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Previous studies have shown that subjecting Drosophila melanogaster flies to a mild stress at young or middle age can increase lifespan and resistance to severe stresses throughout life and that the NF-κB-like transcription factor DIF, the 70 kDa heat-shock proteins, and the Drosophila Forkhead box class O (dFOXO) transcription factor could explain some of these effects. The present study showed that two dFOXO mutants do not survive longer heat if previously subjected to a mild cold stress, contrarily to wild-type flies. This cold pretreatment had nearly no effect on dFOXO nuclear translocation in wild-type males. Heat stress strongly increased dFOXO translocation, but this effect was lowered in cold-pretreated males. Because cold-pretreated wild-type males survived longer heat and had nevertheless a lower dFOXO translocation after this heat stress, one can conclude that dFOXO is required to resist heat but that the cold pretreatment makes that other mechanisms partly substitute to dFOXO translocation.

Gavrilov and colleagues disagree with our article in Gerontology [Vijg and Le Bourg: Gerontology 2017;63:432-434]. Here we address their arguments regarding human life-history strategies, maximal lifespan, and the proposal that one could live soon for 150 years., (© 2017 S. Karger AG, Basel.)

There is a long-lasting debate about a natural limit to human life span, and it has been argued that the maximum reported age at death, which has not increased for ca 25 years, fluctuates around 115 years, even if some persons live beyond this age. We argue that the close connection of species-specific longevity with life history strategies explains why human life span is limited and cannot reach the considerably longer life spans of several other species., (© 2017 S. Karger AG, Basel.)

Many experiments have shown that dietary restriction, for instance by removing live yeast or modifying the protein/carbohydrate ratio, can modulate lifespan, fecundity, resistance to severe stresses and behaviour in Drosophila melanogaster flies. The present study tested whether feeding flies with frozen yeast rather than with fresh yeast could have some effect on these traits, the other components of the food being similar in the two groups. Freezing altered live yeast quality and flies feeding on frozen yeast lived slightly less (males), were less fecund at older ages, and poorly resisted to some severe stresses (cold and starvation), no negative effect being observed on resistance to heat. It seems that, like in humans, feeding on a low quality food can negatively impact healthspan and that an appropriate food is not only a food with optimal number of calories and appropriate ratios of proteins, carbohydrates, and fat., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Log-rank tests are sometimes used to analyse longevity data when other tests should be preferred. When the experimental design involves more than one factor, some authors perform several log-rank tests with the same data, which increases the risk to wrongly conclude that a difference among groups does exist and does not allow to test interactions. When analysing the effect of a single factor with more than two groups, some authors also perform several tests (e.g. comparing a control group to each of the experimental groups), because post hoc analysis is not available with log-rank tests. These errors prevent to fully appreciate the longevity results of these articles and it would be easy to overcome this problem by using statistical methods devoted to one-way or multi-way designs, such as Cox's models, analysis of variance, and generalised linear models.

Several authors have discussed the existence of late-life fecundity plateaus in Drosophila melanogaster. However, all these studies have pooled flies to show such plateaus. Here, we have reanalyzed previously published fecundity results to know whether these plateaus exist at the individual level. We found that these plateaus are observed in ca 20% of females and in more than 50% if only the longer-lived flies are taken into account. We conclude that late-life fecundity plateaus are not a rare phenomenon when considering a whole cohort of flies and are very common in oldest flies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Evolutionary theories of aging explain why we age. These theories take into account the fact that, in the wild, mean lifespan of many species is usually shorter than it could be in protected environments. In such conditions, because most of animals die before reaching old age, there is no selection in favor or against alleles with effects at old age. Alleles with negative effects at this age can thus accumulate in successive generations, particularly if they also have positive effects at young age and are thus retained by selection. This chapter describes the evolutionary theories of aging and their consequences for the understanding of the biology of aging as well as the challenges to these theories. It is argued that these theories offer a reasonable explanation to the existence of the aging process even if they can surely be refined.

Some misconceptions can be an obstacle for biogerontology research. These misconceptions can be classified in two categories: (1) obsolete ideas in biology, for example "aging has a universal cause" and "living beings are like machines", and (2) conceptual and logical confusions, such as "longevity is not dependent on other life-history traits", "between-groups variability allows to infer conclusions about individual variability", and "the burden of the proof lies with the opponents to the hypothesis". This opinion article describes these problems in the hope it will help to overcome them.

A mild cold stress can have positive effects on longevity, aging and resistance to severe stresses in flies (heat, cold, fungal infection), but the causes of these effects remain elusive. In order to know whether these effects could be explained by the DIF transcription factor (a NF-κB-like factor in the Toll innate immunity pathway), the Dif ( 1 ) mutant and its control cn bw strain were subjected to a pretreatment by cold. The DIF factor seems to be involved in the response to fungal infection after a mild cold stress and in the resistance to heat. However, DIF seems to have no role in the increased longevity of non-infected flies and resistance to a severe cold shock, because the cold pretreatment slightly increased longevity in females, mainly in Dif ( 1 ) ones, and resistance to a long cold shock in both sexes of these strains.

Mild stresses may have positive effects on aging, longevity and resistance to severe stresses at various ages in Drosophila melanogaster. However, no study has combined two mild stresses to know whether more positive effects would be observed than with each stress alone. Cold and hypergravity (HG) have positive effects on some traits, but negative ones can also be observed, particularly in females. This study combined in the same flies cold and HG exposure. When cold and HG had each positive or negative effects their combination had additive effects but, when only one of the pretreatments had some effect, the effect of their combination usually reflected this effect. Therefore, combining two mild stresses with positive effects on aging and longevity can be more efficient than each stress alone. However, if one of these mild stresses had negative effects and the other one positive effects, the net result of their combination could be the suppression of the positive effect of the second stress. On the whole, if the net result of the combination of two mild stresses would be negative, it would be preferable not to combine them.

It has been proposed that life expectancy could linearly increase in the next decades and that median longevity of the youngest birth cohorts could reach 105 years or more. These forecasts have been criticized but it seems that their implications for future maximal lifespan (i.e. the lifespan of the last survivors) have not been considered. These implications make these forecasts untenable and it is less risky to hypothesize that life expectancy and maximal lifespan will reach an asymptotic limit in some decades from now., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The Toll pathway of Drosophila melanogaster, when activated by the Beauveria bassiana fungus, directs the expression of the drosomycin and metchnikowin antimicrobial peptide genes by inducing the translocation into the nucleus of the DIF transcription factor. Accordingly, DIF mutants have been reported to have a lower resistance to fungi than control flies. However, as the longevity of non-infected DIF flies has not been measured in previous studies, it could be that survival times after infection are constrained by a low longevity. In the present study, DIF flies reared in conditions similar to those used in these previous studies had much lower survival time after infection than the control flies, but the longevity of non-infected DIF flies was also very low. Using rearing conditions controlling larval crowding, age of parents and mating status of experimental flies increased longevity of non-infected flies and survival time after infection in both strains. However, DIF flies had a similar survival time after infection as control ones or a slightly lower one, which shows that the effect of DIF is weaker than previously thought.

A cold stress applied to young flies can have positive effects on longevity, behavioral aging, and resistance to heat and infection. However, the same mild stress, if applied at older ages, i.e. in frailer flies, could be a strong stress with negative effects. Cold stress was applied at various ages (weeks 1-2, 2-3, 3-4, and 4-5) and its effect on longevity and on resistance at 6 weeks of age to heat or fungal infection was observed. In males, the cold stress had positive effects on longevity and resistance to infection, except when applied at the oldest age. No positive effect on longevity or resistance to infection was detected in cold-stressed females, as already observed in previous experiments using a cold stress at young age only. By contrast, cold stress applied at various ages increased resistance to heat in both sexes. Therefore, a mild stress can have positive effects on longevity and resistance to strong stresses not only when used at a young age, but also at older ages.

Several studies in the fly Drosophila melanogaster have shown that a mild stress can increase longevity, resistance to strong stresses (e.g., heat, fungal infection, cold) and delay behavioral aging. However, not all mild stresses have similar effects on the various studied traits. For instance, exposure to cold increases resistance to a fungal infection, but hypergravity and heat shocks do not. In addition to studies in flies and other invertebrates, it is necessary to perform experiments in mammals, to know whether mild stress could be used in therapy more thoroughly than today., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Dietary restriction (DR) is often considered as a nearly universal means to extend longevity in animal species. This article argues that whether DR will increase longevity is dependent on life-history strategies. Long-lived species are not expected to live much longer under DR, contrarily to short-lived ones. However, species able to cover long distances are not expected to live longer under DR, even if they are short-lived. Human beings are long-lived and can also cover long distances: thus, DR would probably not increase their lifespan. One may wonder whether DR mimetics would have some effects in human beings if DR does not increase longevity in this species., (2010 Elsevier Ireland Ltd. All rights reserved.)

A cold pretreatment has various positive effects on aging, longevity, and resistance to some stresses in Drosophila melanogaster flies. Removing live yeast from food has either favorable or deleterious effects on these traits. This study combined a cold pretreatment and removal of live yeast in the same flies, in order to know whether higher favorable effects would be observed with this combination than with each treatment alone. Each treatment had positive effects on climbing activity and their combination had additive effects, thus giving the highest climbing scores in flies subjected to the two treatments and the lowest ones in flies with live yeast and no cold pretreatment. Therefore, combining the two treatments had favorable effects if each of them had favorable effects. When removing live yeast had very deleterious effects, as on resistance to cold, a cold pretreatment was unable to reverse these effects, which was not unexpected. Finally, when removal had no effect or not a tragic negative effect, as on resistance to infection or to heat, a cold pretreatment was neutral or slightly compensated the negative effects of live yeast removal. These results lead to the conclusion that next studies using a combination of two mild stresses having beneficial effects on aging and longevity could bring more positive effects than each mild stress alone.

It is often accepted that dietary restriction (DR) increases longevity in Drosophila melanogaster, but this is still a controversial issue. In the present study, adult flies were fed on a rich nutritious medium to which live yeast, a source of proteins, was added or not. Suppressing live yeast did not always increased longevity of virgin flies, but increased it in mated flies. It also decreased fecundity, delayed behavioral aging and increased resistance to heat of young females only. However, flies without live yeast suffered from a reduced resistance to cold, starvation and infection. This study thus reports some positive effects of suppressing live yeast on longevity, contrarily to previous studies of the same laboratory using other DR methods, but also shows that the absence of live yeast increases frailty. The effects of live yeast in flies are thus contrasted, and it is probable that flies without a high amount of proteins in the diet would not survive for a long time in the wild, due to their inability to resist stress and their low fecundity.

Many experiments on the effect of mild stress on aging have been done in invertebrates, but not in mammals. Using mild stress to improve healthspan seems to be possible, because the few studies on humans which have been published appear to be promising. Particularly, one may wonder whether heat shocks could be of some use in therapy or as an integrated part of daily life of elderly people. However, the top priority is probably to study more thoroughly the effects of mild stress in rodents, and not only in invertebrates.

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.

The beneficial effects of mild stress (or hormetic effects) on aging and longevity have been studied for several years. Mild stress appears to slightly increase longevity, delay behavioral aging, and increase resistance to some stresses. However, not all stresses have such beneficial effects and, for the time being, only a few studies have been done in mammals.

Exposing young flies to hypergravity has hormetic effects on aging, longevity and resistance to heat stress. The present experiments tested whether cold shocks at young age could also have hormetic effects. Flies were cold-shocked at 0 degrees C daily for 60 min during two periods of 5 days separated by 2 days, starting at 5 days of age. This cold stress increased longevity, resistance to a lethal heat stress or to cold up to 6 weeks of age, resistance to a non-lethal heat stress at middle age, and delayed behavioral aging. Cold and hypergravity exposure at young age have thus similar effects, excepting on resistance to cold stress, which is not increased after exposure to hypergravity. Mild heat stress has also been shown to slightly increase longevity and resistance to a lethal heat stress, but not to delay behavioral aging. Since there are thus at least two mild stresses with large hormetic effects at old age in flies, i.e. cold and hypergravity, hormetic effects in flies are not stress-specific. Therefore, it could be hypothetized that hormetic effects of mild stress on aging and longevity are a general phenomenon and that they could also be observed in other species such as rodents.

According to the disposable soma theory, a cost for reproduction could exist in human beings and other species and, thus, longevity could decrease when women have a higher number of children. The purpose of this article is to review the evidence in populations living or not living under natural fertility conditions, i.e. when fertility is near its biological maximum. The results indicate that in natural fertility conditions longevity does not decrease when the number of children increases but, in modern populations, mortality could slightly increase when women have more than ca 5 children. Complete data for these modern cohorts will tell us, one day, whether these results are still observed when the variable of interest is longevity and not only mortality.

Subjecting flies to a mild stress at a young age may increase longevity and protect against strong stresses occurring at middle age. The purpose of this article is to test whether a mild stress could also increase survival time of flies living in stressful conditions. Flies were transferred at middle age in vials where they could only feed on a saccharose solution without any other nutrient. This poor medium is known to decrease longevity and it was hypothetized that adding hydrogen peroxide to it could minimize this negative effect. While high doses of hydrogen peroxide decreased further longevity, a low dose increased it in 4-week-old males and, only in some experiments, in females. This low dose had however not any positive effect on behavioral aging, resistance to heat and starvation. The positive effect of hydrogen peroxide appeared not to be due to a sanitary action upon the environment. Rather, it seems that hydrogen peroxide was a mild stress helping flies to cope with the negative effects of saccharose on longevity. Therefore, it is concluded that hydrogen peroxide, beyond the deleterious effects of high doses, could have positive effects in organisms when used at a low dose, particularly in stressful living conditions.

This article argues that dietary restriction would not increase longevity in species able to leave a place where they are subjected to starvation. Human beings can emigrate when feeding conditions are a threat to survival and thus they would not live longer if subjected to dietary restriction.

The learned suppression of photopositive tendencies was studied at the individual level in young flies of both sexes. In a T-maze, flies had to choose between an arm leading to a lighted vial associated with an aversive stimulus (i.e., a solution of quinine chlorhydrate deposited on a filter paper in the vial) and another arm leading to a darkened vial free of quinine. The present experiments were carried out to determine the roles of quinine and relative humidity in the maze. The flies avoided the lighted vial containing quinine even if they had no tarsal contact with quinine, and this result was not due to any odor of quinine. Subsequent experiments showed that relative humidity in the lighted vial, and probably in the arm leading to it, was an aversive stimulus, which partly explains why the flies avoided the lighted vial. However, in conditions in which the flies had tarsal contact with water or quinine it was confirmed that flies trained with quinine have higher avoidance scores than those trained with water only. Moreover, individual aversion to humidity was not correlated with the individual avoidance score: At similar levels of motivation (i.e., similar levels of aversion to humidity), some flies learn to avoid the lighted vial containing quinine whereas others do not. All these results show that, in addition to quinine, humidity is an unconditioned aversive stimulus in our paradigm and thus needs to be tightly controlled in experiments of conditioned avoidance.

It is often accepted that dietary restriction (DR) increases longevity in most species so far tested. Showing the same result in the fruit fly Drosophila melanogaster would be of interest, because this species is widely used in aging research. Some studies have shown that dietary restriction decreases longevity in this species while the opposite result has also been reported. However, some recent results appear to be flawed due to the use of not optimal control rearing conditions. It is argued that, for the time being, it cannot be concluded that dietary restriction increases longevity in D. melanogaster. It has also been shown in other fly species that dietary restriction does not increase longevity.

Previous studies have shown that exposing flies to hypergravity (3g or 5g) for the first 2 weeks of adult life slightly increases longevity of male flies and survival time at 37 degrees C for both sexes, and delays an age-linked behavioral change. The present experiment tested whether the hypergravity could also protect flies from four successive deleterious non-lethal heat shocks at 4 and 5 weeks of age. Males that lived in hypergravity for the first 2 weeks of adult life lived slightly longer (ca. +15% or 1.2 day) after heat shocks (30 min or 45 min at 37 degrees C) than flies that always lived at 1g, but this positive effect of hypergravity was not observed in females. Therefore, hypergravity exposure at young age can help the male flies recovering from a heat shock at older ages.

Calorie restriction increases longevity in rodents, delays the onset of certain diseases and has positive effects on ageing. Studies are ongoing in non-human primates. Eight persons following such a diet for 2 years reacted as anticipated (loss of body weight and fat, decrease in glycaemia and body temperature, etc.). Calorie restriction perhaps teaches us more on the means of resisting malnutrition than on ageing in normal dietary conditions. Calorie restriction is a tool for research, but it should not be recommended by practitioners, notably in elderly patients.

The effect of aging on acquisition of a learned suppression of photopositive tendencies was studied in 1-7-week-old flies of both sexes. Flies had to choose in a T-maze between an alley leading to a lighted vial associated with an aversive stimulus, a quinine hydrochloride solution, and another alley leading to a darkened vial free of quinine. Control groups with either no quinine or water in the lighted vial, respectively, did not learn at any age to avoid the lighted vial or had lower scores than flies trained with quinine. Flies of all ages trained with quinine learned to avoid the lighted vial and a slight decrease of the learning score was observed after the first week of age, no other effect of age being clearly observed. This study also tested whether pretraining enhanced (or impaired) learning score. Pretraining was obtained by subjecting 1-6-week-old flies to trials with a lighted vial without quinine before to subject them to trials with quinine in the lighted vial: pretraining increased learning scores to the same extent at all ages.

Previous studies have shown that exposing flies to hypergravity (3 or 5 g) for two weeks at young age slightly increases longevity of male flies and survival time at 37 degrees C of both sexes, and delays an age-linked behavioral change. The present experiments tested whether hypergravity could also protect flies from a non-lethal 37 degrees C heat shock applied at young, middle or old age (2, 4 or 6 weeks of age). Various durations of exposure at 37 degrees C had similar deleterious effects on climbing activity, spontaneous locomotor activity and learning in flies that lived or not in hypergravity at young age. Therefore, hypergravity does not protect the behavior of flies from a deleterious non-lethal heat shock. Hypergravity increased longevity of virgin males and decreased that of mated ones; it also increased longevity of virgins at 25 degrees C, the usual rearing temperature, but not at 30 degrees C. Thus, the positive effect of hypergravity on longevity is observed only if flies are not subjected to living conditions decreasing longevity, like mating and high temperature. Finally, 4 weeks-old males that lived in hypergravity at young age lived slightly longer (+ 15%) after a non-lethal heat shock (60 or 90 min at 37 degrees C) than flies that always lived at 1 g, but this positive effect of hypergravity was not observed in females or in older males. Therefore, all these results show that hypergravity exposure can help male middle-aged flies recovering from a heat shock, but does not protect them from behavioral impairments linked to this shock: a mild stress occurring at young age can partially protect from a moderate stress at middle age.

It has been previously shown that exposing Drosophila melanogaster flies to hypergravity (3g or 5g) at a young age for 2 weeks increases male longevity, resistance to heat in both sexes, and delays behavioural ageing, but the causes of these effects are unknown. We hypothesised that these flies could be well protected against free radical attacks and, if this protection persists after removal from hypergravity, can better resist free radicals and finally live longer than flies that have always lived at 1g. If so, the activity of enzymes detoxifying free radicals superoxide dismutase and catalase should be increased in flies that have lived in hypergravity. Results showed that no effect of hypergravity on the activity of these enzymes was observed at 2, 4 or 6 weeks of age. The greater longevity of male flies that have lived in hypergravity at a young age thus cannot be explained by the activity changes of these major antioxidant enzymes.

Many studies have described the positive effect of food restriction on aging and longevity in rodents as well as a genetic pathway activated in response to starvation in nematodes and mice. This genetic pathway may be conserved across phyla and some authors are convinced that these studies could help delay aging, particularly human aging. I suggest that these studies are analyzing a rescue program used to resist starvation but not active in ad libitum-fed animals. Whether these studies provide an increased understanding and ability to delay aging under the usual living conditions of animals and humans is unclear. The study of hormesis is proposed as a way of studying aging under normal living conditions, because ad libitum-fed animals subjected to mild stresses can live slightly longer than control animals and display increased resistance to strong stresses. It would be of interest to study, in animals subjected to a mild stress inducing hormesis, the response to non-lethal stresses rather than lethal ones, because elderly people are more often confronted by such non-lethal stresses (e.g., temperature drop in winter) than by lethal ones.

A task was designed to teach individual flies to avoid a lighted area after they had displayed an initial preference for it. The flies walked in a T-maze and chose between a lighted and a darkened alley leading, respectively, to a lighted and a darkened vial. Flies that were photopositive on a first trial were subjected to an aversive stimulus (a filter paper inserted into the lighted vial and wetted with a quinine solution), and they performed 16 training trials; they learned to avoid the lighted vial. The flies trained with water instead of quinine in the lighted vial still display avoidance of the lighted vial, but to a lesser extent. The flies trained with a dry filter paper in the lighted vial did not show any increase in avoidance during training. Like the flies trained with no quinine at all, those trained to avoid the lighted vial under a partial reinforcement condition (one half of the trials with quinine, the other half with a dry vial) did not master the task. Finally, removal of the quinine after an avoidance acquisition criterion was reached resulted in an extinction process.

Background: The existence of a positive relationship between stress resistance and longevity is often accepted, but this conclusion mainly stems from studies putting animals in adverse conditions such as food restriction., Objective: It is argued that a positive correlation between stress resistance and longevity has not been clearly observed at the individual level in animals or humans living in nonstressful conditions. Experiments should verify this point., Conclusions: If experiments would fail to show this correlation, there would be no ground for the proposal that treatments stimulating stress resistance could increase longevity and health., (Copyright 2002 S. Karger AG, Basel)

Previous studies have shown that Drosophila melanogaster males live longer if exposed to hypergravity at young age. Similarly, thermotolerance and climbing activity in old age are enhanced and it has been hypothesized that the 70 kDa inducible heat-shock protein (hsp70) may play a role in some of these effects. In this article, longevity, thermotolerance and climbing activity were studied in transgenic flies (OE+ strain) overexpressing hsp70 and in control flies harboring the transfection vector at the same chromosomal location but no extra-copies of the hsp70 gene (OE- strain). No positive effect from exposure to hypergravity at a young age was observed for longevity and climbing activity. Thermotolerance was increased by hypergravity but to the same extent in OE+ and OE- strains. Since no positive effect from hypergravity exposure or similar effects were observed in the two strains, it may be concluded that overexpression of hsp70 does not provide an advantage to flies subjected to a mild stress and that it may not be of any help during aging.