Experimental Gerontology

Clustering effects, such as those introduced by housing animals in shared cages, are often overlooked in preclinical lifespan studies, despite their potential to distort variance estimates and inflate Type I error rates, leading to misleading conclusions. This methodological oversight reduces statistical rigor and may undermine the reliability of findings. To address this gap, the current study examines the impact of accounting for clustering and nesting effects on lifespan analyses by comparing the results of statistical models which both account for and ignore these effects. Using 2019 data from the Interventions Testing Program (ITP), a large-scale initiative evaluating the effects of compounds on lifespan in UM-HET3 mice as a case study, we illustrate how different modeling approaches influence statistical estimates and conclusions. Clustering and nesting effects were addressed using linear mixed effects, and Cox frailty models, both of which explicitly account for cage-level dependencies and different levels of data nesting. Comparisons were made between unadjusted lifespan analyses and those incorporating clustering and nesting adjustments. The results of this case study indicate that properly adjusting for clustering and nesting effects can change the conclusions drawn from statistical significance tests as compared to unadjusted model approaches, and so it remains best practice to properly account for clustering and nesting to reduce the potential for inflated Type I error rates. These findings highlight the importance of accounting for clustering and nesting in preclinical research to ensure valid and robust statistical inference. By demonstrating the practical application of clustering adjustments, this work underscores the broader implications for improving reproducibility and rigor in lifespan studies and other experimental designs.

Human life expectancy has increased dramatically over the past two centuries, marking a significant public health achievement. While some projections predict a future where median lifespans reach 100 years, others contend that further longevity will depend on breakthroughs targeting the biological processes of aging. Recent studies in mice have demonstrated that telomerase activation, achieved via gene therapy and transgenic approaches, can extend both median and maximum lifespans substantially without an accompanying increase in cancer risk. We analysed survival data from three such studies using the Gompertz mortality model and show that these interventions reduce the slope parameter, indicative of a slower aging rate, rather than merely lowering baseline mortality. This observation challenges traditional models that assume independent, additive damage accumulation, suggesting instead that aging is driven by a limited number of interdependent processes with significant cross-talk. Mathematical modelling indicates that only three to five processes with substantial cross-talk may account for the observed deceleration. Extrapolation using Swedish survivorship data further implies that a reduction in the aging rate, similar to that seen in mice, could elevate the median human lifespan from 85 to over 100 years. These findings provide a compelling framework for developing targeted anti-aging interventions and a new perspective on the modifiability of the aging process.

The aim of the study was to explore the role of tennis in the promotion of health and prevention of disease. The focus was on risk factors and diseases related to a sedentary lifestyle. He registered in PROSPERO (CRD420251016042) a comprehensive literature search was performed across eight databases (PubMed, Scopus, Web of Science, EBSCO, Apunts Medicina de lEsport, SciELO, MedlinePlus, and Google Scholar) to identify relevant studies published between 2010 and 2025. 17922 articles were found; 18 in relation to the topic we develop in this article, to be studies of either cross sectional or longitudinal design, case- control studies, or experimental studies. ObjectivesTo evaluate the impact of tennis on life expectancy and its association with the reduction of mortality in different population groups. To investigate the effects of tennis on neuroplasticity and its influence on improving cognitive function, especially in older people. To explore the potential of tennis as a cognitive stimulus for the prevention and rehabilitation of neurological and mental health disorders. To propose practical implications for the incorporation of tennis in public health, active ageing and cognitive rehabilitation programmes. ResultsThe practice of tennis is associated with cognitive benefits, improvements in physical and bone health. It is also beneficial for people who have suffered from problems with their heart. The methods used to assess these effects vary between the studies reviewed. From the research it can be concluded that there are very few studies that relate the parameters of physical activities and executive functions, and that there is no heterogeneity between them. In the present study, we aim to explore the association between tennis training experience and executive functions from 4 to 94 years of age, tennis the sport for life. ConclusionTennis has a positive impact on overall fitness. Some injuries related to this sport can evolve to chronic in the lower limbs, muscles and tendons, with significant gender differences. Therefore, it is necessary to implement injury prevention strategies.

Ageing is associated with a loss of skeletal muscle mass and function that negatively impacts the independence and quality of life of older individuals. Females demonstrate a distinct pattern of muscle ageing compared to males, potentially due to menopause where endogenous sex hormone production declines. This systematic review aims to investigate the current knowledge about the role of oestrogen in female skeletal muscle ageing. A systematic search of MEDLINE complete, Global Health, Embase, PubMed, SPORTDiscus, and CINHAL was conducted. Studies were considered eligible if they compared a state of oestrogen deficiency (e.g. postmenopausal females) or supplementation (e.g. oestrogen replacement therapy) to normal oestrogen conditions (e.g. premenopausal females or no supplementation). Outcome variables of interest included measures of skeletal muscle mass, function, damage/repair, and energy metabolism. Quality assessment was completed with the relevant Johanna Briggs critical appraisal tool, and data were synthesised in a narrative manner. Thirty-two studies were included in the review. Compared to premenopausal females, postmenopausal females display reduced muscle mass and strength, but the effect of menopause on markers of muscle damage and expression of the genes involved in metabolic signalling pathways remains unclear. Some studies suggest a beneficial effect of oestrogen replacement therapy on muscle size and strength, but evidence is largely conflicting and inconclusive, potentially due to large variations in the reporting and status of exposure and outcomes. The findings from this review points toward a potential negative effect of oestrogen deficiency in ageing skeletal muscle, but further mechanistic evidence is needed to clarify its role. Graphical abstract figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/23290199v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@97b4ecorg.highwire.dtl.DTLVardef@1e71a43org.highwire.dtl.DTLVardef@16d4a9corg.highwire.dtl.DTLVardef@3d7ac3_HPS_FORMAT_FIGEXP M_FIG C_FIG The role of oestrogen in female skeletal muscle ageing. {uparrow} = significant increase, {downarrow} = significant decrease, = = significantly different, ? = mixed evidence, p<0.05. ALM: appendicular lean mass; AMPK: adenosine monophosphate kinase; CSA: cross-sectional area; PGC-1: peroxisome proliferator-activated receptor gamma coactivator 1-alpha. Created with BioRender.com.

BackgroundTraining studies typically investigate the cumulative rather than the analytically challenging immediate effect of exercise on cognitive outcomes. MethodsWe investigated the dynamic interplay between single-session exercise intensity and time-locked cognition in older adults with suspected Alzheimers dementia (N = 17) undergoing a 24-week dual-task regime. We specified a state of the art hierarchical Bayesian continuous- time dynamic model with fully connected state variables to analyze the bidirectional effects between physical and cognitive performance over time. ResultsHigher physical performance was dynamically linked to improved memory recognition (-1.335, SD = 0.201, 95 BCI [-1.725, -0.954]). The effect was short-term, lasting up to five days (-0.368, SD = 0.05, 95 BCI [-0.479, -0.266]). Clinical scores supported the validity of the model and observed temporal dynamics. ConclusionHigher physical performance predicted improved memory recognition in a day- by-day manner, providing a proof-of-concept for the feasibility of linking exercise training and cognition in patients with Alzheimers dementia. HighlightsO_LIHierarchical Bayesian continuous-time dynamic modelling approach C_LIO_LI72 repeated physical exercise (PP) and cognitive (COG) performance measurements C_LIO_LIPP is dynamically linked to session-to-session variability of COG C_LIO_LIHigher PP improved COG in subsequent sessions in subjects with Alzheimers dementia C_LIO_LIShort-term effect: lasting up to four days after training session C_LI Research in ContextO_LISystematic review: Training-induced effects on cognitive outcomes in Alzheimers dementia and/or associated dynamic Bayesian modelling approaches were reviewed. Although studies showed exercise-induced cognitive improvements or maintenance, most of these studies fail to capture the dynamic nature of the change and interplay of physical (PP) and cognitive (COG) performance. C_LIO_LIInterpretation: Using a sophisticated hierarchical Bayesian continuous-time dynamic modelling approach, a fully connected state variable model was specified. PP is dynamically linked to COG, i.e. higher PP predicted improved COG in subsequent sessions. This effect was rather short term, lasting for up to five days. C_LIO_LIFuture direction: Our results support exercise-induced effects on cognition. The cognitive system was still able to fluctuate and change favourably even in a sample with Alzheimers dementia. Further studies using dynamic modelling are necessary to replicate findings and examine other contributors to cognitive volatility in dementia. C_LI

Physical activity has been suggested to project again brain atrophy, but also to be a determinant of physical activity in older adults. However, research is needed to confirm this bidirectional relationship. Therefore, this research aimed to study the bidirectional relationship between physical activity and brain structure in older adults from the UK Biobank. A total of 3,027 (62.45 {+/-} 7.27 years old, 51.3% females) had physical activity and MRI data at baseline and follow-up. Physical activity was assessed through a self-reported questionnaire. T1-weighted MRI and diffusion tensor imaging were used to quantify brain volumes and white matter microstructure, respectively. Cross-lagged panel models were performed to estimate bidirectional associations, and linear mixed-effects models (LMM) to investigate the consistency of findings. Overall, our main findings suggest that higher hippocampal volume (Standardized Beta Coefficient ({beta})=0.075, pFDR<0.001), frontal volume ({beta}=0.043, pFDR=0.037), and global fractional anisotropy ({beta}=0.042, pFDR=0.028) were associated with more do-it-yourself (DIY) activities (e.g., watering the lawn or digging) levels at follow-up. In addition, strenuous sports at baseline were positively associated with hippocampal volume over time ({beta}=0.011, pFDR=0.108). Although this association did not survive/was not significant after adjustment for multiple comparisons, was confirmed by the LMM. In contrast, higher levels of walking for pleasure were negatively associated with white matter volume at follow-up ({beta}= -0.026, pFDR=0.008). In conclusion, there is a bidirectional association between physical activity and brain structure in healthy middle-aged and older adults. However, further research is needed to understand why physical activity subdomains are associated differently with brain structures and features during aging.

BackgroundA subset of older adults, known as SuperAgers (SAs), exhibit exceptional resilience to these effects, displaying cognitive abilities at the same level or exceeding those 20-30 years younger. To date however, there is little understanding as to which factors may be responsible for SA enhanced cognitive abilities in old age. This systematic review aimed to identify and evaluate the evidence for an association between lifestyle factors and SA status. MethodsA systematic literature search in accordance with the PRISMA guidelines was conducted across MedLine, Embase, Ovid, Global Health, APA PsychArticles, and PsycINFO from inception to 06/11/23 of studies investigating the link between SA status and one or more lifestyle factors. ResultsA systematic search identified 13 studies which met the inclusion criteria. Eleven investigated the relationship between two or more lifestyle factors with the most common lifestyle factor examined being mental health followed by physical activity, social engagement and smoking. Mixed results were observed across the included studies while social engagement and mental health emerged as the most likely lifestyle factors to be positively associated with SA status, there was considerable heterogeneity in the measures used to assess different lifestyle factors. ConclusionNo clear conclusions could be drawn as to which lifestyle factors are associated with SA status due to scarcity of studies and heterogeneity in the measurement of different lifestyle factors.

DNA methylation-based age estimators (DNAm aging clocks) are currently one of the most promising biomarkers for predicting biological age. However, the relationships between objectively measured physical fitness, including cardiorespiratory fitness, and DNAm aging clocks are largely unknown. We investigated the relationships between physical fitness and the age-adjusted value from the residuals of the regression of DNAm aging clock to chronological age (DNAmAgeAcceleration: DNAmAgeAccel) and attempted to determine the relative contribution of physical fitness variables to DNAmAgeAccel in the presence of other lifestyle factors. DNA samples from 144 Japanese men aged 65-72 years were used to calculate first- (i.e., DNAmHorvath and DNAmHannum) and second- (i.e., DNAmPhenoAge, DNAmGrimAge and DNAmFitAge) generation DNAm aging clocks. Various surveys and measurements were conducted, including physical fitness, body composition, blood biochemical parameters, nutrients intake, smoking, alcohol consumption, disease status, sleep status, and chronotype. The peak oxygen uptake (VO2peak) per kg body weight had a significant negative correlation with GrimAgeAccel (r = -0.222, p = 0.008). A comparison of the tertile groups showed that the GrimAgeAccel of the highest VO2peak group was decelerated by 1.6 years compared to the lowest group (p = 0.035). Multiple regression analysis suggested that rather than physical fitness, serum triglycerides, carbohydrate intake, and smoking status, were significantly associated with DNAmAgeAccel. In conclusion, the contribution of cardiorespiratory fitness to DNAmAgeAccel was relatively low compared to lifestyle factors such as smoking. However, this study reveals a negative relationship between cardiorespiratory fitness and DNAmAgeAccel in older men.

ObjectivesThis systematic review aimed to synthesise the evidence on potential differences in financial, social, health and safety-related decision-making between younger and older adults. MethodsTrial, experimental, and prospective studies including older (60+) and younger adults that reported on quantitative decision-making outcome measures (i.e., performance in relation to achieving a specific prespecified goal) were included. ResultsDecision-making was significantly poorer (i.e., further from prespecified goals) in older compared to younger adults (k = 57, drandom = -0.17, 95% CI -0.29, -0.04, I2 = 92.92%), with high heterogeneity between studies. Age differences were observed for financial and social but not health decision-making domains. DiscussionOlder adults performed more poorly on financial and social decision-making than younger adults. Reasons for observed differences may vary (e.g., different motivation and values) and require exploration in future research. This has implications for how people of different ages are supported, especially at times of important decision-making.

BackgroundMyokines, released from the contracting muscle, enable communication between the working muscles and other tissue. Their release during physical exercise is assumed to depend on mode, duration, and intensity. ObjectiveThe aim of this meta-analysis is to examine the acute changes in circulating levels of the myokines IL-6, IL-10, and IL-1ra induced by a bout of resistance exercise and to consider potential moderators of the results. MethodsSystematic literature search was conducted for resistance exercise intervention studies measuring IL-6, IL-10, or IL-1ra before and immediately after resistance exercise in healthy individuals. Random effects meta-analysis was performed for each myokine. ResultsA small to moderate positive effect of resistance exercise for IL-6 and a moderate to large positive effect for IL-1ra were detected. For IL-10 no significant effect was observed. No moderators (training status, type of exercise, risk of bias, age, exercise volume, exercise intensity, exercise dose) of the results were detected. ConclusionThis systematic review and meta-analysis clearly showed the immediate positive effects of an acute resistance exercise session on IL-6 and IL-1ra levels.

BackgroundVarious studies have shown that social adversity, such as loneliness or low SES, are linked with worse cognitive outcomes, though underlying biological mechanisms remain unclear. This scoping review aims to summarize existing evidence on biological processes that may underline this association. MethodsFollowing PRISMA-ScR guidelines, studies measuring social adversity, cognition, and at least one biological mechanism were included. Results were summarized narratively and in tabular formats. ResultsThirteen studies examined links between social adversity, cognition, and biological mechanisms. Inflammation, allostatic load, genetics and genetic aging markers were identified as potential mediators. ConclusionSeveral studies suggest that these biological mechanisms may mediate the link between social adversity and cognitive decline. However, further research is needed to clarify these complex relationships, which are crucial for developing targeted interventions, especially for socially disadvantaged populations.

BackgroundIncreasing health inequalities among older adults globally illustrate the urgent need for effective interventions. Socio-economic position (SEP) may affect healthy ageing through various life course mechanisms. However, longitudinal associations between life course SEP and healthy ageing as a multidimensional construct remain unclear. MethodsWe conducted a comprehensive systematic review of longitudinal studies investigating the associations between life course SEP indicators and multidimensional healthy ageing outcomes. A systematic literature search was conducted across four databases (MEDLINE, Embase, PsycINFO, and Web of Science) from inception to April 2025. Due to the heterogeneity in the operationalisation of SEP and healthy ageing, a narrative synthesis was performed (Prospero CRD42023418728). Results47 articles were included in the review. Across multiple SEP indicators and life stages, higher educational levels (39/43 studies) and higher income/wealth (31/36 studies) were positively associated with better healthy ageing. Occupation showed inconsistent evidence. Life-course evidence showed childhood SEP disadvantage predicted poorer later-life outcomes (13/17 studies), with cumulative multi-stage disadvantage showing additive effects (5 studies) and upward mobility conferring benefits (3 studies). These patterns manifested in three age-related inequality trajectories: widening (18/23 studies), convergence, and persistence, with education-cognitive disparities showing strongest widening effects. Cross-national evidence revealed regional specificities. Studies also identified gender moderation effects (5 studies) and examined mediating pathways (6 studies). ConclusionEducation showed the most consistent protective effects, while income/wealth effects were complex. Health inequalities widened with age, highlighting lasting childhood impacts. Targeted interventions addressing early educational investment and life stage-specific strategies are needed for reducing healthy ageing inequalities.

BackgroundEmerging research indicates that light exposure may influence sleep quality. Identifying key light-exposure behaviours associated with poor sleep quality in athletes may allow practitioners to efficiently screen for sleep difficulties and prioritise athletes for further assessment. Translating these findings into a practical screening tool could enhance willingness of high-performance professionals to monitor sleep and light exposure in athletes. HypothesisKey predictor variables identified by feature reduction techniques will lead to higher predictive accuracy in determining which light behaviours are associated with poor sleep quality in athletes. Study DesignCross-sectional study. Level of EvidenceLevel 3. Methods121 athletes from varying competitive levels completed questionnaires, including the Light Exposure Behaviour Assessment (LEBA) and Pittsburgh Sleep Quality Index (PSQI). Poor sleep quality was defined using the PSQI cut-off >5. Least absolute shrinkage and selection operator (LASSO) regression identified light exposure variables from the LEBA questionnaire most strongly associated with good and poor sleep quality in athletes. Three models were compared: a full-variable model (23 items), a factor-specific model (Factor 3: screen/device use), and a feature-reduced model (LASSO-selected items). ResultsPhone use before bed, checking phone/watch during the night, were identified as variables of greatest association with poor sleep quality and used for reduced feature set modelling. On an independent test set, the feature-reduced model achieved area under the curve (AUC) 0.83, sensitivity 0.70, and specificity 0.92. ConclusionsOur findings report that phone-related behaviours before and in bed are associated with a higher likelihood of poor sleep quality. These behaviours, combined with the developed nomogram, provide a preliminary, low-burden screening tool to identify athletes who may be experiencing sleep difficulties. The high specificity indicates that athletes flagged by the tool are likely to have genuine poor sleep quality, warranting further assessment to identify underlying causes and appropriate interventions. Clinical RelevanceEducation and interventions focused on light exposure factors were identified as most influencing sleep quality in a multifaceted athletic population and could be prioritised to optimise sleep quality. The developed sleep quality nomogram may be useful as a decision-making tool to improve sleep monitoring practice among practitioners.

The {varepsilon}4 allele of the APOE gene (APOE4) is known for its negative association with human longevity, however, the mechanism is unclear. APOE4 was also linked to changes in body weight, and the latter changes were associated with survival in some studies. Here we explore the role of aging changes in weight in the connection between APOE4 and longevity, using a Causal Mediation Analysis (CMA) approach to uncovering mechanisms of genetic associations. Using the Health and Retirement Study (HRS) data, we tested a hypothesis, whether the association of APOE4 with reduced survival to age 85+ is mediated by key characteristics of age-trajectories of weight, such as age at reaching peak values, and slope of the decline in weight afterwards. Mediation effects were evaluated by the Total Effect (TE), Natural Indirect Effect, and Proportion Mediated. Controlled Direct Effect and Natural Direct Effect are also reported. The CMA results suggest that APOE4 carriers have 19%-22% (TE p=0.019-0.038) lower chances of surviving to age 85 and beyond in part because they reach peak values of weight at younger ages, and their weight declines faster afterwards, compared to non-carriers. This finding is in line with the idea that detrimental effect of APOE4 on longevity is in part related to accelerated physical aging of {varepsilon}4 carriers.

Recent epidemiological studies suggest poor hydration is a modifiable risk factor for aging-related chronic disease. We tested whether serum sodium was associated with accelerated biological aging. We analyzed data from 363,286 adults (18-80 years) from 20 years of electronic medical records from a large healthcare system, as well as 24,611 adults (18-80 years) from National Health and Nutrition Examination Survey (NHANES) continuous (1999-2018). Seven key biomarkers were used to calculate biological age (BA) using the Klemera and Doubal method. We then reran the calculation using only the four variables with highest correlation with age as a robustness check. In both models, there was a significant linear association between age adjusted serum sodium and advanced biological aging, especially in the young cohorts. In the 7-variable model, in the Leumit dataset, the males in the highest sodium level versus the lowest, had a biological age that was 0.88 (95% CI 0.68-1.08) years accelerated and for females 2.32 (2.14-2.51) years. In NHANES dataset biological age of males at the highest sodium level was 1.92 (0.98-2.87) years accelerated as compared to those in the lowest sodium group. For females, the largest difference was for those 41-50 (1 year, .30-1.79). Increased serum sodium in the normal range is associated with accelerated biological aging in the general population, especially among people aged 18-50. Intervention studies are needed to confirm the link between hydration and biological aging.

BackgroundFunctional near-infrared spectroscopy (fNIRS) is a method to measure cerebral hemodynamics response. Changes in the prefrontal cortex during dual-tasking help to identify the risk of falling, particularly in older adults. AimsTo systematically review and meta-analyze the effects of dual-task paradigms on cerebral hemodynamics in older adults. MethodsThe search was conducted in PubMed, Scopus, and Web of Science. A total of 22 studies comprising 1,841 older adults were included in the meta-analysis. ResultsInhibitory control and working memory tasks significantly increased HbO2 in the PFC by 0.54 (p < 0.01, 95%CI = 0.36 - 0.72) and 0.13 (p < 0.01, 95%CI = 0.08 - 0.18) mol/L, respectively. Overall, HbO2 was significantly increased during dual-task paradigms by 0.36 mol/L (P < 0.01, 95%CI = 0.27 - 0.45). However, dual-task paradigms did not change HbR in the PFC (P = 0.14, 95%CI = -0.05 - 0.01). ConclusionCognitive tasks related to inhibitory control required greater cognitive demands, indicating higher PFC activation during dual-task walking in older adults. This finding emphasizes the significance of assessing hemodynamic responses under dual-task paradigms to detect the risk of falling in older adults at an early stage.

The metabolic cost of walking is widely used to evaluate human performance and effectiveness of clinical interventions. Decades of laboratory research, largely based on treadmill experiments, have established a canonical relationship between walking speed and metabolic cost, and suggested that ageing shifts this relationship upward, implying reduced efficiency in older adults. However, this relationship has not been well tested during overground walking across matched speeds. We compared healthy younger (n=16; 26{+/-}2yr) and older (n=11; 74{+/-}3yr) adults across eight outdoor overground walking trials at different speeds: preferred walking speed (PWS), three fixed speeds (0.8, 1.2, 1.6 m{middle dot}s-{superscript 1}), and four speeds at {+/-}5% and {+/-}10% of PWS. Contrary to our hypothesis, older adults did not show higher gross or net metabolic cost of walking (GCOW and NCOW) than younger adults at any speed; rather, both trended consistently lower in older adults, reaching significance for GCOW at 0.8 m{middle dot}s-{superscript 1} only. Comparisons of resting metabolic rate and respiratory exchange ratio to prior reference groups did not indicate that our older cohort was unusually fit. Independent of age, GCOW was significantly higher at 0.8 m{middle dot}s-{superscript 1} than at the remaining speeds (1.2-1.6 m{middle dot}s-{superscript 1}), confirming that walking at slower speeds increases GCOW. These findings challenge the view that ageing intrinsically increases the energetic cost of walking, suggesting instead that previously reported upward shifts in cost may reflect treadmill-specific constraints or speed effects. Future work is needed to explore direct comparisons of outdoor, overground walking with treadmill walking at fixed speeds in both younger and older adults.

A long-lived species of zooplankton microcrustaceans, Daphnia magna, sometimes exhibits late-life rebound of reproduction, briefly reversing reproductive senescence. Such events are often interpreted as terminal investment in anticipation of imminent mortality. We demonstrate that such post-senescence reproductive events (PSREs) neither cause not anticipate increased mortality. We analyze an RNAseq experiment comparing young, old reproductively senescent, and old PSRE Daphnia females. We first show that overall age-related transcriptional changes are dominated by the increase transcription of guanidine monophosphate synthases and guanylate cyclases, as well as two groups of presumed transposon-encoded proteins and by a drop in transcription of protein synthesis-related genes. We then focus on gene families and functional groups in which full or partial reversal of age-related transcriptional changes occur. This analysis reveals reversal, in the PSRE individuals, of age-related up-regulation of apolipoproteins D, lysosomal lipases, and peptidases and of age-related down-regulation of E3 ubiquitin kinases, V-type proton ATPases, and numerous proteins related to mitochondrial and muscle functions. While it is not certain which of these changes enable reproductive rejuvenation, and which are by-products of processes that lead to it, we present some evidence that post-senescence reproductive events are associated with the reversal of age-related protein and lipid aggregates removal, apoptosis, and with restoration of mitochondrial integrity. Significance statementAdvances in aging studies revealed the need to extend the old-age health and functionality data from the Drosophila-C.elegans-yeast triad of model organisms to include those that combine the advantages of non-vertebrate models with stronger similarities to mammalian aging. This paper presents a previously unreported phenomenon: reproductive "rejuvenation" in Daphnia - a classic and a re-emerging choice model for longevity studies. These postsenescence reproductive episodes result in fecundity similar to that of young individuals and are accompanied by transcriptional shifts, often reverting age-related changes to youthful levels. Transcripts that show such reversal point to restoration of aggregate removal and of mitochondrial function. We believe that this finding opens a novel window of research towards mechanistic understanding of healthy aging.

Rationale and ObjectivesAlthough neuroimaging studies suggest that the cerebral ventricle is independently associated with APOE {varepsilon}4, cerebrospinal fluid (CSF) biomarkers, and neuropsychological scores in aging and Alzheimers disease (AD), there is no formal synthesis of these findings. We summarized the association of ventricular changes with APOE {varepsilon}4, CSF biomarkers, and neuropsychological measures. Materials and MethodsThe Preferred Reporting Items for Systematic reviews and Meta-Analyses guideline was used. PubMed, Scopus, Ovid, Cochrane, and grey literature were searched, and assessment of eligible articles was conducted using the Newcastle-Ottawa Scale. Results24 studies met the inclusion criteria. Progressive ventricular volume is increased in AD patients at an average volume of 4.4 - 4.7 cm3/ year compared to average volumes of 2.7 - 2.9 cm3/ year and 1.1 - 1.4 cm3/year for patients with MCI and healthy controls (HCs) respectively. The ventricular volume is estimated to increase by 1.7 cm3/year for progression from MCI to AD. APOE {varepsilon}4 is an independent risk factor for ventricular enlargement in aging and dementia, with AD patients most affected. The combination of CSF A{beta}42 with ventricular volume compared to tau is more robust, for tracking the progression of the AD continuum. Further, the combination of ventricular volume with mini-mental state examination (MMSE) scores is the most robust for differentiating AD and MCI from HCs and tracking the progression of the disease. ConclusionThe combination of ventricular volume with APOE {varepsilon}4, CSF A{beta}42, and MMSE scores independently may be potentially useful biomarkers for differentiating and tracking the progression of AD.

Proteome imbalance can lead to protein misfolding and aggregation which is associated with pathologies. Protein aggregation can also be an active, organized process and can be exploited by cells as a survival strategy. In adverse conditions, it is beneficial to deposit the proteins in a condensate rather degrading and resynthesizing. Membraneless organelles (MLOs) are biological condensates formed through liquid-liquid phase separation (LLPS), involving cellular components such as nucleic acids and proteins. LLPS is a regulated process, which when perturbed, can undergo a transition from a physiological liquid condensate to pathological solid-like protein aggregates. To understand how the MLO-associated proteins (MLO-APs) behave during aging, we performed a comparative meta-analysis with age related proteome of C. elegans. We found that the MLO-APs are highly abundant throughout the lifespan. Interestingly, they are aggregating more in long-lived mutant worms compared to the age matched wildtype worms. GO term analysis revealed that the cell cycle and embryonic development are among the top enriched processes in addition to RNP components in insoluble proteome. Considering antagonistic pleotropic nature of these developmental genes and post mitotic status of C. elegans, we assume that these proteins phase transit during post development. As the organism ages, these MLO-APs either mature to become more insoluble or dissolve in uncontrolled manner. However, in the long-lived daf-2 mutant worms, the MLOs may attain protective states due to extended availability and association of molecular chaperones.