A novel larval diet interacts with nutritional stress to modify juvenile behaviors and glucocorticoid responses

Developmental plasticity can allow the exploitation of alternative diets. While such flexibility during early life is often adaptive, it can leave a legacy in later life that alters the overall health and fitness of an individual. Species of the spadefoot toad genus Spea are uniquely poised to address such carryover effects because their larvae can consume drastically different diets: their ancestral diet of detritus or a derived shrimp diet. Here, we use Spea bombifrons to assess the effects of developmental plasticity in response to larval diet type and nutritional stress on juvenile behaviors and stress axis reactivity. We find that, in an open‐field assay, juveniles fed shrimp as larvae have longer latencies to move, avoid prey items more often, and have poorer prey‐capture abilities. While juveniles fed shrimp as larvae are more exploratory, this effect disappears if they also experienced a temporary nutritional stressor during early life. The larval shrimp diet additionally impairs juvenile jumping performance. Finally, larvae that were fed shrimp under normal nutritional conditions produce juveniles with higher overall glucocorticoid levels, and larvae that were fed shrimp and experienced a temporary nutritional stressor produce juveniles with higher stress‐induced glucocorticoid levels. Thus, while it has been demonstrated that consuming the novel, alternative diet can be adaptive for larvae in nature, doing so has marked effects on juvenile phenotypes that may recalibrate an individual''s overall fitness. Given that organisms often utilize diverse diets in nature, our study underscores the importance of considering how diet type interacts with early‐life nutritional adversity to influence subsequent life stages.     

Prohibitin depletion extends lifespan of a TORC2/SGK‐1 mutant through autophagy and the mitochondrial UPR

Mitochondrial prohibitins (PHB) are highly conserved proteins with a peculiar effect on lifespan. While PHB depletion shortens lifespan of wild‐type animals, it enhances longevity of a plethora of metabolically compromised mutants, including target of rapamycin complex 2 (TORC2) mutants sgk‐1 and rict‐1. Here, we show that sgk‐1 mutants have impaired mitochondrial homeostasis, lipogenesis and yolk formation, plausibly due to alterations in membrane lipid and sterol homeostasis. Remarkably, all these features are suppressed by PHB depletion. Our analysis shows the requirement of SRBP1/SBP‐1 for the lifespan extension of sgk‐1 mutants and the further extension conferred by PHB depletion. Moreover, although the mitochondrial unfolded protein response (UPR^mt) and autophagy are induced in sgk‐1 mutants and upon PHB depletion, they are dispensable for lifespan. However, the enhanced longevity caused by PHB depletion in sgk‐1 mutants requires both, the UPR^mt and autophagy, but not mitophagy. We hypothesize that UPR^mt induction upon PHB depletion extends lifespan of sgk‐1 mutants through autophagy and probably modulation of lipid metabolism.     

Drosophila Sirtuin 6 mediates developmental diet‐dependent programming of adult physiology and survival

Organisms in the wild experience unpredictable and diverse food availability throughout their lifespan. Over‐/under‐nutrition during development and in adulthood is known to dictate organismal survival and fitness. Studies using model systems have also established long‐term effects of developmental dietary alterations on life‐history traits. However, the underlining genetic/molecular factors, which differentially couple nutrient inputs during development with fitness later in life are far less understood. Using Drosophila and loss/gain of function perturbations, our serendipitous findings demonstrate an essential role of Sirtuin 6 in regulating larval developmental kinetics, in a nutrient‐dependent manner. The absence of Sirt6 affected ecdysone and insulin signalling and led to accelerated larval development. Moreover, varying dietary glucose and yeast during larval stages resulted in enhanced susceptibility to metabolic and oxidative stress in adults. We also demonstrate an evolutionarily conserved role for Sirt6 in regulating physiological homeostasis, physical activity and organismal lifespan, known only in mammals until now. Our results highlight gene‐diet interactions that dictate thresholding of nutrient inputs and physiological plasticity, operative across development and adulthood. In summary, besides showing its role in invertebrate ageing, our study also identifies Sirt6 as a key factor that programs macronutrient‐dependent life‐history traits.     

Parasites rather than phoronts: Teratorhabditis synpapillata nematodes reduce lifespan of their Rhynchophorus ferrugineus host in a life stage‐dependent manner

Rhynchophorus ferrugineus Olivier (Coleoptera: Curculionidae) red palm weevils are often reported in association with different organisms including nematodes. The significance of this interaction and whether nematodes can influence their life‐history traits is unclear. We collected Rhynchophorus ferrugineus red palm weevils at different developmental stages and locations in Tunisia, observed and dissected them in search for nematodes and other interacting organisms, established laboratory colonies and identified the nematodes associated with them, and conducted nematode–insect interaction assays to determine the capacity of the nematodes to influence their life‐history traits. We observed Beauveria bassiana fungi in larvae, nymph, and adults; Centrouropoda and Uroobovella acari associated with the adults, and Teratorhabditis synpapillata nematodes associated with larvae and adults. Nematode–insect interaction bioassays revealed that T. synpapillata nematodes reduce the lifespan of the insect larvae in a population‐dependent manner, but do not influence the lifespan of adults. Our study uncovers an important factor that may determine population dynamics of this important palm pests and provides evidence to conclude that these organisms establish a parasitic relationship, rather than a phoretic relationship.     

Mitochondrial aconitase 1 regulates age‐related memory impairment via autophagy/mitophagy‐mediated neural plasticity in middle‐aged flies

Age‐related memory impairment (AMI) occurs in many species, including humans. The underlying mechanisms are not fully understood. In wild‐type Drosophila (w¹¹¹⁸ ), AMI appears in the form of a decrease in learning (3‐min memory) from middle age (30 days after eclosion [DAE]). We performed in vivo, DNA microarray, and behavioral screen studies to identify genes controlling both lifespan and AMI and selected mitochondrial Acon1 (mAcon1). mAcon1 expression in the head of w¹¹¹⁸ decreased with age. Neuronal overexpression of mAcon1 extended its lifespan and improved AMI. Neuronal or mushroom body expression of mAcon1 regulated the learning of young (10 DAE) and middle‐aged flies. Interestingly, acetyl‐CoA and citrate levels increased in the heads of middle‐aged and neuronal mAcon1 knockdown flies. Acetyl‐CoA, as a cellular energy sensor, is related to autophagy. Autophagy activity and efficacy determined by the positive and negative changes in the expression levels of Atg8a‐II and p62 were proportional to the expression level of mAcon1. Levels of the presynaptic active zone scaffold protein Bruchpilot were inversely proportional to neuronal mAcon1 levels in the whole brain. Furthermore, mAcon1 overexpression in Kenyon cells induced mitophagy labeled with mt‐Keima and improved learning ability. Both processes were blocked by pink1 knockdown. Taken together, our results imply that the regulation of learning and AMI by mAcon1 occurs via autophagy/mitophagy‐mediated neural plasticity.     

Toll‐7 promotes tumour growth and invasion in Drosophila

Objectives Drosophila melanogaster has become an excellent model organism to explore the genetic mechanisms underlying tumour progression. Here, by using well‐established Drosophila tumour models, we identified Toll‐7 as a novel regulator of tumour growth and invasion.Materials and methodsTransgenic flies and genetic epistasis analysis were used. All flies were raised on a standard cornmeal and agar medium at 25°C unless otherwise indicated. Immunostaining and RT‐qPCR were performed by standard procedures. Images were taken by OLYMPUS BX51 microscope and Zeiss LSM 880 confocal microscope. Adobe Photoshop 2020 and Zeiss Zen were used to analyse the images. All results were presented in Scatter plots or Column bar graphs created by GraphPad Prism 8.0.ResultsLoss of Toll‐7 suppresses Ras^V12/lgl ^−/−‐induced tumour growth and invasion, as well as cell polarity disruption‐induced invasive cell migration, whereas expression of a constitutively active allele of Toll‐7 is sufficient to promote tumorous growth and cell migration. In addition, the Egr‐JNK signalling is necessary and sufficient for Toll‐7‐induced invasive cell migration. Mechanistically, Toll‐7 facilitates the endocytosis of Egr, which is known to activate JNK in the early endosomes. Moreover, Toll‐7 activates the EGFR‐Ras signalling, which cooperates with the Egr‐JNK signalling to promote Yki‐mediated cell proliferation and tissue overgrowth. Finally, Toll‐7 is necessary and sufficient for the proper maintenance of EGFR protein level.ConclusionsOur findings characterized Toll‐7 as a proto‐oncogene that promotes tumour growth and invasion in Drosophila, which shed light on the pro‐tumour function of mammalian Toll‐like receptors (TLRs).     

The evolution of adult pollen feeding did not alter postembryonic growth in Heliconius butterflies

For many animals, the availability and provision of dietary resources can vary markedly between juvenile and adult stages, often leading to a temporal separation of nutrient acquisition and use. Juvenile developmental programs are likely limited by the energetic demands of many adult tissues and processes with early developmental origins. Enhanced dietary quality in the adult stage may, therefore, alter selection on life history and growth patterns in juvenile stages. Heliconius are unique among butterflies in actively collecting and digesting pollen grains, which provide an adult source of essential amino acids. The origin of pollen feeding has therefore previously been hypothesized to lift constraints on larval growth rates, allowing Heliconius to spend less time as larvae when they are most vulnerable to predation. By measuring larval and pupal life‐history traits across three pollen‐feeding and three nonpollen‐feeding Heliconiini, we provide the first test of this hypothesis. Although we detect significant interspecific variation in larval and pupal development, we do not find any consistent shift associated with pollen feeding. We discuss how this result may fit with patterns of nitrogen allocation, the benefits of nitrogenous stores, and developmental limitations on growth. Our results provide a framework for studies aiming to link innovations in adult Heliconius to altered selection regimes and developmental programs in early life stages.     

Growth,body condition and contest performance after early‐life food restriction in a long‐lived tropical fish

Adverse conditions during early life can cause lasting body size deficits with effects on social and sexual competition, while an accelerated growth response can allow animals to catch up in body size but can be physiologically costly as well. How animals balance growth deficits and growth compensation is predicted to depend on the effects of each on lifetime fitness. We investigated the effects of experimental early‐life food restriction on growth, body condition, and adult contest competition in a cichlid fish (Tropheus sp.). Their longevity and aseasonal breeding suggest that, with view on lifetime reproductive success, temporarily growth‐restricted Tropheus should rather invest extra time in reaching competitive body size than risk the potential costs of accelerated growth. However, size‐selective predation pressure by gape size‐limited piscivores may have favored the evolution of an accelerated growth response to early‐life delays. Experimentally food‐restricted fish temporarily reduced their growth rate compared to a control group, but maintained their body condition factor at the control level throughout the 80‐week study period. There was no evidence for an accelerated growth response following the treatment, as the food‐restricted fish never exceeded the size‐specific growth rates that were measured in the control group. Food‐restricted fish caught up with the body size of the control group several months after the end of the treatment period and were as likely as control fish to win size‐matched contests over territories. Regardless of feeding regime, there were sex‐specific differences in growth rates and in the trajectories of condition factors over time. Females grew more slowly than males but maintained their condition factors at a high level throughout the study period, whereas the males'' condition factors declined over time. These differences may reflect sex‐specific contributions of condition and body size to adult fitness that are associated with female mouthbrooding and male competition for breeding territories.     

Lithium can mildly increase health during ageing but not lifespan in mice

Lithium is a nutritional trace element, used clinically as an anti‐depressant. Preclinically, lithium has neuroprotective effects in invertebrates and mice, and it can also extend lifespan in fission yeast, C. elegans and Drosophila. An inverse correlation of human mortality with the concentration of lithium in tap water suggests a possible, evolutionarily conserved mechanism mediating longevity. Here, we assessed the effects of lithium treatment on lifespan and ageing parameters in mice. Lithium has a narrow therapeutic dose range, and overdosing can severely affect organ health. Within the tolerable dosing range, we saw some mildly positive effects of lithium on health span but not on lifespan.     

Enhanced tethered-flight duration and locomotor activity by overexpression of the human gene SOD1 in Drosophila motorneurons

Mutation of the human gene superoxide dismutase (hSOD1) is associated with the fatal neurodegenerative disease familial amyotrophic lateral sclerosis (Lou Gehrig’s disease). Selective overexpression of hSOD1 in Drosophila motorneurons increases lifespan to 140% of normal. The current study was designed to determine resistance to lifespan decline and failure of sensorimotor functions by overexpressing hSOD1 in Drosophila‘s motorneurons. First, we measured the ability to maintain continuous flight and wingbeat frequency (WBF) as a function of age (5 to 50 days). Flies overexpressing hSOD1 under the D42-GAL4 activator were able to sustain flight significantly longer than controls, with the largest effect observed in the middle stages of life. The hSOD1-expressed line also had, on average, slower wingbeat frequencies in late, but not early life relative to age-matched controls. Second, we examined locomotor (exploratory walking) behavior in late life when flies had lost the ability to fly (age ≥ 60 d). hSOD1-expressed flies showed significantly more robust walking activity relative to controls. Findings show patterns of functional decline dissimilar to those reported for other life-extended lines, and suggest that the hSOD1 gene not only delays death but enhances sensorimotor abilities critical to survival even in late life.     

Metformin induces S‐adenosylmethionine restriction to extend the Caenorhabditis elegans healthspan through H3K4me3 modifiers

Metformin, a widely prescribed first‐line drug for the treatment of type II diabetes mellitus, has been shown to extend lifespan and delay the onset of age‐related diseases. The precisely mechanisms by which these effects are realized remain elusive. We find that metformin exposure is restricted to adults, which is sufficient to extend lifespan. However, limiting metformin exposure to the larvae has no significant effect on Caenorhabditis elegans longevity. Here, we show that after metformin treatment, the level of S‐adenosylmethionine (SAM) is reduced in adults but not in the larvae. Potential mechanisms by which reduced SAM might increase lifespan include altering the histone methylation. However, the molecular connections between metformin, SAM limitation, methyltransferases, and healthspan‐associated phenotypes are unclear. Through genetic screening of C. elegans, we find that metformin promotes the healthspan through an H3K4 methyltransferase/demethylase complex to downregulate the targets, including mTOR and S6 kinase. Thus, our studies provide molecular links between meformin, SAM limitation, histone methylation, and healthspan and elucidate the mode action of metformin‐regulated healthspan extension will boost its therapeutic application in the treatment of human aging and age‐related diseases.     

Early‐life conditions impact juvenile telomere length,but do not predict later life‐history strategies or fitness in a wild vertebrate

Environmental conditions experienced during early life may have long‐lasting effects on later‐life phenotypes and fitness. Individuals experiencing poor early‐life conditions may suffer subsequent fitness constraints. Alternatively, individuals may use a strategic “Predictive Adaptive Response” (PAR), whereby they respond—in terms of physiology or life‐history strategy—to the conditions experienced in early life to maximize later‐life fitness. Particularly, the Future Lifespan Expectation (FLE) PAR hypothesis predicts that when poor early‐life conditions negatively impact an individual''s physiological state, it will accelerate its reproductive schedule to maximize fitness during its shorter predicted life span. We aimed to measure the impact of early‐life conditions and resulting fitness across individual lifetimes to test predictions of the FLE hypothesis in a wild, long‐lived model species. Using a long‐term individual‐based dataset, we investigated how early‐life conditions are linked with subsequent fitness in an isolated population of the Seychelles warbler Acrocephalus sechellensis. How individuals experience early‐life environmental conditions may vary greatly, so we also tested whether telomere length—shorter telomers are a biomarker of an individual''s exposure to stress—can provide an effective measure of the individual‐specific impact of early‐life conditions. Specifically, under the FLE hypothesis, we would expect shorter telomeres to be associated with accelerated reproduction. Contrary to expectations, shorter juvenile telomere length was not associated with poor early‐life conditions, but instead with better conditions, probably as a result of faster juvenile growth. Furthermore, neither juvenile telomere length, nor other measures of early‐life conditions, were associated with age of first reproduction or the number of offspring produced during early life in either sex. We found no support for the FLE hypothesis. However, for males, poor early‐life body condition was associated with lower first‐year survival and reduced longevity, indicating that poor early‐life conditions pose subsequent fitness constraints. Our results also showed that using juvenile telomere length as a measure of early‐life conditions requires caution, as it is likely to not only reflect environmental stress but also other processes such as growth.     

Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures

Defects in DNA single‐strand break repair (SSBR) are linked with neurological dysfunction but the underlying mechanisms remain poorly understood. Here, we show that hyperactivity of the DNA strand break sensor protein Parp1 in mice in which the central SSBR protein Xrcc1 is conditionally deleted (Xrcc1^Nes‐Cre) results in lethal seizures and shortened lifespan. Using electrophysiological recording and synaptic imaging approaches, we demonstrate that aberrant Parp1 activation triggers seizure‐like activity in Xrcc1‐defective hippocampus ex vivo and deregulated presynaptic calcium signalling in isolated hippocampal neurons in vitro. Moreover, we show that these defects are prevented by Parp1 inhibition or deletion and, in the case of Parp1 deletion, that the lifespan of Xrcc1^Nes‐Cre mice is greatly extended. This is the first demonstration that lethal seizures can be triggered by aberrant Parp1 activity at unrepaired SSBs, highlighting PARP inhibition as a possible therapeutic approach in hereditary neurological disease.