Longevity Papers

Aging results in a loss of metabolic flexibility during fasting, characterized by the inability to acutely switch between metabolic substrates and reduced lipid mobilization. However, the drivers of these effects intracellularly remain unclear. Here, in Caenorhabditis elegans, we show that loss of coordinated inter-organelle dynamics causally initiates metabolic inflexibility with age. In young animals, peroxisomes emerge as the priming orchestrators of the fasting response, simultaneously governing lipid droplets (LDs) utilization and mitochondrial bioenergetics. With age, peroxisomal priming is lost, leading to mitochondrial fragmentation and impaired dynamic nutrient responses during fasting. Notably, dietary restriction (DR) exerts a rejuvenating effect on peroxisomal function, thereby preserving mitochondrial integrity and promoting longevity. Our study uncovers the expansive network of organelles enabling lipid mobilization during youth, providing critical context to the poorly understood role of peroxisomes in actively maintaining organelle homeodynamics and metabolic flexibility throughout the aging process.

Meibomian glands secrete lipid-rich meibum, which prevents tear evaporation. Aging-related Meibomian gland shrinkage may result in part from stem cell exhaustion and is associated with evaporative dry eye disease, a common condition lacking effective treatment. The identities and niche of Meibomian gland stem cells and the signals controlling their activity are poorly defined. Using snRNA-seq, in vivo lineage tracing, ex vivo live imaging, and genetic studies in mice, we identify markers for stem cell populations that maintain distinct regions of the gland and uncover Hedgehog (Hh) signaling as a key regulator of stem cell proliferation. Consistent with this, we show that human Meibomian gland carcinoma exhibits increased Hh signaling. Aged glands display decreased Hh and EGF signaling, deficient innervation, and loss of collagen I in niche fibroblasts, indicating that alterations in both glandular epithelial cells and their surrounding microenvironment contribute to age-related degeneration. These findings suggest new approaches to treat aging-associated Meibomian gland loss.

Visual function deteriorates throughout the natural course of aging. Age-related structural and functional adaptations are observed in the retina, the light-sensitive neuronal tissue of the eye where visual perception begins. Molecular mechanisms underlying retinal aging are still poorly understood, highlighting the need to identify biomarkers for better prognosis and alleviation of aging-associated vision impairment. Here, we investigate dynamics of transcriptional dysregulation in the retina and identify affected pathways within distinct retinal cell types. Using an optimized protocol for single-cell RNA sequencing of mouse retinas at 3, 12, 18, and 24 months, we detect a progressive increase in the number of differentially expressed genes across all retinal cell types. The extent and direction of expression changes varies, with photoreceptor, bipolar, and Müller cells showing the maximum number of differentially expressed genes at all age groups. Furthermore, our analyses uncover transcriptionally distinct, heterogeneous subpopulations of rod photoreceptors and bipolar cells, distributed across distinct areas of the retina. Our findings provide a plausible molecular explanation for enhanced susceptibility of rod cells to aging and correlate with the observed loss of scotopic sensitivity in elderly individuals.

Telomere length (TL) has been linked to mortality risk across various populations. However, its predictive value for mortality risk specifically in hypertensive adults remains unclear.

Falls are a significant cause of human disability and death. Risk factors include normal aging, neurodegenerative disease, and sarcopenia. Drosophila melanogaster is a powerful model for study of normal aging and for modeling human neurodegenerative disease. Aging-associated defects in Drosophila climbing ability have been observed to be associated with falls, and immobility due to a fall is implicated as one cause of death in old flies. An automated method for quantifying Drosophila falls might facilitate the study of causative factors and possible interventions. Here, machine learning methods were developed to identify Drosophila falls in video recordings of 2D movement trajectories. The study employed existing video of aged flies as they approached death, and young flies subjected to lethal dehydration/starvation stress. Approximately 9,000 frames of video were manually annotated using open-source tools and used as the training set for You Only Look Once (YOLOv4) software. The software was tested on specific hours within a 22 hour video that was originally manually-annotated for number of falls per hour and corresponding timestamps. The model predictions were evaluated against the manually-annotated ground truth, revealing a strong correlation between the predicted and actual falls. The frequency of falls per hour increased dramatically 2-4 hours prior to death caused by dehydration/starvation stress, whereas extended periods of increased falls were observed in aged flies prior to death. This automated method effectively quantifies falls in video data without observer bias, providing a robust tool for future studies aimed at understanding causative factors and testing potential interventions.

The study of biomarkers in biofluids and tissues expanded our understanding of the biological processes that drive physiological and functional manifestations of aging. However, most of these studies were limited to examining one biological compartment, an approach that fails to recognize that aging pervasively affects the whole body. The simultaneous modeling of hundreds of metabolites and proteins across multiple compartments may provide a more detailed picture of healthy aging and point to differences between chronological and biological aging. Herein, we report proteomic analyses of plasma and urine collected in healthy men and women, age 22-92 years. Using these data, we developed a series of metabolomic and proteomic predictors of chronological age for plasma, urine, and skeletal muscle. We then defined a biological aging score, which measures the departure between an individual's predicted age and the expected predicted age for that individual based on the full cohort. We show that these predictors are significantly and independently related to clinical phenotypes important for aging, such as inflammation, iron deficiency anemia, muscle mass, and renal and hepatic functions. Despite a different set of selected biomarkers in each compartment, the different scores reflect a similar degree of deviation from healthy aging in single individuals, thus allowing identification of subjects with significant accelerated or decelerated biological aging.

Gut microbes play a crucial role in modulating host lifespan. However, the microbial factors that influence host longevity and their mechanisms of action remain poorly understood. Using the expression of Caenorhabditis elegans FAT-7, a stearoyl-CoA 9-desaturase, as a proxy for lifespan modulation, we conduct a genome-wide bacterial mutant screen and identify 26 Escherichia coli mutants that enhance host lifespan. Transcriptomic and biochemical analyses reveal that these mutant diets induce oxidative stress and activate the mitochondrial unfolded protein response (UPRmt). Lifespan extension requires the oxidative stress response regulators SKN-1, SEK-1, and HLH-30. Mechanistically, these effects are linked to reduced iron availability, as iron supplementation restores FAT-7 expression, suppresses UPRmt activation, and abolishes lifespan extension. Iron chelation mimics the pro-longevity effects of the mutant diets, highlighting dietary iron as a key modulator of aging. Our findings reveal a bacterial-host metabolic axis that links iron homeostasis, oxidative stress, and longevity in C. elegans.

Redox imbalance induced by the accumulation of reactive oxygen species (ROS) accelerates age-related processes, often accompanied by a decrease in circadian rhythm amplitude. However, the underlying mechanisms by which ROS modulate circadian rhythms remain poorly understood. In this study, we found that ROS disrupt circadian rhythms in both zebrafish, as indicated by changes in diurnal behavior and clock gene expression, and in a human cell model. Using weighted gene co-expression network analysis (WGCNA) and machine learning approaches (RF, LASSO, SVM), EZH2 was identified as a key gene involved in regulating circadian rhythms under oxidative stress conditions. To further investigate the role of EZH2, we employed ezh2

Musculoskeletal health is strongly influenced by regulatory interactions of bone and muscle. Recent discoveries have identified a number of key mechanisms through which soluble factors released during exercise by bone exert positive effects on muscle and by muscle on bone. Although exercise can delay the negative effects of aging, these beneficial effects are diminished with aging. The limited response of aged muscle and bone tissue to exercise are accompanied by a failure in bone and muscle communication. Here, we propose that exercise induced beneficial factors must battle changes in circulating endocrine and inflammatory factors that occur with aging. Furthermore, sedentary behavior results in the release of negative factors impacting the ability of bone and muscle to respond to physical activity especially with aging. In this review we report on exercise responsive factors and evidence of modification occurring with aging.

Skeletal muscle atrophy is commonly present in various pathological states, posing a huge burden on society and patients. Increased protein hydrolysis, decreased protein synthesis, inflammatory response, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) are all important molecular mechanisms involved in the occurrence and development of skeletal muscle atrophy. The potential mechanisms of ERS and UPR in skeletal muscle atrophy are extremely complex and have not yet been fully elucidated. This article elucidates the molecular mechanisms of ERS and UPR, and discusses their effects on different types of muscle atrophy (muscle atrophy caused by disuse, cachexia, chronic kidney disease (CKD), diabetes mellitus (DM), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy (SBMA), aging, sarcopenia, obesity, and starvation), and explores the preventive and therapeutic strategies targeting ERS and UPR in skeletal muscle atrophy, including inhibitor therapy and drug therapy. This review aims to emphasize the importance of endoplasmic reticulum (ER) in maintaining skeletal muscle homeostasis, which helps us further understand the molecular mechanisms of skeletal muscle atrophy and provides new ideas and insights for the development of effective therapeutic drugs and preventive measures for skeletal muscle atrophy.

Age-related macular degeneration (AMD), characterized by pathologic choroidal neovascularization (CNV), is a leading cause of vision loss in the elderly. Vascular endothelial growth factor A (VEGFa) antagonists can prevent acute vision loss, but high treatment burden and loss of efficacy with chronic therapy highlight the need to explore alternative mechanisms. Recently, microRNA-34a (miR-34a) has emerged as a key regulator in aging and age-related diseases, but its role in neovascular AMD is unclear. In an injury-induced murine CNV model, we discovered miR-34a promoted pathological angiogenesis, without altering expression of Vegfa or its receptor Kdr, the canonical regulators of CNV. Mechanistically, miR-34a directly targets and inhibits the transcription factor KLF2 thereby upregulating the pro-angiogenic factors CXCR4 and CXCL12. Finally, we show miR-34a exacerbates CNV in aged mice and is expressed in CNV lesions excised from wet AMD patients. These findings establish a causal link between the age-related miR-34a and neovascularization in AMD.

Exercise can improve health via skeletal muscle remodeling. Elucidating the underlying mechanism may lead to new therapeutics for aging-related loss of skeletal muscle mass. Here, we show that endurance exercise suppresses expression of YT521-B homology domain family (Ythdf1) in skeletal muscle, which recognizes the N6-methyladenosine (m6A). Ythdf1 deletion phenocopies endurance exercise-induced muscle hypertrophy in mice increases muscle mitochondria content and type I fiber specification. At the molecular level, Ythdf1 recognizes and promotes the translation of m6A-modified Mstn mRNA, which encodes a muscle growth inhibitor, Myostatin. Loss of Ythdf1 leads to hyperactivation of skeletal muscle stem cells (MuSCs), also called satellite cells (SCs), enhancing muscle growth and injury-induced regeneration. Our data reveal Ythdf1 as a key regulator of skeletal muscle homeostasis, provide insights into the mechanism by which endurance exercise promotes skeletal muscle remodeling and highlight potential strategies to prevent aging-related muscle degeneration.

Flavin-containing monooxygenases (FMOs) are a conserved family of xenobiotic enzymes upregulated in multiple longevity interventions, including nematode and mouse models. Previous work supports that

Intracranial cardiac impulse propagation along penetrating arterioles is vital for both nutrient supply via blood circulation and waste clearance via CSF circulation. However, current neuroimaging methods are limited to simultaneously detecting impulse propagation at pial arteries, arterioles, and between them. We hypothesized that this propagation could be detected via paravascular CSF dynamics and that it may change with aging. Using dynamic diffusion-weighted imaging (dynDWI), we detected oscillatory CSF motion synchronized with the finger photoplethysmography in the subarachnoid space (SAS) and cerebral cortex, with a delay revealing an impulse propagation pathway from the SAS to the cortex, averaging 84 milliseconds. Data from 70 subjects aged 18 to 85 years showed a bimodal age-related change in the SAS-Cortex travel time: it initially increases with age, peaks around 45 years, then decreases. Computational biomechanical modeling of the cardiovascular system was performed and replicated this 84-millisecond delay. Sensitivity analysis suggests that age-related variations in travel time are primarily driven by changes in arteriolar compliance. These findings support the use of dynDWI for measuring intracranial impulse propagation and highlight its potential in assessing related vascular and waste clearance functions.

Aging strongly affects the peripheral nervous system (PNS), triggering alterations that vary depending on the innervated tissue. The most frequent alteration in peripheral nerve aging is reduced nerve fiber and glial density which can lead to abnormal nerve functionality. Interestingly, the activation of a destructive phenotype takes place in macrophages across the PNS while a reduced number of neuronal bodies is a unique feature of some enteric ganglia. Single cell/nucleus RNA-sequencing has unveiled a striking complexity of cell populations in the peripheral nerves, and these refined cell type annotations could facilitate a better understanding of PNS aging. While the effects of senescence on individual PNS cell types requires further characterization, the use of senolytics appears to improve general PNS function in models of aging. Here, we review the current understanding of age-related changes of the intracardiac, musculoskeletal, and enteric nervous system sub-sections of the PNS, highlighting their commonalities and differences.

Brain aging leads to reduced cerebral blood flow and cognitive decline, but how normal aging affects neurovascular coupling (NVC) in the awake brain is unclear. Here, we investigated NVC in relation to calcium changes in vascular mural cells (VMCs) in awake adult and aged mice. We show that NVC responses are reduced and prolonged in the aged brain and that this is more pronounced at the capillary level than in arterioles. However, the overall NVC response, measured as the time integral of vasodilation, is the same in the two age groups. In adult, but not in aged mice, the NVC response correlated with Ca2+ signaling in VMCs, while the overall Ca2+ kinetics were slower in aged than in adult mice. In particular, the rate of Ca2+ transport, and the Ca2+ sensitivity of VMCs were reduced in aged mice, explaining the reduced and prolonged vasodilation. Spontaneous locomotion was less frequent and reduced in aged mice as compared to young adult mice, and this was reflected in the 'slow but prolonged' NVC and vascular Ca2+ responses. Taken together, our data characterize the NVC in the aged, awake brain as slow but prolonged, highlighting the remodeling processes associated with aging.

The prevailing focus of lifespan health research has predominantly centered on "healthy aging". This oversight may hinder the understanding of health across the lifespan, as disorders in earlier stages can substantially impact overall health and longevity. Aging, conceptually, begins at gestation. The trajectory of an individual's health is influenced from the earliest stages of life, where adverse conditions can set a foundation for lifelong health challenges. For example, suboptimal conditions during gestation leading to premature birth can predispose individuals to various health issues later in life. Additionally, precocious puberty defined as the onset of sexual maturity before eight years of age or early menopause-occurring before 50 years of age requires medical intervention and is indicative of atypical aging processes. To address these critical gaps in lifespan health research, the expansion of medical lexicons and research categorizations is advocated to include "healthy gestation," "healthy development," and "healthy reproduction" alongside "healthy aging." This broader terminology will enable a more comprehensive investigation of disorders at all life stages. An integrative approach underscores the interconnectedness of all life stages and the continuous nature of aging, advocating for a seamless continuum in health research and interventions from gestation through late adulthood.

Recent findings have shown that dietary restriction (DR) may extend lifespan by improving late life gut health. Given that recent work has shown that micronutrients such as sterols can mediate the effects of macronutrient ratios on longevity, we decided to examine the effects of sterol limitation on gut health. We found that mothers fed low sterol diets both suffer from increased incidence of intestinal permeability and reduced lifespans. Moreover, epithelial cells in the anterior region of the guts of flies fed low sterol diets showed signs of dysfunction prematurely when compared to flies fed adequate sterols. These findings indicate that the relationship between gut dysfunction and death in D. melanogaster females is conditional on dietary sterol limitation and may point to different paths of physiological decline with ageing that depend on the precise nutritional composition of the diet.

Understanding how diverse cell types come together to form a functioning brain relies on the ability to specifically target these cells. This is often done using genetic tools such as the GAL4/UAS system in Drosophila melanogaster. Surprisingly, despite its extensive usage during studies of the aging brain, detailed spatiotemporal characterization of GAL4 driver lines in adult flies has been lacking. Here, we show that 3 commonly used neuronal drivers (elav[C155]-GAL4, nSyb[R57C10]-GAL4, and ChAT-GAL4) and the commonly used glial driver repo-GAL4 all show rapid and pronounced decreases in activity over the first 1.5 weeks of adult life, with activity becoming undetectable in some regions after 30 days (at 18°C). In addition to an overall decrease in GAL4 activity over time, we found notable differences in spatial patterns, mostly occurring soon after eclosion. Although all lines showed these changes, the nSyb-GAL4 line exhibited the most consistent and stable expression patterns over aging. Our findings suggest that gene transcription of key loci decreases in the aged brain, a finding broadly similar to previous work in mammalian brains. Our results also raise questions over past work on long-term expression of disease models in the brain and stress the need to find better genetic tools for ageing studies.

Lead and cadmium are among the most prevalent environmental toxicants and are highly detrimental to human health. While prior studies link heavy metal exposure to reduced telomere length and increased DNA methylation age, their relationship with epigenetic age acceleration (EAA) remains understudied. This study investigates whether exposure to lead and cadmium accelerates biological aging.

COVID-19 is an ongoing pandemic caused by the SARS-CoV-2 coronavirus that is one of the most significant challenges to public health over the past few years. Most people are vulnerable to SARS-CoV-2, but older adults are more vulnerable. Aging is one of the major risk factors for the detrimental consequences of COVID-19, likely due to chronic inflammation and immunosenescence, both of which are the characteristics of old age. Immunosenescence refers to the weakening of the immune system with age while inflammaging describes the low-grade chronic inflammation seen in older individuals. One key aspect of human aging is immune deficiency. During aging, our body's defense system weakens, resulting in decreased responses to infection by novel pathogens and a reduced ability to become immunized. The presence of chronic inflammation and viral infection in old age may cause several adverse unpredictable outcomes increasing the propensity and severity of the disease and requires to be considered, enabling people to better prepare for the potential consequences of this ongoing pandemic. This requires consideration so that individuals can better be prepared to address the potential consequences of this ongoing pandemic. In this review, we discuss the clinical characteristics of elderly COVID-19 patients and survey the associated molecular pathways that are pivotal for the interactions of the coronavirus and host cellular responses, including immunosenescence, inflammation, telomere attrition, impaired autophagy, mitochondrial dysfunction and alterations in major aging signaling pathways, which are crucial for the discovery of new therapeutic and preventive methods in the ongoing pandemic.

Cellular senescence is a stable cell cycle arrest that occurs in response to various stress stimuli and affects multiple cell types, including endothelial cells (ECs). Senescent cells accumulate with age, and their removal has been linked to reduced age-related diseases. However, some senescent cells are important for tissue homeostasis. Therefore, understanding the diversity of senescent cells in a cell-type-specific manner and their underlying molecular mechanisms is essential. Senescence impairs key ECs functions which are necessary for vascular homeostasis, leading to endothelial dysfunction and age-related vascular diseases. In order to gain insights into these mechanisms, we analyzed publicly available RNA-seq datasets to identify gene expression changes in senescent ECs induced by doxorubicin, irradiation, and replication exhaustion. While only a few genes were consistently differentially expressed across all conditions, some gene ontologies (GO) were shared. Among these, our analysis focused on validating the expression of genes associated with the matrisome, which includes genes encoding for extracellular matrix (ECM) structural components and ECM-associated proteins, in a doxorubicin-induced senescence model. Our results show that the matrisome transcriptome undergoes significant remodeling in senescent endothelial cells, regardless of the specific inducers of senescence, highlighting the importance of understanding how ECM alterations affect senescence.

The aging brain experiences a significant decline in proteasome function. The proteasome is critical for many key neuronal functions including neuronal plasticity, and memory formation/retention. Treatment with proteasome inhibitors impairs these processes. Our study reveals a marked reduction in 20S and 26S proteasome activities in aged mice brains, including in the hippocampus, this is driven by reduced functionality of aged proteasome. The decline in proteasome activity is matched by a decline in 20S proteasome assembly. In contrast, 26S proteasome assembly was found to increase with age, though 26S proteasome activity was still found to decline. Our data suggests that age-related declines in proteasome activity is driven predominantly by reduced functionality of proteasome rather than altered composition. By overexpressing the proteasome subunit PSMB5 in the neurons of mice to increase the proteasome content and thus enhance its functionality, we slowed age-related declines in spatial learning and memory. We then showed acute treatment with a proteasome activator to rescue spatial learning and memory deficits in aged mice. These findings highlight the potential of proteasome augmentation as a therapeutic strategy to mitigate age-related cognitive declines.

Senescent mandibular bone repair poses a formidable challenge without a completely satisfactory strategy. Endogenous cell recruitment and osteogenic differentiation are two sequential stages in bone regeneration, and disruptions in these two processes present significant obstacles to senescent bone repair. To address these issues, engineered extracellular vesicles (EV) with sequential stem cell recruitment and osteogenic functions were developed. This study demonstrated that Apt19s-engineered extracellular vesicles (Apt19s-EV) recognize and recruit bone marrow mesenchymal stem cells derived from old rats (O-BMSCs) specifically and effectively. MiR-376b-5p, identified by RNA sequencing and transfection, was significantly decreased in O-BMSCs, and it was selected to construct miR-376b-5p-engineered extracellular vesicles (376b-EV). 376b-EV could promote osteogenesis and alleviate senescence of O-BMSCs by targeting Camsap1. To combine the advantages of Apt19s and miR-376b-5p, dual engineered extracellular vesicles (Apt-376b-EV) comprising both Apt19s and miR-376b-5p modifications were constructed. To further validate its function, Gelatin methacryloyl (GelMA) hydrogel was used as a carrier to construct the Apt-376b-EV@GelMA delivery system. The in vitro results have demonstrated that Apt-376b-EV@GelMA could recruit O-BMSCs, alleviate senescence and promote osteogenic differentiation sequentially. Notably, the in vivo study also showed that Apt-376b-EV@GelMA could sequentially recruit endogenous stem cells and enhance new bone formation in senescent bone fracture and critical-sized defect models. In summary, the dual engineered extracellular vesicles, Apt-376b-EV, offer an appealing solution for recruiting endogenous stem cells and promoting bone repair sequentially in the senescent microenvironment, which may broaden the clinical applications of engineered EV and provide valuable strategies for treating senescent bone-related diseases in the future clinical work.

Age-associated thymic involution leads to a significant decline in thymic T cell output, a major contributor to immunosenescence in the elderly. Accurately measuring thymic output is therefore critical for understanding the mechanisms behind immune aging. Furthermore, robust quantification of thymic output is essential in various other clinical and research settings, including the diagnosis of immunodeficiencies and the monitoring of T cell reconstitution following therapeutic interventions like hematopoietic stem cell transplantation. Current methodologies for measuring thymic output include T cell receptor excision circle (TREC) quantification via quantitative polymerase chain reaction and the enumeration of recent thymic emigrants (RTEs) using flow cytometry. However, TREC-based assays are inherently insensitive to subtle changes in thymic output, limiting their applicability beyond neonatal immunodeficiency screening. Similarly, RTE enumeration presents challenges; while surface markers exist for CD4⁺ RTEs, validated markers for CD8⁺ cytotoxic T lymphocytes are lacking. This represents a significant knowledge gap, particularly as aging has been shown to disproportionally affect the CD8 T cell pool. Moreover, while flow cytometry effectively measures mature naïve T cells, these cells do not accurately represent real-time thymic output, as they can persist in peripheral circulation for extended periods. These limitations highlight the pressing need for more accurate and sensitive methods to assess thymic output. Improved measurement techniques would not only enhance our understanding of thymic involution in the context of aging but also enable large-scale investigations into thymic function and the mechanisms driving its decline in both health and disease. In this review, we examine current methodologies for measuring thymic output in humans, critically evaluate their limitations, and discuss emerging approaches to address these gaps in the field.

Adults older than 45 years old are at higher risk of developing venous blood clotting known as venous thrombosis/thromboembolism than a cohort <45 years old. Complement activation, which can be mediated by oxidative stress, plays a central role in venous thrombosis. Yet, whether RBCs contribute to complement activation triggering thrombosis in aging and in patients with venous thrombosis/thromboembolism remains an open question. RBCs from healthy Mid-life stage (55-68 years old) adults and patients with venous thrombosis/thromboembolism showed higher deposition of the complement C3 and the anaphylatoxin C3a, and NADPH oxidase (Nox)1 expression than a younger cohort (21-30 years old). Increased C3/C3a deposition on RBCs from mid-life stage adults and patients with venous thrombosis/thromboembolism triggered prothrombin activation via Nox1-dependent reactive oxygen species (ROS) generation, and G protein-coupled receptor kinase 2 (GRK2) activation. Interaction of C3/C3a positive RBCs from mid-life stage adults with endothelial cells led to increased endothelial ROS production. TGF-β1-stimulated GRK2 and Nox1 activation in RBCs from the younger and older adults exacerbated RBC C3/C3a deposition and C3/C3a-mediated prothrombotic activation, which appears to result from ROS-mediated increased RBC phosphatidylserine exposure. Using human RBCs, and Rpl13a snoRNA knockout aged mice, we show that Rpl13a snoRNAs, the master regulators of ROS levels and oxidative stress response, regulate human and murine RBC C3a deposition and prothrombic activation in aging by modulating Nox1 mRNA expression. In vivo Rpl13a snoRNA knockout in aged mice decreased thrombi size by blunting RBC C3a deposition, and RBCs-triggering prothrombin activation. These findings point out to a novel role of RBC Rpl13a snoRNAs in dysregulating RBC ROS-induced C3a deposition promoting venous thrombosis in aging.

Maintenance of organismal function requires tightly regulated biomolecular communication. However, with aging, communication deteriorates, thereby disrupting effective information flow. Using information theory applied to skeletal muscle single cell RNA-seq data from young, middle-aged, and aged animals, we quantified the loss of communication efficiency over time. We considered communication channels between transcription factors (TF; input message) and corresponding target genes (TG; output message). Mutual information (MI), defined as the information effectively transmitted between TFs and TGs, declined with age. This decline was attributed to escalating biological noise and loss of precision with which TFs regulate TGs (i.e., channel capacity). When we ranked TF:TG pairs by MI, pairs associated with fatty acid oxidation displayed the greatest loss of communication with aging, while the system preserved communication between pairs related to RNA synthesis. These data suggest ineffective communication with aging against a backdrop of resource reallocation to support essential cellular functions.

Aging alters signaling that involves brain-derived neurotrophic factor (BDNF) in the hippocampus. An adequate level of BDNF is essential for maintaining cognitive function in older adults. Previously, we showed that repeated intraperitoneal administration of the chemokine ligand CX3CL1 modulates peritoneal immune cells and the vagal nerve to increase hippocampal BDNF, consequently improving cognitive decline in aged mice. Here, we examined the contribution of endogenous CX3CL1 in the peritoneal cavity to the age-associated regulation of hippocampal BDNF levels. Hippocampal BDNF protein levels were comparable between 5-month-old and 10-month-old mice but were reduced in 18-month-old. CX3CL1 expression in the visceral adipose tissue, which is prominent in the peritoneal cavity, was also lower in 18-month-old mice than in 10-month-old mice. Visceral adipose tissue-specific knockdown of CX3CL1 reduced hippocampal BDNF levels in 10-month-old mice. Reciprocally, a single intraperitoneal injection of CX3CL1 recovered hippocampal BDNF levels in 18-month-old mice. Moreover, the naturally occurring glucocorticoids, corticosterone and hydrocortisone, increased CX3CL1 expression in a concentration-dependent manner. In the visceral adipose tissue, both protein level and enzymatic activity of the glucocorticoid activating enzyme 11β hydroxysteroid dehydrogenase type 1 (11β-HSD1) were lower in 18-month-old mice than in 10-month-old. Tissue-specific knockdown of 11β-HSD1 in visceral adipose tissue decreased both adipose CX3CL1 expression and hippocampal BDNF levels in 10-month-old mice. Our results demonstrate that adipose CX3CL1 is involved in maintaining hippocampal BDNF levels. This inter-tissue crosstalk is impaired in aged mice due to low 11β-HSD1 expression in visceral adipose tissue, which contributes to the age-associated decline in hippocampal BDNF.

Ageing is an independent factor for cognitive dysfunction. Ageing-associated alterations in the gut microbiota also affect cognition. The present study is designed to investigate changes in the gut microbiota and their participation in ageing-associated cognitive impairment. Both 10-week-old and 18-month-old mice are used. Mouse cognition is examined by novel object recognition and T-maze tests. Mouse feces are collected for sequencing and transplantation. Protein expression in the mouse intestine and hippocampus is studied using immunohistochemistry and immunofluorescence staining. Senescent neurons are induced by hydrogen peroxide

In our aging society, the degeneration of the musculoskeletal system and adjacent tissues is a growing orthopedic concern. As bones age, they become more fragile, increasing the risk of fractures and injuries. Furthermore, tissues like cartilage accumulate damage, leading to widespread joint issues. Compounding this, the regenerative capacity of these tissues declines with age, exacerbating the consequences of fractures and cartilage deterioration. With rising demand for fracture and cartilage repair, bone-derived stem cells have attracted significant research interest. However, the therapeutic use of stem cells has produced inconsistent results, largely due to ongoing debates and uncertainties regarding the precise identity of the stem cells responsible for musculoskeletal growth, maintenance and repair. This review focuses on the potential to leverage endogenous skeletal stem cells (SSCs)-a well-defined population of stem cells with specific markers, reliable isolation techniques, and functional properties-in bone repair and cartilage regeneration. Understanding SSC behavior in response to injury, including their activation to a functional state, could provide insights into improving treatment outcomes. Techniques like microfracture surgery, which aim to stimulate SSC activity for cartilage repair, are of particular interest. Here, we explore the latest advances in how such interventions may modulate SSC function to enhance bone healing and cartilage regeneration.

Deep learning (DL) and explainable artificial intelligence (XAI) have emerged as powerful machine-learning tools to identify complex predictive data patterns in a spatial or temporal domain. Here, we consider the application of DL and XAI to large omic datasets, in order to study biological aging at the molecular level. We develop an advanced multi-view graph-level representation learning (MGRL) framework that integrates prior biological network information, to build molecular aging clocks at cell-type resolution, which we subsequently interpret using XAI. We apply this framework to one of the largest single-cell transcriptomic datasets encompassing over a million immune cells from 981 donors, revealing a ribosomal gene subnetwork, whose expression correlates with age independently of cell-type. Application of the same DL-XAI framework to DNA methylation data of sorted monocytes reveals an epigenetically deregulated inflammatory response pathway whose activity increases with age. We show that the ribosomal module and inflammatory pathways would not have been discovered had we used more standard machine-learning methods. In summary, the computational deep learning framework presented here illustrates how deep learning when combined with explainable AI tools, can reveal novel biological insights into the complex process of aging.

Dementia, characterized by loss of cognitive abilities in the elderly, poses a significant global health challenge. This study explores the role of astrocytes, one of most representative glial cells in the brain, in mitigating cognitive decline. Specifically, we investigated the impact of Hevin (also known as SPARC-like1/SPARCL-1), a secreted glycoprotein, on cognitive decline in both normal and pathological brain aging. By using adeno-associated viruses, we overexpressed Hevin in hippocampal astrocytes of middle-aged APP/PSEN mice, an established Alzheimer's disease (AD) model. Results demonstrated that Hevin overexpression attenuates cognitive decline, as evidenced by cognitive tests, increased pre- and postsynaptic markers colocalization, and altered expression of synaptic mediators, as revealed by proteomic profiling. Importantly, Hevin overexpression did not influence the deposition of Aβ plaques in the hippocampus, a hallmark of AD pathology. Furthermore, the study extended its findings to middle-aged wild-type animals, revealing improved cognitive performance following astrocytic Hevin overexpression. In conclusion, our results propose astrocytic Hevin as a potential therapeutic target for age-associated cognitive decline.

Cognitive impairment is a typical hallmark of aging in mice and humans. Here, we reported that downregulation of STAT1 improved learning and memory impairments in aging mice by enhancing the expression of synaptic protein and inhibiting the expression of inflammatory factors. Proteomic analysis revealed 139 differentially expressed proteins (DEPs) in the hippocampus of downregulated-STAT1 aging mice, compared with aging control mice. Functional classification of DEPs indicated that these mainly involved in inflammation, autophagy, synapse, mitochondria and apoptosis. The ClueGo analysis uncovered that the Wiki pathway of these DEPs were involved in proteasome degradation, IL-6 signaling pathway, signaling of hepatocyte growth factor receptor and so on. Taken together, downregulation of STAT1 may delay aging with multiple mechanisms.

Recent advancements in metabolism research have demonstrated its critical roles in a lot of critical biological processes, including stemness maintenance, cell differentiation, proliferation, and function. Hematopoiesis is the fundamental cell differentiation process with the production of millions of red blood cells per second in carrying oxygen and white blood cells in fighting infection and cancers. The differentiation processes of hematopoietic stem and progenitor cells (HSPCs) are accompanied by significant metabolic reprogramming. In hematological malignancy, metabolic reprogramming is also essential to the malignant hematopoiesis processes. The metabolic rewiring is driven by distinct molecular mechanisms that meet the specific demands of different target cells. Leukemic cells, for instance, adopt unique metabolic profiles to support their heightened energy needs for survival and proliferation. Moreover, aging HSPCs exhibit altered energy consumption compared to their younger counterparts, often triggering protective mechanisms at the cellular level. In this review, we provide a comprehensive analysis of the metabolic processes involved in hematopoiesis and the metabolic rewiring that occurs under adverse conditions. In addition, we highlight current research directions and discuss the potential of targeting metabolic pathways for the management of hematological malignancies and aging.

Aging is a natural process that affects the majority of organs within the organism. The liver, however, plays a pivotal role in maintaining the organism's homeostasis due to its robust regenerative and metabolic capabilities. Nevertheless, the liver also undergoes the effects of aging, which can result in a range of metabolic disorders. The function of extracellular vesicles and the signals they convey represent a significant area of interest within the field of ageing research. However, research on liver ageing from the perspective of EVs remains relatively limited.

Perineuronal nets (PNNs) form at the end of the critical period of plasticity in the mouse primary somatosensory cortex. PNNs are said to have functions that control neuroplasticity and provide neuroprotection. However, it is not clear which molecules in PNNs have these functions. We have previously reported that Cat-315-positive molecules were not expressed in the PNNs of the senescence-accelerated model (SAM)P10 strain model mice at 12 months of age. To confirm whether the loss of Cat-315-positive molecules occurred early in life in SAMP10 mice, we examined Cat-315-positive PNNs in the primary somatosensory cortex during postnatal development. This research helps to elucidate the function of PNNs and the mechanism of cognitive decline associated with ageing. To confirm whether Cat-315-positive PNNs changed in an age-dependent manner in SAMP10 mice, we examined the primary somatosensory cortex at 21, 28, and 56 days after birth. We compared these results with those of senescence-accelerated mouse-resistant (SAMR) mice. In SAMP10 mice, Cat-315-positive PNNs were expressed in the primary somatosensory cortex early after birth, but their expression was significantly lower than that in SAMR1 mice. Many other molecules that calibrated the PNN were unchanged between SAMP10 and SAMR1 mice. This study revealed that the expression of the Cat-315 epitope was decreased in the primary somatosensory cortex of SAMP10 mice during postnatal development. SAMP10 mice have had histological abnormalities in their brains since early life. Furthermore, using SAMP10 will be useful in elucidating the mechanism of age-related abnormalities in brain function as well as in elucidating the function and structure of PNNs.

Heart disease is the leading cause of death in the elderly population and the heart is a highly energy-consuming tissue. Aging-related heart failure is often driven by energy depletion in cardiomyocytes (CM), which rely on their abundant, cristae-dense mitochondria for ATP production. ATP synthase, localized along the cristae rims, plays a critical role in energy conversion, but the connection between its organization and function remains unclear. Here, we explored the spatiotemporal organization of ATP synthase in senescent CM at the level of individual complexes. Using single-molecule localization and tracking microscopy, we observed reduced enzyme mobility within the cristae, coinciding with decreased ATP synthase activity, despite a stable resting mitochondrial membrane potential. This reduction in activity was independent of changes in ATP synthase expression or dimerization. Electron tomography revealed an increased prevalence of curved inner membranes and fenestrated cristae in senescent CM, explaining the reduced enzyme mobility. Senescent CM displayed irregular autonomous and paced beating patterns. These abnormalities suggest that impaired cardiac function is directly driven by disrupted energy metabolism, rooted in the suboptimal organization and function of ATP synthase in altered cristae.

Robust 3D tissue culture models to activate aged fibroblasts for cell-based therapies and identify regulators of such activation are still missing. In our previous study, we showed that aged fibroblasts can be activated simply through applying compressive force, without the need for exogenous factors, leading to increased migration. In this study, we develop a pipeline to evaluate the role of specific pharmacological inhibitors for transcription factor inference and cell migration involved in aged fibroblast activation. By integrating RNA-seq data with bioinformatic tools (prize collecting Steiner tree method and iRegulon) we inferred 15 candidates. In addition, we used cell migration and heterochromatin content as readouts for validating these candidates. Furthermore, we identified three potential master regulators of fibroblast activation and rejuvenation: FOXO1, STAT3, and PDK1. These findings offer valuable insights for future drug discovery, disease modeling, and regenerative medicine.

The decline in oocytes quality and developmental potential with female reproductive aging is well recognized, yet the underlying mechanisms remain insufficiently investigated. In this study, through an integrative analysis of transcriptomes and morphologies of individual oocytes from young and aged mice, morphologically defective aged oocytes are identified with distinct transcriptomic features. Further analysis demonstrates that both apoptotic and ferroptotic pathways are activated in the defective aged oocytes, and simultaneously blocking both pathways reverses the defective morphology to the largest extent. The Plat gene, which encodes tissue-type plasminogen activator (tPA), is downregulated with oocyte aging, and Plat knockdown increases oocytes susceptibility to both apoptosis and ferroptosis. Mechanistically, tPA functions as an upstream signaling molecule for Erk1/2 activation by interacting with particular phosphorylation kinases such as Alk. Consequently, Plat loss downregulates Erk1/2 pathway activity in oocytes, leading to degeneration through programmed cell death. Supplementing exogenous tPA in in vitro oocyte maturation cultures reduces defect rate of aged oocytes, thereby improving oocyte quality and developmental potential. Collectively, Plat plays a pivotal role in protecting aged mouse oocytes from programmed cell death, and tPA supplementation may serve as a potential clinical strategy to enhance oocyte quality in females of advanced maternal age.

Skin aging represents a multifactorial process influenced by both intrinsic and extrinsic factors, collectively known as the skin exposome. Cellular senescence, characterized by stable cell cycle arrest and secretion of pro-inflammatory molecules, has been implicated as a key driver of physiological and pathological skin aging. Increasing evidence points towards the role of senescence in a variety of dermatological diseases, where the accumulation of senescent cells in the epidermis and dermis exacerbates disease progression. Emerging therapeutic strategies such as senolytics and senomorphics offer promising avenues to target senescent cells and mitigate their deleterious effects, providing potential treatments for both skin aging and senescence-associated skin diseases. This review explores the molecular mechanisms of cellular senescence and its role in promoting age-related skin changes and pathologies, while compiling the observed effects of senotherapeutics in the skin and discussing the translational relevance.

DNA methylation (DNAm) is a chemical modification of DNA that can be influenced by various factors, including age, environment, and lifestyle. An epigenetic clock is a predictive tool that measures biological age based on DNAm levels. It can provide insights into an individual's biological age, which may differ from their chronological age. This difference, known as the epigenetic age acceleration, may indicate the state of one's health and risk for age-related diseases. Moreover, epigenetic clocks are used in studies of aging to assess the effectiveness of anti-aging interventions and to understand the underlying mechanisms of aging and disease. Various epigenetic clocks have been developed using samples from different populations, tissues, and cell types, typically by training high-dimensional linear regression models with an elastic net penalty. While these models can predict mean biological age with high precision, there is a lack of uncertainty quantification which is important for interpreting the precision of age estimations and for clinical decision-making. To understand the distribution of a biological age clock beyond its mean, we propose a general pipeline for training epigenetic clocks, based on an integration of high-dimensional quantile regression and conformal prediction, to effectively reveal population heterogeneity and construct prediction intervals. Our approach produces adaptive prediction intervals not only achieving nominal coverage but also accounting for the inherent variability across individuals. By using the data collected from 728 blood samples in 11 DNAm datasets from children, we find that our quantile regression-based prediction intervals are narrower than those derived from conventional mean regression-based epigenetic clocks. This observation demonstrates an improved statistical efficiency over the existing pipeline for training epigenetic clocks. In addition, the resulting intervals have a synchronized varying pattern to age acceleration, effectively revealing cellular evolutionary heterogeneity in age patterns in different developmental stages during individual childhoods and adolescent cohort. Our findings suggest that conformalized high-dimensional quantile regression can produce valid prediction intervals and uncover underlying population heterogeneity. Although our methodology focuses on the distribution of aging in children, it is applicable to a broader range of populations to improve understanding of epigenetic age beyond the mean. This inference-based toolbox could provide valuable insights for future applications of epigenetic interventions for age-related diseases.

Inactivation of telomerase (TERT) in adipocyte progenitor cells (APC) expedites telomere attrition, and the onset of diabetes in mice fed high-fat diet (HFD), which promotes APC over-proliferation and replicative senescence. Here, we show that time-restricted feeding or caloric restriction in the postnatal development of mice subsequently subjected to HFD prevents telomere attrition but not glucose intolerance. This metabolic effect of dietary intervention was not observed for mice with TERT KO in endothelial or myeloid cells. To characterize the telomere-independent effects of TERT in the APC lineage, we analyzed mice with TERT knockout in mature adipocytes (AD-TERT-KO), which do not proliferate and avoid telomere attrition. Analysis of adipocytes from AD-TERT-KO mice indicated reliance on glycolysis and decreased mitochondrial oxidative metabolism. We show that AD-TERT-KO mice have reduced cold tolerance and metabolism abnormality indicating a defect in adaptive thermogenesis, characteristic of aging. Conversely, ectopic TERT expression in brown adipocytes-induced mitochondrial oxidation and thermogenic gene expression. We conclude that TERT plays an important non-canonical function in the mitochondria of adipocytes.

Fruits and vegetables contain biologically active phenolic compounds that show mitigating effects against free radical damage and inflammation. The unique properties of phenolic compounds are protection against oxidative stress, and inception and potentiating of inflammation in the body. Aging is manifest with changes in epigenetic modifications and as with living systems undergo entropy. The gradual decline of body functions and in many cases with aging the cellular processes of senescence are contributors to age-related diseases. Herein the focus is on phenolic compounds as a diet approach to delay the negative consequences of aging. The actions of phenolic compounds on the biology of aging and senescence are presented. The phenolic compounds called flavonoids which are found in many fruits are potential antisenescence factors that benefit health by reducing damage to DNA and the senescence-associated phenotypic cell changes in healthy cells during aging. Flavonoids are proposed to delay and palliate aging where senescence is involved. The dietary sources of natural phenolic compounds afford protection in the aging process and include as some examples naringenin, hesperidin, quercetin, kaempferol, luteolin, genistein, epigallocatechin gallate, and resveratrol. Many of these compounds possess antisenescence effects. The purpose of the review is to discuss where food flavonoids interact with the targets of senescence and how these compounds can attenuate aging-related events. The goal is to provide greater insight into dietary flavonoids and how they improve health and lower the consequences of aging. A novel aspect of this review is the application of flavonoids to neuroprotective effects in brain to reduce pain and improve health with aging.

Despite the high prevalence of age-dependent intervertebral disc calcification, there is a glaring lack of treatment options for this debilitating pathology. We investigated the efficacy of long-term oral K

Aging alters brain structure and function, and studying such changes may help understand the neural basis underlying aging and devise interventions to detect deviations from healthy progression. Electroencephalogram (EEG) offers an effective way to study healthy aging owing to its high temporal resolution and affordability. Recent studies have shown that narrow-band stimulus-induced gamma oscillations (20-70 Hz) in EEG, induced with cartesian gratings in a fixation task paradigm, weaken with healthy aging and onset of Alzheimer's Disease (AD) while remaining highly reproducible for a given subject, and thus hold promise as potential biomarkers. However, functional connectivity (FC) sometimes changes in a different way compared to sensor power with aging. This difference could be potentially addressed by studying how underlying gamma sources change with aging, since either a reduction in source power or a shrinkage of the sources (or both) could reduce the power in the sensors but may have different effects on other measures such as FC. We therefore reconstructed EEG gamma sources through a linear inverse method called exact Low-resolution Tomography Analysis (eLORETA) on a large (N=217) cohort of healthy elderly subjects (>50 years). We further characterized gamma distribution in cortical space as an exponential fall-off from a seed voxel with maximal gamma source power to delineate a reduction in magnitude versus shrinkage. We found significant reduction in magnitude but not shrinkage with healthy aging. Overall, our results shed light on changes in EEG gamma source distribution with healthy aging, which could provide clues about underlying neural mechanisms.

Longevity individuals have lower susceptibility to chronic hypoxia, inflammation, oxidative stress, and aging-related diseases. It has long been speculated that "rejuvenation molecules" exist in their blood to promote extended lifespan. We unexpectedly discovered that longevity individuals exhibit erythrocyte oxygen release function similar to young individuals, whereas most elderly show reduced oxygen release capacity. Untargeted erythrocyte metabolomics profiling revealed that longevity individuals are characterized by youth-like metabolic reprogramming and these metabolites effectively differentiate the longevity from the elderly. Quantification analyses led us to identify multiple novel longevity-related metabolites within erythrocytes including adenosine, sphingosine-1-phosphate (S1P), and glutathione (GSH) related amino acids. Mechanistically, we revealed that increased bisphosphoglycerate mutase (BPGM) and reduced MFSD2B protein levels in the erythrocytes of longevity individuals collaboratively work together to induce elevation of intracellular S1P, promote the release of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from membrane to the cytosol, and thereby orchestrate glucose metabolic reprogramming toward Rapoport-Luebering Shunt to induce the 2,3-BPG production and trigger oxygen delivery. Furthermore, increased glutamine and glutamate transporter expression coupled with the enhanced intracellular metabolism underlie the elevated GSH production and the higher anti-oxidative stress capacity in the erythrocytes of longevity individuals. As such, longevity individuals displayed less systemic hypoxia-related metabolites and more antioxidative and anti-inflammatory metabolites in the plasma, thereby healthier clinical outcomes including lower inflammation parameters as well as better glucose-lipid metabolism, and liver and kidney function. Overall, we identified that youthful erythrocyte function and metabolism enable longevity individuals to better counteract peripheral tissue hypoxia, inflammation, and oxidative stress, thus maintaining healthspan.

The impact of mid-late-life exercise on the aging heart remains unclear, particularly the effects of high-intensity interval training (HIIT) and continuous moderate-intensity training (CMIT). This study was the first to examine cardiac function, tissue characteristics, electrical remodeling, mitochondrial morphology and homeostasis in old mice subjected to CMIT or HIIT, compared to untrained controls. Our results showed that 8-week HIIT significantly improved the survival rate of old mice. HIIT presented advantages on cardiac function, deposition of collagen fibers, neovascularization, aging biomarkers and mitochondrial homeostasis. Only CMIT alleviated age-related cardiac hypertrophy. However, CMIT potentially exacerbated adverse cardiac electrical remodeling. Those findings suggested HIIT as a particularly appealing option for clinical application for aging populations.

Cardiotoxicity remains a major limiting factor in the clinical implementation of anthracycline chemotherapy. Though the etiology of doxorubicin-dependent heart damage has yet to be fully elucidated, the ability of doxorubicin to damage DNA and trigger oxidative stress have been heavily implicated in the pathogenesis of chemotherapy-associated cardiomyopathy. Here, we demonstrate that fibronectin type III domain-containing protein 5 (FNDC5), the precursor protein for myokine irisin, is depleted in the hearts of human cancer patients or mice exposed to chemotherapeutics. In cardiomyocytes, restoration of FNDC5 expression was sufficient to mitigate reactive oxygen species (ROS) accumulation and apoptosis following doxorubicin exposure, effects dependent on the irisin encoding domain of FNDC5 as well as signaling via the putative irisin integrin receptor. Intriguingly, we identified two parallel signaling cascades impacted by FNDC5 in cardiomyocytes: the ROS-driven intrinsic mitochondrial apoptosis pathway and the ROS-independent Ataxia Telangiectasia and Rad3-Related Protein (ATR)/Checkpoint Kinase 1 (Chk1) pathway. In fact, FNDC5 forms a co-precipitable complex with Chk1 alluding to possible intracellular actions for this canonically membrane-associated protein. Whereas FNDC5 overexpression in murine heart was cardioprotective, introduction of FNDC5-targeted shRNA into the myocardium was sufficient to trigger Bax up-regulation, ATR/Chk1 activation, oxidative stress, cardiac fibrosis, loss of ventricular function, and compromised animal survival. The detrimental impact of FNDC5 depletion on heart function could be mitigated via treatment with a Chk1 inhibitor identifying Chk1 hyperactivity as a causative factor in cardiac disease. Though our data point to the potential clinical utility of FNDC5/irisin-targeted agents in the treatment of chemotherapy-induced cardiotoxicity, we also found significant down regulation in FNDC5 expression in the hearts of aged mice that attenuated the cardioprotective impacts of FNDC5 overexpression following doxorubicin exposure. Together our data underscore the importance of FNDC5/irisin in maintenance of cardiac health over the lifespan.

Aging is associated with cognitive decline and memory impairment, but the underlying neural mechanisms remain unclear. Phase-amplitude coupling (PAC) between mid-frontal theta (5 Hz) and occipital gamma (>30 Hz) oscillations is a proposed marker for parallel storage of multiple items in working memory. However, research has mainly focused on young individuals and epilepsy patients, with only a few studies on aging populations. Moreover, these studies have relied on univariate PAC methods, which can be flawed by potential spurious or biased PAC estimates due to non-stationarity of EEG signals. Additionally, these methods typically assess PAC at the level of individual electrodes, potentially overlooking the broader functional significance of theta-gamma coupling in coordinating neural activity across distant brain regions. To address these gaps, we employed multivariate PAC (mPAC) through generalized eigendecomposition (GED) analysis, which avoids the pitfalls of non-sinusoidal oscillations. 113 young and 117 older healthy participants engaged in a sequence learning paradigm (6423 sequence repetitions, 55\'944 stimuli), in which they learned a fixed sequence of visual stimuli over repeated observations, allowing us to track the mPAC during the incremental process of learning. Behavioral results revealed that younger participants learned significantly faster than older participants. Neurophysiological data showed that mPAC increased over the course of learning in both age groups and could identify fast and slow learners. However, older participants exhibited lower mPAC compared to younger counterparts, which suggest compromised parallel storage of items in working memory in older age. Finally, stratification analysis revealed that mPAC effects persist across performance groups with similar mid-frontal theta levels, suggesting that theta alone does not account for these effects. These findings shed light on the age-related differences in memory formation processes and may guide interventions to enhance memory performance in older adults and slow learners.

Deterioration in nutritional condition with aging could reduce reproductive success but coincides with declines in residual reproductive potential, thus invoking opposing expectations for late-life reproduction. Yet, the mechanisms regulating energy accrual and allocation to reproduction and survival throughout the lifetime of long-lived, iteroparous animals have remained elusive owing to variation in energetic costs across their extended reproductive cycle (from conception to juvenile independence). Using 10 years of repeated measures of both nutrition (i.e., body fat and food availability) and reproductive allocation across the reproductive cycle of 232 free-ranging, adult, female mule deer, we revealed that nutrition is a critical piece in understanding patterns of reproductive senescence and terminal investment. From conception to weaning, age-related patterns of reproduction were influenced by both body fat and environmental conditions. Reproductive senescence was clear across the entire reproductive cycle, although allocation to offspring was partly mediated by nutrition. Terminal investment, however, was most evident towards the end of the annual reproductive cycle and unveiled only when considering nutritional condition and food availability; during years with poor resource availability, older mothers raised larger juveniles (i.e., 6-months old). Our work evokes nutrition as a lurking variable in end-of-life reproductive tactics for long-lived animals, while demonstrating the necessity of accounting for energy when considering patterns of reproductive senescence and terminal investment in wild animals.

Idiopathic pulmonary fibrosis (IPF) is an age-related interstitial lung disease, characterized by inadequate alveolar regeneration and ectopic bronchiolization. While some molecular pathways regulating lung progenitor cells have been described, the role of metabolic pathways in alveolar regeneration is poorly understood. We report that expression of fatty acid oxidation (FAO) genes is significantly diminished in alveolar epithelial cells of IPF lungs by single-cell RNA sequencing and tissue staining. Genetic and pharmacological inhibition in AT2 cells of carnitine palmitoyltransferase 1a (CPT1a), the rate-limiting enzyme of FAO, promoted mitochondrial dysfunction and acquisition of aberrant intermediate states expressing basaloid, and airway secretory cell markers SCGB1A1 and SCGB3A2. Furthermore, mice with deficiency of CPT1a in AT2 cells show enhanced susceptibility to developing lung fibrosis with an accumulation of epithelial cells expressing markers of intermediate cells, airway secretory cells, and senescence. We found that deficiency of CPT1a causes a decrease in SMAD7 protein levels and TGF-β signaling pathway activation. These findings suggest that the mitochondrial FAO metabolic pathway contributes to the regulation of lung progenitor cell repair responses and deficiency of FAO contributes to aberrant lung repair and the development of lung fibrosis.

Neuronal architecture established embryonically must persist lifelong to ensure normal brain function. However, little is understood about the mechanisms behind the long-term maintenance of neuronal organization. To uncover maintenance mechanisms, we performed a suppressor screen in sax-7/L1CAM mutants, which exhibit progressive disorganization with age. We identified the conserved extracellular matrix protein MIG-6/papilin as a key regulator of neuronal maintenance. Combining incisive molecular genetics, structural predictions, in vivo quantitative imaging, and cutting-edge Brillouin microscopy, we show that MIG-6/papilin remodels extracellular matrix collagen IV, working in concert with the secreted enzymes MIG-17/ADAMTS and PXN-2/peroxidasin. This remodeling impacts tissue biomechanics and ensures neuronal stability, even under increased mechanical stress. Our findings highlight an extracellular mechanism by which MIG-6/papilin supports the integrity of neuronal architecture throughout life. This work provides critical insights into the molecular basis of sustaining neuronal architecture and offers a foundation for understanding age-related and neurodegenerative disorders.

Several progeroid syndromes' causative mutations have been linked to epigenetic age acceleration as measured via several epigenetic clocks. At the same time, several protective variants have also been discovered that can reduce the risk of developing certain age-related disorders. However, the impact of these protective variants on epigenetic aging has not been well elucidated. Our research, which involved screening over 14,669 healthy individuals enrolled in the Qatar BioBank (QBB) and sequenced by the Qatar Genome Project (QGP), identified individuals carrying protective variants against age-related disorders, including Alzheimer's disease (AD), type 2 diabetes (T2D), and atherosclerosis. In this study, we measured methylation levels in blood DNA using the EPIC v2 arrays. In addition, epigenetic age was calculated using various epigenetic clocks. Our analysis revealed that the APOE*E2 protective variant reduces the rate of GrimAge epigenetic aging when compared to individuals with the APOE4 AD risk allele. Furthermore, our differential DNA methylation analysis discovered the association of the PCSK9 protective variant with specific biological processes related to immune function and the cardiovascular system. In conclusion, APOE*E2 protective variants have a positive impact on epigenetic aging, while PCSK9 protective variants have a significant effect on DNA methylation signatures. Further studies are needed to better understand the underlying mechanisms by which protective variants influence epigenetic aging, particularly the role of APOE*E2 protective variants in biological aging. Furthermore, additional research is required to fully uncover the processes that might enable specific targeted therapies to mimic the effects of beneficial mutations, such as LOF variants in PCSK9, in reducing the risk of geriatric disorders.

Genome-wide association studies (GWAS) have been successful in identifying genetic variation associated with a wide range of phenotypes. However, more detailed knowledge of their functional significance is required to provide insights into the molecular mechanisms involved. Single Nucleotide Polymorphisms (SNPs) that influence gene expression (Expression Quantitative Trait Loci-eQTLs) may be one such functional mechanism. As gene expression may change over the lifespan, it is important to identify eQTLs for specific age groups. In this study, we aimed to identify blood eQTLs in older adults. Peripheral blood was collected from participants of the Sydney Memory and Ageing Study (Sydney MAS, N = 445, mean age ± SD = 83.38 ± 4.31) and RNA extracted. Gene expression and SNP genotyping were assessed using arrays. Genome-wide eQTL analyses were undertaken using linear mixed-models. Replication was undertaken in the Older Australian Twins Study (OATS, N = 283, mean age = 75.86 ± 5.28). In the discovery cohort (Sydney MAS), a total of 10,468 unique eQTLs were identified influencing the expression of 1402 probes (1229 genes). A total of 6554 eQTLs were replicated in OATS, out of the 7339 that were available for analysis. We have identified, replicated, and described a catalogue of blood eQTLs in older adults. Noting that replication of these results in independent samples of older adults is required given our modest sample size. However, this information will be a useful resource for further studies, particularly in assessing the potential functions of SNPs identified in GWAS focussing on age-related traits.

Chronic low-level inflammation or "inflammaging" is hypothesized to contribute to sarcopenia and frailty. Resident microbiota are thought to promote inflammaging, frailty, and loss of skeletal muscle mass. We tested immunity and frailty in male C57BL6/N germ-free (GF), specific-pathogen-free (SPF), and mice that were born germ-free and colonized (COL) with an SPF microbiota. Male and female GF mice had lower systemic cellular inflammation indicated by lower blood Ly6C

In recent years, the focus on human inflammation in research has increased, with aging-related inflammation widely recognized as a defining characteristic of aging. Inflammation is strongly correlated with mitochondrial dysfunction. Phosphoglycerate mutase family member 5 (PGAM5) is a novel modulator of mitochondrial homeostasis in response to mechanical stimulation. Here we review the structure and sublocalization of PGAM5, introduce its importance in programmed cell death and summarize its crucial roles in the development and progression of inflammatory diseases such as pneumonia, hepatitis, neuroinflammation and aging. Notably, PGAM5 has dual effects on controlling inflammation: distinct PGAM5-mediated mitochondrial functions exhibit cellular heterogeneity, leading to its dual functions in inflammation control. We therefore highlight the double-edged sword nature of PGAM5 as a potential critical regulator and innovative therapeutic target in inflammation. Finally, the challenges and future directions of the use of PGAM5, which has dual properties, as a target molecule in the clinic are discussed. This review provides crucial insights to guide the development of intelligent therapeutic strategies targeting PGAM5-specific regulation to treat intractable inflammatory conditions, as well as the potential extension of its broader application to other diseases to achieve more precise and effective treatment outcomes.