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Aging is accompanied by disrupted information flow, resulting from accumulation of molecular mistakes. These mistakes ultimately give rise to debilitating disorders including skeletal muscle wasting, or sarcopenia. To derive a global metric of growing ‘disorderliness’ of aging muscle, we employed a statistical physics approach to estimate the state parameter, entropy, as a function of genes associated with hallmarks of aging. Escalating network entropy reached an inflection point at old age, while structural and functional alterations progressed into oldest-old age. To probe the potential for restoration of molecular ‘order’ and reversal of the sarcopenic phenotype, we systemically overexpressed the longevity protein, Klotho, via AAV. Klotho overexpression modulated genes representing all hallmarks of aging in old and oldest-old mice, but pathway enrichment revealed directions of changes were, for many genes, age-dependent. Functional improvements were also age-dependent. Klotho improved strength in old mice, but failed to induce benefits beyond the entropic tipping point.

Beginning with the pioneering hybridoma technology developed in 1975, antibody generation methodologies have advanced substantially, culminating in today’s single-cell techniques. Each successive approach contributes unique applications, advantages, and drawbacks that reflect the field’s dynamic progress. We highlight the impact of integrating single-cell RNA sequencing (scRNA-seq) with display technologies. This holds potential for the healthcare industry by enabling efficient identification and development of diagnostic and therapeutic antibodies. Monoclonal antibodies (MAbs) produced via each major technology are discussed to illustrate practical outcomes. We have also explored the essential role of glycosylation in maintaining antibody stability and function. Furthermore, we discussed single-cell RNA sequencing (scRNA-seq) that enables high-resolution profiling of immune repertoires and tumour heterogeneity, facilitating the identification of antigen-specific antibodies and rare cell populations. Integration with microfluidics and computational analysis enhances biomarker discovery and cell-specific resolution. These advances support personalised therapies and accelerate next-generation antibody discovery. Finally, we address the emerging integration of machine learning and artificial intelligence in antibody discovery, emphasising recent advances in epitope mapping and predicting three-dimensional protein structures from primary amino acid sequences. Collectively, these developments are poised to revolutionise antibody engineering and expand its impact on therapeutic innovation.

Concurrent resistance and endurance exercise training (CET) has well‐studied benefits; however, inherent hormonal and genetic differences alter adaptive responses to exercise between sexes. Extracellular vesicles (EVs) are factors that contribute to adaptive signaling. Our purpose was to test if EV characteristics differ between men and women following CET. 18 young healthy participants underwent 12‐weeks of CET. Prior to and following CET, subjects performed an acute bout of heavy resistance exercise (AHRET) consisting of 6 × 10 back squats at 75% 1RM. At rest and following AHRET, EVs were isolated from plasma and characteristics and miRNA contents were analyzed. AHRET elevated EV abundance in trained men only (+51%) and AHRET‐induced changes were observed for muscle‐derived EVs and microvesicles. There were considerable sex‐specific effects of CET on EV miRNAs, highlighted by larger variation following the 12‐week program in men compared to women at rest. Pathway analysis based on differentially expressed EV miRNAs predicted that AHRET and 12 weeks of CET in men positively regulates hypertrophy and growth pathways more so than in women. This report highlights sex‐based differences in the EV response to resistance and concurrent exercise training and suggests that EVs may be important adaptive signaling factors altered by exercise training.

Background We previously showed that the autophagy inhibitor chloroquine (CQ) increases inflammatory cleaved caspase-1 activity in myocytes, and that caspase-1/11 is protective in sterile liver injury. However, the role of caspase-1/11 in the recovery of muscle from ischemia caused by peripheral arterial disease is unknown. We hypothesized that caspase-1/11 mediates recovery in muscle via effects on autophagy and this is modulated by CQ. Methods C57Bl/6 J (WT) and caspase-1/11 double-knockout (KO) mice underwent femoral artery ligation (a model of hind-limb ischemia) with or without CQ (50 mg/kg IP every 2nd day). CQ effects on autophagosome formation, microtubule associated protein 1A/1B-light chain 3 (LC3), and caspase-1 expression was measured using electron microscopy and immunofluorescence. Laser Doppler perfusion imaging documented perfusion every 7 days. After 21 days, in situ physiologic testing in tibialis anterior muscle assessed peak force contraction, and myocyte size and fibrosis was also measured. Muscle satellite cell (MuSC) oxygen consumption rate (OCR) and extracellular acidification rate was measured. Caspase-1 and glycolytic enzyme expression was detected by Western blot. Results CQ increased autophagosomes, LC3 consolidation, total caspase-1 expression and cleaved caspase-1 in muscle. Perfusion, fibrosis, myofiber regeneration, muscle contraction, MuSC fusion, OCR, ECAR and glycolytic enzyme expression was variably affected by CQ depending on presence of caspase-1/11. CQ decreased perfusion recovery, fibrosis and myofiber size in WT but not caspase-1/11KO mice. CQ diminished peak force in whole muscle, and myocyte fusion in MuSC and these effects were exacerbated in caspase-1/11KO mice. CQ reductions in maximal respiration and ATP production were reduced in caspase-1/11KO mice. Caspase-1/11KO MuSC had significant increases in protein kinase isoforms and aldolase with decreased ECAR. Conclusion Caspase-1/11 signaling affects the response to ischemia in muscle and effects are variably modulated by CQ. This may be critically important for disease treated with CQ and its derivatives, including novel viral diseases (e.g. COVID-19) that are expected to affect patients with comorbidities like cardiovascular disease.

To examine the cognitive benefits of 6 months of prescribed intermittent exercise (10-min bouts totaling 150 weekly minutes) in community-dwelling older adults, comparing effects of low-intensity movement (LIM) and moderate-intensity aerobic exercise (aerobic exercise; AE) training; and exploring biological mechanisms of exercise-related cognitive improvement. Twenty-five adults (>60 years old) participated in a 6-month controlled trial and were randomized into LIM or AE intermittent training. Cognition was assessed using a neuropsychological test battery including the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), California Verbal Learning Test, 2nd Edition (CVLT-II), and Delis-Kaplan Executive Function System (D-KEFS). Neuroimaging measures were collected using a 7 T human MRI scanner. Serologic neurotrophic and inflammatory factors were analyzed using Luminex multiplex assays [brain derived neurotrophic factor (BDNF); vascular endothelial growth factor (VEGF)]; interleukin-6 (IL-6), C-reactive protein (CRP), plasminogen activator inhibitor (PAI-1). LIM and AE intermittent training had dissociable effects on cognition, with LIM resulting in improved learning and memory and AE resulting in improved executive functioning. Intervention groups differed on change in cognitive performance on CVLT-II learning and D-KEFS trail making test. Increase in right dorsolateral prefrontal cortex (DLPFC) surface area was linked to executive improvement (i.e., phonemic fluency) regardless of intervention group. A decline in circulating PAI-1 was linked to learning and memory improvement in response to LIM over 6 months. Moderate-intensity AE and LIM intermittent training likely have distinct cognitive benefits, though low-intensity activity is often included as a control group in exercise trials in aging.

Resistance exercise augments circulating extracellular vesicle (EV) and metabolite signalling in manners that assist musculoskeletal and systemic adaptations. Women are often underrepresented in exercise research and recent attention has focused on whether hormonal fluctuations during the menstrual cycle and use of hormonal contraception (HC) impact exercise performance and adaptation. We investigated if menstrual phase (follicular and luteal) or HC usage (oral contraceptive pill and hormonal intrauterine device) impact the EV and metabolite response to exercise. Overall, we observed an exercise‐induced response across all four groups for EV microRNAs and circulating metabolites. Women in the follicular phase had baseline differences in the most abundant miRNAs and exercise‐relevant miRNAs and had the greatest miRNA response to exercise compared to other groups. Relevant metabolites were observed in EVs, but the overall response to exercise was minimally influenced by group among annotated metabolites. Multi‐omic analysis showed potential presence of molecular signatures based on circulating hormone concentrations, but trends were not differentiated enough to suggest clear phenotypic differences. Overall, our data highlights unique miRNA profiles at baseline in follicular phase women but does not support the notion that circulating EV and metabolite responses to exercise are heavily influenced by menstrual cycle phase or HC use. Trial Registration: ClinicalTrials.gov identifier: NCT06972862

Extracellular vesicles (EVs) transport biological content between cells to mediate physiological processes. The association between EVs and resilience, the ability to cope with stress, is unknown. Using unbiased machine learning approaches, we aimed to identify a biological profile of resilience. Twenty servicemen (27.8 ± 5.9 years) completed the Connor Davidson Resilience (CD‐RISC) questionnaire and were exposed to daily physical and cognitive exertion with 48‐hr sleep and caloric restriction. Blood samples from baseline and the second day of stress were analyzed for neuroendocrine biomarkers impacted by military stress. EVs were isolated from plasma and stained with antibodies associated with exosomes (CD63), microvesicles (VAMP3), and apoptotic bodies (THSD1). Individuals were separated into high (n = 10, CD‐RISC > 90) and low (n = 10, CD‐RISC < 79) resilience. EV features were stratified by size, then down‐selected using regression trees and compared between groups. Diagnostic accuracy was assessed using receiver operating characteristic curves. Compared to low resilience, high resilience demonstrated a greater increase in variability of THSD1 local bright spot intensities among large‐sized EVs in response to stress (p = 0.002, Hedges’ g = 1.59). Among medium‐sized EVs, high resilience exhibited a greater decrease in side scatter intensity (p = 0.014, Hedges’ g = 1.17). Both features demonstrated high to moderate diagnostic accuracy for high resilience (AUC = 0.90 and 0.79). In contrast, neuroendocrine biomarker concentrations were similar between groups. The increase in variability among THSD1 + EVs in high, but not low, resilient individuals following stress may suggest high resilience is accompanied by stress‐triggered apoptotic adaptations to the environment that are not detected in neuroendocrine biomarkers. Individuals with high self‐report resilience demonstrated extracellular vesicle adaptations during a multifactorial stress environment that were not observed in low‐resilient individuals. Extracellular vesicles may be more sensitive than circulating neuroendocrine biomarkers, as no differences were observed between groups at the hormone/peptide level.

We have previously demonstrated that circulating extracellular vesicles (EVs) are essential to the beneficial effect of young serum on the skeletal muscle regenerative cascade. Here, we show that infusions of young serum significantly improve age-associated memory deficits, and that these effects are abolished after serum depletion of EVs. RNA-seq analysis of the choroid plexus demonstrates EV-mediated effects on genes involved in barrier function and trans-barrier transport. Comparing the differentially expressed genes to recently published chronological aging clock genes reveals a reversal of transcriptomic aging in the choroid plexus. Following young serum treatment, the hippocampal transcriptome demonstrates significant upregulation of the anti-aging gene Klotho, along with an abrogated effect after EV depletion. Transcriptomic profiling of Klotho knockout and heterozygous mice shows the downregulation of genes associated with transport, exocytosis, and lipid transport, while upregulated genes are associated with activated microglia. The results of our study indicate the significance of EVs as vehicles to deliver signals from the periphery to the brain and the importance of Klotho in maintaining brain homeostasis.

Mobility decline with aging is a major health concern, associated with a higher risk for disability. Despite the prevalence of gait slowing in elderly adults, this issue has not been adequately addressed. The central nervous and skeletal muscle systems are key regulators of gait speed. However, direct molecular communication along the brain‐muscle axis and their interactions in mobility resilience remain poorly studied. Extracellular vesicles (EVs) have emerged as a key player in long‐distance inter‐cellular communication. Nevertheless, the potential of EVs as biological predictors of mobility resilience in older adults has not been studied. We used serum from 23 participants with gait speed > 1.0 m/s (resilient) and 22 participants with gait < 1.0 m/s (non‐resilient) from the Health, Aging and Body Composition (Health ABC) study. Total circulating serum EVs were isolated and small noncoding RNAs characterized using un‐biased sequencing. Given the central role of mitochondria in muscle energy metabolism and link to age‐related physical decline, next, muscle‐derived EVs (MDE) were isolated and characterized for mitochondrial markers (TOM20, mtCox2, PDH, and VDAC) by flow cytometry, 13 miRNAs related to mitochondrial function by RT‐PCR, and PPAR‐γ by ELISA. The results showed differential enrichment of various miRNAs, circRNAs, and mitochondrial proteins in total EVs and/or MDE between mobility resilient and non‐resilient groups, highlighting their potential as non‐invasive biomarkers for mobility outcomes. Overall, these findings suggest a role for serum EVs in mediating molecular communication related to functional aging phenotypes and underscore the potential of EV biomarkers in modulating mobility and promoting healthy aging. We show unique signatures of small noncoding RNA cargos and mitochondrial proteins in serum EVs and muscle‐derived EVs associated with age‐related mobility resilience. These findings suggest a role for serum EVs in mediating molecular communication related to functional aging phenotypes and underscore the potential of EV biomarkers.