γδ T-Cell Immunophenotype for the Study of Human Aging.

Flow cytometry serves as a crucial tool in immunology, allowing for the detailed analysis of immune cell populations. γδ T cells, a subset of T cells, play pivotal roles in immune surveillance and immune aging. Assessing the phenotype and functional capabilities of γδ T cells isolated from whole blood or tissue within the context of human aging yields invaluable insights into the dynamic changes affecting immune function, tissue homeostasis, susceptibility to infections, and inflammatory responses.

Assessing rapid spatial working memory in community-living older adults in a virtual adaptation of the rodent water maze paradigm.

Aging often leads to a decline in various cognitive domains, potentially contributing to spatial navigation challenges among older individuals. While the Morris water maze is a common tool in rodents research for evaluating allocentric spatial memory function, its translation to studying aging in humans, particularly its association with hippocampal dysfunction, has predominantly focused on spatial reference memory assessments. This study expanded the adaptation of the Morris water maze for older adults to assess flexible, rapid, one-trial working memory. This adaptation involved a spatial search task guided by allocentric cues within a 3-D virtual reality (VR) environment. The sensitivity of this approach to aging was examined in 146 community-living adults from three Chinese cities, categorized into three age groups. Significant performance deficits were observed in participants over 60 years old compared to younger adults aged between 18 and 43. However, interpreting these findings was complicated by factors such as psychomotor slowness and potential variations in task engagement, except during the probe tests. Notably, the transition from the 60 s to the 70 s was not associated with a substantial deterioration of performance. A distinction only emerged when the pattern of spatial search over the entire maze was examined in the probe tests when the target location was never revealed. The VR task's sensitivity to overall cognitive function in older adults was reinforced by the correlation between Montreal Cognitive Assessment (MoCA) scores and probe test performance, demonstrating up to 17 % shared variance beyond that predicted by chronological age alone. In conclusion, while implementing a VR-based adaptation of rodent water maze paradigms in older adults was feasible, our experience highlighted specific interpretative challenges that must be addressed before such a test can effectively supplement traditional cognitive assessment tools in evaluating age-related cognitive decline.

Recording of Age-Related Changes on Murine and Human Brain Slices.

Preparation of brain slices for electrophysiological and imaging experiments has been developed several decades ago, and the method is still widely used due to its simplicity and advantages over other techniques. It can be easily combined with other well established and recently developed methods as immunohistochemistry and morphological analysis or opto- and chemogenetics. Several aspects of this technique are covered by a plethora of excellent and detailed review papers, in which one can gain a deep insight of variations in it. In this chapter, I briefly describe the solutions, equipment, and preparation techniques routinely used in our laboratory. I also aim to present how certain "old school" brain slice lab devices can be made in a cost-efficient way. These devices can be easily adapted for the special needs of the experiments. I also aim to present some differences in the preparatory techniques of acutely isolated human brain tissue.

Application of Multiplex Immunoassay in Aging Research: A Methodological Approach.

One of the characteristics of aging and age-related disorders is the formation and evolution of a chronic, low-grade, and hence subclinical, inflammatory state known as inflammaging. Although the progression of inflammaging is now recognized as one of the main driving forces of aging and one of the main risk factors for morbidity and mortality in older subjects, current knowledge on the causative agents of inflammaging itself and chronic, aging-related diseases is still incomplete. In this chapter, we offer a methodological approach for assessing inflammation associated with aging through the use of multiplex immunoassay, which enables the rapid, reproducible, and simultaneous dosage of several cytokines, chemokines, and inflammatory mediators with little biological sample usage.

Analysis of Cytokine-Inducible SH2-Containing Protein (CISH) in the Study of Immunosenescence.

The aging immune system undergoes significant changes, leading to a state known as immunosenescence. Understanding the molecular mechanisms underlying immunosenescence is crucial for developing targeted interventions to enhance immune functions in older individuals. This bio-protocol review focuses on the application of quantitative reverse transcription-polymerase chain reaction (qRT-PCR) for the mRNA quantification of cytokine-inducible SH2-containing protein (CISH), an immune regulator overexpressed in T-cell responses from older adults. We outline a comprehensive protocol for the quantitative assessment of CISH mRNA expression, providing a valuable tool for researchers investigating immunosenescence.

Characterization of Age-Dependent Changes in Skeletal Muscle Repair and Regeneration Using a Mouse Model of Acute Muscle Injury.

Acute skeletal muscle injury initiates a process of necrosis, debris clearance, and ultimately tissue regeneration via myogenesis. While skeletal muscle stem cells (MuSCs) are responsible for populating the proliferative myogenic progenitor pool to fuel muscle repair, recruited and resident immune cells have a central role in the regulation of muscle regeneration via the execution of phagocytosis and release of soluble factors that act directly on MuSCs to regulate myogenic differentiation. Therefore, the timing of MuSC proliferation and differentiation is closely linked to the populations and behaviors of immune cells present within skeletal muscle. This has important implications for aging and muscle repair, as systemic changes in immune system function contribute to a decline in muscle regenerative capacity. Here, we present adapted protocols for the isolation of mononuclear cells from skeletal muscles for the quantification of immune cell populations using flow cytometry. We also describe a cardiotoxin skeletal muscle injury protocol and detail the expected outcomes including immune cell infiltration to the injured sites and formation of new myocytes. As immune cell function is substantially influenced by aging, we extend these approaches and outcomes to aged mice.

Analysis of Forsythia suspensa fruit and leaf extracts using UHPLC-Q-Exactive-Orbitrap/MS: In vivo antioxidant activity on D-galactose-induced aging mice.

Making health-enhancing tea from Forsythia suspensa leaves has been a tradition of Chinese folk culture for centuries. However, these leaves were not officially recognized as a new food source until 2017 by the Chinese government. In this study, ethyl acetate fractions from Forsythia suspensa fruit and leaves exhibited excellent antioxidant activity in vitro antioxidant assays and in vivo D-galactose-induced aging mice model. The antioxidant activity of the leaves was higher than that of fruit both in vitro and in vivo. The chemical constituents present in these ethyl acetate fractions were comprehensively analyzed using UHPLC-Q-Exactive-Orbitrap/MS. A total of 20 compounds were identified, among which forsythoside E, (+)-epipinoresinol, dihydromyricetin, chlorogenic acid, and ursolic acid were exclusively detected in the ethyl acetate fraction of Forsythia suspensa leaves, but absent in the ethyl acetate fraction derived from its fruit. This study provides theoretical support for the utilization of Forsythia suspensa fruit and leaves.

A scenario for an evolutionary selection of ageing.

Signs of ageing become apparent only late in life, after organismal development is finalized. Ageing, most notably, decreases an individual's fitness. As such, it is most commonly perceived as a non-adaptive force of evolution and considered a by-product of natural selection. Building upon the evolutionarily conserved age-related Smurf phenotype, we propose a simple mathematical life-history trait model in which an organism is characterized by two core abilities: reproduction and homeostasis. Through the simulation of this model, we observe (1) the convergence of fertility's end with the onset of senescence, (2) the relative success of ageing populations, as compared to non-ageing populations, and (3) the enhanced evolvability (i.e. the generation of genetic variability) of ageing populations. In addition, we formally demonstrate the mathematical convergence observed in (1). We thus theorize that mechanisms that link the timing of fertility and ageing have been selected and fixed over evolutionary history, which, in turn, explains why ageing populations are more evolvable and therefore more successful. Broadly speaking, our work suggests that ageing is an adaptive force of evolution.

It is a question as old as Darwin's theory of evolution itself: how is ageing affected by natural selection? The prevailing view is that the process of biological ageing is not adaptive and therefore not directly subject to selection pressures. Take for example a gene causing a fatal disease late after an average individual had reproduced, thus being passed on to the next generation despite its detriment to the individual. This suggests that natural selection acts less strongly on such genes, which can therefore accumulate and cause aging if they do not impact an organism's reproductive fitness earlier in life. However, many studies have shown that specific genes control an animal's lifespan and the onset of ageing through evolutionarily conserved mechanisms. For example, in fruit flies, aging can be categorised into two distinct phases determined by the manifestation of the so-called Smurf phenotype associated with accelerated signs of ageing and an increased risk of death. A pattern where the offspring of older parents live less long than those of younger parents has also been observed across species, also known as the Lansing effect. In this case, ageing can affect the reproductive success of future generations and can therefore be subject to selection pressures. Roget et al. looked at the trade-offs between an individual's reproduction and homeostasis using a mathematical model to address whether the distinct phases of aging ­ as seen in the Smurf phenotype ­ can appear and be maintained throughout evolution. Using a mathematical model, Roget et al. simulated individuals possessing only one copy of two genes. One controls the duration of reproductive ability, and the other defines the age at which the risk of death becomes non-zero. This revealed that a simple hypothetical haploid and asexually reproducing system can evolve a life history separated into two phases in the computer simulations. Interestingly, the modelled organisms evolved in a way that the duration of reproduction exceeded the homeostatic maintenance duration. This generated a phase where individuals are capable of reproduction with a high risk of death, similar to the previously described Smurf phase. Roget et al. observed that aging populations showed a lower risk of extinction than non-aging ones, as well as an increased genetic variability of the offspring. The apparent benefits of ageing in this model imply that ageing can be an adaptive force of evolution and subject to positive selection or, at least less negative selection than expected. This minimal model helps explain trade-offs between reproduction and homeostatic maintenance during evolution. Further work may include parameters such as sexual reproduction and multiple gene copies.

Evidence for a role of human blood-borne factors in mediating age-associated changes in molecular circadian rhythms.

Aging is associated with a number of physiologic changes including perturbed circadian rhythms; however, mechanisms by which rhythms are altered remain unknown. To test the idea that circulating factors mediate age-dependent changes in peripheral rhythms, we compared the ability of human serum from young and old individuals to synchronize circadian rhythms in culture. We collected blood from apparently healthy young (age 25-30) and old (age 70-76) individuals at 14:00 and used the serum to synchronize cultured fibroblasts. We found that young and old sera are equally competent at initiating robust ~24 hr oscillations of a luciferase reporter driven by clock gene promoter. However, cyclic gene expression is affected, such that young and old sera promote cycling of different sets of genes. Genes that lose rhythmicity with old serum entrainment are associated with oxidative phosphorylation and Alzheimer's Disease as identified by STRING and IPA analyses. Conversely, the expression of cycling genes associated with cholesterol biosynthesis increased in the cells entrained with old serum. Genes involved in the cell cycle and transcription/translation remain rhythmic in both conditions. We did not observe a global difference in the distribution of phase between groups, but found that peak expression of several clock-controlled genes (PER3, NR1D1, NR1D2, CRY1, CRY2, and TEF) lagged in the cells synchronized ex vivo with old serum. Taken together, these findings demonstrate that age-dependent blood-borne factors affect circadian rhythms in peripheral cells and have the potential to impact health and disease via maintaining or disrupting rhythms respectively.

Targeting the hypothalamus for modeling age-related DNA methylation and developing OXT-GnRH combinational therapy against Alzheimer's disease-like pathologies in male mouse model.

The hypothalamus plays an important role in aging, but it remains unclear regarding the underlying epigenetics and whether this hypothalamic basis can help address aging-related diseases. Here, by comparing mouse hypothalamus with two other limbic system components, we show that the hypothalamus is characterized by distinctively high-level DNA methylation during young age and by the distinct dynamics of DNA methylation and demethylation when approaching middle age. On the other hand, age-related DNA methylation in these limbic system components commonly and sensitively applies to genes in hypothalamic regulatory pathways, notably oxytocin (OXT) and gonadotropin-releasing hormone (GnRH) pathways. Middle age is associated with transcriptional declines of genes which encode OXT, GnRH and signaling components, which similarly occur in an Alzheimer's disease (AD)-like model. Therapeutically, OXT-GnRH combination is substantially more effective than individual peptides in treating AD-like disorders in male 5×FAD model. In conclusion, the hypothalamus is important for modeling age-related DNA methylation and developing hypothalamic strategies to combat AD.

Spatial selective auditory attention is preserved in older age but is degraded by peripheral hearing loss.

Interest in how ageing affects attention is long-standing, although interactions between sensory and attentional processing in older age are not fully understood. Here, we examined interactions between peripheral hearing and selective attention in a spatialised cocktail party listening paradigm, in which three talkers spoke different sentences simultaneously and participants were asked to report the sentence spoken by a talker at a particular location. By comparing a sample of older (N = 61; age = 55-80 years) and younger (N = 58; age = 18-35 years) adults, we show that, as a group, older adults benefit as much as younger adults from preparatory spatial attention. Although, for older adults, this benefit significantly reduces with greater age-related hearing loss. These results demonstrate that older adults with excellent hearing retain the ability to direct spatial selective attention, but this ability deteriorates, in a graded manner, with age-related hearing loss. Thus, reductions in spatial selective attention likely contribute to difficulties communicating in social settings for older adults with age-related hearing loss. Overall, these findings demonstrate a relationship between mild perceptual decline and attention in older age.

Dose response of leisure time physical activity and biological aging in type 2 diabetes: a cross sectional study.

To investigate the relationship between Leisure time physical activity (LTPA) patterns and PhenoAgeAccel in patients with Type 2 diabetes (T2D), emphasizing the role of regular LTPA in mitigating biological aging. This study utilized data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018, including 4,134 adults with T2D. Multivariable linear regression models and restricted cubic spline (RCS) methods were employed to assess the relationship between LTPA and Phenotypic age acceleration (PhenoAgeAccel), with segmented likelihood ratio tests to detect nonlinear thresholds. Stratified regression and interaction tests were conducted for robust analysis. Compared to individuals with no LTPA patterns, those with regular LTPA patterns had significantly lower PhenoAgeAccel scores (ß = -1.164, 95% CI: -1.651 to -0.677, P < 0.0001), while the "Weekend Warrior" and "Inactive-LTPA" patterns showed no significant effects. A nonlinear threshold effect was identified; below 594.57 min of weekly LTPA, there was a significant negative correlation (ß = -0.002, 95% CI: -0.003 to -0.001, P = 0.000), with gender-specific effects present. Regular LTPA significantly reduces phenotypic age acceleration in T2D patients, with a nonlinear threshold effect indicating that moderate physical activity is most beneficial. These findings highlight the necessity of personalized physical activity recommendations and provide evidence for public health strategies to promote healthy aging in T2D patients.

Noninvasive, epigenetic age estimation in an elasmobranch, the cownose ray (Rhinoptera bonasus).

Age data are essential for estimating life history parameters and are thus critical for population assessment, management, and conservation. Traditional vertebrae-based age estimation in elasmobranchs can be costly, time intensive, of low accuracy, and is by necessity lethal. Herein, epigenetic clocks were developed for an elasmobranch, the cownose ray (Rhinoptera bonasus), using aquarium-born individuals (n = 42) with known dates of birth (age range: 7-7,878 days or 0-21 years) and two tissue types (fin clips and whole blood) that can be sampled in a relatively non-invasive manner. Enzymatically-converted restriction site-associated DNA sequencing (ECrad-seq) was used to identify CpG sites that exhibited age-correlated DNA methylation. The epigenetic clocks developed were highly accurate (mean absolute error, MAE, < 0.75 years) and precise (R2 > 0.98). Age-associated CpG sites were identified across tissues, and a multi-tissue clock was also highly accurate (MAE < 1 year) and precise (R2 = 0.97). Using the developed fin clip clock, three wild-caught individuals of unknown age but managed in aquariums for > 22 years were predicted to be 22.10-23.49 years old. Overall, the results have important implications for future epigenetic clock development and noninvasive age estimation in elasmobranchs.

Causal linkage of Graves' disease with aging: Mendelian randomization analysis of telomere length and age-related phenotypes.

BACKGROUND: Aging is an irreversible progressive decline in physical function. Graves' disease (GD) is a common cause of hyperthyroidism and is characterized by elevated levels of the thyroid hormone (TH). High TH levels are associated with aging and a shortened lifespan. The causal relationship between GD and aging has yet to be investigated. METHODS: We used genome-wide association study (GWAS) datasets and Mendelian randomization (MR) analysis to explore the causal link between GD and aging. To assess the statistical power of instrumental variables (IVs), F-statistics and R2 were used. MR analysis was conducted using inverse-variance weighting (IVW), MR-Egger, weighted median, and weighted mode. The odds ratio (OR) and 95% CI were calculated to estimate the relative risk of GD to the outcomes. The Cochran Q test, I2, MR-PRESSO test, and MR-Egger regression intercept were calculated using statistical and leave-one-out analyses to test the heterogeneity, horizontal pleiotropy, and stability of the IVs on the outcomes. RESULTS: F-statistics of the five IVs were greater than 10, and the R2 values ranged from 0.033 to 0.156 (R2 > 0.01). According to the results of the IVW analysis, GD had no causal effect on facial aging (p = 0.189), age-related macular degeneration (p = 0.346), and Alzheimer's disease (p = 0.479). There was a causal effect of GD on the remaining outcomes: telomere length (TL) (OR = 0.982; 95%CI:0.969-0.994; p = 0.004), senile cataract (OR = 1.031; 95%CI:1.002-1.060; p = 0.033), age-related hearing impairment (OR = 1.009; 95%CI:1.004-1.014; p = 0.001), chronic obstructive pulmonary disease (COPD) (OR = 1.055; 95%CI:1.008-1.103; p = 0.020), and sarcopenia (OR = 1.027; 95%CI:1.009-1.046; p = 0.004). CONCLUSIONS: GD accelerates the occurrence of age-related phenotypes including TL, senile cataracts, age-related hearing impairment, COPD, and sarcopenia. In contrast, there are no causal linkages between GD and facial aging, age-related macular degeneration, or Alzheimer's disease. Further experimental studies could be conducted to elucidate the mechanisms by which GD facilitates aging, which could help slow down the progress of aging.

A single risk assessment for the most common diseases of ageing, developed and validated on 10 cohort studies.

BACKGROUND: We aimed to develop risk tools for dementia, stroke, myocardial infarction (MI), and diabetes, for adults aged ≥ 65 years using shared risk factors. METHODS: Data were obtained from 10 population-based cohorts (N = 41,755) with median follow-up time (years) for dementia, stroke, MI, and diabetes of 6.2, 7.0, 6.8, and 7.4, respectively. Disease-free participants at baseline were included, and 22 risk factors (sociodemographic, medical, lifestyle, laboratory biomarkers) were evaluated. Two risk tools (DemNCD and DemNCD-LR based on Fine and Gray sub-distribution and logistic regression [LR], respectively) were developed and validated. Predictive accuracies of these risk tools were assessed using Harrel's C-statistics and area under the curve (AUC) and 95% confidence interval (CI). Model calibration was conducted using Hosmer-Lemeshow goodness of fit test along calibration plots. RESULTS: Both the DemNCD and DemNCD-LR resulted in similar predictive accuracy for each outcome. The overall AUC (95% CI) for dementia, stroke, MI, and diabetes risk tool were 0·68 (0·65, 0·70), 0·58 (0·54, 0·61), 0·65 (0·61, 0·68), and 0·68 (0·64, 0·72), respectively, for males. For females, these figures were 0·65 (0·63, 0·67), 0·55 (0·52, 0·57), 0·65 (0·62, 0·68), and 0·61 (0·57, 0·65). CONCLUSIONS: The DemNCD is the first tool to predict both dementia and multiple cardio-metabolic diseases using comprehensive risk factors and provided similar predictive accuracy to existing risk tools. It has similar predictive accuracy as tools designed for single outcomes in this age-group. DemNCD has the potential to be used in community and clinical settings as it includes self-reported and routinely available clinical measures.

The association between sleep duration trajectories and successful aging: a population-based cohort study.

BACKGROUND: Insufficient or excessive sleep duration are associated with increased risk of individual adverse outcomes. However, it remains largely unknown whether sleep duration trajectories are associated with overall health among older adults. This study aimed to examine the association between sleep duration trajectories and successful aging. METHODS: In the China Health and Retirement Longitudinal Study (CHARLS), 3,306 participants without major chronic diseases at baseline and survived to aged 60 years and older at the end of follow-up were potentially eligible participants. Total sleep duration was assessed in 2011, 2013, and 2015, and successful aging was evaluated in 2020 and was defined as being free of major chronic diseases, no physical impairment, high cognitive function, good mental health, and active engagement with life. Latent class mixed model (LCMM) was used to identify sleep duration trajectories and logistic regression was performed to explore the association between these trajectories and successful aging. RESULTS: During the 9-year follow-up, 455 individuals (13.8%) met the criteria for successful aging. Five sleep duration trajectories were identified: normal stable, long stable, decreasing, increasing, and short stable. Compared with the normal stable trajectory, the adjusted ORs (95% CI) for achieving successful aging for participants with long stable, decreasing, increasing, and short stable trajectories were 1.00 (0.77, 1.30), 0.64 (0.40, 1.03), 0.64 (0.45, 0.92), and 0.48 (0.35, 0.66), respectively. The stratified and sensitivity analyses were generally consistent with the main results. CONCLUSIONS: Increasing and short stable trajectories of sleep duration are associated with lower odds of successful aging relative to participants in the normal stable trajectory. The findings underscore the critical importance of monitoring dynamic changes in sleep duration in middle-aged and older Chinese adults.

The impact of short video usage on the mental health of elderly people.

BACKGROUND: In the context of a gradual increase in aging, improving the mental health of the elderly is particularly vital for coping with aging. Leveraging data from the 2020 China Family Panel Studies, this study rigorously examines the influence of short video on the mental health of the elderly. METHODS: We use a multiple linear regression model to investigate the influence of short video usage on the mental health of the elderly. To address endogeneity concerns, this study employs two-stage least squares and propensity score matching to estimate the impact of short video usage on the mental health of the elderly. RESULTS: The empirical analysis reveals a substantive and statistically significant enhancement in the mental health of elderly people attributable to the use of short videos. To ensure the reliability and robustness of our estimations, a comprehensive battery of robustness tests is conducted, all of which consistently support the conclusion of a positive association between short video usage and improved mental health among the elderly. Furthermore, the results of the heterogeneity analysis suggest that short videos have less of an impact on elderly males and individuals with higher levels of education. The results of the mechanism analysis indicate that the use of short videos can enhance the mental health of elderly individuals by positively impacting the intergenerational relationships between them and their children, as well as their leisure consumption habits. CONCLUSIONS: This study can provide policy inspiration for the government to improve the mental health of the elderly and achieve active aging.

Perivascular space enlargement accelerates in ageing and Alzheimer's disease pathology: evidence from a three-year longitudinal multicentre study.

BACKGROUND: Perivascular space (PVS) enlargement in ageing and Alzheimer's disease (AD) and the drivers of such a structural change in humans require longitudinal investigation. Elucidating the effects of demographic factors, hypertension, cerebrovascular dysfunction, and AD pathology on PVS dynamics could inform the role of PVS in brain health function as well as the complex pathophysiology of AD. METHODS: We studied PVS in centrum semiovale (CSO) and basal ganglia (BG) computationally over three to four annual visits in 503 participants (255 females; meanage = 70.78 ± 5.78) of the ongoing observational multicentre "DZNE Longitudinal Cognitive Impairment and Dementia Study" (DELCODE) cohort. We analysed data from subjects who were cognitively unimpaired (n = 401), had amnestic mild cognitive impairment (n = 71), or had AD (n = 31). We used linear mixed-effects modelling to test for changes of PVS volumes in relation to cross-sectional and longitudinal age, as well as sex, years of education, hypertension, white matter hyperintensities, AD diagnosis, and cerebrospinal-fluid-derived amyloid (A) and tau (T) status (available for 46.71%; A-T-/A + T-/A + T + n = 143/48/39). RESULTS: PVS volumes increased significantly over follow-ups (CSO: B = 0.03 [0.02, 0.05], p < 0.001; BG: B = 0.05 [0.03, 0.07], p < 0.001). PVS enlargement rates varied substantially across subjects and depended on the participant's age, white matter hyperintensities volumes, and amyloid and tau status. PVS volumes were higher across elderly participants, regardless of region of interest (CSO: B = 0.12 [0.02, 0.21], p = 0.017; BG: B = 0.19 [0.09, 0.28], p < 0.001). Faster BG-PVS enlargement related to lower baseline white matter hyperintensities volumes (ρspearman = -0.17, pFDR = 0.001) and was more pronounced in individuals who presented with combined amyloid and tau positivity versus negativity (A + T + > A-T-, pFDR = 0.004) or who were amyloid positive but tau negative (A + T + > A + T-, pFDR = 0.07). CSO-PVS volumes increased at a faster rate with amyloid positivity as compared to amyloid negativity (A + T-/A + T + > A-T-, pFDR = 0.021). CONCLUSION: Our longitudinal evidence supports the relevance of PVS enlargement in presumably healthy ageing as well as in AD pathology. We further discuss the region-specific involvement of white matter hyperintensities and neurotoxic waste accumulation in PVS enlargement and the possibility of additional factors contributing to PVS progression. A comprehensive understanding of PVS dynamics could facilitate the understanding of pathological cascades and might inform targeted treatment strategies. TRIAL REGISTRATION: German Clinical Trials Register DRKS00007966. Registered 04.05.2015 - retrospectively registered, https://drks.de/search/en/trial/DRKS00007966 .

Sex dimorphism and tissue specificity of gene expression changes in aging mice.

BACKGROUND: Aging is a complex process that involves all tissues in an organism and shows sex dimorphism. While transcriptional changes in aging have been well characterized, the majority of studies have focused on a single sex and sex differences in gene expression in aging are poorly understood. In this study, we explore sex dimorphism in gene expression in aging mice across three tissues. METHODS: We collected gastrocnemius muscle, liver and white adipose tissue from young (6 months, n = 14) and old (24 months, n = 14) female and male C57BL/6NIA mice and performed RNA-seq. To investigate sex dimorphism in aging, we considered two levels of comparisons: (a) differentially expressed genes between females and males in the old age group and (b) comparisons between females and males across the aging process. We utilized differential expression analysis and gene feature selection to investigate candidate genes. Gene set enrichment analysis was performed to identify candidate molecular pathways. Furthermore, we performed a co-expression network analysis and chose the gene module(s) associated with aging independent of sex or tissue-type. RESULTS: We identified both tissue-specific and tissue-independent genes associated with sex dimorphism in aged mice. Unique differentially expressed genes between old males and females across tissues were mainly enriched for pathways related to specific tissue function. We found similar results when exploring sex differences in the aging process, with the exception that in the liver genes enriched for lipid metabolism and digestive system were identified in both females and males. Combining enriched pathways across analyses, we identified amino acid metabolism, digestive system, and lipid metabolism as the core mechanisms of sex dimorphism in aging. Although the vast majority of age-related genes were sex and tissue specific, we identified 127 hub genes contributing to aging independent of sex and tissue that were enriched for the immune system and signal transduction. CONCLUSIONS: There are clear sex differences in gene expression in aging across liver, muscle and white adipose. Core pathways, including amino acid metabolism, digestive system and lipid metabolism, contribute to sex differences in aging.

Aging is a complex process that occurs differently across tissues, and in men compared to women. However, the mechanisms that cause sex differences are not well understood. Using naturally aging mouse models we compared how specific genes were differently expressed in muscle, liver and fat of old and young female and male mice. We found that the vast majority of genes that were changed with age were only changed in one sex and specific tissues. Overall, sex differences in aging across tissues were related to genes involved in amino acid metabolism, digestive system and lipid metabolism. Notably, lipid metabolism is important in aging females across all tissues. We also identified a set of genes associated with aging independent of sex and tissue-type involved in immune pathways and signaling. These results enhance our understanding of sex differences in aging.

The future of physiological research: A greater understanding of female master athletes and aging?

High caliber master athletes provide a valuable model for studying inherent physiological aging and performance capacity, without the confounding factor of physical inactivity. Despite the remarkable achievements of female master athletes, their participation rates remain significantly lower than those of their male counterparts, particularly at more advanced ages. This review examines the biological sex gap in sports participation among master athletes and the subsequent disparity in empirical research, thereafter exploring possible contributing factors. It highlights the importance of studying female master athletes to better understand the aging process and offers recommendations to address current evidence gaps. The need for more comprehensive mechanistic data on highly trained older women, novel cataloguing and analysis of real-world datasets, case studies/series, and longitudinal research are also emphasized. Although analyzing the records of female master athletes as a surrogate to determine age-related physiological and performance changes is a common approach, the process may be hindered by the considerably lower participation rates of women. Therefore, an important step toward bridging these gaps is the longitudinal, integrative study of female athletes engaged in lifelong exercise. Such analyses would improve our understanding of senescence in women and may inform interventions targeting the promotion of physical function in older adults.