Sex differences in lifespan exist world-wide, with women outliving men by more than a decade in some countries. The gender gap is not a uniquely human phenomenon; most sexually reproducing species ...examined show sex differences in patterns of ageing, yet a comprehensive explanation does not exist. Here, we discuss how ageing responds to natural selection on traits that arise as a consequence of sexuality. Sexual dimorphisms in vertebrates are mediated by sex-steroids, such as androgens and oestrogens, and we examine their regulation of biological processes that can affect ageing and lifespan. The sexes can respond differently to dietary restriction and altered activity of nutrient-sensing pathways, with females showing a greater plasticity for life extension. We suggest that the cross-regulation of steroid hormone and nutrient-sensing signalling pathways is a promising process for further study in understanding the biological basis for the gender gap.
Women live on average longer than men but have greater levels of late-life morbidity. We have uncovered a substantial sex difference in the pathology of the aging gut in Drosophila. The intestinal ...epithelium of the aging female undergoes major deterioration, driven by intestinal stem cell (ISC) division, while lower ISC activity in males associates with delay or absence of pathology, and better barrier function, even at old ages. Males succumb to intestinal challenges to which females are resistant, associated with fewer proliferating ISCs, suggesting a trade-off between highly active repair mechanisms and late-life pathology in females. Dietary restriction reduces gut pathology in aging females, and extends female lifespan more than male. By genetic sex reversal of a specific gut region, we induced female-like aging pathologies in males, associated with decreased lifespan, but also with a greater increase in longevity in response to dietary restriction.
Increased cellular degradation by autophagy is a feature of many interventions that delay ageing. We report here that increased autophagy is necessary for reduced insulin-like signalling (IIS) to ...extend lifespan in Drosophila and is sufficient on its own to increase lifespan. We first established that the well-characterised lifespan extension associated with deletion of the insulin receptor substrate chico was completely abrogated by downregulation of the essential autophagy gene Atg5. We next directly induced autophagy by over-expressing the major autophagy kinase Atg1 and found that a mild increase in autophagy extended lifespan. Interestingly, strong Atg1 up-regulation was detrimental to lifespan. Transcriptomic and metabolomic approaches identified specific signatures mediated by varying levels of autophagy in flies. Transcriptional upregulation of mitochondrial-related genes was the signature most specifically associated with mild Atg1 upregulation and extended lifespan, whereas short-lived flies, possessing strong Atg1 overexpression, showed reduced mitochondrial metabolism and up-regulated immune system pathways. Increased proteasomal activity and reduced triacylglycerol levels were features shared by both moderate and high Atg1 overexpression conditions. These contrasting effects of autophagy on ageing and differential metabolic profiles highlight the importance of fine-tuning autophagy levels to achieve optimal healthspan and disease prevention.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The sexes show profound differences in responses to infection and the development of autoimmunity. Dimorphisms in immune responses are ubiquitous across taxa, from arthropods to vertebrates.
shows ...strong sex dimorphisms in immune system responses at baseline, upon pathogenic challenge, and over aging. We have performed an exhaustive survey of peer-reviewed literature on
immunity, and present a database of publications indicating the sex(es) analyzed in each study. While we found a growing interest in the community in adult immunity and in reporting both sexes, the main body of work in this field uses only one sex, or does not stratify by sex. We synthesize evidence for sexually dimorphic responses to bacterial, viral, and fungal infections. Dimorphisms may be mediated by distinct immune compartments, and we review work on sex differences in behavioral, epithelial, cellular, and systemic (fat body-mediated) immunity. Emerging work on sexually dimorphic aging of immune tissues, immune senescence, and inflammation are examined. We consider evolutionary drivers for sex differences in immune investment, highlight the features of
biology that make it particularly amenable to studies of immune dimorphisms, and discuss areas for future exploration.
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.
Coupling immunity and development is essential to ensure survival despite changing internal conditions in the organism. Drosophila metamorphosis represents a striking example of drastic and systemic ...physiological changes that need to be integrated with the innate immune system. However, nothing is known about the mechanisms that coordinate development and immune cell activity in the transition from larva to adult. Here, we reveal that regulation of macrophage-like cells (hemocytes) by the steroid hormone ecdysone is essential for an effective innate immune response over metamorphosis. Although it is generally accepted that steroid hormones impact immunity in mammals, their action on monocytes (e.g. macrophages and neutrophils) is still not well understood. Here in a simpler model system, we used an approach that allows in vivo, cell autonomous analysis of hormonal regulation of innate immune cells, by combining genetic manipulation with flow cytometry, high-resolution time-lapse imaging and tissue-specific transcriptomic analysis. We show that in response to ecdysone, hemocytes rapidly upregulate actin dynamics, motility and phagocytosis of apoptotic corpses, and acquire the ability to chemotax to damaged epithelia. Most importantly, individuals lacking ecdysone-activated hemocytes are defective in bacterial phagocytosis and are fatally susceptible to infection by bacteria ingested at larval stages, despite the normal systemic and local production of antimicrobial peptides. This decrease in survival is comparable to the one observed in pupae lacking immune cells altogether, indicating that ecdysone-regulation is essential for hemocyte immune functions and survival after infection. Microarray analysis of hemocytes revealed a large set of genes regulated at metamorphosis by EcR signaling, among which many are known to function in cell motility, cell shape or phagocytosis. This study demonstrates an important role for steroid hormone regulation of immunity in vivo in Drosophila, and paves the way for genetic dissection of the mechanisms at work behind steroid regulation of innate immune cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dietary restriction (DR) is the most consistent environmental manipulation to extend lifespan. Originally thought to be caused by a reduction in caloric intake, recent evidence suggests that ...macronutrient intake underpins the effect of DR. The prevailing evolutionary explanations for the DR response are conceptualized under the caloric restriction paradigm, necessitating reconsideration of how or whether these evolutionary explanations fit this macronutrient perspective. In the authors’ opinion, none of the current evolutionary explanations of DR adequately explain the intricacies of observed results; instead a context‐dependent combination of these theories is suggested which is likely to reflect reality. In reviewing the field, it is proposed that the ability to track the destination of different macronutrients within the body will be key to establishing the relative roles of the competing theories. Understanding the evolution of the DR response and its ecological relevance is critical to understanding variation in DR responses and their relevance outside laboratory environments.
The evolutionary explanations for lifespan extension in response to dietary restriction are frequently applied to macronutrient manipulations but were not all conceived in this context. It is argued that none of these theories alone can explain the patterns observed, instead suggesting a context dependant combination of all three is more likely.
Age-related changes to histone levels are seen in many species. However, it is unclear whether changes to histone expression could be exploited to ameliorate the effects of ageing in multicellular ...organisms. Here we show that inhibition of mTORC1 by the lifespan-extending drug rapamycin increases expression of histones H3 and H4 post-transcriptionally, through eIF3-mediated translation. Elevated expression of H3/H4 in intestinal enterocytes in
alters chromatin organization, induces intestinal autophagy through transcriptional regulation, prevents age-related decline in the intestine. Importantly, it also mediates rapamycin-induced longevity and intestinal health. Histones H3/H4 regulate expression of an autophagy cargo adaptor Bchs (WDFY3 in mammals), increased expression of which in enterocytes mediates increased H3/H4-dependent healthy longevity. In mice, rapamycin treatment increases expression of histone proteins and
transcription
and alters chromatin organisation in the small intestine, suggesting the mTORC1-histone axis is at least partially conserved in mammals and may offer new targets for anti-ageing interventions.
Pharmacological therapies are promising interventions to slow down aging and reduce multimorbidity in the elderly. Studies in animal models are the first step toward translation of candidate ...molecules into human therapies, as they aim to elucidate the molecular pathways, cellular mechanisms, and tissue pathologies involved in the anti-aging effects. Trametinib, an allosteric inhibitor of MEK within the Ras/MAPK (Ras/Mitogen-Activated Protein Kinase) pathway and currently used as an anti-cancer treatment, emerged as a geroprotector candidate because it extended lifespan in the fruit fly
. Here, we confirm that trametinib consistently and robustly extends female lifespan, and reduces intestinal stem cell (ISC) proliferation, tumor formation, tissue dysplasia, and barrier disruption in guts in aged flies. In contrast, pro-longevity effects of trametinib are weak and inconsistent in males, and it does not influence gut homeostasis. Inhibition of the Ras/MAPK pathway specifically in ISCs is sufficient to partially recapitulate the effects of trametinib. Moreover, in ISCs, trametinib decreases the activity of the RNA polymerase III (Pol III), a conserved enzyme synthesizing transfer RNAs and other short, non-coding RNAs, and whose inhibition also extends lifespan and reduces gut pathology. Finally, we show that the pro-longevity effect of trametinib in ISCs is partially mediated by Maf1, a repressor of Pol III, suggesting a life-limiting Ras/MAPK-Maf1-Pol III axis in these cells. The mechanism of action described in this work paves the way for further studies on the anti-aging effects of trametinib in mammals and shows its potential for clinical application in humans.
Using a school-based (N = 1,060) and clinic-referred (N = 303) youth sample, the authors developed a 25-item shortened version of the Revised Child Anxiety and Depression Scale (RCADS) using ...Schmid-Leiman exploratory bifactor analysis to reduce client burden and administration time and thus improve the transportability characteristics of this youth anxiety and depression measure. Results revealed that all anxiety items primarily reflected a single "broad anxiety" dimension, which informed the development of a reduced 15-item Anxiety Total scale. Although specific "DSM"-oriented anxiety subscales were not included in this version, the items comprising the Anxiety Total scale were evenly pulled from the 5 anxiety-related content domains from the original RCADS. The resultant 15-item Anxiety Total scale evidenced significant correspondence with anxiety diagnostic groups based on structured clinical interviews. The scores from the 10-item Depression Total scale (retained from the original version) were also associated with acceptable reliability in the clinic-referred and school-based samples (alpha = 0.80 and 0.79, respectively); this is in contrast to the alternate 5-item shortened RCADS Depression Total scale previously developed by Muris, Meesters, and Schouten (2002), which evidenced depression scores of unacceptable reliability (alpha = 0.63). The shortened RCADS developed in the present study thus balances efficiency, breadth, and scale score reliability in a way that is potentially useful for repeated measurement in clinical settings as well as wide-scale screenings that assess anxiety and depressive problems. These future applications are discussed, as are recommendations for continued use of exploratory bifactor modeling in scale development. (Contains 4 tables and 9 footnotes.)
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