Epigenetic modifications play a critical role in regulating gene expression under various physiological and pathological conditions. Epigenetic modifications reprogramming is a recognized hallmark of aging and a key component of the aging clock used to differentiate between chronological and biological age. The potential for prospective diagnosis and regulatory capabilities position epigenetic modifications as an emerging drug target to extend longevity and alleviate age-related organ dysfunctions. In the past few decades, numerous preclinical studies have demonstrated the therapeutic potential of natural products in various human diseases, including aging, with some advancing to clinical trials and clinical application. This review highlights the discovery and recent advancements in the aging clock, as well as the potential use of natural products as anti-aging therapeutics by correcting disordered epigenetic reprogramming. Specifically, the focus is on the imbalance of histone modifications, alterations in DNA methylation patterns, disrupted ATP-dependent chromatin remodeling, and changes in RNA modifications. By exploring these areas, new insights can be gained into aging prediction and anti-aging interventions.

Over the past decade, epigenetic clocks have emerged as powerful machine learning tools, not only to estimate chronological and biological age but also to assess the efficacy of anti-ageing, cellular rejuvenation and disease-preventive interventions. However, many computational and statistical challenges remain that limit our understanding, interpretation and application of epigenetic clocks. Here, we review these computational challenges, focusing on interpretation, cell-type heterogeneity and emerging single-cell methods, aiming to provide guidelines for the rigorous construction of interpretable epigenetic clocks at cell-type and single-cell resolution.

Osteoarthritis (OA) is the most prevalent joint disorder occurring with articular cartilage degradation. It includes a switch from an articular to a growth plate chondrocyte phenotype. Here, we investigated the histone modification profiles and found significant H3K27me3 loss in OA, which led to disease-associated gene expression. Surprisingly, these genes were occupied by both H3K27me3 and H3K4me3 in normal chondrocytes, showing a poised bivalent state. Furthermore, we observed the derepression of similar bivalent genes in growth plate chondrocytes. Finally, a KDM6B inhibitor GSK-J4 prevented the H3K27me3 loss and cartilage damage in the rat OA model. Our results reveal an inherited bivalent epigenetic signature on developmental genes that makes articular chondrocytes prone to hypertrophy and contributes to a promising epigenetic therapy for OA.

Cellular senescence and cellular reprogramming represent two fundamentally intertwined processes that profoundly influence aging and cancer. This paper explores how the permanent cell-cycle arrest of senescent cells and the identity-resetting capacity of reprogramming jointly shape biological outcomes in later life and tumor development. We synthesize recent findings to show that senescent cells, while halting the proliferation of damaged cells, can paradoxically promote tissue dysfunction and malignancy via their secretory phenotype. Conversely, induced reprogramming of somatic cells-exemplified by Yamanaka factors-resets cellular age and epigenetic marks, offering a potential to rejuvenate aged cells. Key findings highlight shared mechanisms (e.g., DNA damage responses and epigenetic remodeling) and bidirectional crosstalk between these processes: senescence signals can facilitate neighboring cell plasticity, whereas reprogramming attempts can trigger intrinsic senescence programs as a barrier. In aging tissues, transient (partial) reprogramming has been shown to erase senescence markers and restore cell function without inducing tumorigenesis, underlining a novel strategy to combat age-related degeneration. In cancer, we discuss how therapy-induced senescence of tumor cells may induce stem-cell-like traits in some cells and drive relapse, revealing a delicate balance between tumor suppression and tumor promotion. Understanding the interplay between senescence and reprogramming is crucial for developing innovative therapies. By targeting the senescence-reprogramming axis-for instance, via senolytic drugs, SASP inhibitors, or safe reprogramming techniques-there is significant therapeutic potential to ameliorate aging-related diseases and improve cancer treatment. Our findings underscore that carefully modulating cellular senescence and rejuvenation processes could pave the way for novel regenerative and anti-cancer strategies.

Precision health is a person-centered approach to health and well-being that is operationalized through evaluating omics-level profiles and their associations with the exposome. A precision health approach addresses the challenge that "one size does not fit all" in the management of an individual's health.

The purpose of this white paper is to introduce a Precision Health Model and its application in research and clinical care.

An expert panel reviewed and synthesized the extant literature related to precision health, the current state of omics' science, and common exposome factors that influence the health/illness continuum. A case study provides the framework for the application of the Precision Health Model.

Precision health and key domains are defined and serve as the platform for the development of the Precision Health Model.

Application of the Precision Health Model will provide inclusive, equitable, person-centered research and clinical care.

Longitudinal studies now document how leukocyte telomere attrition and epigenetic aging may be accelerated in people with HIV (PWH), in particular, around the time of HIV acquisition, during primary HIV infection, and during untreated chronic HIV infection. Whether chronic low-level inflammation and epigenetic aging go hand in hand or may be partially independent continues to be investigated in PWH and other settings. Epigenetic age acceleration (EAA) in PWH has now clearly been shown to be potentially reversible during successful antiretroviral therapy (ART). These studies point to how the beneficial effects of modern ART also include EAA-decelerating effects that seem large enough to regard ART as a kind of epigenetic rejuvenation therapy. Progress in the field has been limited in part due to the high cost of assessing EAA based on DNA methylation measures ("epigenetic clocks"). Demonstration of the clinical relevance of EAA and its reversion by ART will depend on large studies associating EAA with cardiovascular events and other adverse aging-associated endpoints in PWH.

Cellular senescence is intricately linked with numerous changes observed in the aging process, including the depletion of the stem cell pool and the decline in tissue and organ functions. Over the past three decades, efforts to halt and reverse aging have intensified, bringing rejuvenation closer to reality. Current strategies involve treatments using stem cells or their derivatives, such as the secretome. This article aims to highlight key points and evaluate the utilization of secretome derived from mesenchymal stromal cells (MSCs) as an antisenescent approach. Employing a quasi-systematic research approach, the authors conducted a comprehensive analysis based on a search algorithm targeting the in vitro effects of MSC-derived secretome on rescuing cells from a senescent state. Reviewing 39 articles out of 687 hits retrieved from PubMed and Scopus without a time limit, the authors synthesized information and identified common types of MSC-tissue sources utilized (including bone marrow-MSCs, umbilical cord-MSCs, iPSC-derived MSCs, adipose tissue-MSCs, dental pulp-MSCs, amniotic membrane-MSCs, placenta-MSCs, gingival-MSCs, urine-MSCs, and commercially available MSC lineages) from both human and other species (such as mice and rats). The authors also examined the forms of secretome tested (including conditioned media and extracellular vesicles), the cell types treated (MSCs or other cell types), methods/biomarkers of monitoring senescence/rejuvenation, and the mechanisms involved. Ultimately, this review underscores the proof-of-principle of the beneficial effects of MSC-derived secretome in reversing cellular senescence across various cell types. Such insights might aid the scientific community in designing improved in vitro and in vivo assays for future research and clinical validation of this promising cell-free therapy.

Partial reprogramming induced by the controlled and cyclical overexpression of Yamanaka factors in the nervous system has so far succeeded in reversing some aging-associated phenotypes, such as improving memory function. These promising results suggest that partial reprogramming could be a potential strategy to prevent or mitigate aging-related pathologies like tauopathies, including Alzheimer's disease. Here, we explore the potential of this strategy in addressing tauopathy development in the P301S mouse model. To achieve this, a new transgenic animal was created that can inducibly overexpress Yamanaka factors upon doxycycline administration and carries the Tau-P301S mutation, which leads to tauopathy development. The results of this study show a significant improvement in key pathological features of tauopathies in the hippocampus, including reversed tauopathy, alleviated reactive astrogliosis, age-related reduction of the H3K9me3 epigenetic marker, along with improved spatial memory, which has been described as deteriorated in this model. These findings reinforce the potential of partial reprogramming as a therapeutic strategy to combat brain pathologies associated with aging.

Dental mesenchymal stem cells (DMSCs) are pivotal for tooth development and periodontal tissue health and play an important role in tissue engineering and regenerative medicine because of their multidirectional differentiation potential and self-renewal ability. The cellular microenvironment regulates the fate of stem cells and can be modified using various optimization techniques. These methods can influence the cellular microenvironment, activate disparate signaling pathways, and induce different biological effects. "Epigenetic regulation" refers to the process of influencing gene expression and regulating cell fate without altering DNA sequences, such as histone methylation. Histone methylation modifications regulate pivotal transcription factors governing DMSCs differentiation into osteo-/odontogenic lineages. The most important sites of histone methylation in tooth organization were found to be H3K4, H3K9, and H3K27. Histone methylation affects gene expression and regulates stem cell differentiation by maintaining a delicate balance between major trimethylation sites, generating distinct chromatin structures associated with specific downstream transcriptional states. Several crucial signaling pathways associated with osteogenic differentiation are susceptible to modulation via histone methylation modifications. A deeper understanding of the regulatory mechanisms governing histone methylation modifications in osteo-/odontogenic differentiation and immune-inflammatory responses of DMSCs will facilitate further investigation of the epigenetic regulation of histone methylation in DMSC-mediated tissue regeneration and inflammation. Here is a concise overview of the pivotal functions of epigenetic histone methylation at H3K4, H3K9, and H3K27 in the regulation of osteo-/odontogenic differentiation and renewal of DMSCs in both non-inflammatory and inflammatory microenvironments. This review summarizes the current research on these processes in the context of tissue regeneration and therapeutic interventions.

In vitro models of neuronal aging and gene manipulation in human neurons (hNeurons) are valuable tools for investigating human brain aging and diseases. Here, we present a protocol for applying human embryonic stem cell (hESC)-derived neurons to model aging and the further application of small interfering RNA (siRNA)-mediated gene silencing for functional investigations. We describe steps for neuronal differentiation and culture, siRNA transfection, and technical considerations to ensure reproducibility. Our protocol enables investigations of the molecular mechanism underlying neuronal aging and facilitates drug evaluation. For complete details on the use and execution of this protocol, please refer to Zhang et al.1.

Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment, profoundly influencing both the onset and progression of various diseases. Under physiological conditions, oxidative free radicals generated by the mitochondrial oxidative respiratory chain, endoplasmic reticulum, and NADPH oxidases can be effectively neutralized by NRF2-mediated antioxidant responses. These responses elevate the synthesis of superoxide dismutase (SOD), catalase, as well as key molecules like nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), thereby maintaining cellular redox homeostasis. Disruption of this finely tuned equilibrium is closely linked to the pathogenesis of a wide range of diseases. Recent advances have broadened our understanding of the molecular mechanisms underpinning this dysregulation, highlighting the pivotal roles of genomic instability, epigenetic modifications, protein degradation, and metabolic reprogramming. These findings provide a foundation for exploring redox regulation as a mechanistic basis for improving therapeutic strategies. While antioxidant-based therapies have shown early promise in conditions where oxidative stress plays a primary pathological role, their efficacy in diseases characterized by complex, multifactorial etiologies remains controversial. A deeper, context-specific understanding of redox signaling, particularly the roles of redox-sensitive proteins, is critical for designing targeted therapies aimed at re-establishing redox balance. Emerging small molecule inhibitors that target specific cysteine residues in redox-sensitive proteins have demonstrated promising preclinical outcomes, setting the stage for forthcoming clinical trials. In this review, we summarize our current understanding of the intricate relationship between oxidative stress and disease pathogenesis and also discuss how these insights can be leveraged to optimize therapeutic strategies in clinical practice.

Aging is a complicated process, featuring the progressive deterioration of physiological functions and a heightened susceptibility to diseases including neurodegenerative disorders, cardiovascular diseases, and cancer. Apigenin, a flavonoid existing in various plants, has attracted attention due to its potential role in anti-aging. In this investigation, the potential effect of apigenin on extending lifespan in Saccharomyces cerevisiae (yeast) and Drosophila melanogaster (flies) was explored. The results indicate that apigenin significantly extends both replicative and chronological life duration in yeast, as well as longevity in male and female flies. Apigenin treatment also improves resistance to oxidative stress in both organisms, as manifested by enhanced survival, decreased reactive oxygen species (ROS) levels and upregulation of antioxidant enzymes. Furthermore, apigenin activates crucial elements of the proteostasis network (PN), such as upregulation of proteostasis-related enzymes activity and genes expression. Network analysis revealed that apigenin affects aging conserved in the longevity-regulating pathway. Notably, Pten is a hub target in flies. Apigenin regulated DmPten at both mRNA and protein expression level while modulating downstream targets, including the phosphorylation of AKT and associated signalling pathways. In a high-sucrose diet (HSD) model, Apigenin treatment extended lifespan, reduced hemolymph glucose levels, enhanced Pten expression, suppressed AKT phosphorylation, and modulated the phosphorylation status of S6K and expression of DmFoxo. These results demonstrate that apigenin could serve as a longevity research object and potential therapeutic drug for promoting health and longevity through its antioxidant and proteostatic properties.

Dermal white adipose tissue (dWAT), distinguished by its origin from cells within the dermis and independence from subcutaneous fat tissue, has garnered significant attention for its non-metabolic functions. Characterized by strong communication with other components of the skin, dWAT mediates the proliferation and recruitment of various cell types by releasing adipogenic and inflammatory factors. Here, we focus on the modulatory role of dWAT at different stages during wound healing, highlighting its ability to mediate the adipocyte-to-myofibroblast transition which plays a pivotal role in the physiology and pathology processes of skin fibrosis, scarring, and aging. This review highlights the regulatory potential of dWAT in modulating wound healing processes and presents it as a target for developing therapeutic strategies aimed at reducing scarring and enhancing regenerative outcomes in skin-related disorders.

Atherosclerosis and aortic aneurysms are prevalent cardiovascular diseases in the elderly, characterized by chronic inflammation and oxidative stress. This study explores the role of CircXYLT1 in regulating oxidative stress and vascular remodeling in age-related vascular diseases. RNA sequencing revealed a significant upregulation of CircXYLT1 in the vascular tissues of aged mice, highlighting its potential role in age-related vascular diseases. Using a carotid artery wire injury model, we performed adeno-associated virus (AAV)-mediated knockdown and overexpression of CircXYLT1. Key oxidative stress markers, including reactive oxygen species (ROS) and malondialdehyde (MDA), were measured. Knockdown of CircXYLT1 increased oxidative stress and reduced antioxidant protein expression (SOD, GPX), while overexpression led to decreased oxidative damage and enhanced vascular smooth muscle cell (VSMC) proliferation. Mechanistically, CircXYLT1 interacted with PTBP1, reducing its nuclear localization and modulating downstream chemokine signaling pathways. These findings suggest that CircXYLT1 plays a critical role in vascular remodeling and oxidative stress regulation, offering potential as a therapeutic target for managing cardiovascular diseases in aging populations.

The central premise of this article is that a portion of the established relationships between social determinants of health and racial and ethnic disparities in cancer morbidity and mortality is mediated through differences in rates of biological aging processes. We further posit that using knowledge about aging could enable discovery and testing of new mechanism-based pharmaceutical and behavioral interventions ("gerotherapeutics") to differentially improve the health of cancer survivors from minority populations and reduce cancer disparities. These hypotheses are based on evidence that lifelong differences in adverse social determinants of health contribute to disparities in rates of biological aging ("social determinants of aging"), with individuals from minoritized groups experiencing accelerated aging (ie, a steeper slope or trajectory of biological aging over time relative to chronological age) more often than individuals from nonminoritized groups. Acceleration of biological aging can increase the risk, age of onset, aggressiveness, and stage of many adult cancers. There are also documented negative feedback loops whereby the cellular damage caused by cancer and its therapies act as drivers of additional biological aging. Together, these dynamic intersectional forces can contribute to differences in cancer outcomes between survivors from minoritized vs nonminoritized populations. We highlight key targetable biological aging mechanisms with potential applications to reducing cancer disparities and discuss methodological considerations for preclinical and clinical testing of the impact of gerotherapeutics on cancer outcomes in minoritized populations. Ultimately, the promise of reducing cancer disparities will require broad societal policy changes that address the structural causes of accelerated biological aging and ensure equitable access to all new cancer control paradigms.

Cis-regulatory elements (CREs) control gene expression and are dynamic in their structure and function, reflecting changes in the composition of diverse effector proteins over time1. However, methods for measuring the organization of effector proteins at CREs across the genome are limited, hampering efforts to connect CRE structure to their function in cell fate and disease. Here we developed PRINT, a computational method that identifies footprints of DNA-protein interactions from bulk and single-cell chromatin accessibility data across multiple scales of protein size. Using these multiscale footprints, we created the seq2PRINT framework, which uses deep learning to allow precise inference of transcription factor and nucleosome binding and interprets regulatory logic at CREs. Applying seq2PRINT to single-cell chromatin accessibility data from human bone marrow, we observe sequential establishment and widening of CREs centred on pioneer factors across haematopoiesis. We further discover age-associated alterations in the structure of CREs in murine haematopoietic stem cells, including widespread reduction of nucleosome footprints and gain of de novo identified Ets composite motifs. Collectively, we establish a method for obtaining rich insights into DNA-binding protein dynamics from chromatin accessibility data, and reveal the architecture of regulatory elements across differentiation and ageing.

Single-cell three-dimensional (3D) genome techniques have advanced our understanding of cell-type-specific chromatin structures in complex tissues, yet current methodologies are limited in cell throughput. Here we introduce a high-throughput single-cell Hi-C (dscHi-C) approach and its transcriptome co-assay (dscHi-C-multiome) using droplet microfluidics. Using dscHi-C, we investigate chromatin structural changes during mouse brain aging by profiling 32,777 single cells across three developmental stages (3 months, 12 months, and 23 months), yielding a median of 78,220 unique contacts. Our results show that genes with significant structural changes are enriched in pathways related to metabolic process and morphology change in neurons, and innate immune response in glial cells, highlighting the role of 3D genome organization in physiological brain aging. Furthermore, our multi-omics joint assay, dscHi-C-multiome, enables precise cell type identification in the adult mouse brain and uncovers the intricate relationship between genome architecture and gene expression. Collectively, we developed the sensitive, high-throughput dscHi-C and its multi-omics derivative, dscHi-C-multiome, demonstrating their potential for large-scale cell atlas studies in development and disease.

Aging is characterized by cellular degeneration and impaired physiological functions, leading to a decline in male sexual desire and reproductive capacity. Oxidative stress (OS) lead to testicular aging by impairing the male reproductive system, but the potential mechanisms remain unclear. In the present study, the functional status of testicular tissues from young and aged boars was compared, and the transcriptional responses of Leydig cells (LCs) to hydrogen peroxide (H2O2)-induced senescence were explored, revealing the role of OS in promoting aging of the male reproductive system. 601 differentially expressed genes (DEGs) associated with OS, cell cycle regulation, and intracellular processes were identified. These DEGs were significantly enriched in critical aging pathways, including the p53 signaling pathway, autophagy, and cellular senescence. Protein-protein interaction (PPI) network analysis unveiled 15 key genes related to cell cycle and DNA replication, with polo-like kinase 3 (PLK3) exhibiting increased expression under OS. In vitro, PLK3 knockdown significantly enhanced the viability and antioxidant capacity of LCs under OS. This study deepens our understanding of how LCs respond to OS and provides new therapeutic targets for enhancing cellular resistance to oxidative damage and promoting tissue health.

Excessive abdominal fat deposition in chickens disadvantages feed conversion, meat production, and reproductive performance. Intramuscular fat contributes to meat texture, tenderness, and flavor, serving as a vital indicator of overall meat quality. Therefore, a comprehensive analysis of the regulatory mechanisms governing differential deposition of abdominal versus intramuscular fat is essential in breeding higher-quality chickens with ideal fat distribution. This review systematically summarizes the regulatory mechanisms underlying intramuscular and abdominal fat traits at chromatin, genomic, transcriptional, post-transcriptional, translational, and epigenetic-modification scales. Additionally, we summarize the role of non-coding RNAs and protein-coding genes in governing intramuscular and abdominal fat deposition. These insights provide a valuable theoretical foundation for the genetic engineering of high-quality and high-yielding chicken breeds.

Cardiac fibrosis, a key contributor to ventricular pathologic remodeling and heart failure, currently lacks effective therapeutic approaches.

Small extracellular vesicles from young healthy human plasma (Young-sEVs) were characterized via protein marker, transmission electron microscopy, and nanoparticle tracking analysis, then applied in cellular models and mouse models of cardiac fibrosis. Western blotting and qRT-PCR were used to identify protective signaling pathways in cardiac fibroblasts (CFs).

Young-sEVs significantly inhibited cardiac fibrosis and subsequent cardiac dysfunction post-myocardial infarction (MI) in mice. The main findings included that echocardiographic assessments four weeks post-MI indicated that Young-sEVs improved left ventricular ejection fraction (LVEF) and fractional shortening (LVFS), and reduced left ventricular internal diameter in diastole (LVIDd) and systole (LVIDs). Treatment with Young-sEVs also decreased Masson-positive fibroblast areas and collagen synthesis in cardiac tissue. However, sEVs from the old control group did not achieve the above effect. Consistent with in vivo results, Young-sEVs could also inhibit the proliferation, migration, and collagen synthesis of CFs in the TGF-β1-induced cellular fibrosis model. High-throughput microRNA (miRNA) sequencing and qRT-PCR analysis revealed that miR-664a-3p was abundant in Young-sEVs. The high expression of miR-664a-3p significantly inhibited the proliferation, migration, and collagen synthesis of TGF-β1-induced CFs. However, suppressing the expression of miR-664a-3p in Young-sEVs eliminated their therapeutic effect on cardiac fibrosis in mice. Further studies confirmed SMAD4 as a direct downstream target of miR-664a-3p, whose overexpression could reverse the anti-fibrotic effects of miR-664a-3p.

In summary, these findings firstly revealed that Young-sEVs could directly bind to the 3'-untranslated region of SMAD4 mRNA through miR-664a-3p, thereby inhibiting the TGF-β/SMAD4 signaling pathway to protect heart from fibrosis and improve cardiac function. Considering the ease of obtaining plasma-derived sEVs, our study offers a promising therapeutic strategy for heart failure, with the potential for rapid clinical translation in the near future.

Aging often triggers dental pulp fibrosis, resulting in clinical repercussions such as increased susceptibility to dental infections, compromised tooth vitality, and reduced responsiveness to dental interventions. Despite its prevalence, the precise molecular mechanisms underlying this condition remains unclear. Leveraging single-cell transcriptome analysis from both our own and publicly available datasets, we identified Ccrl2+ macrophages as particularly vulnerable during the early stages of aging. Notably, dental pulp progenitors with high expression of RARRES2, a unique ligand for CCRL2, facilitate the selective recruitment of a specific macrophage population to the stem cell niches. This process culminates in the formation of the ligand-receptor complex that engages CMKLR1, a receptor broadly expressed across macrophage populations. This interaction drives macrophage activation and expansion through the RARRES2/CCRL2/CMKLR1 axis. Through rigorous experimental validation, we demonstrated that macrophage activation and expansion within stem cell niches lead to increased secretion of proinflammatory factors, promoting dental pulp fibrosis during aging. Our findings uncover the intricate molecular dynamics of dental pulp aging, emphasizing immune microenvironment interactions. This study provides a novel perspective on potential therapeutic strategies for age-related pulp diseases by targeting macrophages and modulating the immune microenvironment.

DNA methylation (DNAm) data from human samples has been leveraged to develop "epigenetic clock" algorithms that predict age and other aging-related phenotypes. Some DNAm clocks were trained using DNAm obtained from blood cells, while other clocks were trained using data from diverse tissue/cell types. To assess how DNAm clocks perform across non-blood tissue types, we applied DNAm algorithms to DNAm data generated from 9 different human tissue types.

We generated array-based DNAm measurements for 973 samples from deceased tissue donors from the GTEx (Genotype Tissue Expression) project representing nine distinct tissue types: lung, colon, prostate, ovary, breast, kidney, testis, skeletal muscle, and whole blood. For all samples, we generated DNAm clock estimates for 8 epigenetic clocks and characterized these tissue-specific clock estimates in terms of their distributions, correlations with chronological age, correlations of clock estimates between tissue types, and association with participant characteristics.

For each clock, the mean DNAm age estimate varied substantially across tissue types, and the mean values for the different clocks varied substantially within tissue types. For most clocks, the correlation with chronological age varied across tissue types, with blood often showing the strongest correlation. Each clock showed strong correlation across tissues, with some evidence of some residual correlation after adjusting for chronological age. In lung tissue, smoking generally had a positive association with epigenetic age.

This work demonstrates how differences in epigenetic aging among tissue types leads to clear differences in DNAm clock characteristics across tissue types. Tissue or cell-type specific epigenetic clocks are needed to optimize predictive performance of DNAm clocks in non-blood tissues and cell types.

Aging is a complex and universal process marked by gradual functional declines at the cellular and tissue levels, often leading to a range of aging-related diseases such as diabetes, cardiovascular diseases, and cancer. Delaying the aging process can help prevent, slow down, and alleviate the severity of these various conditions, enhancing overall health and well-being. Alpha-glucosidase inhibitors (AGIs) are a class of widely used antidiabetic drugs that inhibit alpha-glucosidase in the small intestinal mucosa, delaying carbohydrate absorption and reducing postprandial hyperglycemia. Beyond their roles in diabetes treatment, AGIs have shown potential in extending lifespan and effectively treating aging-related diseases by modulating oxidative stress, gut microbiota, inflammatory responses, and nutrient-sensing pathways. This review summarizes recent advancements in the application of AGIs for preventing and treating aging and aging-related diseases, with a focus on their mechanisms and roles in these processes.

The DNA methylation field has matured from a phase of discovery and genomic characterization to one seeking deeper functional understanding of how this modification contributes to development, ageing and disease. In particular, the past decade has seen many exciting mechanistic discoveries that have substantially expanded our appreciation for how this generic, evolutionarily ancient modification can be incorporated into robust epigenetic codes. Here, we summarize the current understanding of the distinct DNA methylation landscapes that emerge over the mammalian lifespan and discuss how they interact with other regulatory layers to support diverse genomic functions. We then review the rising interest in alternative patterns found during senescence and the somatic transition to cancer. Alongside advancements in single-cell and long-read sequencing technologies, the collective insights made across these fields offer new opportunities to connect the biochemical and genetic features of DNA methylation to cell physiology, developmental potential and phenotype.

The aging process is a multifactorial biological phenomenon starting at birth and persisting throughout life, characterized by a decline in physiological functions and adaptability. This decline results in the diminished capacity of aging organisms to respond to environmental changes and stressors, leading to reduced efficiency in metabolic, immune, and hormonal functions. As behavioral flexibility wanes, older individuals face longer recovery times and increased vulnerability to diseases. While early research proposed nine core hallmarks of mammalian aging, recent studies have expanded this framework to twelve key characteristics: epigenetic changes, genomic instability, telomere shortening, loss of proteostasis, altered metabolism, mitochondrial dysfunction, cellular senescence, disrupted intercellular communication, stem cell depletion, immune system dysfunction, accumulation of toxic metabolites, and dysbiosis. Given the growing interest in the aging area, we propose to add a new hallmark: impaired water homeostasis. This potential hallmark could play a critical role in aging processes and might open new directions for future research in the field. This review enhances our understanding of the physiological aspects of aging in dogs, suggesting new clinical intervention strategies to prevent and control issues that may arise from the pathological degeneration of these hallmarks.

Human lungs consist of a distinctive array of cell types, which are subjected to persistent challenges from chemical, mechanical, biological, immunological, and xenobiotic stress throughout life. The disruption of endoplasmic reticulum (ER) homeostatic function, triggered by various factors, can induce ER stress. To overcome the elevated ER stress, an adaptive mechanism known as the unfolded protein response (UPR) is activated in cells. However, persistent ER stress and maladaptive UPR can lead to defects in proteostasis at the cellular level and are typical features of the lung aging. The aging lung and associated lung diseases exhibit signs of ER stress-related disruption in cellular homeostasis. Dysfunction resulting from ER stress and maladaptive UPR can compromise various cellular and molecular processes associated with aging. Hence, comprehending the mechanisms of ER stress and UPR components implicated in aging and associated lung diseases could enable to develop appropriate therapeutic strategies for the vulnerable population.

Aging is a natural physiological process involving biological and genetic pathways. Growing evidence suggests that alterations in the epigenome during aging result in transcriptional changes, which play a significant role in the onset of age-related diseases, including cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. For this reason, the epigenetic alterations in aging and age-related diseases have been reviewed, and the major extrinsic factors influencing these epigenetic alterations have been identified. In addition, the role of the gut microbiome and its metabolites as epigenetic modifiers has been addressed.

Long-term exposure to extrinsic factors such as air pollution, diet, drug use, environmental chemicals, microbial infections, physical activity, radiation, and stress provoke epigenetic changes in the host through several endocrine and immune pathways, potentially accelerating the aging process. Diverse studies have reported that the gut microbiome plays a critical role in regulating brain cell functions through DNA methylation and histone modifications. The interaction between genes and the gut microbiome serves as a source of adaptive variation, contributing to phenotypic plasticity. However, the molecular mechanisms and signaling pathways driving this process are still not fully understood.

Extrinsic factors are potential inducers of epigenetic alterations, which may have important implications for longevity. The gut microbiome serves as an epigenetic effector influencing host gene expression through histone and DNA modifications, while bidirectional interactions with the host and the underexplored roles of microbial metabolites and non-bacterial microorganisms such as fungi and viruses highlight the need for further research.

The risks of obesity and epigenetic age acceleration (EAA) have drawn widespread attention. Lipid accumulation product (LAP) is a simple and reliable indicator of obesity; however, the relationship between LAP and EAA remains unclear.

Data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2002 were used. The EAA was assessed using a self-administered questionnaire in the database. LAP was calculated based on triglycerides and waist circumference. The association between LAP and EAA was analyzed using logistic regression models, subgroup analysis, and smooth curve fitting.

A total of 1796 participants were included in the study, of whom 1055 had EAA. After adjusting for relevant covariates, participants with EAA generally had higher LAP levels than those without EAA (258.1 vs. 244.6). Logistic regression analysis showed that individuals in the highest LAP quartile (Q4) were more likely to have EAA than those in the lowest quartile (Q1) (OR = 1.77; 95% CI 1.31-2.39; P < 0.001). The area under the curve of the adjusted logistic regression analysis was 0.706.

This research indicates that elevated LAP levels are independently linked to an increased risk of EAA, and early intervention to reduce high LAP levels is necessary to mitigate the progression of EAA.

Ageing is a complex biological process in which a gradual decline in physiological fitness increases susceptibility to diseases such as neurodegenerative disorders and cancer. Cellular senescence, a state of irreversible cell-growth arrest accompanied by functional deterioration, has emerged as a pivotal driver of ageing. In this Review, we discuss how heterochromatin loss, telomere attrition and DNA damage contribute to cellular senescence, ageing and age-related diseases by eliciting genome instability, innate immunity and inflammation. We also discuss how emerging therapeutic strategies could restore heterochromatin stability, maintain telomere integrity and boost the DNA repair capacity, and thus counteract cellular senescence and ageing-associated pathologies. Finally, we outline current research challenges and future directions aimed at better comprehending and delaying ageing.

Poly-L-lactic acid (PLLA), a well-established biostimulator that induces collagenases, is widely used among clinical practice to treat skin aging. However, the precise regulatory effect of PLLA on different dermal cell subsets beyond fibroblast has not been fully elucidated. In this study, we constructed in vivo PLLA injection and in vitro PLLA-adipocyte co-culture models to analyze the regulatory effects of PLLA on the volume, differentiation, lipolysis, and thermogenic capacity of dermal adipocyte. We found that PLLA injection significantly reduced the thickness of dermal fat in mice. In co-culture assay, PLLA showed no effect on adipogenesis, but stimulated the lipolysis activity. Interestingly, PLLA also enhanced the differentiation of fat cells into beige fat cells, which possess higher thermogenic capacity. In mechanical study, we blocked adipocyte lactate uptake with a monocarboxylate transporter (MCT1/4) inhibitor and found that the regulatory effect of PLLA on dermal adipocyte relies on its metabolite lactate. In summary, our results suggest that PLLA has complex regulatory effects on the dermal cells, and its ability to improve skin aging is not fully attributed to stimulating collagen synthesis, but also partially involves adipocytes.No Level Assigned This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

While observational studies have suggested associations linking aging and mental disorders, the question of causality has remained unclear. This study aimed to explore the causal relationship between aging level and major mental disorders.

We utilized Two-Sample Mendelian randomization (2SMR) with mental disorders data and aging indicators information from an extensive genome-wide association study (GWAS) database. The GWAS database is a comprehensive resource that compiles genetic association data, encompassing a sample size of over 450,000 individuals. We employed five methods for 2SMR and single nucleotide polymorphisms were chosen as instrumental variables.

Our analyses consistently supported a bidirectional causal association between the Frailty Index (FI) and Major Depressive Disorder (MDD). Furthermore, our findings indicated potential influences, such as Attention-Deficit/Hyperactivity Disorder (ADHD) and Bipolar Disorder (BD) affecting GrimAge, and Anxiety Disorder (AD) impacting Left Hand Grip Strength (LHGS). In contrast, we observed no significant correlations for other mental disorders on FI, Telomere Length (TL), GrimAge, Appendicular Lean Mass (ALM), and LHGS. In the reverse direction, FI showed a significant impact on the risk of MDD, AD, and ADHD, while LHGS affected the risk of MDD. Importantly, no significant associations were found between other factors and the risk of MDD, BD, AD, Schizophrenia (SZ), and ADHD.

This 2SMR analysis has presented evidence for a bidirectional causal relationship between FI and MDD, while the relationship between ADHD, BD, and GrimAge should be more considered. Our study provides genetic evidence supporting a causal link between aging indicators and several mental illnesses.

Chronic myelomonocytic leukemia (CMML) is a severe myeloid malignancy affecting the elderly, for which therapeutic options are limited. DNA hypomethylating agents (HMAs) provide transient responses, failing to eradicate the malignant clone. Hematopoietic stem cell (HSC) aging involves heterochromatin reorganization, evidenced by alterations in histone marks H3K9me2 and H3K9me3. These repressive marks together with DNA methylation are essential for suppressing transposable elements (TEs). In solid cancers, the antitumor efficacy of HMAs involves the derepression of TEs, mimicking a state of viral infection. In this study, we demonstrate a significant disorganization of heterochromatin in CMML HSCs and progenitors (HSPCs) characterized by an increase in the repressive mark H3K9me2, mainly at the level of TEs, and a repression of immune and age-associated transcripts. Combining HMAs with G9A/GLP H3K9me2 methyltransferase inhibitors reactivates these pathways, selectively targeting mutated cells while preserving wild-type HSCs, thus offering new therapeutic avenues for this severe myeloid malignancy.

The intricate organization of distinct cellular compartments is paramount for the maintenance of normal biological functions and the orchestration of complex biochemical reactions. These compartments, whether membrane-bound organelles or membraneless structures like Cajal bodies and RNA transport granules, play crucial roles in cellular function. Liquid-liquid phase separation (LLPS) serves as a reversible process that elucidates the genesis of membranelles structures through the self-assembly of biomolecules. LLPS has been implicated in a myriad of physiological and pathological processes, encompassing immune response and tumor genesis. But the association between LLPS and aging has not been clearly clarified. A recent advancement in the realm of aging research involves the introduction of a new edition outlining the twelve hallmarks of aging, categorized into three distinct groups. By delving into the role and mechanism of LLPS in the formation of membraneless structures at a molecular level, this review encapsulates an exploration of the interaction between LLPS and these aging hallmarks, aiming to offer novel perspectives of the intricate mechanisms underlying the aging process and deeper insights into aging therapeutics.

The impressive achievements made in the last century in extending the lifespan have led to a significant growth rate of elderly individuals in populations across the world and an exponential increase in the incidence of age-related conditions such as cardiovascular diseases, diabetes mellitus type 2, and neurodegenerative diseases. To date, geroscientists have identified 12 hallmarks of aging (genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, impaired macroautophagy, mitochondrial dysfunction, impaired nutrient sensing, cellular senescence, stem cell exhaustion, defective intercellular communication, chronic inflammation, and gut dysbiosis), intricately linked among each other, which can be targeted with senolytic or senomorphic drugs, as well as with more aggressive approaches such as cell-based therapies. To date, side effects seriously limit the use of these drugs. However, since rejuvenation is a dream of mankind, future research is expected to improve the tolerability of the available drugs and highlight novel strategies. In the meantime, the medical community, healthcare providers, and society should decide when to start these treatments and how to tailor them individually.

RE-1 silencing transcription factor (REST) is a key repressor of neural genes. REST is upregulated under stress signals, aging and neurodegenerative diseases, but although it is upregulated, its function is lost in Alzheimer's Disease. However, why it becomes inactive remains unclear. Here, we show that the NAD-dependent deacetylase SIRT6 regulates REST expression, location and activity. In the absence of SIRT6, REST is overexpressed but mislocalized, leading to a partial loss of its activity and causing it to become toxic. SIRT6 deficiency abrogates REST and EZH2 interaction, perturbs the location of REST to the heterochromatin Lamin B ring, and leads to REST target gene overexpression. SIRT6 reintroduction or REST methyl-mimic K494M expression rescues this phenotype, while an acetyl-mimic mutant loses its function even in WT cells. Our studies define a novel regulatory switch where, depending on SIRT6 presence, the function of REST is regulated by post-translational modifications on K494 (Ac/me), affecting neuronal gene expression. In WT cells (left), REST functions as a repressor due to its methylation, which allows proper localization and interaction with EZH2. In SIRT6 KO cells (right), REST is overexpressed, but it is mislocalized and acetylated instead of methylated, impairing its interaction with EZH2. REST localizes in the cytoplasm in autophagosomes. The overall increase in REST without SIRT6 results in non-functional and toxic REST proteins. During aging, SIRT6 declines in the brain, while REST is upregulated to protect it. In pathological aging, where SIRT6 levels are very low, the increase in REST without SIRT6 results in non-functional and toxic REST.

Hypertrophic cardiomyopathy is an autosomal dominant cardiac disease. The mechanisms that determine its variable expressivity are poorly understood. Epigenetics could play a crucial role in bridging the gap between genotype and phenotype by orchestrating the interplay between the environment and the genome regulation. In this study we aimed to establish a possible correlation between the peripheral blood DNA methylation patterns and left ventricular hypertrophy severity in patients with hypertrophic cardiomyopathy, evaluating the potential impact of lifestyle variables and providing a biological context to the observed changes.

Methylation data were obtained from peripheral blood samples (Infinium MethylationEPIC BeadChip arrays). We employed multiple pair-matched models to extract genomic positions whose methylation correlates with the degree of left ventricular hypertrophy in 3 monozygotic twin pairs carrying the same founder pathogenic variant (MYBPC3 p.Gly263Ter). This model enables the isolation of the environmental influence, beyond age, on DNA methylation changes by removing the genetic background. Our results revealed a more anxious personality among more severely affected individuals. We identified 56 differentially methylated positions that exhibited moderate, proportional changes in methylation associated with left ventricular hypertrophy. These differentially methylated positions were enriched in regions regulated by repressor histone marks and tended to cluster at genes involved in left ventricular hypertrophy development, such as HOXA5, TRPC3, UCN3, or PLSCR2, suggesting that changes in peripheral blood may reflect myocardial alterations.

We present a unique pair-matched model, based on 3 monozygotic twin pairs carrying the same founder pathogenic variant and different phenotypes. This study provides further evidence of the pivotal role of epigenetics in hypertrophic cardiomyopathy variable expressivity.

DNA methylation (DNAm) has unique properties which makes it a potential biomarker for lifestyle-related exposures. Epigenetic clocks, particularly DNAm-based biological age predictors [epigenetic age (EA)], represent an exciting new area of clinical research and deviations of EA from chronological age [epigenetic age acceleration (EAA)] have been linked to overall health, age-related diseases, and environmental exposures.

This observational study investigates the relationships between biological aging and various dietary factors within the LifeLines-DEEP Cohort. These factors include diet quality, processed food consumption, dietary glycemic load, and intake of vitamins involved in maintaining the epigenetic homeostasis (vitamins B-9, B-12, B-6, B-2, and C).

Dietary records collected using food-frequency questionnaires were used to estimate diet quality [LifeLines Diet Score (LLDS)], measure the intake of unprocessed/ultraprocessed food according to the NOVA food classification system, and the adequacy of the dietary intake of vitamins B-9, B-12, B-2, B-6, and C. EA using Horvath, Hannum, Levine, and Horvath2 epigenetic clock models and DNAm-predicted telomere length (DNAm-TL) were calculated from DNAm data in 760 subjects. Associations between dietary factors and EAA were tested, adjusting for sex, energy intake, and body composition.

LLDS was associated with EAA (EAA_Horvath: β: -0.148; P = 1 × 10-4; EAA_Hannum: β: -0.148; P = 9 × 10-5; EAA_Levine: β: -0.174; P = 1 × 10-5; and EAA_Horvath2: β: -0.176; P = 4 × 10-6) and DNAm-TL (β: 0.116; P = 0.003). Particularly, EAA was associated with dietary glycemic load (EAA_Horvath: β: 0.476; P = 9 × 10-10; EAA_Hannum: β: 0.565; P = 1 × 10-13; EAA_Levine: β: 0.469; P = 5 × 10-9; EAA_Horvath2: β: 0.569; P = 1 × 10-13; and DNAmTL adjusted for age: β: -0.340; P = 2 × 10-5) and different measures of food processing (NOVA classes 1 and 4). Positive EAA was also associated with inadequate intake of vitamin B-12 (EAA_Horvath: β: -0.167; P = 0.002; EAA_Hannum: β: -0.144; P = 0.007; and EAA_Horvath2: β: -0.126; P = 0.019) and C (EAA_Hannum: β: -0.136; P = 0.010 and EAA_Horvath2: β: -0.151; P = 0.005).

Our findings corroborate the hypothesis that nutrition plays a pivotal role in influencing epigenetic homeostasis, especially DNAm, thereby contributing to individual health trajectories and the pace of aging.