Resistance to prooxidant agent paraquat in the short- and long-lived lines of the seed beetle (Acanthoscelides obtectus)

In the present study we test whether variation in resistance to paraquat (PQ), a free radical generator, correlates with variation in longevity in two sets of seed beetles (Acanthoscelides obtectus) experimental lines that were selected either for early reproduction and short-life or late reproduction and long-life. Long-lived late reproduction lines (L) showed increased resistance to PQ, while opposite was true for short-lived early reproduction line (E). Striking outcome of the selection for early and late reproduction in A. obtectus is asymmetry of responses to alternate mating schedules. The intensity of response depended on selection regime, sex and PQ dose. Evolution of longevity and PQ resistance was faster in L than E selection regime, and in females than males. To understand how age-specific mortality rates are affected by PQ we decomposed post-stress mortality data (using Gompertz mortality model) into initial mortality rate, which reflects basal vulnerability to stresses and age-specific mortality rate, which concerns the rate of increase in stress vulnerability, i.e. the rate of senescence. By estimating the parameters of the Gompertz mortality model we have shown that longevity reduction caused by PQ was the consequence of the increased baseline mortality rather than a speed up of the rate of ageing.     

Slowing of age-specific mortality rates in Drosophila melanogaster

We have studied age-dependent mortality in large cohorts of male and female D. melanogaster from four inbred lines. Average longevity varies substantially between genotypes (broad-sense heritability = 22%). Contrary to the predictions of the Gompertz model, mortality rates tend to decelerate at the most advanced ages. Fitting Gompertz, Weibull, Logistic, and Two-stage Gompertz mortality models to the data, we find that the best fit is obtained with the two-stage model, with exponentially increasing mortality at early ages, and zero or nearly zero increase at older ages. There is little microenvironmental effect from cage to cage. There is a sex-dependent mortality crossover: males and females differ in initial mortality rate and degree of acceleration of mortality rate, but the ordering of the sexes according to mortality parameters depends on genotype. Model fitting can be affected by gaps between deaths in the tail of the survivorship distribution. The observations are inconsistent with the limited life-span paradigm, which predicts sudden and well-defined drops in survivorship and corresponding sharp increases in mortality at advanced ages for large cohorts of genetically identical individuals.     

Hormesis in Caenorhabditis elegans dauer-defective mutants

We have shown that increased longevity and stress resistance can be induced by sub-lethal exposure to stressors (hormesis). Here we ask whether genes of the dauer formation pathway that are known to modulate life span in Caenorhabditis elegans are required for this hormesis. We find that loss-of-function mutations in any of three genes (daf-16,daf-18, or daf-12) not only reduce or abolish the ability to form dauers but also block the hormetic response increasing life span following sub-lethal heat stress. Indeed, the life expectancy of these dauer-defective mutants is decreased by the same pretreatments that increase the life expectancy of wild-type animals. Additionally, we find that daf-16 and daf-12 are not required for the induction of thermotolerance, but daf-18 is required for its full induction. Our results underscore the importance of the dauer-formation pathway in specifying life span by demonstrating a similar, but not identical, role in life extension attributed to hormesis.This revised version was published online in October 2005 with corrections to the Cover Date.     

Evolutionary patterns among measures of aging

Maximum lifespan has been one of the most common aging measures in comparative studies, while the Gompertz model has recently attracted both proponents and critics of its capacity to adequately describe the acceleration of mortality in the oldest age classes. The Gompertz demographic model describes age-dependent mortality rate acceleration and age-independent mortality using the parameters α and A, respectively. Evolutionary biologists have predominantly used average longevity in studies of aging. Little is known about the evolutionary relationships of these measures on the microevolutionary time scale. We have simultaneously compared Gompertz parameters, average longevity, and maximum longevity in 50 related populations of Drosophila melanogaster, many of which have been selected for postponed aging. Overall, these populations have differentiated significantly for the A and α parameter of the Gompertz equation, as well as average and maximum longevity. These indices of aging appear to measure the same genetic changes in aging. However, in some specific population comparisons, the relationships among these measures are more complex. In a second experiment, environmental manipulation of longevity had substantially different effects from genetic differentiation, with the A parameter accounting for changes in overall mortality. The adequacy of the maximum lifespan and the Gompertz equation as indices of aging in evolutionary studies is discussed.     

Determinants of life expectancy in medullary thyroid cancer: age does not matter

OBJECTIVE: In medullary thyroid cancer (MTC) age is considered an important prognostic factor but survival has never been properly adjusted for baseline mortality in the general population. We aimed to identify prognostic factors by analysing patients with MTC regarding life expectancy. DESIGN: We described a retrospective cohort study with a median follow-up of 8 years (range 1-35 years). PATIENTS: We included 120 consecutive patients of whom 66 (55%) had sporadic MTC. Male/female ratio was 1 : 1; median age was 45 years (range 3-83 years). MEASUREMENTS: Measurements were overall and disease-specific survival and life expectancy expressed as survival adjusted for baseline mortality rate in the general population. RESULTS: Overall and disease-specific 10-year survival was 65% and 73%, respectively. After 10 years, 29% of patients were biochemically and 63% clinically cured. Median overall life expectancy was 0.58 (95%CI 0.37-0.80). Detectable recurrence occurred in 60 patients after a median of 36 months (range 5-518 months). On multivariate regression analysis only stage of disease and extrathyroidal extension predicted recurrence-free life expectancy. Extrathyroidal extension was the only independent predictor of overall life expectancy. Persistent biochemical MTC did not independently affect life expectancy but calcitonin doubling time of less than one year indicated worse prognosis. Patients without detectable recurrences after initial treatment had a life expectancy similar to the general population. CONCLUSIONS: In MTC patients, extrathyroidal extension and stage at diagnosis are the only independent predictors of (recurrence-free) life expectancy. Patients diagnosed in an early stage of disease and patients without detectable recurrence have favourable life expectancy independently of biochemical cure.     

Why do life spans differ? Partitioning mean longevity differences in terms of age-specific mortality parameters

Populations typically differ in mean life spans because of genetic, environmental, or experimental factors. In this paper methods are presented that clarify the relationship between differences in the longevity of two populations and differences in their underlying age-specific patterns of mortality. Data are examined from rodent and fruit fly (Drosophila melanogaster) experiments that investigated the longevity effects of a variety of environmental and genetic manipulations, including temperature, dietary restriction, laboratory selection for increased longevity, and severe inbreeding. Analyses suggest that longevity differences mediated by temperature and dietary restriction result predominantly from differences in the rate of increase in mortality with age. Increases in longevity through laboratory selection result primarily from a reduction in baseline mortality and not a slowing of the rate of aging. Although the methods are applied primarily in the context of simple mathematical models of mortality (e.g., the Gompertz model), they are quite general and can be applied to mortality models of arbitrary complexity. Mathematica protocols ("notebooks") and computer software have been developed to perform all the analyses discussed and are available from the first author.     

The Gompertz equation as a predictive tool in demography

The Gompertz demographic model describes rates of aging and age-independent mortality with the parameters and A, respectively. Estimates of these parameters have traditionally been based on the assumption that mortality rates are constant over short to moderate time periods. This assumption is questionable even for very large samples assayed over short time intervals. In this article, we compare several methods for estimating the Gompertz parameters, including some that do not assume constant mortality rates. A maximum likelihood method that does not assume constant mortality rates is shown to be best, based on the bias and variance of the Gompertz parameter estimates. Moreover, we show how the Gompertz equation can then be used to predict mean longevity and the time of the n_th percentile of mortality. Methods are also developed that assign confidence intervals to such estimates. In some cases, these statistics may be estimated accurately from only the early deaths of a large cohort, thus providing an opportunity to estimate longevity on long-lived organisms quickly.     

Heat-induced hormesis in longevity of two sibling <Emphasis Type="Italic">Drosophila</Emphasis> species

Previous work showed that mild-heat stress induces longevity hormesis in a model organism, D. melanogaster. Here we compared the possible heat-induced hormesis in longevity of other species of Drosophila, D. buzzatii and its sibling species D. koepferae, in a single-sex environment. Possible correlations between longevity and heat-stress resistance were also tested by measuring longevity, heat-knockdown resistance and the heat-induced Hsp70 expression for each species in a common environment. D. buzzatii was longer lived than D. koepferae at benign temperature. Knockdown resistance to heat stress was positively correlated to longevity within species. However, the shorter-lived species was more resistant to knockdown by heat stress than the longer-lived species. The heat-induced Hsp70 expression was similar between species. A heat-shock treatment (37°C for 1 h at 4 days of age) extended mean longevity in the longer lived species but not in the shorter lived species. In D. koepferae, the demographic rate of senescence decreased but the baseline mortality rate increased by heat-shock, resulting in no extension of mean longevity. Sympatric populations of closely related species can be differentially sensitive to temperature and exhibit different patterns of 37°C-induced hormesis in demographic senescence and longevity. The results also show that positive correlations between stress resistance and life span within species can shift in sign across closely related species. Finally, this study shows that heat-induced hormesis in longevity can be found across different Drosophila species, as hormetic effects are not limited to the previously studied D. melanogaster.     

The U-shaped response of initial mortality in Caenorhabditis elegans to mild heat shock: does it explain recent trends in human mortality?

U-shaped dose-response relationships (hormesis) have been documented in numerous biological, toxicological, and pharmacological investigations. For example, in response to a mild 35 degrees C heat shock, the longevity of Caenorhabditis elegans exhibits an inverted U-shaped dose-response. By applying the demographic concept of heterogeneity, we find that this U-shaped curve for longevity response is driven by a U-shaped dose-response of initial mortality. When worms are subjected to mild heat shock, the initial mortality decreases compared to the control. This initial mortality benefit increases with moderate increases in the length of heat shock, peaking at a point that coincides with the induction of damage to the worms. The dose of heat shock that coincided with this benefit in initial mortality did not affect the rate of increase in mortality.     

Heating stress patterns in Caenorhabditis elegans longevity and survivorship

Survival data from Caenorhabditis elegans strain TJ1060 (spe-9; fer-15) following brief exposure to 35 °C have been investigated. Three experiments with 3-day-old worms were conducted with heat duration ranging between 0 and 12 hours. A statistically significant increase in life expectancy was observed in the groups heated for less than 2 hours, as compared to the unheated control groups. In different experiments P-values for the observed life spans under the hypothesis that heating has no influence on longevity were P < 0.004 after 0.5 hour heat, P < 0.012 after 1 hour heat and P < 0.055 after 2 hours of heating. A biphasic survival model with Gamma distributed frailty has been constructed to describe the survival of worms after heating. The increase in the remaining life expectancy is determined by more effective protection by heat-induced substances in the ages yanger than 27 days. The unheated control group demonstrated acquired heterogeneity of frailty with chronological age while the heat-induced substances defend the worms in a universal way and protect against the development of frailty.     

Age-specific demographic profiles of longevity mutants in Caenorhabditis elegans show segmental effects

Demographic profiles of several single-gene longevity mutants of the nematode Caenorhabditis elegans reveal segmental (age-specific) effects on mortality. The mortality profiles of wild-type worms were examined across multiple replicate cultures containing 100,000 or more nematodes and found to be quite replicable, although clear environmental effects are routinely found. The combined profile of wild type was compared with those of three long-lived mutants to determine how age-specific mortality is altered by mutations in age-1, clk-1, or spe-26. In all four genotypes, death rates fit a two-stage Gompertz model better than a one-stage Gompertz; that is, mortality levels off at later ages. The largest genetic effect on mortality was that of an age-1 mutation, which lowered mortality more than fivefold at most later ages. In contrast, a spe-26 mutant had a tenfold lower mortality until approximately 2 weeks of age but ultimately achieved a higher mortality, whereas clk-1 mutants show slightly higher mortality than wild type during the fertile period, early in life, but ultimately level off at lower mortality. Each mutant thus has a distinctive profile of age-specific mortalities that could suggest the time of action of each gene.     

Rate of aging, rate of dying and non-Gompertzian mortality - encore...

That the steep increase of mean life expectancy in the developed countries during the first decades of this century has now come to a halt is neither news nor reason for panic. Mean life span cannot exceed the apparent biological limit for the human species, a maximum life span LSmax of 100-110 years, that has remained unchanged across time, races and civilizations; it will moreover remain about 20% less than LSmax even if major diseases were to be eliminated due to the inherent individual differences - only a few individuals are endowed with a genetic-physiologic profile that allows them to reach LSmax. Some concepts on the relation of rates of aging and dying and the mechanism of mortality are here pertinent and are amplified. Finally, though the author has extensively criticized the general applicability of the Gompertz 'law of mortality', he has some reservations concerning the recently expressed view that the course of the rate of increase of force of mortality with age may be different in men and women, chiefly slowing down versus continuously increasing; this conclusion may well be an artifact of the analysis.     

Lifespan extension of Caenorhabditis elegans following repeated mild hormetic heat treatments

Mild hormetic heat treatments early in life can significantly increase the lifespan of the nematode C. elegans. We have examined the effects of heat treatments at different ages and show that treatments early in life cause the largest increases in lifespan. We also find that repeated mild heat treatments throughout life have a larger effect on lifespan compared to a single mild heat treatment early in life. We hypothesize that the magnitude of the hormetic effect is related to the levels of heat shock protein expression. Following heat treatment young worms show a dramatic increase in the levels of the small heat shock protein HSP-16 whereas old worms are a 100-fold less responsive. The levels of the heat shock proteins HSP-4 and HSP-16 correlate well with the effects on lifespan by the hormetic treatments.     

From the Cover: Demographic perspectives on the rise of longevity

This article reviews some key strands of demographic research on past trends in human longevity and explores possible future trends in life expectancy at birth. Demographic data on age-specific mortality are used to estimate life expectancy, and validated data on exceptional life spans are used to study the maximum length of life. In the countries doing best each year, life expectancy started to increase around 1840 at a pace of almost 2.5 y per decade. This trend has continued until the present. Contrary to classical evolutionary theories of senescence and contrary to the predictions of many experts, the frontier of survival is advancing to higher ages. Furthermore, individual life spans are becoming more equal, reducing inequalities, with octogenarians and nonagenarians accounting for most deaths in countries with the highest life expectancy. If the current pace of progress in life expectancy continues, most children born this millennium will celebrate their 100th birthday. Considerable uncertainty, however, clouds forecasts: Life expectancy and maximum life span might increase very little if at all, or longevity might rise much faster than in the past. Substantial progress has been made over the past three decades in deepening understanding of how long humans have lived and how long they might live. The social, economic, health, cultural, and political consequences of further increases in longevity are so significant that the development of more powerful methods of forecasting is a priority.     

Cholesterol lowering and life expectancy: a critical evaluation]

Numerous studies have confirmed a positive correlation between serum cholesterol levels and the occurrence of coronary artery disease. Lowering cholesterol by 1% is accompanied by a reduction of coronary events by 2%. The rate of fatal coronary events is not significantly influenced. Coronary angiography demonstrated only a mild average reduction of coronary lesions after cholesterol-lowering therapy. This might be explained by the low lipid content of a coronary plaque (5-15%). The majority of intervention trials revealed an increase of the extracardiac mortality in treatment groups. Thus, up to the present, it remains unproven that cholesterol-lowering therapy leads to an increase in life expectancy.     

Biological implications of the Weibull and Gompertz models of aging

Gompertz and Weibull functions imply contrasting biological causes of demographic aging. The terms describing increasing mortality with age are multiplicative and additive, respectively, which could result from an increase in the vulnerability of individuals to extrinsic causes in the Gompertz model and the predominance of intrinsic causes at older ages in the Weibull model. Experiments that manipulate extrinsic mortality can distinguish these biological models. To facilitate analyses of experimental data, we defined a single index for the rate of aging (omega) for the Weibull and Gompertz functions. Each function described the increase in aging-related mortality in simulated ages at death reasonably well. However, in contrast to the Weibull omega(W), the Gompertz omega(G) was sensitive to variation in the initial mortality rate independently of aging-related mortality. Comparisons between wild and captive populations appear to support the intrinsic-causes model for birds, but give mixed support for both models in mammals.     

Patient survival with pacemaker (author's transl)]

The survival rate for age groups from 50--59, 60--69, 70--79, 80--89 was worked out from 1065 patients with implanted pacemakers form 1963 to the end of 1977. In all age groups the life expectancy was under the survival of the general population in the Federal Republic of Germany. Analysing the data it seems that two groups of different longevity superimpose in all age groups; the first group shows an unproportional high mortality rate in the first 12 months while the other has an almost identical survival to the tenth year. The initial high mortality rate respective to the increasing age probably results in accompaning diseases; in this aspect further studies are required.     

Cold stress increases resistance to fungal infection throughout life in Drosophila melanogaster

Flies were subjected to one of three mild stresses known to have positive effects on longevity (heat, hypergravity, cold), prior to an infection with the entomopathogenic fungus Beauveria bassiana. Flies subjected to cold survived longer to infection, while the other mild stresses had no positive effect. These positive effects of a cold stress on resistance to infection were observed mainly in males and throughout life, i.e., a long time after the cold stress was applied. It was confirmed that cold and hypergravity stresses increased longevity of non-infected flies, but no positive effect of heat shocks were however observed.     

Validated analysis of mortality rates demonstrates distinct genetic mechanisms that influence lifespan

A key goal of gerontology is to discover the factors that influence the rate of senescence, which in this context refers to the age-dependent acceleration of mortality, inversely related to the morality rate doubling time. In contrast factors that influence only initial mortality rate are thought to be less relevant to the fundamental processes of aging. To resolve these two determinants of mortality rate and lifespan, initial morality rate and rate of senescence are calculated using the Gompertz equation. Despite theoretical and empirical evidence that the Gompertz parameters are most consistently and reliably estimated by maximum-likelihood techniques, and somewhat less so by non-linear regression, many researchers continue to use linear regression on the log-transformed hazard rate. The present study compares these three methods in the analysis of several published studies. Estimates of the mortality rate parameters were then used to compare the theoretical values to the actual values of the following parameters: maximal lifespan, 50% survival times, variance in control groups and agreement with the distribution of deaths. These comparisons indicate that maximum-likelihood and non-linear regression estimates provide better estimates of mortality rate parameters than log-linear regression. Of particular interest, the improved estimates indicate that most genetic manipulations in mice that increase lifespan do so by decreasing initial mortality rate, not rate of senescence, whereas most genetic manipulations that decrease lifespan surprisingly do so by increasing the rate of senescence, not initial mortality rate.