Male <Emphasis Type="Italic">Drosophila melanogaster</Emphasis> flies exposed to hypergravity at young age are protected against a non-lethal heat shock at middle age but not against behavioral impairments due to this shock

Previous studies have shown that exposing flies to hypergravity (3 or 5g) for two weeks at young age slightly increases longevity of male flies and survival time at 37 °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 °C heat shock applied at young, middle or old age (2, 4 or 6weeks of age). Various durations of exposure at 37 °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 °C, the usual rearing temperature, but not at 30 °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 °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.     

A cold stress applied at various ages can increase resistance to heat and fungal infection in aged <Emphasis Type="Italic">Drosophila melanogaster</Emphasis> flies

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.     

Using Drosophila melanogaster to study the positive effects of mild stress on aging

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.     

Hormetic effects on longevity of hydrogen peroxide in <Emphasis Type="Italic">Drosophila melanogaster</Emphasis> flies living on a poorly nutritious medium

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.     

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.     

A mild stress due to hypergravity exposure at youngage increases longevity in Drosophila melanogaster males

Drosophila melanogaster flies were exposed to hypergravity starting at two days of age, the range of gravity levels used being 2.58–7.38 g. No longevity change was observed for exposures of less than 14 days. The longevity of males increased if they were submitted to hypergravity for durations ranging from 14 to 24 days. This increase in longevity was never observed in females. The positive effect of exposure to hypergravity has been replicated in two laboratories using two wild-type strains and different rearing conditions. A short hypergravity exposure seems to be a mild stress, yielding positive effects on longevity. This is in accordance with two previous studies showing a slight longevity increase after heat shock in the nematode Caenorhabditis elegans and in Drosophila melanogaster.     

Combined effects of two mild stresses (cold and hypergravity) on longevity, behavioral aging, and resistance to severe stresses in Drosophila melanogaster

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.     

Is Lifespan Extension Accompanied by Improved Antioxidant Defences? A Study of Superoxide Dismutase and Catalase in Drosophila Melanogaster Flies that Lived in Hypergravity at a Young 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.     

A mild stress, hypergravity exposure, postpones behavioral aging in Drosophila melanogaster.

Flies were submitted to two weeks of hypergravity in a centrifuge (3 or 5 g), starting at the second day of imaginal life, and their behavior (spontaneous locomotor activity, patterns of movement, and climbing activity) was observed from removal of the centrifuge to an older age; the usual effects of age on these behaviors were generally observed. Hypergravity-kept flies had worse behavioral scores on removal of centrifuge than those always kept at 1 g. When they aged, they got either similar or better scores than 1 g flies, which indicates that their behavioral aging may be slower. These results show that a mild stress such as hypergravity, which has been previously shown to increase the longevity of males and resistance to heat shock in both sexes, is an environmental manipulation postponing aging in flies.     

Combined effects of suppressing live yeast and of a cold pretreatment on longevity,aging and resistance to several stresses in <Emphasis Type="Italic">Drosophila melanogaster</Emphasis>

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.     

Lack of hypergravity-associated longevity extension in Drosophila melanogaster flies overexpressing hsp70

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 hypothetized 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) over expressing 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 over expression ofhsp70 does not provide an advantage to flies subjected to a mild stress and that it may not be of any help during aging. This revised version was published online in July 2006 with corrections to the Cover Date.     

Fasting can protect young and middle-aged Drosophila melanogaster flies against a severe cold stress

Flies were starved with water before being subjected to various severe stresses (heat, cold, fungal infection, hydrogen peroxide) immediately after starvation or after a delay. Starvation of young and middle-aged flies increased resistance to a long cold stress (0 °C for up to 48 h), mainly if there was a 2–6 h delay between starvation and the cold stress, but positive effects in old flies were hardly observed. No positive effect was observed on resistance to the other stresses and starvation rather decreased resistance to them. It thus seems that fasting increases frailty but also puts at play mechanisms increasing resistance to cold. Starvation also increased learning scores but this could be linked to decreased positive phototaxis tendencies, and not to a better learning ability. Starvation appears to be a mild stress with limited hormetic effects, but studying the mechanisms of these effects is of interest because fasting is maybe of therapeutic value in human beings.     

Life-time protection against severe heat stress by exposing young <Emphasis Type="Italic">Drosophila melanogaster</Emphasis> flies to a mild cold stress

Previous studies in the laboratory of the author have shown that subjecting flies to a mild stress (e.g. a cold stress) during the first 2 weeks of adult life can increase lifespan and resistance to severe stresses (e.g. heat and fungal infection) at 6 weeks of age (ca the mean lifespan at 25 °C). This result could either show that a mild stress protects flies against severe stress for the entire life or for a duration of 4 weeks. To clarify the issue, young flies living at 25 °C were pretreated with a cold stress and thereafter transferred at 19 or 22 °C, which increases lifespan. The mild cold stress protected these flies from heat at ages when flies kept at 25 °C are dead, i.e. at 10 weeks of age or 8 weeks after the end of cold stress. Thus, a mild stress protects flies for life, even if the duration of life is increased. Because temperature can strongly vary from day to day in the wild, and lifespan of flies too, it would be a selective advantage if the ability to survive a strong stress after having been subjected to a mild stress would be maintained not only for a few days but for life, whatever its duration could be. If flies would be subjected to a mild stress when living at 25 °C, a temperature change from e.g. 25 to 22 °C would increase their lifespan and they could survive a strong stress at an age when flies kept at 25 °C are dead.     

Contrasted effects of suppressing live yeast from food on longevity,aging and resistance to several stresses in Drosophila melanogaster

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.     

Effects of mild heat shocks at young age on aging and longevity in Drosophila melanogaster

Young adult flies were submitted to heat shocks (37°C) ofvarious durations (5, 10, 20, 40 or 60 min daily) for 1, 2 or 3 weeks. Aslight longevity increase, in both sexes, was only observed with thelowest heat shock. Longer shocks had neutral or negative effects. Fliessubmitted to the procedure providing a longevity increase did not show adelayed behavioral aging but survived longer at 37°C thancontrol flies. This higher thermotolerance was not associated with anincreased hsp70 induction. The results are discussed in connection withhormesis and previous results showing that hypergravity, an other mildstress, increases longevity and delays behavioral aging: different mildstresses may have contrasting effects on aging and longevity.     

Longevity and aging: beneficial effects ofexposure to mild stress

Every organism has to deal with exposure to stresses.Animals have developed various strategies to cope with stress. It appears that the developed resistanceto stress is often related to longevity. Somescientists have advanced the hypothesis that thestress response may also counteract the negativeeffects of aging, and that exposing organisms to amild, sublethal stress, inducing a stress response,may help them to live longer. Several mild stresseshave been reported to increase longevity (irradiation,heat and cold shock, hypergravity, exercise, etc.), andone of them, hypergravity, to decrease the rate ofbehavioral aging. The mechanisms whereby thesestresses increase longevity have not yet been elucidated.However, the studies conducted so far show that theymay involve metabolic regulation and stress protein(hsps) induction.     

Lifespan extension of Drosophila melanogaster through hormesis by repeated mild heat stress

We assessed the impact of repeated episodes of a mild heat stress on lifespan, fecundity, heat stress resistance and Hsp70 expression in Drosophila melanogaster. There was a significant increase in lifespan of females repeatedly exposed to a mild heat stress when measured in both a pair and a group situation. There was no effect on fecundity when the flies were first exposed to the mild heat stress at an age later than 3 days old, but when it did occur on day 3, there was a significant effect on cumulative fecundity levels over 18 days. The negative fitness effect appears to be the result of a direct cessation or reduction of oviposition during the first bout of stress exposure, and is influenced by the age at which this first exposure occurs. The mild heat stress had no impacton egg viability. The mild heat stress exposures increased resistance to potentially lethal heat stress and levels of Hsp70 expression in heat-exposed flies were higher than those in controls. This revised version was published online in July 2006 with corrections to the Cover Date.     

Hormetic mechanisms of anti-aging and rejuvenating effects of repeated mild heat stress on human fibroblasts in vitro

The phenomenon of hormesis is represented by mild stress-induced stimulation of maintenance and repair pathways, resulting in beneficial effects for cells and organisms. We have reported that repeated mild heat stress (RMHS) has anti-aging hormetic effects on growth and various cellular and biochemical characteristics of human skin fibroblasts undergoing aging in vitro. These effects of RMHS include the maintenance of the stress protein profile, reduction in the accumulation of oxidatively and glycoxidatively damaged proteins, stimulation of the activities of the proteasome and its 11S activator, improvement in cellular resistance to ethanol, hydrogen peroxide, and ultraviolet rays, and increased antioxidative activity of the cells. We have also reported that RMHS prolongs the lifespan of Drosophila. Others have reported anti-aging and life prolonging effects of a wide variety of so-called stressors, such as pro-oxidants, aldehydes, calorie restriction, irradiation, heat shock, and hypergravity. Although molecular mechanisms of hormesis are yet to be elucidated, there are indications that relatively small hormetic effects become biologically amplified, resulting in significant improvement of cellular and organic functions and survival. Hormesis, therefore, can be an effective approach for modulating aging, for preventing or delaying the onset of age-related diseases, and for improving the quality of life in old age.