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Aims/hypothesis Sodium–glucose co-transporter 2 (SGLT2) inhibitors (SGLT2i) are antihyperglycaemic drugs that protect the kidneys of individuals with type 2 diabetes mellitus. However, the underlying mechanisms mediating the renal benefits of SGLT2i are not fully understood. Considering the fuel switches that occur during therapeutic SGLT2 inhibition, we hypothesised that SGLT2i induce fasting-like and aestivation-like metabolic patterns, both of which contribute to the regulation of metabolic reprogramming in diabetic kidney disease (DKD). Methods Untargeted and targeted metabolomics assays were performed on plasma samples from participants with type 2 diabetes and kidney disease ( n =35, 11 women) receiving canagliflozin (CANA) 100 mg/day at baseline and 12 week follow-up. Next, a systematic snapshot of the effect of CANA on key metabolites and pathways in the kidney was obtained using db/db mice. Moreover, the effects of glycine supplementation in db/db mice and human proximal tubular epithelial cells (human kidney-2 [HK-2]) cells were studied. Results Treatment of DKD patients with CANA for 12 weeks significantly reduced HbA 1c from a median (interquartile range 25–75%) of 49.0 (44.0–57.0) mmol/mol (7.9%, [7.10–9.20%]) to 42.2 (39.7–47.7) mmol/mol (6.8%, [6.40–7.70%]), and reduced urinary albumin/creatinine ratio from 67.8 (45.9–159.0) mg/mmol to 47.0 (26.0–93.6) mg/mmol. The untargeted metabolomics assay showed downregulated glycolysis and upregulated fatty acid oxidation. The targeted metabolomics assay revealed significant upregulation of glycine. The kidneys of db/db mice undergo significant metabolic reprogramming, with changes in sugar, lipid and amino acid metabolism; CANA regulated the metabolic reprogramming in the kidneys of db/db mice. In particular, the pathways for glycine, serine and threonine metabolism, as well as the metabolite of glycine, were significantly upregulated in CANA-treated kidneys. Glycine supplementation ameliorated renal lesions in db/db mice by inhibiting food intake, improving insulin sensitivity and reducing blood glucose levels. Glycine supplementation improved apoptosis of human proximal tubule cells via the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway. Conclusions/interpretation In conclusion, our study shows that CANA ameliorates DKD by inducing fasting-like and aestivation-like metabolic patterns. Furthermore, DKD was ameliorated by glycine supplementation, and the beneficial effects of glycine were probably due to the activation of the AMPK/mTOR pathway. Graphical Abstract

Dietary restriction (DR) under laboratory conditions generally extends life span and delays ageing across species as diverse as yeast, nematode worms, flies and mice, and is underpinned by taxonomically conserved physiological pathways, notably the insulin‐like signalling pathway (IIS). Despite growing excitement about the links between DR/IIS and ageing within biogerontology, our understanding of why the DR response and associated pathways evolved under natural selection remains controversial and limited. Here, we provide a brief overview of current understanding of the relationship between DR and IIS and ageing from modern biogerontology and go on to summarize the evidence that the IIS pathway integrates a range of important environmental cues including photoperiod, temperature and humidity, as well as nutrition. We go on to discuss the main existing evolutionary explanations for DR and argue that they are not mutually exclusive and are too nutrition‐focussed to fully explain the evolutionary origin of the IIS pathway. In the wild, environmental cues and pressures are dynamic and multivariate, and physiological pathways capable of integrating multiple predictive cues could be strongly favoured by natural selection. We hypothesize that the IIS and related pathways, such as mTOR, evolved to detect and integrate a wide range of environmental cues (not just diet) that are predictive of important selective pressures in the wild. Available evidence suggests the pathway is capable of triggering a range of phenotypic responses, depending on the cues provided, ranging from profound physiological remodelling (e.g. diapause, aestivation, hibernation) associated with promoting survival through challenging environments, to more subtle responses to acute, fine‐scale variation in the environment which may allow individuals to better match their level of reproductive investment to their conditions. We argue that the IIS pathway underpins important adaptive phenotypic plastic responses to a wide range of environmental inputs, of which diet is just one. A multi‐disciplinary approach combining perspectives and methods from biogerontology, cell biology, ecology and evolutionary biology will be essential to develop our understanding of the evolutionary origins of this pathway and the way natural selection and the environment have shaped variation in the IIS pathway's response to different environmental cues. A free Plain Language Summary can be found within the Supporting Information of this article. A free Plain Language Summary can be found within the Supporting Information of this article.

LncRNAs are long non-coding RNAs that are widely recognized as crucial regulators of gene expression and metabolic control, involved in numerous dormancy-related processes. Aestivation is a common hypometabolism strategy of sea cucumber ( Apostichopus japonicus ) in response to high-temperature conditions and is typically characterized by the degradation of the intestine and respiratory tree. Although the aestivation process has been extensively studied in sea cucumbers, the role of lncRNAs in the context of aestivation states remains a conspicuous knowledge gap. Here, we identified and characterized 14,711 lncRNAs in A. japonicus and analyzed their differential expression patterns during the aestivation process in the intestine and respiratory tree. The results revealed the physiological differences, especially the metabolic processes, between the intestine and respiratory tree during the aestivation. The co-expression network of lncRNA-mRNA suggested the dominant role of lncRNA in regulating the differential response of the intestine and respiratory trees. Differentially co-expressed factors were significantly enriched in the deep-aestivation stage-specific modules. Conserved co-expressed factors included several transcription factors known to be involved in rhythm regulation, such as Klf2 and Egr1 . Furthermore, a specific trans-acting lncRNA ( lncrna.1393.1 ) was identified as a potential regulator of Klf2 and Egr1 . Overall, the systematic identification, characterization, and expression analysis of lncRNAs in A. japonicus enhanced our knowledge of long non-coding regulation of aestivation in sea cucumber and provided new clues for understanding the common “toolkit” of dormancy regulatory mechanisms.

The Cretaceous–Palaeogene mass extinction around 66 million years ago was triggered by the Chicxulub asteroid impact on the present-day Yucatán Peninsula 1 , 2 . This event caused the highly selective extinction that eliminated about 76% of species 3 , 4 , including all non-avian dinosaurs, pterosaurs, ammonites, rudists and most marine reptiles. The timing of the impact and its aftermath have been studied mainly on millennial timescales, leaving the season of the impact unconstrained. Here, by studying fishes that died on the day the Mesozoic era ended, we demonstrate that the impact that caused the Cretaceous–Palaeogene mass extinction took place during boreal spring. Osteohistology together with stable isotope records of exceptionally preserved perichondral and dermal bones in acipenseriform fishes from the Tanis impact-induced seiche deposits 5 reveal annual cyclicity across the final years of the Cretaceous period. Annual life cycles, including seasonal timing and duration of reproduction, feeding, hibernation and aestivation, vary strongly across latest Cretaceous biotic clades. We postulate that the timing of the Chicxulub impact in boreal spring and austral autumn was a major influence on selective biotic survival across the Cretaceous–Palaeogene boundary. Examination of fish that died on the day the Mesozoic ended reveal that the impact that caused the Cretaceous–Palaeogene mass extinction occurred during boreal spring.

DNAJ proteins function as co-chaperones of HSP70 and play key roles in cell physiology to promote protein folding and degradation, especially under environmental stress. Based on our previous study on HSP70, a systematic study of DNAJ was performed in sea cucumber Apostichopus japonicus using the transcriptomic and genomic data, identifying 43 AjDNAJ genes, including six AjDNAJA genes, eight AjDNAJB genes, and 29 AjDNAJC genes. Slight expansion and conserved genomic structure were observed using the phylogenetic and syntenic analysis. Differential period-specific and tissue-specific expression patterns of AjDNAJs were observed between adult and juvenile individuals during aestivation. Strong tissue-specific expression correlations between AjDNAJ and AjHSP70 genes were found, indicating that the involvements of AjHSP70IVAs in the aestivation of sea cucumbers were regulated by AjDNAJs. Several key genes with significant expression correlations, such as AjDNAJB4L and AjHSP70IVAs, were suggested to function together under heat stress. Together, these findings provide early insight into the involvement of AjDNAJs in the aestivation and their roles as co-chaperones of AjHSP70s.

Marine invertebrates are facing increasing pressure from climate change, such as increasing temperature. Sea cucumber (Apostichopus japonicus) is an ectotherm and marine model organism for the study of aestivation, a state of dormancy caused by high temperature. The adaptive mechanism of successive temperature stress and aestivation remains unclear in A. japonicus. This study experimentally exposed A. japonicus to constant temperature (14 ℃) in 20 days, successive increasing temperature (14–20 and 14–26 ℃) in 15 days and then constant aestivation temperature (20 ℃ and 26 ℃) in 5 days, aiming to explore how biogenic amines and signal transduction pathways regulated energy metabolism to response to temperature increasing and aestivation in the A. japonicus. Together with correlation analysis, this experiment suggested that (1) when temperature increased, serotonin might react first to down-regulate cyclic AMP and protein kinase A signal transduction pathway through the receptor 5-HT1A, which led to the suppression of key metabolic enzymes; (2) during aestivation, calmodulin (CaM) and AMP-activated protein kinase (AMPK) increased, and then up-regulated the catabolism of carbohydrates and proteins to provide energy for aestivation. The sea cucumber on aestivation under the higher temperature stress (26 ℃) showed the higher contents of CaM and AMPK, and similar trends were found in glycogen phosphorylase and pyruvate kinase activities, meaning a higher energy catabolism; this implied that under the scenario of successive heatwaves happened in ocean, the aestivation mechanism itself might not be able to guarantee the sea cucumber's survival in the future.

Aestivation is considered to be one of the “purest” hypometabolic states in nature, as it involves aerobic dormancy that can be induced and sustained without complex factors. Animals that undergo aestivation to protect themselves from environmental stressors such as high temperatures, droughts, and food shortages. However, this shift in body metabolism presents new challenges for survival, including oxidative stress upon awakening from aestivation, accumulation of toxic metabolites, changes in energy sources, adjustments to immune status, muscle atrophy due to prolonged immobility, and degeneration of internal organs due to prolonged food deprivation. In this review, we summarize the physiological and metabolic strategies, key regulatory factors, and networks utilized by aestivating animals to address the aforementioned components of aestivation. Furthermore, we present a comprehensive overview of the advancements made in aestivation research across major species, including amphibians, fish, reptiles, annelids, mollusks, and echinoderms, categorized according to their respective evolutionary positions. This approach offers a distinct perspective for comparative analysis, facilitating an understanding of the shared traits and unique features of aestivation across different groups of organisms.

The nocturnal Bogong moth (Agrotis infusa) is an iconic and well-known Australian insect that is also a remarkable nocturnal navigator. Like the Monarch butterflies of North America, Bogong moths make a yearly migration over enormous distances, from southern Queensland, western and northwestern New South Wales (NSW) and western Victoria, to the alpine regions of NSW and Victoria. After emerging from their pupae in early spring, adult Bogong moths embark on a long nocturnal journey towards the Australian Alps, a journey that can take many days or even weeks and cover over 1000 km. Once in the Alps (from the end of September), Bogong moths seek out the shelter of selected and isolated high ridge-top caves and rock crevices (typically at elevations above 1800 m). In hundreds of thousands, moths line the interior walls of these cool alpine caves where they \"hibernate\" over the summer months (referred to as \"estivation\"). Towards the end of the summer (February and March), the same individuals that arrived months earlier leave the caves and begin their long return trip to their breeding grounds. Once there, moths mate, lay eggs and die. The moths that hatch in the following spring then repeat the migratory cycle afresh. Despite having had no previous experience of the migratory route, these moths find their way to the Alps and locate their estivation caves that are dotted along the high alpine ridges of southeastern Australia. How naïve moths manage this remarkable migratory feat still remains a mystery, although there are many potential sensory cues along the migratory route that moths might rely on during their journey, including visual, olfactory, mechanical and magnetic cues. Here we review our current knowledge of the Bogong moth, including its natural history, its ecology, its cultural importance to the Australian Aborigines and what we understand about the sensory basis of its long-distance nocturnal migration. From this analysis it becomes clear that the Bogong moth represents a new and very promising model organism for understanding the sensory basis of nocturnal migration in insects.

Abstract Aestivation and hibernation represent distinct forms of animal quiescence, characterized by physiological changes, including ion composition. Intracellular ion flows play a pivotal role in eliciting alterations in membrane potential and facilitating cellular communication, while outward K+ currents aid in the restitution and upkeep of the resting membrane potential. This study explores the relationship between inward and outward currents during aestivation in Achatina fulica snails. Specimens were collected near MSUBIT University in Shenzhen and divided into two groups. The first group was kept on a lattice diet, while the second one consisted of aestivating individuals, that were deprived of food and water until a cork-like structure sealed their shells. Recording of current from isolated neurons were conducted using the single-electrode voltage clamp mode with an AxoPatch 200B amplifier. Electrophysiological recordings on pedal ganglia neurons revealed significant differences in the inactivation processes of the Ia and Ikdr components. Alterations in the Ikdr component may inhibit pacemaker activity in pedal ganglion neurons, potentially contributing to locomotion cessation in aestivated animals. The KS current remains unaffected during aestivation. Changes in slow K+ current components could disrupt the resting membrane potential, possibly leading to cell depolarization and influx of Ca2+ and Na+ ions, impacting cell homeostasis. Thus, maintaining the constancy of outward K+ current is essential for cell stability. Resumo A estivação e a hibernação representam formas distintas de quiescência animal, caracterizadas por alterações fisiológicas, incluindo a composição de íons. Os fluxos de íons intracelulares desempenham papel fundamental na provocação de alterações no potencial de membrana e na facilitação da comunicação celular, enquanto as correntes de K+ de saída ajudam na restituição e manutenção do potencial de membrana em repouso. Este estudo explora a relação entre as correntes de entrada e de saída durante a estivação em caracóis Achatina fulica. Os espécimes foram coletados perto da Universidade MSUBIT, em Shenzhen, e divididos em dois grupos. O primeiro grupo foi mantido em uma dieta de treliça, enquanto o segundo consistia em indivíduos estivados, que foram privados de alimento e água até que uma estrutura semelhante a uma rolha selasse suas conchas. O registro da corrente de neurônios isolados foi realizado usando o modo de grampo de tensão de eletrodo único com amplificador AxoPatch 200B. Os registros eletrofisiológicos nos neurônios dos gânglios pedais revelaram diferenças significativas nos processos de inativação dos componentes Ia e Ikdr. As alterações no componente Ikdr podem inibir a atividade do marcapasso nos neurônios do gânglio pedal, contribuindo potencialmente para a interrupção da locomoção em animais estivados. A corrente KS não é afetada durante a estivação. As alterações nos componentes da corrente lenta de K+ podem perturbar o potencial de membrana em repouso, possivelmente levando à despolarização celular e ao influxo de íons Ca2+ e Na+, afetando a homeostase celular. Portanto, manter a constância da corrente de K+ de saída é essencial para a estabilidade celular.

Human activities and climate change are altering wetland hydrology, potentially affecting freshwater turtle habitats. Understanding freshwater turtle habitat requirements is important for conservation. Chelodina oblonga , a freshwater turtle endemic to southwestern Australia, inhabits wetlands undergoing hydrological changes due to reductions in rainfall and urbanisation. Urban populations of C. oblonga are declining, but limited knowledge of their habitat requirements hinders conservation efforts. This study used radio-telemetry to determine the habitat associations of 100 adult female C. oblonga in three urban wetlands with varying hydrological regimes between 2018 and 2020. During wetland inundation, turtles occupied dense stands of two emergent macrophytes: Typha orientalis (naturalised, invasive) and Machaerina articulata (native). When wetlands dried, turtles aestivated in shallow areas beneath these plants, contrasting with previous reports that aestivation occurred within the deepest areas. As inundation was the trigger for emergence from aestivation, some individuals in the shallowest areas aestivated for > 581 consecutive days and missed a reproductive season. This study indicates that complex vegetation is key aquatic and aestivation habitat for female C. oblonga , and alterations to hydro-regimes, particular increased drying, may have severe implications for isolated freshwater turtle populations through limiting recruitment. Hydrological regimes that incorporate an annual wetted period are recommended for conserving C. oblonga , in view of projected ongoing drying of wetlands due to climate change. Maintenance and restoration of dense emergent macrophyte stands, preferably the native M. articulata , is recommended to help conserve C. oblonga populations in wetlands that regularly retain surface water in the future.