Longevity Papers

An in-depth understanding of the molecular processes composing aging is crucial to develop therapeutic approaches that decrease aging as a key risk factor for cognitive decline. Herein, we present a spatio-temporal brain atlas (15 different regions) of microRNA (miRNA) expression across the mouse lifespan (7 time points) and two aging interventions composed of 1009 samples. MiRNAs are promising therapeutic targets, as they silence genes by complementary base-pair binding of messenger RNAs and are known to mediate aging speed. We first established sex- and brain-region-specific miRNA expression patterns in young adult samples. Then we focused on sex-dependent and independent brain-region-specific miRNA expression changes during aging. The corpus callosum in males and the choroid plexus in females exhibited strong sex-specific age-related signatures. In this work, we identified three sex-independent brain aging miRNAs (miR-146a-5p, miR-155-5p and miR-5100). We showed for miR-155-5p that these expression changes are driven by aging microglia. MiR-155-5p targets mTOR signaling pathway components and other cellular communication pathways and is hence a promising therapeutic target.

Background: Cyclin A2 (CCNA2), the master regulatory gene of the cell cycle is commonly silenced in postnatal mammalian cardiomyocytes. We have previously demonstrated that it can induce significant cardiac repair in both small and large animals when delivered to the heart via a viral vector. To date, whether CCNA2 gene delivery can induce cytokinesis in isolated cardiomyocytes from adult human hearts has not been investigated. Here we report that CCNA2 delivery can induce cytokinesis in cardiomyocytes isolated from adult human hearts. Methods: We designed a human gene therapy vector featuring a replication-deficient, E1/E3-deleted human adenovirus five encoding human CCNA2 driven by the cardiac Troponin T promoter to enable the expression of CCNA2 in freshly isolated human cardiomyocytes. We utilized time-lapse microscopy with live imaging to study cultured adult human cardiomyocytes isolated from a 21-year-old male, a 41-year-old female, and a 55-year-old male. To elucidate the mechanistic underpinnings of CCNA2-dependent gene regulation in governing cardiomyocyte cytokinesis, we conducted single nucleus transcriptomics (snRNA-seq, 10X Genomics) analysis of hearts isolated from adult transgenic mice that constitutively express CCNA2 in cardiomyocytes (CCNA2-Tg) and non-transgenic mice (nTg). Results: We now report that human adult cardiomyocytes can be induced to undergo complete cytokinesis in response to CCNA2 gene delivery with preservation of sarcomere integrity in the resulting daughter cells and maintaining active calcium mobilization in redifferentiated cardiomyocytes. Remarkably, snRNA-seq analysis revealed a subpopulation of cardiomyocytes enriched with cytokinesis, proliferative and reprogramming genes in hearts obtained from CCNA2-Tg mice as compared to hearts obtained from nTg mice. Additionally, bulk RNA sequencing of human adult and fetal hearts identified key reprogramming genes relevant for understanding the mechanisms of CCNA2-induced effects observed in our experimental models. Conclusion: These results provide a compelling path forward for the clinical development of cardiac regenerative therapy based on strategic manipulation of CCNA2 in cardiomyocytes.

The aging of the population is a global concern. In the post-COVID-19 pandemic era, there are no effective methods to identify aging acceleration due to infection. In this study, we conducted whole-transcriptome sequencing on peripheral blood samples from 35 healthy individuals (22-88 years old). By analysing the changes in mRNA, lncRNA, and miRNA expression, we investigated the characteristics of transcriptome alterations during the aging process. ceRNA networks were constructed, and ten genes (CD248, PHGDH, SFXN2, MXRA8, NOG, TTC24, PHYKPL, CACHD1, BPGM, and TWF1) were identified as potential aging markers and used to construct an aging clock. Moreover, our aging clock categorized individuals into slow-, average-, and quick-aging groups, highlighting a link between accelerated aging and infection-related clinical parameters. Pseudotime analysis further revealed two distinct aging trajectories, corroborating the variations in the aging rate identified by the aging clock. Furthermore, we validated the results using the OEP001041 dataset (277 healthy individuals aged 17-75), and datasets comprising patients with infectious diseases (n = 1558). Our study revealed that infection accelerates aging via increased inflammation and oxidative stress in infectious disease patients. Besides, the aging clock exhibited alterations after infection, highlighting its potential for assessing the aging rate after patient recovery. In conclusion, our study introduces a novel aging clock to assess the aging rate in healthy individuals and those with infections, revealing a strong link between accelerated aging and infections through inflammation and oxidative stress. These findings offer valuable insights into aging mechanisms and potential strategies for healthy aging.

The water exchange between brain parenchyma and cerebrospinal fluid (CSF) is considered to be responsible for glymphatic clearance of solutes and metabolic wastes from the brain, including amyloid-β, a biomarker in neurodegeneration. Despite the potential significance, no noninvasive technique for in vivo measurement of parenchyma-CSF water exchange has been demonstrated in humans, capable of investigating age-related changes in glymphatic clearance.

Geroscience has helped to usher in a new and exciting era of aging drug development and evaluation of novel and repurposed agents, as well as natural compounds purported to target one or more aging hallmarks. Among the latter, curcumin has long been pursued as a promising strategy but has failed to provide convincing evidence in human trials. Oral intake is the typical route of administration tested for the vast majority of gerotherapeutic candidates, including curcumin, but efficacy is dependent upon good oral bioavailability and pharmacokinetics. However, unlike FDA-approved oral medications, many natural compounds, such as curcumin, have poor oral bioavailability, which may explain their limited success in translation. To overcome these inherent limitations, we tested a novel solvent-based formulation of concentrated curcumin (VASCEPTOR®), developed for effective skin penetration and delivery of high amounts of bioactive curcuminoids directly to the circulation on aging and age-related conditions. We demonstrate that short-term topical treatment (7.5 mg per dose) with VASCEPTOR® twice per week can improve both vascular health in a rat model of hypertension, while a late-life intervention in aged mice improves multiple indices of health span, including improved exercise tolerance, motor coordination, diastolic function (p < 0.05), a reduction in frailty status (p < 0.05) and expression of some age-related markers in tissues, particular heart and kidney. Thus, these data suggest that the therapeutic potential of curcumin can potentially be dramatically enhanced by topical delivery and, along with other promising candidates, should be prioritized for further development, testing and deployment to potentially target some manifestations of aging in humans.

The coordination of protein homeostasis from the brain to periphery is essential for the health and survival of all animals. In C. elegans, glia serve a central role in coordinating organismal protein homeostasis and longevity via the unfolded protein response of the endoplasmic reticulum (UPRER). However, the full extent of the cell non-autonomous response and the identity of the signaling molecules required remained unknown. Here, we show that glial UPRER activation induces robust transcriptomic changes in specific tissue types across the animal, particularly in pathways related to neuropeptide signaling. We performed neuropeptidomics and loss and gain-of-function genetic screens and identified a single neuropeptide, FLP-17, that is sufficient but not necessary to induce cell non-autonomous activation of the UPRER. FLP-17 is sufficient to protect against chronic ER stress and age-dependent protein aggregation. We determined that FLP-17 acts through the receptor, EGL-6, to activate cell non-autonomous UPRER. This work reveals a complex peptidergic signaling network initiated by glial activation of the UPRER to regulate organismal protein homeostasis.

Background: We present EpImAge, an explainable deep learning tool that integrates epigenetic and immunological markers to create a highly accurate, disease-sensitive biological age predictor. This novel approach bridges two key hallmarks of aging - epigenetic alterations and immunosenescence. Methods: First, epigenetic and immunologic data from the same participants was used for AI models predicting levels of 24 cytokines from blood DNA methylation. Second, open-source epigenetic data (25 thousand samples) was used for generating synthetic immunological biomarkers and training an age estimation model. Results: Using state-of-the-art deep neural networks optimized for tabular data analysis, EpImAge achieves competitive performance metrics against 33 epigenetic clock models, including an overall mean absolute error of 7 years and a Pearson correlation of 0.85 in healthy controls, while demonstrating robust sensitivity across multiple disease categories. Explainable AI revealed the contribution of each immunological feature to the age prediction. Conclusions: The sensitivity to multiple diseases due to combining immunologic and epigenetic profiles is promising for both research and clinical applications. EpImAge is released as an easy-to-use web tool that generates the age estimates and levels of immunological parameters for methylation data, with the detailed report on the contribution of input variables to the model output for each sample.

Natural light is severely affected by human impact on Earth, yet little is known about the roles light receptors have outside vision and rhythmic processes. Here we show that loss-of-function of the light-receptive cryptochrome (l-cry) in marine bristleworms significantly increases lifespan and adult size, similarly to wild-types reared in constant darkness. Quantitative transcriptomics revealed hormonal players crucial for invertebrate and vertebrate sexual development and reproduction affected in l-cry mutants. These include nr0b1/2, ortholog of dax-1 (nr0b1) and shp (nr0b2), long considered vertebrate novelties. Depending on moon-phase, nr0b1/2 is up- or down-regulated in l-cry mutants. Matching the complex regulation, loss of nr0b1/2 function partially recapitulates l-cry phenotypes. Molecularly, Platynereis Nr0b1/2 affects steroidogenic and other endocrine pathways, nuclear receptor signaling, and transcription factor orthologs, involved in sexual developmental, reproductive, and timing processes in other organisms. Thus, our study reveals profound effects of light on adult animal life-time, likely at least in part by conserved endocrine pathways involved in sexual maturation and reproduction in annelids and vertebrates.

Clonal hematopoiesis (CH), characterized by the expansion of hematopoietic stem and progenitor cells harboring somatic mutations, has emerged as a significant age-related phenomenon with profound implications for human health. While initially recognized in the 1960s, recent technological advances have revealed its complex nature and widespread prevalence, affecting up to 84% of individuals aged ≥ 70 years. The clinical significance of CH extends beyond its well-established role as a precursor to hematological malignancies, encompassing its association with cardiovascular diseases, chronic kidney disease, and other non-malignant disorders. This comprehensive review synthesizes the current understanding of CH, focusing on recent advances in genetic and molecular mechanisms, particularly the roles of commonly mutated genes such as DNMT3A, TET2, and ASXL1. We address the emerging distinction between myeloid and lymphoid CH, their differential impacts on disease progression, and the complex interplay between CH and inflammation. Special attention is given to newly identified genetic determinants of clonal expansion rates and their implications for disease progression. The review also examines the revolutionary concept of passenger-approximated clonal expansion rate and its utility in understanding CH dynamics. Furthermore, we discuss therapeutic strategies targeting inflammatory pathways and their potential in mitigating CH-associated complications. By integrating recent findings from genetic, molecular, and clinical studies, this review provides a framework for understanding CH as a systemic condition and highlights promising directions for therapeutic interventions.

Age-related changes in human dermal fibroblasts (HDFs) contribute to impaired wound healing and skin aging. While these changes result in altered mechanotransduction, the epigenetic basis of rejuvenating aging cells remains a significant challenge. This study investigates the effects of compressive forces on nuclear mechanotransduction and epigenetic rejuvenation in aged HDFs. Using a compressive force application model, the activation of HDFs through alpha-smooth muscle actin (ɑ-SMA) is demonstrated. Sustained compressive forces induce significant epigenetic modifications, including chromatin remodeling and altered histone methylation patterns. These epigenetic changes correlate with enhanced cellular migration and rejuvenation. Small-scale drug screening identifies the extracellular signal-regulated kinase (ERK) signaling pathway as a key mediator of compression-induced epigenetic activation. Furthermore, implanting aged cell spheroids into an aged skin model and subjecting the tissue to compressive forces resulted in increased collagen I protein levels. Collectively, these findings demonstrate that applying compressive force to aged fibroblasts activates global epigenetic changes through the ERK signaling pathway, ultimately rejuvenating cellular functions with potential applications for wound healing and skin tissue regeneration.

Osteoarthritis (OA) is a progressive degenerative joint disease that significantly impairs mobility and quality of life, particularly in aging populations. Current therapeutic approaches primarily focus on symptom relief, but fail to address the underlying mechanisms of cartilage degeneration. In recent years, epigenetic reprogramming has emerged as a promising strategy for cellular rejuvenation, offering new perspectives for regenerative medicine. This study investigates the potential of a selected set of small chemical molecules (SCM) to induce epigenetic reprogramming of chondrocytes and promote cartilage regeneration in an in vivo model of chemically induced OA. The experiments were conducted on aging female rats, a translational model chosen for its relevance to human age-related OA and postmenopausal cartilage deterioration. OA was induced via intra-articular administration of trypsin, and a subset of animals was further subjected to estrogen receptor blockade using clomiphene citrate to simulate postmenopausal conditions. The SCM cocktail was administered intra-articularly to evaluate its effects on cartilage repair. Chondroitin sulfate was used as a comparative treatment control. The results demonstrated that SCM administration led to significant improvements in joint tissue integrity, including increased cartilage thickness, enhanced synthesis of mucopolysaccharides, and restoration of chondrocyte metabolic activity. Histological analysis revealed that SCM-treated groups exhibited reduced cartilage erosion, lower inflammatory marker expression, and improved nuclear-cytoplasmic index (NCI) values, suggesting enhanced chondrocyte function. Notably, the group with estrogen receptor blockade responded more favorably to SCM treatment than the non-blocked OA group, highlighting the potential interaction between hormonal status and epigenetic reprogramming. These findings provide strong evidence for the feasibility of epigenetic modulation as a therapeutic strategy for OA. The ability of SCMs to restore cartilage structure and function suggests a novel approach to treating age-related degenerative diseases. Further research is required to elucidate the precise molecular mechanisms underlying this rejuvenation process and optimize therapeutic protocols for clinical applications.

Senescent cells (SnCs) accumulate because of aging and external cellular stress throughout the body. They adopt a senescence-associated secretory phenotype (SASP) and release inflammatory and degenerative factors that actively contribute to age-related diseases, such as low back pain (LBP). The senolytics,

Aging entails a progressive decline in physiological functions, elevating the risk of age-related diseases like heart failure or aortic stenosis. Stem cell therapies, especially those that use paracrine signaling, can potentially mitigate the adverse effects of aging.

Aging is a major risk factor for disease, and developing effective pharmaceutical interventions to improve healthspan and promote longevity has become a high priority for society. One of the molecular pathways related to longevity in various model organisms revolves around lowering AKT1 levels. This prompted our in silico drug screen for small molecules capable of mimicking the transcriptional effects of AKT1 knockdown. We found topoisomerase inhibitors as a top candidate longevity-drug class. Evaluating multiple compounds from this class in C. elegans revealed that the topoisomerase inhibitor amonafide has the greatest benefit on healthspan and lifespan. Intriguingly, the longevity effect of amonafide was not solely dependent on DAF-16/FOXO, the canonical pathway for lifespan extension via AKT1 inhibition. We performed RNA-seq on amonafide-treated worms and revealed a more youthful transcriptional signature, including the activation of diverse molecular and cellular defense pathways. We found the mitochondrial unfolded protein response (UPR

Yeast replicative aging is cell autonomous and thus a good model for mechanistic study from a dynamic systems perspective. Utilizing an engineered strain of yeast with a switchable genetic program to arrest daughter cells (without affecting mother cell divisions) and a high throughput microfluidic device, we systematically analyze the dynamic trajectories of thousands of single yeast mother cells throughout their lifespan, using fluorescent reporters that cover a range of biological processes, including some major aging hallmarks. We found that the markers of proteostasis stand out as most predictive of the lifespan of individual cells. In particular, nuclear proteasome concentration at middle age is a good predictor. We found that cell size (measured by area) grows linearly with time, and that nuclear size grows in proportion to maintain isometric scaling in young cells. As the cells become older, their nuclear size increases faster than linear and isometric size scaling breaks down. We observed that proteasome concentration in the nucleus exhibits dynamics very different from that in cytoplasm, with much more rapid decrease during aging; such dynamic behavior can be accounted for by the change of nuclear size in a simple mathematical model of transport. We hypothesize that the gradual increase of cell size and the associated nuclear size increase lead to the dilution of important nuclear factors (such as proteasome) that drives aging. We also show that perturbing proteasome changes mitochondria morphology and function, but not vice versa, potentially placing the change of proteosome upstream of the change of mitochondrial phenotypes. Our study produced large scale single cell dynamic data that can serve as a valuable resource for the aging research community to analyze the dynamics of other markers and potential causal relations between them. It is also a useful resource for building and testing physics/AI based models that identify early dynamics events predictive of lifespan and can be targets for longevity interventions.

A passive consequence of macromolecular condensation is the establishment of an ion concentration gradient between the dilute and dense phases, which in turn governs distinct electrochemical properties of condensates. However, the mechanisms that regulate the electrochemical equilibrium of condensates and their impacts on emergent physicochemical functions remain unknown. Here we demonstrate that the electrochemical environments and the physical and chemical activities of biomolecular condensates, dependent on the electrochemical potential of condensates, are regulated by aging-associated intermolecular interactions and interfacial effects. Our findings reveal that enhanced dense-phase interactions during condensate maturation continuously modulate the ion distribution between the two phases. Moreover, modulating the interfacial regions of condensates can affect the apparent pH within the condensates. To directly probe the interphase and interfacial electric potentials of condensates, we have designed and implemented electrochemical potentiometry and second harmonic generation-based approaches. Our results suggest that the non-equilibrium nature of biomolecular condensates might play a crucial role in modulating the electrochemical activities of living systems.

Aim: Blood flow-induced mechanical forces, particularly wall shear stress (WSS), play a fundamental role in aortic valve remodeling and maturation. Dysregulation of these processes contributes to age-related valve diseases, such as aortic stenosis and regurgitation. While epidermal growth factor receptor (EGFR) signaling has been implicated in valve development, its role in mechanotransduction remains unclear. This study aims to investigate how EGFR regulates WSS-induced signaling in valvular cells and explore its interaction with the mechanosensitive ion channel PIEZO1. Methods and Results: To investigate the role of EGFR in valvular cell mechanotransduction, we used conditional Egfrflox allele to selectively delete Egfr in valvular cells. Histological analysis revealed increased valve leaflet thickness and hyperproliferation of mesenchymal cells when Egfr was deleted both endothelial (Tie2-Cre lineage) and mesenchymal (Sm22 alpha-Cre lineage) cells. This was accompanied by a reduction in maturation-related genes (Egr1, Nos3, Tgf-beta) and extracellular matrix (ECM) components. We previously demonstrated that Egr1 expression is regulated by WSS in valvular endothelial cells, prompting further exploration of Egr1\'s role in valvular cells. In vitro, Egr1 overexpression and shRNA-mediated knockdown confirmed its role in regulating Nos3, Col1a1, and Tgf-beta, key mediators of valve remodeling. Using a pulsatile WSS-mimicking device, we found that WSS induces Erk1/2 phosphorylation and Egr1 expression in valvular cells, both of which were abolished by EGFR inhibition. However, direct EGFR activation via EGF failed to replicate WSS-induced Egr1 expression, suggesting the involvement of additional mechanosensitive pathways. Pharmacological studies further revealed that PIEZO1 inhibition impaired WSS-induced Egr1 expression, while PIEZO1 activation (via YODA) mimicked WSS effects on Erk1/2 phosphorylation and Egr1 expression. These findings suggest a functional interaction between EGFR and PIEZO1 in mechanotransduction, linking mechanical forces to key molecular pathways in valve remodeling. Conclusion: Our findings establish EGFR as a critical mediator of WSS-induced mechanotransduction in valve remodeling, working in synergy with PIEZO1 to regulate flow-sensitive transcription factors such as Egr1. This study provides new insights into the molecular mechanisms governing valve maturation and highlights potential therapeutic targets for age-related valve pathologies linked to abnormal WSS responses.

Aging is a pivotal risk factor for intervertebral disc degeneration (IVDD) and chronic low back pain (LBP). The restoration of aging nucleus pulposus cells (NPCs) to a youthful epigenetic state is crucial for IVDD treatment, but remains a formidable challenge. Here, we proposed a strategy to partially reprogram and reinstate youthful epigenetics of senescent NPCs by delivering a plasmid carrier that expressed pluripotency-associated genes (Oct4, Klf4 and Sox2) in Cavin2-modified exosomes (OKS@M-Exo) for treatment of IVDD and alleviating LBP. The functional OKS@M-Exo efficaciously alleviated senescence markers (p16

Astrocytes are the most abundant glial cell type in the central nervous system (CNS). Astrocytes are born during the early postnatal period in the rodent brain and mature alongside neurons, demonstrating remarkable morphological structural complexity, which is attained in the second postnatal month. Throughout this period of development and across the remainder of the lifespan, astrocytes participate in CNS homeostasis, support neuronal partners, and contribute to nearly all aspects of CNS function. In the present study, we analyzed astrocyte gene expression in the cortex of wild-type male rodents throughout their lifespan (postnatal 7 days to 18 months). A pairwise timepoint comparison of differential gene expression during early development and CNS maturation (7-60 days) revealed four unique astrocyte gene clusters, each with hundreds of genes, which demonstrate unique temporal profiles. These clusters are distinctively related to cell division, cell morphology, cellular communication, and vascular structure and regulation. A similar analysis across adulthood and in the aging brain (3 to 18 months) identified similar patterns of grouped gene expression related to cell metabolism and cell structure. Additionally, our analysis identified that during the aging process astrocytes demonstrate a bias toward shorter transcripts, with loss of longer genes related to synapse development and a significant increase in shorter transcripts related to immune regulation and the response to DNA damage. Our study highlights the critical role that astrocytes play in maintaining CNS function throughout life and reveals molecular shifts that occur during development and aging in the cortex of male mice.

Patients with chronic obstructive pulmonary disease (COPD) often develop complications associated with sarcopenia; however, the underlying mechanisms remain unclear. Through a combination of in vitro and in vivo experiments, as well as bioinformatics analysis, our study identified YAP/TAZ as a key regulator of the aging phenotype in the skeletal muscle of COPD patients. In skeletal muscle affected by cigarette smoke-induced COPD, we observed significant reductions in YAP/TAZ levels, alongside markers indicative of skeletal muscle aging and dysfunction. Notably, overexpression of YAP/TAZ significantly improved these conditions. Our results suggest a novel mechanism whereby the maintenance of YAP/TAZ activity interacts with ACTR2 to preserve nuclear membrane integrity and reduce cytoplasmic dsDNA levels, thereby attenuating STING activation and cellular senescence. Additionally, we found that YAP is involved in the transcriptional regulation of the ACTR2 promoter region. Overall, preserving YAP/TAZ activity may help prevent skeletal muscle aging associated with COPD, representing a new strategy for intervening in COPD-related sarcopenia.

Telomere dysfunction is a key hallmark of aging linked to numerous age--related diseases including cardiovascular disorders, pulmonary fibrosis, and metabolic syndromes. Despite decades of research yielding strong evidence linking telomere biology to aging processes, the field faces a critical bottleneck: current telomere measurement methods require specialized molecular techniques that prevent large--scale studies and clinical implementation. Here we present TLPath, a novel deep learning framework that extracts normal tissue architecture from routine histopathology (H&E) images to predict bulk--tissue telomere length. Trained on the Genotype--Tissue Expression cohort comprising >7.3 million patch images from >5,000 whole--slide images across 919 individuals, TLPath makes a remarkable discovery: the extracted morphological features spontaneously separate young, middle--aged, and elderly individuals within most tissue types--demonstrating for the first time that aging causes substantial architectural changes in tissues detectable without explicit age supervision. These extracted features can predict bulk--telomere length with significant accuracy (>0.51 in well--represented tissues), outperforming chronological age as a predictor (correlation = 0.20) and identifying age--discordant cases -- detecting both accelerated telomeres shortening in young individuals and preserved telomeres in older individuals. Mechanistic interpretation reveals that TLPath leverages established senescence morphological markers, including nuclear--to--cytoplasmic ratio and nuclear shape variation, for its predictions. We applied TLPath in ~2,800 new GTEx biopsies where concordant with known association, the predicted telomere length is shorter across most tissues from individuals with Type 1/2 diabetes. Overall, we demonstrate that aging substantially alters tissue morphology, which TLPath captures and uses to predict telomere length, enabling large--scale telomere biology studies using existing tissue archives.

Age-related alterations in the skeletal system are linked to decreased bone mass, a reduction in bone strength and density, and an increased risk of fractures and osteoporosis. Therapeutics are desired to stimulate bone regeneration and restore imbalance in the bone remodeling process. Quercetin (Qu), a naturally occurring flavonoid, induces osteogenesis; however, its solubility, stability, and bioavailability limit its therapeutic use. Nanoformulation can improve the physical properties of Qu and enhance its bioactivity and bioavailability. Further, localized delivery of Qu nanoformulations at the site of bone defects could ensure high local concentration, augmenting its osteogenic properties. Thus, this study aims to synthesize selenium nanoparticles-based Qu nanoformulation (Qu-SeNPs) and evaluate their osteogenic stimulation ability along with localized bone regeneration ability. Here, the spontaneously synthesized Qu-SeNPs showed uniform size distribution and rough flower-shaped morphology. The confocal images indicate improved cellular uptake and even cellular distribution of Qu-SeNPs in osteoblasts, resulting in increased osteogenic activity as indicated by enhanced expression of early and late osteoprogenitor differentiation markers. Qu-SeNPs also decreased osteoblasts' RANKL/OPG ratio and inhibited osteoclast formation. Mechanistically, Qu-SeNPs activate critical signaling pathways, including WNT and BMP, and utilize the miR-206/Connexin43 pathway to enhance osteogenesis. In vivo, experiments utilizing a drill-hole bone defect model in mice indicate that hydrogel-mediated localized delivery of Qu-SeNPs significantly accelerates bone defect healing. Thus, well-characterized and mechanistic, detailed synthesized Qu-SeNPs can restore bone remodeling, and Qu-SeNPs embedded in hydrogels may improve Qu cellular uptake and bioavailability in clinical settings, enabling innovative orthopedic and regenerative therapies for bone loss/defects.

Aging decreases the metabolic rate and increases the risk of metabolic diseases, highlighting the need for alternative strategies to improve metabolic health. Heat treatment (HT) has shown various metabolic benefits, but its ability to counteract aging-associated metabolic slowdown remains unclear. This study aimed to investigate the impact of whole-body HT on energy metabolism, explore the potential mechanism involving the heat sensor TRPV1, and examine the modulation of gut microbiota.

Transient receptor potential ankyrin 1 (TRPA1) is a sensory channel expressed in vagal afferent nerves that detect noxious stimuli. Trpa1 knockout accelerates age-related cardiac fibrosis and dysfunction in mice. This study investigated whether TRPA1 activation with its selective agonist, allyl isothiocyanate (AITC), prevents cardiac aging. Male and female 18-month-old C57BL/6 J mice were randomized to receive either a control diet or a diet containing 15 mg of AITC per kilogram of food for 6 months. At 24 months, aged mice on the control diet exhibited increased left ventricular wall thickness but maintained similar left ventricular volume and preserved systolic function compared to 18-month-old middle-aged mice. Additionally, aged mice on a control diet developed restrictive-like cardiomyopathy, characterized by a pathologically elevated E/A ratio. AITC treatment significantly improved diastolic function by normalizing the E/A ratio (P < 0.01) and shortening isovolumetric relaxation time (P < 0.01), without affecting left ventricular wall thickness, volume, or systolic function. Electrocardiographic analysis demonstrated that AITC treatment significantly increased heart rate variability (P < 0.01) and parasympathetic nervous system index (P < 0.05), indicating enhanced vagal activity. Histological analyses revealed decreased cardiac fibrosis and collagen I/III deposition in AITC-treated mice (all P < 0.01). Proteomics analysis demonstrated that differentially expressed proteins in myocardial tissue were mainly enriched in pathways of collagen metabolism, extracellular matrix-receptor interaction, and fatty acid metabolism. These findings suggest that long-term dietary AITC may improve vagal tone, reduce cardiac fibrosis, and enhance diastolic function in aged mice, potentially through TRPA1 activation. TRPA1 could be a promising therapeutic target for age-related diastolic dysfunction.

Physical activity (PA) is linked to lower dementia risk, but molecular pathways underpinning PA-related dementia risk are poorly understood. We conducted plasma proteomics (SomaScan v4.1) and 30-day Fitbit-based PA monitoring (average daily step count) in 65 cognitively unimpaired older adults from the UCSF BrANCH cohort. Differential regression and network analyses identified PA plasma proteomic signatures tied to extracellular matrix (ECM), immune response, and lipid metabolism. Protein module M12 ECM/neurodevelopment positively correlated with PA in BrANCH and external cohorts, inversely predicted cognitive aging outcomes in BrANCH, and decreased across multiple neurodegenerative conditions. M12 was enriched for proteins from Alzheimers disease (AD) risk genes and antemortem plasma abundance of ANTXR2, an M12 hub protein, forecasted longitudinal cognitive decline and postmortem brain tissue protein signatures of AD cognitive resilience in the ROSMAP cohort. Our integrated analysis across six proteomic datasets identified blood-detectable molecular signatures of PA and neurodegenerative disease, including ECM-related proteins (e.g., ANTXR2) that may represent key molecular targets for dementia prevention.

Aging of the heart is accompanied by impairment of cardiac structure and function. At molecular level, autophagy plays a crucial role in preserving cardiac health. Autophagy maintains cellular homeostasis by facilitating balanced degradation of cytoplasmic components including organelles and misfolded or aggregated proteins. The age-related decline in autophagy favors an accumulation of protein aggregates such as lipofuscin particularly in the heart, which is composed primarily of non-proliferating cells. Therefore, this study investigates whether lipofuscin accumulation contributes to age-related functional decline of primary adult cardiomyocytes isolated from C57BL/6J mice and examines the role of autophagic flux in mediating these effects. Results showed an age-associated reduction in cardiomyocyte contraction amplitude and an increase in autofluorescence, indicating the accumulation of lipofuscin with age. In vitro treatment of adult primary cardiomyocytes with artificial lipofuscin increased autofluorescence and decreased both contraction amplitude and cellular autophagic flux. Induction of autophagy with rapamycin mitigated contractile dysfunction in lipofuscin-treated cardiomyocytes, whereas inhibition of autophagic flux revealed stage-dependent effects. Late-stage autophagy inhibition using chloroquine or concanamycin A reduced cardiomyocyte contraction amplitude, whereas early-stage autophagy inhibition via 3-methyladenine did not affect contraction within 24 h. In conclusion, our results indicate that lipofuscin directly impairs cardiomyocyte function by diminishing late-stage autophagic flux. These findings highlight the essential role of the autophagy-lysosomal system in preserving age-related loss of cardiomyocyte function caused by accumulating protein aggregates.

The autophagy-lysosomal system comprises a highly dynamic and interconnected vesicular network that plays a central role in maintaining proteostasis and cellular homeostasis. In this study, we uncovered the deubiquitinating enzyme (DUB), dUsp45/USP45, as a key player in regulating autophagy and lysosomal activity in Drosophila and mammalian cells. Loss of dUsp45/USP45 results in autophagy activation and increased levels of V-ATPase to lysosomes, thus enhancing lysosomal acidification and function. Furthermore, we identified the actin-binding protein Coronin 1B (Coro1B) as a substrate of USP45. USP45 interacts with and deubiquitinates Coro1B, thereby stabilizing Coro1B levels. Notably, the ablation of USP45 or Coro1B promotes the formation of F-actin patches and the translocation of V-ATPase to lysosomes in an N-WASP-dependent manner. Additionally, we observed positive effects of dUsp45 depletion on extending lifespan and ameliorating polyglutamine (polyQ)-induced toxicity in Drosophila. Our findings highlight the important role of dUsp45/USP45 in regulating lysosomal function by modulating actin structures through Coro1B.

Aging is driven by fundamental mechanisms like oxidative stress, telomere shortening and changes in DNA methylation, which together prepare the ground for age-related diseases. Botanical extracts, rich in bioactive phytoconstituents, represent a promising resource for developing therapies that target these mechanisms to promote healthy aging. This study explores the geroprotective potential of Monarda didyma L. extract. In vitro analyses revealed the extract's strong antioxidant activity, ability to reduce telomere shortening, and capacity to protect against DNA damage, thereby decreasing cellular senescence and improving endothelial function. The randomized, double-blind clinical trial demonstrated that daily oral supplementation with the extract significantly improved leukocyte telomere length (LTL) and stabilized DNA methylation age (DNAmAge) in the intervention group, while the placebo group experienced accelerated epigenetic aging and hypermethylation of critical age-related genes (ELOVL2 and FHL2). The intervention group also reported enhanced quality of life, particularly in the physical domain, along with improved movement and quality sleep indices detected by questionnaire and wearable sensors. These compelling findings position Monarda didyma L. extract as a powerful candidate for future geroprotective therapies, with the potential to significantly impact healthy aging.

The accumulation of senescent cells (SEN) with aging produces a chronic inflammatory state that accelerates age-related diseases. Eliminating SEN has been shown to delay, prevent, and in some cases reverse aging in animal disease models and extend lifespan. There is thus an unmet clinical need to identify and target SEN while sparing healthy cells. Here, we show that the lysosomal membrane protein Lysosomal-Associated Membrane Protein 1 (LAMP1) is a membrane-specific biomarker of cellular senescence. We have validated selective LAMP1 upregulation in SEN in human and mouse cells. Lamp1+ cells express high levels of prototypical senescence markers p16, p21, Glb1, and have low Lmnb1 expression as compared to Lamp1- cells. The percentage of Lamp1+ cells is increased in mice with fibrotic lungs due to bleomycin instillation. Finally, we use a dual antibody-drug conjugate (ADC) strategy to eliminate LAMP1+ senescent cells.

The progressive loss of cerebral white matter during aging contributes to cognitive decline, but whether reduced blood flow is a cause or consequence remains debated. Using deep multi-photon imaging in mice, we examined microvascular networks perfusing myelinated tissues in cortical layer 6 and corpus callosum. We identified sparse, wide-reaching venules, termed principal cortical venules, that exclusively drain deep tissues and resemble vasculature at the human cortex and U-fiber interface. Aging involved selective constriction and rarefaction of capillaries in deep branches of principal cortical venules. This resulted in mild hypoperfusion that was associated with microgliosis, astrogliosis and demyelination in deep tissues, but not upper cortex. Inducing a comparable hypoperfusion in adult mice using carotid artery stenosis triggered a similar tissue pathology specific to layer 6 and corpus callosum. Thus, impaired capillary-venous drainage is a contributor to hypoperfusion and a potential therapeutic target for preserving blood flow to white matter during aging.

Among epigenetic modifiers, telomeres represent attractive modulators of the genome in part through position effects. Telomere Position Effect-Over Long Distances (TPE-OLD) modulates gene expression by changes in telomere-dependent long-distance loops. To gain insights into the molecular mechanisms of TPE-OLD, we performed a genome-wide transcriptome and methylome analysis in proliferative fibroblasts and myoblasts or differentiated myotubes with controlled telomere lengths. By integrating omics data, we identified a common TPE-OLD dependent cis-acting motif that behaves as an insulator or enhancer. Next, we uncovered trans partners that regulate these activities and observed the consistent depletion of one candidate factor, RBPJ, at TPE-OLD associated loci upon telomere shortening. Importantly, we confirmed our findings by unbiased comparisons to recent Human transcriptomic studies, including those from the Genotype-Tissue Expression (GTEx) project. We concluded that TPE-OLD acts at the genome-wide level and can be relayed by RBPJ bridging Alu-like elements to telomeres. In response to physiological (i.e., aging) or pathological cues, TPE-OLD might coordinate the genome-wide impact of telomeres through recently evolved Alu elements acting as enhancers in association with RBPJ.

The concept of aging has evolved from being primarily attributed to genetic factors to recognizing the critical role of epigenetic mechanisms. Recent advancements, such as epigenetic clocks, have provided tools to assess biological age and offer insights into aging processes at the molecular level. In aesthetic dermatology, understanding these processes allows for more personalized, effective interventions targeting the root causes of skin aging. This review explores the interplay of epigenetic changes, aging, and the potential of personalized care to enhance longevity and skin rejuvenation. This review is based on an extensive literature search conducted across PubMed and other scientific databases. Studies focused on epigenetic mechanisms such as DNA methylation, histone modifications, and their relationship to skin aging. Particular attention was given to recent advancements in biological clocks, including Horvath's Clock and GrimAge, and their implications for personalized dermatological treatments. Epigenetic clocks, such as Horvath's Clock, have demonstrated utility in assessing biological age through methylation markers, revealing actionable insights into aging processes. Energy-based devices like fractional lasers and radiofrequency have shown promise in reversing age-related epigenetic changes, promoting collagen synthesis, and reducing biological skin age. Additionally, lifestyle factors such as diet, sleep, and circadian rhythm alignment significantly influence epigenetic aging and skin health. Integrating epigenetic insights into aesthetic dermatology represents a paradigm shift in skin rejuvenation, allowing for personalized treatments that address visible signs of aging and underlying molecular mechanisms. Using biological clocks provides a framework for tailoring interventions to individual patient needs, optimizing outcomes, and extending the longevity of aesthetic results. Future research should focus on longitudinal studies, accessibility, and ethical considerations to fully harness the potential of epigenetics in promoting skin health and overall well-being.

Substantial heterogeneity in cognitive ageing is well documented. Such heterogeneity has been attributed to individual differences in brain maintenance - i.e., the relative preservation of neural resources in ageing. However, large-scale longitudinal evidence is lacking. We pooled data from three population-based Swedish cohorts (Betula, N = 196; SNAC-K, N = 472; H70, N = 688; aged 60-93 years at baseline, follow-up duration up to 7 years) to assess whether global brain maintenance is associated with better preserved cognition in ageing, and to identify lifestyle predictors of brain maintenance. In each cohort, global brain integrity was indexed by the volume of the lateral ventricles (adjusted for total intracranial volume), and general cognitive function based on a principal component analysis of four age-sensitive cognitive domains. Participants were classified into subgroups of low (i.e., \'aged\') versus high (i.e., \'youth-like\') brain integrity based on ventricular volume estimates available for a younger reference sample in one of the cohorts (Betula, 25-55 years, N = 60). Subgroup differences in cognition at baseline and over the follow-up were assessed with ANCOVAs and linear mixed effects models. Logistic regressions were used to examine lifestyle predictors of brain maintenance. Across cohorts, 881 individuals (64.97%) were classified into the high brain integrity subgroup at baseline and 409 individuals (49.82%) over the follow-up. Maintenance of more youth-like brain integrity was associated with better baseline cognition (p < .001) and less cognitive decline longitudinally (p < .001). Moreover, lower cardiovascular disease (CVD) risk and the absence of diabetes predicted brain maintenance at baseline (CVD risk, OR = 0.80, 95% CI [0.68, 0.93]; diabetes, OR = 0.39, 95% CI [0.26, 0.59]) and over the follow-up (CVD risk, OR = 0.79, 95% CI [0.64, 0.96]; diabetes, OR = 0.53, 95% CI [0.29, 0.94]). These findings underscore brain maintenance as a key determinant of cognitive ageing and highlight the importance of managing cardiovascular and metabolic disease risk factors for promotion of brain and cognitive health in later life.

In early postnatal and young adult bone marrow, Leptin receptor-expressing (LepR

The degenerative loss of muscle associated with aging leading to muscular atrophy is called sarcopenia. Currently, practicing regular physical exercise is the only efficient way to delay sarcopenia onset. Identification of therapeutic targets to alleviate the symptoms of aging requires in vivo model organisms of accelerated muscle degeneration and atrophy. The zebrafish undergoes aging, with hallmarks including mitochondrial dysfunction, telomere shortening, and accumulation of senescent cells. However, zebrafish age slowly, and no specific zebrafish models of accelerated muscle atrophy associated with molecular events of aging are currently available. We have developed a new genetic tool to efficiently accelerate muscle-fiber degeneration and muscle-tissue atrophy in zebrafish larvae and adults. We used a gain-of-function strategy with a molecule that has been shown to be necessary and sufficient to induce muscle atrophy and a sarcopenia phenotype in mammals: Atrogin-1 (also named Fbxo32). We report the generation, validation, and characterization of a zebrafish genetic model of accelerated neuromuscular atrophy, the atrofish. We demonstrated that Atrogin-1 expression specifically in skeletal muscle tissue induces a muscle atrophic phenotype associated with locomotion dysfunction in both larvae and adult fish. We identified degradation of the myosin light chain as an event occurring prior to muscle-fiber degeneration. Biological processes associated with muscle aging such as proteolysis, inflammation, stress response, extracellular matrix (ECM) remodeling, and apoptosis are upregulated in the atrofish. Surprisingly, we observed a strong correlation between muscle-fiber degeneration and reduced numbers of neuromuscular junctions in the peripheral nervous system, as well as neuronal cell bodies in the spinal cord, suggesting that muscle atrophy could underly a neurodegenerative phenotype in the central nervous system. Finally, while atrofish larvae can recover locomotive functions, adult atrofish have impaired regenerative capacities, as is observed in mammals during muscle aging. In the future, the atrofish could serve as a platform for testing molecules aimed at treating or alleviating the symptoms of muscle aging, thereby opening new therapeutic avenues in the fight against sarcopenia.