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Transient rapamycin treatment during developmental stage extends lifespan in Mus musculus and Drosophila melanogaster.

ABSTRACT: Lifespan is determined by complex and tangled mechanisms that are largely unknown. The early postnatal stage has been proposed to play a role in lifespan, but its contribution is still controversial. Here, we show that a short rapamycin treatment during early life can prolong lifespan in Mus musculus and Drosophila melanogaster. Notably, the same treatment at later time points has no effect on lifespan, suggesting that a specific time window is involved in lifespan regulation. We also find that sulfotransferases are upregulated during early rapamycin treatment both in newborn mice and in Drosophila larvae, and transient dST1 overexpression in Drosophila larvae extends lifespan. Our findings unveil a novel link between early-life treatments and long-term effects on lifespan.

SUBMITTER: Aiello G

PROVIDER: S-EPMC9442325 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Transient rapamycin treatment during developmental stage extends lifespan in Mus musculus and Drosophila melanogaster.

Aiello Giuseppe G Sabino Cosimo C Pernici Davide D Audano Matteo M Antonica Francesco F Gianesello Matteo M Ballabio Claudio C Quattrone Alessandro A Mitro Nico N Romanel Alessandro A Soldano Alessia A Tiberi Luca L

EMBO reports 20220707 9

Lifespan is determined by complex and tangled mechanisms that are largely unknown. The early postnatal stage has been proposed to play a role in lifespan, but its contribution is still controversial. Here, we show that a short rapamycin treatment during early life can prolong lifespan in Mus musculus and Drosophila melanogaster. Notably, the same treatment at later time points has no effect on lifespan, suggesting that a specific time window is involved in lifespan regulation. We also find that ...[more]

PMID: 35796299

Similar Datasets

Transient rapamycin treatment during developmental stage extends lifespan in Mus musculus and Drosophila melanogaster

Project description:Lifespan is determined by complex and tangled mechanisms that are largely unknown. The early postnatal stage has been proposed to play a role in lifespan, but its contribution is still controversial. Here, we show that a short rapamycin treatment during early life can prolong lifespan in Mus musculus and Drosophila melanogaster. Notably, the same treatment at later time points has no effect on lifespan, suggesting that a specific time-window is involved in lifespan regulation. We also find tha sulfotransferases are upregulated during early rapamycin treatment both in newborn mice and Drosophila larvae, and transient dST1 overexpression in Drosophila larvae extends lifespan [OK?]. Our findings unveil a novel link between early-life treatments and long-term effects on lifespan.

| S-SCDT-EMBOR-2022-55299V1 | biostudies-other

LKB1 is physiologically required for sleep from Drosophila melanogaster to the Mus musculus.

Project description:Liver Kinase B1 (LKB1) is known as a master kinase for 14 kinases related to the adenosine monophosphate-activated protein kinase. Two of them salt inducible kinase 3 and adenosine monophosphate-activated protein kinase α have previously been implicated in sleep regulation. We generated loss-of-function mutants for Lkb1 in both Drosophila and mice. Sleep, but not circadian rhythms, was reduced in Lkb1-mutant flies and in flies with neuronal deletion of Lkb1. Genetic interactions between Lkb1 and threonine to alanine mutation at residue 184 of adenosine monophosphate-activated protein kinase in Drosophila sleep or those between Lkb1 and Threonine to Glutamic Acid mutation at residue 196 of salt inducible kinase 3 in Drosophila viability have been observed. Sleep was reduced in mice after virally mediated reduction of Lkb1 in the brain. Electroencephalography analysis showed that nonrapid eye movement sleep and sleep need were both reduced in Lkb1-mutant mice. These results indicate that liver kinase B1 plays a physiological role in sleep regulation conserved from flies to mice.

| S-EPMC9252283 | biostudies-literature

Dietary restriction extends lifespan in wild-derived populations of Drosophila melanogaster.

Project description:Dietary restriction (DR) can result in lifespan-extension and improved function and health during ageing. Although the impact of DR on lifespan and health has been established in a variety of organisms, most DR experiments are carried out on laboratory strains that have often undergone adaptation to laboratory conditions. The effect of DR on animals recently derived from wild populations is rarely assessed. We measured the DR response of four populations of Drosophila melanogaster within two generations of collection from the wild. All populations responded to DR with an increase in lifespan and a decrease in female fecundity, similarly to a control, laboratory-adapted strain. These effects of DR are thus not a result of adaptation to laboratory conditions, and reflect the characteristics of natural populations.

| S-EPMC3769260 | biostudies-other

<i>Atg4b</i> Overexpression Extends Lifespan and Healthspan in <i>Drosophila melanogaster</i>.

Project description:Autophagy plays important but complex roles in aging, affecting health and longevity. We found that, in the general population, the levels of ATG4B and ATG4D decreased during aging, yet they are upregulated in centenarians, suggesting that overexpression of ATG4 members could be positive for healthspan and lifespan. We therefore analyzed the effect of overexpressing Atg4b (a homolog of human ATG4D) in Drosophila, and found that, indeed, Atg4b overexpression increased resistance to oxidative stress, desiccation stress and fitness as measured by climbing ability. The overexpression induced since mid-life increased lifespan. Transcriptome analysis of Drosophila subjected to desiccation stress revealed that Atg4b overexpression increased stress response pathways. In addition, overexpression of ATG4B delayed cellular senescence, and improved cell proliferation. These results suggest that ATG4B have contributed to a slowdown in cellular senescence, and in Drosophila, Atg4b overexpression may have led to improved healthspan and lifespan by promoting a stronger stress response. Overall, our study suggests that ATG4D and ATG4B have the potential to become targets for health and lifespan interventions.

| S-EPMC10298381 | biostudies-literature

Proteasome β5 subunit overexpression improves proteostasis during aging and extends lifespan in Drosophila melanogaster.

Project description:The β5 subunit of the proteasome has been shown in worms and in human cell lines to be regulatory. In these models, β5 overexpression results in upregulation of the entire proteasome complex which is sufficient to increase proteotoxic stress resistance, improve metabolic parameters, and increase longevity. However, fundamental questions remain unanswered, including the temporal requirements for β5 overexpression and whether β5 overexpression can extend lifespan in other species. To determine if adult-only overexpression of the β5 subunit can increase proteasome activity in a different model, we characterized phenotypes associated with β5 overexpression in Drosophila melanogaster adults. We find that adult-only overexpression of the β5 subunit does not result in transcriptional upregulation of the other subunits of the proteasome as they do in nematodes and human cell culture. Despite this lack of a regulatory role, boosting β5 expression increases the chymotrypsin-like activity associated with the proteasome, reduces both the size and number of ubiquitinated protein aggregates in aged flies, and increases longevity. Surprisingly, these phenotypes were not associated with increased resistance to acute proteotoxic insults or improved metabolic parameters.

| S-EPMC6395709 | biostudies-literature

Methionine restriction extends lifespan of Drosophila melanogaster under conditions of low amino-acid status.

Project description:Reduced methionine (Met) intake can extend lifespan of rodents; however, whether this regimen represents a general strategy for regulating aging has been controversial. Here we report that Met restriction extends lifespan in both fruit flies and yeast, and that this effect requires low amino-acid status. Met restriction in Drosophila mimicks the effect of dietary restriction and is associated with decreased reproduction. However, under conditions of high amino-acid status, Met restriction is ineffective and the trade-off between longevity and reproduction is not observed. Overexpression of InRDN or Tsc2 inhibits lifespan extension by Met restriction, suggesting the role of TOR signalling in the Met control of longevity. Overall, this study defines the specific roles of Met and amino-acid imbalance in aging and suggests that Met restiction is a general strategy for lifespan extension.

| S-EPMC4350766 | biostudies-literature

Reduced expression of alpha-1,2-mannosidase I extends lifespan in Drosophila melanogaster and Caenorhabditis elegans.

Project description:Exposure to sub-lethal levels of stress, or hormesis, was a means to induce longevity. By screening for mutations that enhance resistance to multiple stresses, we identified multiple alleles of alpha-1,2-mannosidase I (mas1) which, in addition to promoting stress resistance, also extended longevity. Longevity enhancement is also observed when mas1 expression is reduced via RNA interference in both Drosophila melanogaster and Caenorhabditis elegans. The screen also identified Edem1 (Edm1), a gene downstream of mas1, as a modulator of lifespan. As double mutants for both mas1 and Edm1 showed no additional longevity enhancement, it appeared that both mutations function within a common pathway to extend lifespan. Molecular analysis of these mutants revealed that the expression of BiP, a putative biomarker of dietary restriction (DR), is down-regulated in response to reductions in mas1 expression. These findings suggested that mutations in mas1 may extend longevity by modulating DR.

| S-EPMC4191686 | biostudies-literature

PGAM5 promotes lasting FoxO activation after developmental mitochondrial stress and extends lifespan in Drosophila.

Project description:The mitochondrial unfolded protein response (UPRmt) has been associated with long lifespan across metazoans. In Caenorhabditis elegans, mild developmental mitochondrial stress activates UPRmt reporters and extends lifespan. We show that similar developmental stress is necessary and sufficient to extend Drosophila lifespan, and identify Phosphoglycerate Mutase 5 (PGAM5) as a mediator of this response. Developmental mitochondrial stress leads to activation of FoxO, via Apoptosis Signal-regulating Kinase 1 (ASK1) and Jun-N-terminal Kinase (JNK). This activation persists into adulthood and induces a select set of chaperones, many of which have been implicated in lifespan extension in flies. Persistent FoxO activation can be reversed by a high-protein diet in adulthood, through mTORC1 and GCN-2 activity. Accordingly, the observed lifespan extension is prevented on a high-protein diet and in FoxO-null flies. The diet-sensitivity of this pathway has important implications for interventions that seek to engage the UPRmt to improve metabolic health and longevity.

| S-EPMC5614561 | biostudies-literature

Probiotic Limosilactobacillus Reuteri (Lactobacillus Reuteri) Extends the Lifespan of Drosophila Melanogaster through Insulin/IGF-1 Signaling.

Project description:The term probiotic refers to bacteria that provide a beneficial effect to the host. Limosilactobacillus reuteri (Lactobacillus reuteri) is a probiotic isolated from human breast milk. Although L. reuteri has antimicrobial and anti-inflammatory activities occasionally linked to anti-aging effects, there are no reports of the effects of L. reuteri on longevity. This study evaluated the anti-aging effects of L. reuteri on the lifespan and physiology of Drosophila melanogaster. L. reuteri increased the mean lifespan of fruit flies significantly without reducing the reproductive output, food intake, or locomotor activity. Furthermore, the data suggested that the longevity effect of L. reuteri is mediated by the reduction of the insulin/IGF-1 signaling pathway and the action of reuterin, an antimicrobial compound produced by L. reuteri. These results show that L. reuteri can be used as a probiotic that acts as a dietary restriction mimetic with anti-aging effects.

| S-EPMC10389828 | biostudies-literature

Rapamycin extends murine lifespan but has limited effects on aging.

Project description:Aging is a major risk factor for a large number of disorders and functional impairments. Therapeutic targeting of the aging process may therefore represent an innovative strategy in the quest for novel and broadly effective treatments against age-related diseases. The recent report of lifespan extension in mice treated with the FDA-approved mTOR inhibitor rapamycin represented the first demonstration of pharmacological extension of maximal lifespan in mammals. Longevity effects of rapamycin may, however, be due to rapamycin's effects on specific life-limiting pathologies, such as cancers, and it remains unclear if this compound actually slows the rate of aging in mammals. Here, we present results from a comprehensive, large-scale assessment of a wide range of structural and functional aging phenotypes, which we performed to determine whether rapamycin slows the rate of aging in male C57BL/6J mice. While rapamycin did extend lifespan, it ameliorated few studied aging phenotypes. A subset of aging traits appeared to be rescued by rapamycin. Rapamycin, however, had similar effects on many of these traits in young animals, indicating that these effects were not due to a modulation of aging, but rather related to aging-independent drug effects. Therefore, our data largely dissociate rapamycin's longevity effects from effects on aging itself.

| S-EPMC3726163 | biostudies-literature

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