity: past, present, and future trends.

Life expectancy at birth has roughly tripled over the course of human history. Early gains were due to a general improvement in living standards and organized efforts to control the spread of infectious disease. Reductions in infant and child mortality in the late 19th and early 20th century led to a rapid increase in life expectancy at birth. Since 1970, the main factor driving continued gains in life expectancy in industrialized countries is a reduction in death rates among the elderly. In particular, death rates due to cardiovascular disease and cancer have declined in recent decades thanks to a variety of factors, including successful medical intervention. Based on available demographic evidence, the human life span shows no sign of approaching a fixed limit imposed by biology or other factors. Rather, both the average and the maximum human life span have increased steadily over time for more than a century. The complexity and historical stability of these changes suggest that the most reliable method of predicting the future is merely to extrapolate past trends. Such methods suggest that life expectancy at birth in industrialized countries will be about 85-87years at the middle of the 21st century.

Female↗
PubMed2001

Heterogeneity and its biodemographic implications for longevity and mortality.

In the visible world, heterogeneity typically refers to the differences that exist among individuals in a defined population. These differences can arise from a variety of sources--biological, behavioral and social. Ever since Darwin, scientists have argued over the biological significance of differences observed at the individual, morphological, physiological, genetic, molecular and structural levels. A general consensus has been reached. Heterogeneity is ubiquitous, it is important, and it increases as observations are made at finer levels of biological resolution. Debates over the significance of heterogeneity have emerged once again as biologists and demographers work together in order to create the emerging field of biodemography. For these scientists, the debates center around the relative impact that individual heterogeneity has on population level statistics. It is argued here that in a world where the mortality barriers to long life for individuals have been dramatically weakened, the population consequences of heterogeneity are already visible and will grow in importance as biomedical technologies continue to usher progressively more people into the post-reproductive period of the lifespan.

Animals↗
PubMed2002

Longevity minimalists: life table studies of two species of northern Michigan adult mayflies.

Life table studies were conducted on both sexes of newly emerged subimagoes of the mayfly species, Hexagenia limbata (n = 4472) and Ephemera simulans (n = 1254), which have two- and one-year life cycles, respectively. The expectation of life at emergence for H. limbata was approximately 2.6 days for both sexes with the last individual (a female) dying on day 8. Expectation of life for E. simulans was 1.6 and 2.0 days for males and females, respectively, with the last individuals (both sexes) dying on day 3. The results reveal that mortality does not occur in one large step in this group of rapidly senescing organisms. Rather deaths are spread over several days when the adult mayflies are maintained under laboratory conditions.

Animals↗
PubMedDate not supplied

What studies on human longevity tell us about the risk for cancer in the oldest old: data and hypotheses on the genetics and immunology of centenarians.

Centenarians are people who escaped from major common diseases, including cancer, and reached the extreme limits of human life-span. The analysis of demographic data indicates that cancer incidence and mortality show a levelling off around the age of 85-90 years, and suggests that oldest old people and centenarians are protected from cancer onset and progression. In this paper, we review data of recent literature on the distribution in centenarians of germ-line polymorphisms, which are supposed to affect the individual susceptibility to cancer (p53, HRAS1, BRCA1, glutathione transferases, cytochrome oxidases, steroid-5 alpha-reductase enzyme type II). Moreover, we add new data on two p53 polymorphisms in a total of 1086 people of different age, including 307 centenarians. In addition, we put forth the hypothesis that the remodelling of the immune system occurring with age is capable of creating a hostile environment for the growth of cancer cells in these exceptional individuals. We conclude that future studies on centenarians regarding the germ-line variability of genes involved in the control of the immune response, including apoptosis (ApoJ), are likely to be of fundamental importance in understanding the basic mechanisms for cancer, aging and their complex relationship.

Adult↗
PubMedDate not supplied

Poly(ADP-ribose) polymerase-1, DNA repair and mammalian longevity.

Cellular DNA repair activities can be expected to control the rate of the ageing process by keeping the steady-state levels of DNA damage, which is continuously induced by endogenous and exogenous damaging agents, at low levels. Poly(ADP-ribosyl)ation is one of the immediate biochemical reactions of eukaryotic cells to DNA damage and is functionally associated with DNA base-excision repair and strand break repair. Here we review the current state of the art concerning the relationship between DNA strand break repair, poly(ADP-ribosyl)ation, maintenance of genomic stability and mammalian life span.

Aging↗
PubMed1998

CD28 expression in T cell aging and human longevity.

Functional decrements of the immune system have a major contribution to aging and age-related diseases. Here, we further characterize the decline in proportion of CD28-positive T cells previously identified in centenarians. Cohorts of 97 centenarians, 40 subjects aged 70-90 (ELD group), and 40 young adults (under age 40) were phenotyped for T cell surface expression of CD28, CD4, and CD8 antigens. The significant decline in T cells expressing CD28 (p < 10(-4) for comparisons between adults and either ELD or centenarians) affects preferentially the CD8+ subset of T cells. This decline accounts largely for the age-related diminution of T cell responsiveness to mitogenic signals. CD28 expression is modulated in T cell cultures in a growth-related fashion and this modulation is dampened in cultures from centenarians. We propose that the decrease in CD28 expression reflects a compensatory adaptation of the immune system during aging in the face of chronic stimulation.

Adult↗
PubMed2004

Positive impact of social intervention on disturbed neurobehavioral function in an elderly community-dwelling population: longitudinal investigation for longevity and aging in Hokkaido County (LILAC).

Several kinds of health consultation and rehabilitation for functional disorders aimed at stroke prevention and maintenance of cognitive function in an elderly population in Hokkaido county, Japan. Changes in cardiovascular and neurobehavioral endpoints between 2000 and 2002 were assessed in 72 of 115 subjects over 75 years of age. Direct social intervention, including lifestyle modification can have a positive impact, notably on subjects with cardiovascular disorders.

Aged↗
PubMed2005

Arterial stiffness independently predicts cardiovascular events in an elderly community -- Longitudinal Investigation for the Longevity and Aging in Hokkaido County (LILAC) study.

We investigated the predictive value of arterial stiffness to assess cardiovascular risk in elderly community-dwelling people by means of a multivariate Cox model. In 298 people older than 75 years (120 men and 178 women, average age: 79.6 years), brachial-ankle pulse wave velocity (baPWV) was measured between the right arm and ankle in a supine position. The LILAC study started on July 25, 2000, consultation was repeated yearly, and the last follow-up ended on November 30, 2004. During this follow-up span of 1227 days, there were nine cardiovascular deaths, the cause of death being myocardial infarction for two men and three women or stroke for two men and two women. In Cox proportional hazard models, baPWV as well as age, Mini-Mental State Examination (MMSE), Hasegawa Dementia Scale Revised (HDSR) and the low-frequency/high-frequency (LF/HF) ratio showed a statistically significant association with the occurrence of cardiovascular death. A two-point increase in MMSE and HDSR score significantly protected against cardiovascular death, the relative risk (RR) being 0.776 (P = 0.0369) and 0.753 (P = 0.0029), respectively. The LF/HF ratio also was significant (P = 0.025), but the other indices of HRV were not. After adjustment for age and HDSR, a 200 cm/s increase in baPWV was associated with a 30.2% increase in risk (RR = 1.302, 95% CI: 1.110-1.525), and a 500 cm/s increase in baPWV with a 93.3% increase in risk (RR = 1.933, 95% CI: 1.300-2.874, P = 0.0011), whereas the LF/HF ratio was no longer associated with a statistically significant increase in cardiovascular mortality. In elderly community-dwelling people, arterial stiffness measured by means of baPWV predicted the occurrence of cardiovascular death beyond the prediction provided by age, gender, blood pressure and cognitive functions. baPWV should be added to the cardiovascular assessment in various clinical settings, including field medical surveys and preventive screening. The early detection of risk by chronomics allows the timely institution of prophylactic measures, thereby shifting the focus from rehabilitation to prehabilitation medicine, as a public service to several Japanese towns.

Aged↗
PubMed2005

Fractal analysis of heart rate variability and mortality in elderly community-dwelling people -- Longitudinal Investigation for the Longevity and Aging in Hokkaido County (LILAC) study.

AIM: Fractal analysis of heart rate (HR) variability (HRV) has been used as a new approach to evaluate the risk of mortality in various patient groups. Aim of this study is to examine the prognostic power of detrended fluctuation analysis (DFA) and traditional time- and frequency-domain analyses of HR dynamics as predictors of mortality among elderly people in a community. METHODS: We examined 298 people older than 75 years (average age: 79.6 years) and 1-h ambulatory ECG was monitored. During the last 10 min, deep respiration (6-s expiration and 4-s inspiration) was repeated six times in a supine position. Time-domain and frequency-domain measures were determined by the maximum entropy method. Scaling exponents of short-term (<11 beats, alpha 1) and longer-term (>11 beats, alpha 2) were determined by the DFA method. Six estimates, obtained from 10-min segments, were averaged to derive mean values for the entire recording span. These average values were denoted Alpha 1 and Alpha 2, estimates obtained during the first 10-min segment Alpha 1 S and Alpha 2 S, and those during the last 10-min segment Alpha 1E and Alpha 2E, respectively. The LILAC study started on July 25, 2000 and ended on November 30, 2004. We used Cox regression analysis to calculate relative risk (RR) and 95% confidence interval (CI) for all-cause mortality. Significance was considered at a value of P < 0.05. RESULTS: Gender, age and Alpha 2E showed a statistically significant association with all-cause mortality. In univariate analyses, gender was significantly associated with all-cause mortality, being associated with a RR of 3.59 (P = 0.00136). Age also significantly predicted all-cause mortality and a 5-year increase in age was associated with a RR of 1.49 (P = 0.01809). The RR of developing all-cause mortality predicted by a 0.2-unit increase in Alpha 2E was 0.58 (P = 0.00390). Other indices of fractal analysis of HRV did not have predictive value. In multivariate analyses, when both Alpha 2E and gender were used as continuous variables in the same model, Alpha 2E remained significantly associated with the occurrence of all-cause mortality (P = 0.02999). After adjustment for both gender and age, a 0.2-unit increase in Alpha 2E was associated with a RR of 0.61 (95% CI: 0.42-0.90, p = 0.01151). CONCLUSION: An intermediate-term fractal-like scaling exponent of RR intervals was a better predictor of death than the traditional measures of HR variability in elderly community-dwelling people. It is noteworthy that the longer-term (alpha 2) rather than the short-term fractal component (alpha 1) showed predictive value for all-cause mortality, which suggests that an increase in the randomness of intermediate-term HR behavior may be a specific marker of neurohumoral and sympathetic activation and therefore may also be associated with an increased risk of mortality.

Aged↗
PubMed2005

Common carotid intima-media thickness is predictive of all-cause and cardiovascular mortality in elderly community-dwelling people: Longitudinal Investigation for the Longevity and Aging in Hokkaido County (LILAC) study.

Several cohort studies have examined the association of carotid intima-media thickness (IMT) with the risk of stroke or myocardial infarction in apparently healthy persons. We investigated the predictive value of IMT of cardiovascular mortality in elderly community-dwelling people, beyond the prediction provided by age and MMSE, assessed by means of a multivariate Cox model. Carotid IMT and plaque were evaluated bilaterally with ultrasonography in 298 people older than 75 years (120 men and 178 women, average age: 79.6 years). The LILAC study started on July 25, 2000. Consultations were repeated every year. The follow-up ended on November 30, 2004. During the mean follow-up span of 1152 days, 30 subjects (21 men and nine women) died. Nine deaths were attributable to cardiovascular causes (myocardial infarction: two men and three women; stroke: two men and two women). The age- and MMSE-adjusted relative risk (RR) and 95% confidence interval (95% CI) of developing all-cause mortality was assessed. A 0.3 mm increase in left IMT was associated with a RR of predicted 1.647 (1.075-2.524), and a similar increase in right IMT with a RR of 3.327 (1.429-7.746). For cardiovascular mortality, the corresponding RR values were 2.351 (1.029-5.372) and 2.890 (1.059-7.891), respectively. Carotid IMT assessed by ultrasonography is positively associated with an increased risk of all-cause and cardiovascular death in elderly community-dwelling people.

Age Factors↗
PubMed2003

Nutrition, diet, physical activity, smoking, and longevity: from primitive hunter-gatherer to present passive consumer--how far can we go?

In millennia past, and until recently, among hunter-gatherers and like populations, in all populations, in measure, down through the ages, the securing of sufficient food was life's primary purpose. Virtually all people were physically very active during early life and later in their everyday occupations. In contrast, nowadays, in Western populations, with relative abundance of food, the way of life is mainly one of enjoyment of meals, of work, and of leisure time, in a context of as few as one child per family, and with long survival times of about 75 to 80 y, due in large part to much reduced child mortality and the effective treatments of disorders and diseases. As to changes in food consumption, compared with the erratic and often monotonous fares of the past, both far and not so distant, everyday diets have changed tremendously in variety, nutritional value, and palatability such that, inter alia, overeating is almost inevitable. Compounding the latter, sedentariness is the rule, in contrast to the previously very high level of everyday physical activity in the masses of populations. In consequence, one speculation is that, by 2230, "all Americans will be obese." Although the living of much longer lives is highly gratifying, understandably, all wish to have longer "healthy life expectancy," i.e. to suffer as little as possible before death. However, with regard to the present-day "passive consumer," although the practical recommendations for leading still healthier lives, dietarily and non-dietarily, are well known, very few are interested, and still fewer practice them. Nevertheless, for the few who, with determination, are eager to improve their lifestyles, there could be highly profitable lengthening of years of "healthy life expectancy" by eating less, eating more plant foods, being much more physically active, and restricting non-dietary risk factors (smoking, alcohol consumption).

Diet↗
PubMed2002

Molecular mechanisms linking calorie restriction and longevity.

Calorie-restricted feeding retards the rate of ageing in mammalian and invertebrate species. The molecular mechanisms underlying this effect include a lower rate of accrual of tissue oxidative damage that is associated with a significantly lower rate of mitochondrial free radical generation in rodent species. To identify the important sites of control and regulation for mitochondrial free radical generation during ageing and calorie-restricted feeding, metabolic control analysis is being applied to the study of mitochondrial bioenergetics. With ageing an increase in the mitochondrial proton leak is observed in mouse hepatocytes and in rat skeletal muscle. Limited data suggest that calorie-restricted feeding lowers the inner mitochondrial membrane potential and this may explain the reduced rate of free radical generation. A lowered unsaturation/saturation index is observed for mitochondrial membrane lipids in calorie-restricted rodents resulting in an altered membrane structure and function. Plasma concentrations of insulin and triiodothyronine are significantly lower under calorie-restricted feeding conditions and these hormones exert transcriptional control over desaturase enzymes that are important in the control of membrane lipid unsaturation. A loss of double bonds should make the mitochondrial membranes more resistant to peroxidation damage and would also reduce the proton conductance of the membrane, raising the membrane potential at a given respiration rate. This effect however, appears to be offset by other membrane changes that may include increased activity of uncoupling proteins. These unidentified adaptations increase the proton leak in calorie-restricted animals resulting in a lowering of the membrane potential and ROS generation.

Animals↗