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This article examines the go-along method as a transformative, participatory approach for exploring how older adults experience aging through movement and interaction within their everyday environments. Drawing on a UK-based study, Enabling Person-Centered Integrated Care Networks (EPICS), it demonstrates how walking alongside participants allows researchers to access embodied, sensory, and relational dimensions of daily life that conventional interviews often overlook. The go-along fosters inclusivity by enabling participants to guide routes, pace, and topics, co-creating data that illuminate how mobility, memory, and emotion shape the experience of aging. Positioned within broader qualitative and socio-material traditions, the paper highlights the methodological value of the go-along for generating reflexive, context-rich insights into the relationships between people, place, and everyday practice.
This article reviews Larry Jacoby's experimental and theoretical work on age-related differences in perception and memory. Starting with a dual-processing model involving familiarity and recollection, Jacoby's work identified two broad patterns: one showing an age-related decrement in recollection but none in familiarity; the second proposing that the age-related impairment in recollection often fails to oppose the misleading effects of familiarity and habit associated with erroneous incoming information. These ideas, and the further notions of processing fluency, accessibility bias, source-constrained retrieval and capture are illustrated by an impressive array of experiments, a selection of which are described in the article. The review is accompanied by a commentary on Jacoby's views and some contrasts with findings and perspectives of the present author.
Purpose: Many older women experience urinary incontinence (UI). However, access to pelvic floor muscle (PFM) training, an effective first-line treatment, is limited. Group-based telerehabilitation appears cost-effective and could improve accessibility. Recent evidence suggests a group-based PFM telerehabilitation programme for treating UI in older women (teleGROUP) is feasible and clinically relevant. This qualitative study assessed teleGROUP's acceptability to both patients and a clinician. Method: Thirty-three older women who completed the teleGROUP programme, and the physiotherapist who led it, discussed their experiences in focus groups or interviews. We transcribed qualitative data and analyzed them using thematic analysis. Results: Participating women enhanced self-efficacy in managing symptoms and contracting PFMs, reporting high self-efficacy in attending sessions and completing home exercises. The programme fostered positive affective attitudes in participants and the physiotherapist, aligned with their values, and improved self-efficacy with technology. Participants and the physiotherapist perceived clinical effectiveness as high. Women identified time commitment as a burden; the physiotherapist found time management challenging. However, the women found remote participation convenient. They recognized that PFM exercises led to symptom improvement. Conclusion: The programme proved acceptable for older women and the physiotherapist. Pragmatic trials in real-life clinical settings and implementation studies are necessary for further validation. Many older women experience urinary incontinence. While pelvic floor muscle training is the first-line recommended treatment, access can be limited. Group-based telerehabilitation may offer a cost-effective and accessible option. While promising results have been shown for feasibility and clinical outcomes, its acceptability remains unknown. In this study, older women who participated in a group-based pelvic floor muscle training telerehabilitation, along with the physiotherapist who led it, were interviewed. The women felt more confident in their capacity to manage urinary incontinence symptoms, contract pelvic floor muscles, and their ability to attend the programme’s sessions and complete home exercises. The women and the physiotherapist both reported positive feelings toward the programme, which aligned with their values. They felt more confident using technology. They viewed the programme as effective in reducing urinary incontinence symptoms. However, the women identified the time commitment as a burden, and the physiotherapist found weekly session management challenging. Yet, the women found remote participation convenient. They also saw how completing the exercises led to an improvement in their urinary incontinence symptoms. Overall, group-based pelvic floor muscle training telerehabilitation appeared acceptable to both older women and the physiotherapist. Further research on the programme in real-life clinical settings is needed. Objectif: de nombreuses femmes âgées présentent de l’incontinence urinaire (IU). L’accès au renforcement des muscles du plancher pelvien (RPP), traitement recommandé en première intention, demeure toutefois limité. La téléréadaptation de groupe pourrait représenter une option abordable susceptible d’améliorer l’accessibilité. Des données récentes ont démontré qu’un programme de RPP en téléréadaptation de groupe (teleGROUP) destiné aux femmes âgées était faisable et prometteur sur le plan clinique. Cette étude qualitative visait à évaluer l’acceptabilité de teleGROUP pour les patientes et la physiothérapeute. Méthodologie: trente-trois femmes âgées ayant complété téléGROUP, ainsi que la physiothérapeute ayant animé le programme, ont partagé leurs expériences via des groupes de discussion et entrevues, qui ont été retranscrits puis analysés par analyse thématique. Résultats: les femmes ont renforcé leur auto-efficacité à gérer leurs symptômes et contracter les muscles de leur plancher pelvien et étaient confiantes quant à leur capacité à assister aux séances et à réaliser les exercices à la maison. Le programme a suscité des attitudes affectives positives chez les femmes et la physiothérapeute, s’alignait avec leurs valeurs, a amélioré leur aisance avec la technologie, et a été perçu comme cliniquement efficace. Les participantes ont toutefois mentionné que le temps requis représentait un fardeau, tandis que la physiothérapeute a souligné des défis de gestion du temps. Néanmoins, les femmes ont apprécié la commodité d’être à distance et ont reconnu que les exercices contribuaient à améliorer leurs symptômes. Conclusion: le programme teleGROUP s’est avéré acceptable pour les femmes âgées et la physiothérapeute. Des études pragmatiques en contexte clinique réel et de mise en œuvre seraient maintenant nécessaires.
Aging is recognized as the most significant risk factor for neurodegenerative diseases. Emerging evidence indicates that inflammation contributes to the progression of aging-related neurodegeneration. As a transmembrane immune receptor, triggering receptor expressed on myeloid cells 1 (TREM1) plays a crucial role in the regulation of inflammatory responses. Previously, our research group and others showed that the levels of a soluble form of TREM1 (sTREM1) were increased in the plasma or cerebrospinal fluid (CSF) of patients with Alzheimer's disease, the most common type of neurodegenerative disease among the elderly. Moreover, the elevated levels of CSF sTREM1 were closely associated with a more rapid rate of hippocampal degeneration in cognitively impaired older adults. However, the precise mechanisms by which sTREM1 contributes to aging-related neurodegeneration remain largely unclear. In this study, by utilizing senescence accelerated mouse prone 8 mice, an animal model of accelerated aging, we confirmed that serum sTREM1 levels were significantly increased during the aging process. Importantly, we demonstrated that roundabout guidance receptor 2 (ROBO2) functioned as a receptor for sTREM1 in hippocampal neurons, and its expression was also upregulated with aging. Additionally, we revealed for the first time that knockdown of neuronal ROBO2 mitigated aging-related hippocampal synaptic degeneration and cognitive impairments. Furthermore, we provided the first evidence that sTREM1 reduced the expression of synaptic proteins via the ROBO2/extracellular signal-regulated kinase pathway. These findings elucidated the mechanisms through which sTREM1 contributed to aging-related neurodegeneration and suggested that the inhibition of sTREM1-mediated signaling might represent a novel therapeutic strategy for the treatment of neurodegeneration and cognitive decline induced by aging.
Aging in the immune system results in increased susceptibility to infections, exacerbated autoimmunity, and reduced responsiveness to vaccines. However, there are no current established interventions for immune aging. Ketogenic diets and fasting have been researched as interventions against other aspects of aging and age-related diseases, and they work in part by increasing circulating levels of ketone bodies, which have anti-inflammatory properties and can boost T cell function. Exogenous ketones, such as ketone esters, are currently being studied as a more accessible approach to obtain the benefits of ketone bodies through direct supplementation. Here, we investigated whether ketone ester supplementation improves immune function during aging. Aged (19-month-old) C57BL/6JN mice were given a diet supplemented with the ketone ester or a control diet for 15 weeks. We found that the ketone ester diet decreased activation of B cells, especially age-associated B cells, in the spleen. In spite of this decrease in activation, mice on the ketone ester diet showed no impairment in antibody production after nitrophenyl-ovalbumin immunization. The ketone ester diet also inhibited glucose dependence and translation of age-associated B cells, likely through inhibition of mTOR signaling via ketone bodies. Our study elucidates the effect of ketone esters on B cells in the context of aging and unveils a new immunoregulatory role of ketone bodies on B cells.
Cyclin-dependent kinase 5 (Cdk5) plays a critical role in pain transmission by phosphorylating key nociceptive proteins. One of its recently identified substrates, the P2X2 subunit, is part of the P2X2/3 purinergic receptor (P2X2/3R), which is implicated in nociceptive signaling. However, the specific contribution of Cdk5 to purinergic receptor-mediated pain responses remains unclear. This study aimed to investigate the role of Cdk5 in pain responses elicited by α,β-methylene ATP (α,β-meATP), an agonist of P2X2/3R and P2X3R. Both pharmacological inhibition and genetic loss-of-function approaches were used to assess the role of Cdk5. Calcium (Ca2+) imaging was performed in cultured murine trigeminal ganglion (TG) neurons to characterize α,β-meATP-evoked responses. Surface biotinylation assays in HEK293 cells were used to assess P2X2 receptor membrane expression. In vivo, facial pain was induced by injecting α,β-meATP into the whisker pad of mice. Behavioral responses were evaluated in conditional Cdk5 knockout mice targeting sensory neurons and in control littermates. In TG neuron cultures, α,β-meATP evoked both fast and slow Ca2+ transients, which were sensitive to P2X3 or P2X2/3 channel blockade. Inhibition or genetic loss-of-function of Cdk5 predominantly accelerated the decay of slow responses, with minimal effects on fast responses. In HEK293 cells, Cdk5 activation did not alter the surface expression of P2X2 receptors. In vivo, α,β-meATP induced facial pain-like behaviors, including grooming and head flinching, which were significantly reduced in conditional Cdk5 knockout mice compared to controls. These findings indicate that Cdk5 modulates orofacial pain by regulating purinergic receptor-mediated signaling in trigeminal neurons. Specifically, Cdk5 appears to influence the functional properties of P2X2-containing channels, most likely P2X2/3 heteromeric receptors, without affecting their membrane expression. This modulation of receptor kinetics may underlie the observed changes in nociceptive behavior, highlighting Cdk5 and P2X receptors as a potential target for pain modulation.
Family caregivers of adults with cognitive impairment, including dementia, often face complex challenges. However, social exclusion among caregivers aged 50 years and older particularly within the distinctive Central and Eastern European context, remains critically underexplored. This study uses Poland, a country where strong family care norms coexist with limited formal support, as a crucial case study to examine how social exclusion manifests in the caregiving experiences of older family caregivers. Using photovoice, a novel participatory action research method for this context, the study engaged six family caregivers aged 50 and above from a single city in Poland. Participants photographed aspects of their caregiving experiences and took part in reflective group discussions. Data from these discussions were analyzed thematically to identify key domains of social exclusion. No statistical tests were applied due to the qualitative and exploratory nature of the study. Thematic analysis revealed four interconnected domains of social exclusion: (1) Relational exclusion-including the erosion of social networks and experiences of stigma; (2) Institutional exclusion-such as difficulties accessing care services, transportation, and public infrastructure; (3) Material exclusion-highlighting financial strain and unmet resource needs; and (4) Paradoxical caregiving roles-reflecting the simultaneous marginalization and moral elevation of caregivers. These findings illustrate the layered and dynamic nature of exclusion in the caregiving trajectory. A key contribution of this work is the methodological approach. Despite the study's small and localized sample, it demonstrates the pioneering value of photovoice in capturing the context-specific dimensions of social inequality in caregiving acting as a critical tool to amplify caregiver voices. By centering older caregivers in Poland, the study offers novel insights into how familial care responsibilities intersect with systemic gaps in formal support. Despite limitations in generalizability, these context-specific findings demonstrate the impact of Polish systemic gaps and can enrich cross-national discussions on caregiver vulnerability and resilience, emphasizing the need for targeted social protection policies and inclusive service design.
Cognitive function is closely linked to brain energy metabolism and may be compromised by aging, metabolic stress, and neuropsychiatric disease. Ketone bodies can serve as an alternative cerebral fuel and may also exert signaling effects relevant to cognition. Exogenous ketones (EK) offer a practical means of increasing circulating ketone concentrations without dietary carbohydrate restriction. However, the overall effect of EK supplementation on cognitive performance in humans has not been systematically quantified. A systematic review and meta-analysis were conducted in accordance with PRISMA guidelines. PubMed, Web of Science, and Embase were searched through October 2025 for randomized controlled trials investigating the effects of EK on cognitive outcomes in healthy adults or individuals with neuropsychiatric conditions. Data extraction and quality assessment were performed independently by multiple reviewers using the PEDro scale. Standardized mean differences (SMD) were calculated using random-effects models. Subgroup and meta-regression analyses examined the influence of ketone formulation, intervention duration, dose, population type, and presence of acute cognitive stressors. 38 studies comprising 41 protocols (1,602 participants) were included in the systematic review, with 29 protocols (1,117 participants) eligible for meta-analysis. EK supplementation was associated with a statistically significant improvement in cognitive performance compared with placebo (SMD = 0.29, 95% CI 0.16-0.41; p < 0.001). Sub-group analyses did not show statistically significant differences between the type of supplementation (p = 0.083), study duration (acute vs. intermediate; p = 0.11), population type (healthy vs. Alzheimer's disease; p = 0.077), or the presence of acute cognitive stressors (p = 0.89). Meta-regression revealed a positive association between daily EK dose and cognitive improvement. EK supplementation is associated with modest improvements in cognitive performance across diverse populations and study designs. These findings support EK as a flexible nutritional strategy for cognitive support and warrant further investigation in well-powered, long-term trials to clarify optimal dosing, formulation, and clinical applicability. https://www.crd.york.ac.uk/PROSPERO/view/CRD42023471727, CRD42023471727.
Emerging evidence suggests that vascular disease is linked with poorer muscle strength and higher falls risk. We evaluated the association between abdominal aortic calcification (AAC), scored using a well-established and validated 24-point machine learning algorithm (ML-AAC24), with magnetic resonance imaging-derived fat-free muscle volume (FFMV, n=33,640) and muscle fat infiltration (MFI, n=33,640), appendicular lean mass (ALM, n=36,526), handgrip strength (HGS, n=49,049), sarcopenia (n=35,834) and incident falls (n=48,482) in community-dwelling adults (mean age 64.6 ± 7.8 years, 50.9% women). ML-AAC24 was assessed on dual-energy X-ray absorptiometry (DXA)-derived lateral spine images and classified into established categories based on severity; low (<2), moderate (2-5) and high (≥6). Age and sex specific cut-points for low FFMV and sex-specific high MFI were based on previous work. Low ALM, weak HGS and sarcopenia were based on the revised European sarcopenia guidelines. The associations between ML-AAC24 extent, odds of having poorer muscle health measures and incident falls were tested in multivariable-adjusted logistic and Cox proportional hazards regressions, respectively. Individuals with moderate and high, compared to low ML-AAC24, had greater odds for low FFMV (1.58, 95%CI: 1.28-1.95 and 2.52, 95%CI: 1.88-3.38, respectively), high MFI (1.09, 95%CI: 1.01-1.18 and 1.45, 95%CI: 1.29-1.64, respectively), and low ALM (1.14, 95%CI: 1.04-1.24 and 1.28, 95%CI: 1.11-1.47, respectively). They also had higher odds for weak HGS (1.18, 95%CI: 1.07-1.29 and 1.24, 95%CI:1.09-1.42, respectively) and sarcopenia (1.40, 95%CI:1.12-1.76 and 1.69, 95%CI:1.24-2.29, respectively). Compared to low ML-AAC24, high ML-AAC24 was associated with greater hazards for an incident fall-related hospitalisation (1.31, 95%CI: 1.02-1.68). Greater ML-AAC24 extent, which can be opportunistically identified during routine bone density testing, was associated with poorer muscle composition and, function, sarcopenia and incident falls in community-dwelling adults. Such findings may explain previous reports between AAC and higher fall and fracture risk, supporting a nexus between vascular and musculoskeletal health. Studies investigating associations between machine-learning derived abdominal aortic calcification (AAC) with advanced imaging derived muscle composition and mass, as well as functional measures are limited. For the first time, we demonstrate that AAC identified automatically from bone density images was associated with poorer thigh muscle composition, lower muscle mass, weaker muscle strength, as well as increased sarcopenia and falls risk in middle-aged and older community-dwelling adults. Collectively, our findings demonstrate the need to consider vascular health during musculoskeletal health assessments. This is particularly important given AAC can be opportunistically identified on images from widely available bone density machines.
Sex differences in lifespan and age-associated phenotypes are pervasive across species, yet the mechanisms remain poorly understood. Mitochondrial dysfunction is a major hallmark of aging, but whether skeletal muscle mitochondria age along sex specific trajectories remains incompletely defined. Here, we profiled mitochondrial bioenergetics and DNA integrity in flexor digitorum brevis (FDB) muscle from young (3-4 months) and aged (20-24 months) male and female C57BL/6 mice. We quantified cellular respiration in intact myofibers, measured mitochondrial DNA (mtDNA) copy number, and assessed expression of genes involved in mitochondrial dynamics, electron transport chain (ETC) function, and mtDNA maintenance. Cellular respiration differed by sex at baseline and changed with age in a sex-dependent manner. Aged females exhibited a lower basal and ATP-linked respiration than aged males. In contrast, spare respiratory capacity increased in aged females relative to aged males, consistent with age- and sex-specific remodeling of the bioenergetic reserve. mtDNA copy number increased with age in both sexes, with a greater increase in mtDNA content in aged males. Gene-expression analyses revealed age- and/or sex-dependent changes, including lower Pink1 expression in females compared to males, an age-related increase in the mtDNA maintenance gene Polg2 only in males, though most genes were not significantly different. As an exploratory systemic readout, we additionally assessed DNA damage responsiveness in whole-blood leukocytes using the alkaline comet assay following oxidative challenge; young females exhibited greater induced DNA damage than young males. Together, these data define sex- and age-associated mitochondrial remodeling in FDB and provide an initial assessment of sex-dependent inducible DNA damage responses in blood, underscoring the importance of sex as a biological variable in studies of aging.
The human broad ligament connects the uterus laterally to the pelvis as part of the uterine support system. Although being an integral part of this system, its role in the context of pelvic organ prolapse remains elusive. There is still limited knowledge if aging affects the composition and biomechanics of the broad ligament as observed in other uterine ligaments. Here, the mesometrium, the largest portion of the broad ligament, from young (n = 7) and aged female individuals (n = 19) was investigated ex vivo. First, extracellular matrix composition and collagen orientation were assessed using histology and immunofluorescence labeling. Second, nanoscale collagen deformation was quantified using small-angle X-ray scattering (SAXS) during macroscale biaxial tensile testing within physiological ranges. Muscle and collagen type I and III content varied between individuals but not with age. Glycosaminoglycan content was not significantly different between age groups. Histology and SAXS demonstrated two orthogonal collagen fiber/fibril families. Under SAXS, unloaded mesometrium samples showed high collagen fibril dispersion (82-121°) and no difference in median d-spacing (young: 64.96 nm (interquartile range, IQR, 64.94-64.98 nm); aged: 64.96 nm (IQR 64.92-64.97 nm)). Young samples showed no significant variance in nanoscale fibril strain, while aged samples varied notably in fibril strain response. The observed orthogonal fibril families with high dispersion underline the mesometrium's adaptation to multiaxial loading. While no age-related difference in median nanoscale collagen deformation response was observed, the variable response within aged samples indicates additional influencing factors beyond aging such as AGE accumulation. This highlights the need to examine how clinical factors and diseases impact collagen in the uterine support system. STATEMENT OF SIGNIFICANCE: The mesometrium, part of the broad ligament, supports the uterus and may be affected by aging, yet its mechanical properties remain under-researched. This research used advanced imaging (SAXS) and biaxial tension to explore how collagen, a key structural protein, responds to load in young and aged samples and mapped ECM composition using histology. Unlike other uterine ligaments, the broad ligament showed no major age-related differences in ECM composition or structure. Aged samples demonstrated a variable collagen nanoscale response suggesting changes in load transfer in the ECM co-occurring with age. This study advances understanding of the uterine support system and provides a foundation for future research on aging and pelvic health.
This study examines how older adults in a rural Thai community enterprise experience participation in the context of digital transformation and active aging. Drawing on participatory communication and intergenerational learning frameworks, it investigates how older women artisans integrate digital media into livelihood practices and selfexpression. Using a qualitative case study design (n = 12), the study identifies a continuum of communicative participation ranging from passive presence and assisted engagement to active self-representation and digital storytelling. The findings show that participation is not a linear process of skill acquisition, but a relational trajectory shaped by trust, mentorship, and emotional confidence. Intergenerational collaboration functions as a form of social infrastructure that supports experimentation and the development of communicative agency. The study contributes by reframing active aging as communicative participation and offering a context-sensitive framework for understanding participation in rural settings.
Genome-wide association studies (GWAS) have identified APOE2 allele as linked to exceptional longevity, with carriers exhibiting a reduced risk of Alzheimer's disease (AD). Apolipoprotein E (APOE), a glycoprotein involved in lipid transport, has three major alleles. However, alterations in lipid metabolism alone do not fully explain APOE2's protective effects. In contrast, APOE4 is the strongest genetic risk factor for AD. To investigate how APOE2 promotes neuronal longevity and confers neuroprotection, we generated human isogenic APOE iPSC-derived models of both inhibitory GABAergic and excitatory neurons. In GABAergic neurons, APOE alleles differentially influenced endogenous DNA damage, DNA repair, and neuronal motility. Single-cell RNA sequencing revealed APOE4-specific gene expression signatures associated with AD, whereas APOE2 GABAergic neurons were enriched for DNA repair and signaling pathways. Consistent with this, APOE2 neurons exhibited significantly lower levels of DNA damage. APOE4 GABAergic neurons exhibit increased expression of repetitive ribosomal RNA, which is associated with DNA damage and cellular senescence. To determine whether the effects extended to excitatory neurons, we used a separate human model of Ngn2-induced glutamatergic neurons, and found that APOE2 excitatory neurons were more resistant to cellular senescence and DNA damage than isogenic APOE3 and APOE4 neurons. Similarly, we found human APOE2-targeted replacement mice exhibited less nucleolar enlargement and increased nuclear Lamin A/C, Hmgb1, and H3K9me3 compared to APOE4 counterparts. Together, our findings identify DNA repair and suppression of senescence-associated processes as key mechanisms by which APOE2 is associated with neuronal resilience, providing mechanistic insight into its association with exceptional longevity and protection against AD.
Capsaicin has been investigated as a phytogenic feed additive in animal production due to reported growth-promoting and immunomodulatory properties; however, its pungency limits practical application. Capsiate, a naturally occurring non-pungent capsaicin analog present in specific Capsicum annuum accessions, conserves many of its bioactive properties without inducing sensory irritation and has not been studied as a potential growth-promoting alternative. The present study evaluated whether dietary exposure to a capsiate-producing chili pepper influences growth and assessed associated intestinal responses using a murine model. A capsiate-producing Capsicum annuum accession (509-45-1) was characterized and incorporated into experimental diets providing 30 or 50 mg/kg capsiate to male C57BL/6J mice for 12 weeks. The dietary intervention was associated with dose-dependent increases in body weight and longitudinal femoral growth without altering body composition. Femoral elongation was accompanied by increased growth plate area and higher osteocyte number and area. At the intestinal level, the intervention was associated with downregulation of colonic transient receptor potential vanilloid 1 (TRPV1) gene expression, modulation of redox-associated responses, including catalase (CAT) and superoxide dismutase (SOD) expression, and differential modulation of innate immune signaling, including upregulation of Toll-like receptor 2 (TLR2) and downregulation of Toll-like receptor 4 (TLR4), together with reduced interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) expression. Collectively, these findings indicate that dietary supplementation with a capsiate-producing chili is associated with increased somatic growth and enhanced femoral development in mice, accompanied by intestinal transcriptional changes consistent with immunometabolic responses, while preserving body composition.
Senescent cells accumulate with age following stress-induced cell cycle arrest triggered by DNA damage, oncogene activation, and replicative exhaustion. While they contribute to tissue repair and tumor suppression, their persistent senescence-associated secretory phenotypes (SASPs) drive age-related diseases. The heterogeneity of senescent cell populations, particularly the distinction between primary and secondary senescence, remains incompletely understood at single-cell resolution. Here, we established models of primary senescence by X-ray irradiation of human renal epithelial cells and secondary senescence by exposing proliferating cells to conditioned media from primary senescent cells. Single-cell RNA sequencing revealed structured transcriptional trajectories culminating in distinct terminal clusters in primary (C5, C6, and C8) and secondary (C3, C5, and C7) senescence. Primary senescence preferentially converged on extracellular matrix- and fibrosis-associated programs, whereas secondary senescence exhibited more inflammatory and signaling-responsive programs, while both contexts shared a partially overlapping transcriptional module enriched in stress-response and cytokine-related transcriptional modules. We identified subtype-associated genes distinguishing primary from secondary senescent cells, as well as candidate transcriptional regulators-such as HMGA1, NFKB1, and JUNB-associated with conserved and context-specific senescence programs. This study provides a single-cell-resolved transcriptional map of divergent and shared molecular features relevant to renal aging and disease.
Aging is one of the most complex biological processes, which leads to a gradual decline in the function of organs, tissues and cells, and significant increases in the risks of many age-associated diseases, including cancer, neurodegenerative disorders, and cardiovascular diseases. Protein biomarkers have attracted increasing attention in research on aging and age-related diseases. Considering the fact that proteins are large heterogenous biomolecules due to coding polymorphisms, alternative RNA splicing and post-translational modifications (PTMs), including glycosylation, phosphorylation, and methylation, mass spectrometry (MS)-based top-down proteomics (TDP) is a powerful technology that allows for measuring proteins without proteolysis, thus characterizing intact forms of proteins, which provides information on primary sequences, including their modifications. This review provides an overview of TDP technologies, with a particular focus on the separation, ionization, and fragmentation of intact proteins and introduces the most recent applications of TDP to the discovery of proteoform-resolved biomarkers associated with aging and age-related diseases.
The cumulative use of anticholinergic and sedative medications has been associated with lower physical function in older adults. This study aimed to identify which physical function attributes are most impacted in subgroups aged 45-64 and 65-85 years. Baseline data from 30,097 community-living Canadians in the Canadian Longitudinal Study on Aging were analysed using a cross-sectional design. Anticholinergic and sedative medications use was quantified using the Drug Burden Index (DBI). Physical functioning was measured via the timed 4-meter walk, Timed Up and Go (TUG), single leg balance, chair rise and grip strength. Physical functioning profiles were generated using latent profile analysis of the five tests. Associations between DBI scores and physical functioning were assessed through linear regression and multinomial logistic regression. The mean age of participants was 63.0, 50.9% were female, 18.3% had a DBI score 0 < DBI < 1 and 8.7% a DBI score ≥ 1. Adjusted regression models showed the greatest reduction in standardized scores for the TUG test among participants with DBI ≥ 1 (β: -6.05; -6.77 to - 5.33) relative to DBI = 0. Latent profile analysis indicated that the two profiles with the poorest physical functioning were associated with higher odds of exposure to 0 < DBI < 1 and DBI ≥ 1, whereas the profile reflecting the best functioning was associated with reduced odds of exposure to DBI ≥ 1. Associations of similar magnitude were observed across age strata (45-64 and 65-85 years). Cumulative anticholinergic and sedative medication burden was inversely associated with physical functioning. These findings were consistent across middle-aged and older adults.
Navigation programs support people and families by addressing barriers to care and mitigating physical, psychosocial, and practical challenges. While navigation programs are increasingly recognized within European healthcare systems, evidence on implementation strategies for scale-up across settings such as a Train-the-Trainer program remains limited and rarely comprehensively evaluated. This study evaluates a Train-the-Trainer program developed within the EU NAVIGATE project as an implementation strategy to deliver a navigation program for older people with cancer living at home in six European countries. The multi-method evaluation follows the four levels of the Kirkpatrick model. Levels 1 and 2 (Reaction and Learning) were assessed via questionnaires completed by trainers; Level 3 (Behavior) through weekly diaries and group interviews with (international) trainers; and Level 4 (Results) through questionnaires completed by navigators and the intervention beneficiaries (older people with cancer). Quantitative data were analyzed descriptively; qualitative data were analyzed using qualitative content or narrative analysis. At Levels 1 and 2, trainers (n = 11) rated the program as highly useful on a five-point Likert-scale ranging from 1 to 5 (median = 5, IQR = 0.75), reporting strong alignment with their role, clear understanding of the program, and high confidence (median scores 4-5). At Level 3, according to weekly diaries and group interviews, trainers applied the competencies they learned. Successes included positive navigator feedback and training adaptation. Challenges included workload and time constraints, limited team collaboration, and difficulties adapting materials. The ability to contextually adapt the training was facilitated by applying the competencies. At Level 4, reported high levels of overall understanding and confidence following the training, with median scores of 4 (IQR = 1) for both outcomes on a 5-point Likert scale, with highest scores reported for addressing quality of life, and lower scores for supporting technology use. Older people with cancer (n = 101) responded that navigators generally demonstrated the intended competencies with median scores ranging from 1 (IQR = 2) to 5 (IQR = 1) on a 5-point Likert scale. Findings demonstrate the potential of training to implement a navigation program to improve long-term age-appropriate support, emphasize the importance of contextually adapting to local settings, and underline the need for further research to enhance the transferability of navigation programs across diverse health systems. Clinicaltrials.gov: identifier NCT06110312 (2023/10/31).
While mitochondria are recognized as promising therapeutic targets for common pathologies of aging, existing drug discovery platforms fail to capture the adequate physiological and biological contexts necessary to identify translatable, clinically-relevant leads. The goal of this study was to identify marine natural products that modulate mitochondrial function using a screening pipeline leveraging primary human cells in a cell-based phenotypic primary screen. Using this approach, we identified leptochelin A, a recently described metallophore, as a candidate hit with strong potency and efficacy towards the inhibition of mitochondrial function. Using high-resolution respirometry and fluorescence imaging, we validated the mitochondrial-modulatory ("mito-modulatory") effects of leptochelin A and found that it inhibits multiple pathways in the electron transfer system (ETS) while having little effect on mitochondrial mass or superoxide production. It also increases mitochondrial ATP levels, though this may be attributable to a parallel increase in glycolysis. Our findings demonstrate the utility of phenotypic screening using human primary cells to identify novel mitochondrial modulators with translational potential. Leptochelin A's ability to inhibit mitochondrial function without imposing significant toxicity, coupled with its metal-chelating properties, make it a unique compound with therapeutic potential for aging and age-related disorders. Screening strategies focused on mitochondrial respiration can serve as a platform for the advancement of drug discovery within the pharmacology space of human aging.
Nearly all cellular processes are pH dependent. The acidic pH inside the lysosome (vacuole in yeast) is essential for cellular content degradation, signaling, and autophagy. Defects in lysosome/vacuole acidification are a conserved hallmark of aging and age-related diseases. Traditionally, the lysosome/vacuole is thought to import free protons (H⁺) from the surrounding neutral cytosol. Here, we uncovered a conserved lysosome/vacuole acidification mechanism from yeast to human involving lysosomal/vacuolar uptake of H+ pumped out by mitochondrial electron transport chain through mitochondria-lysosomes/vacuoles membrane contacts. Aging/senescence-associated disruption of mitochondria-lysosome/vacuole contacts causes lysosomal/vacuolar de-acidification, which can be reversed by either expressing an engineered linker to connect these two organelles or through an asymmetry-dependent rejuvenation process in daughter cells. Preserving lysosomal acidification in senescent human cells prevents the induction of major senescence-associated secretory phenotype factors and restores autophagic flux. These findings reshape our current understanding of the mechanisms underlying lysosomal/vacuolar (de-)acidification in both young and aged/senescent cells.