Longevity Papers

Aging is an inevitable process integrating chronological alterations of multiple organs. A growing aging population necessitates feasible anti-aging strategies to deal with age-associated health problems. We previously performed a proteomics analysis in a healthy-aging cohort, and revealed an age-related downregulation of ARMH4. Here we generate a whole-body Armh4-knockout mouse line, and investigate its impact on systemic aging. Under normal feeding conditions, Armh4 deficiency significantly lowers spontaneous mortality and extends maximum lifespan. In the female mice, Armh4 deficiency postpones sexual maturity for one week. At the organ level, the age-related pathologies of the heart, liver, kidney, and spleen are substantially alleviated by Armh4 deletion. Mechanistically, ARMH4 interacts with IGF1R/FGFR1 to sensitize the activation of PI3K-Akt-mTORC1 and Ras-MEK-ERK pathways, consequently promoting protein synthesis and inhibiting autophagy. Moreover, ARMH4 is required for the maintenance of IGF1R/FGFR1 expressions through regulating the transcription factor c-Myc. Therefore, ARMH4 maintains a positive-feedback growth signaling to promote aging.

Targeting senescent pancreatic β-cells represents a promising therapeutic avenue for age-related diabetes; however, current anti-senescence strategies often compromise β-cell mass. In this study, human amniotic mesenchymal stem cell-derived small extracellular vesicles (hAMSC-sEVs) were identified as a novel intervention that can be used to effectively counteract cellular senescence and preserve β-cell integrity. We aimed to systemically delineate the molecular mechanisms underlying hAMSC-sEV-mediated reversal of β-cell senescence in age-related diabetes. In oxidative stress-induced and naturally aged β-cell models, hAMSC-sEVs mitigated senescence-associated phenotypes, restored mitochondrial homeostasis, and enhanced insulin secretion capacity. In aged diabetic mice, administering these vesicles significantly ameliorated hyperglycemia, improved glucose tolerance, and reversed β-cell functional decline by reducing senescent β-cell populations, reinstating β-cell identity markers, and suppressing senescence-associated secretory phenotype (SASP) component production. Mechanistic investigations revealed that the miR-21-5p-enriched hAMSC-sEVs directly target the interleukin (IL)-6 receptor α subunit (IL-6RA), thereby inhibiting signal transducer and activator of transcription 3 (STAT3) phosphorylation at tyrosine 705 and its subsequent nuclear translocation. This epigenetic modulation alleviated STAT3-mediated transcriptional repression of the mitochondrial calcium uniporter (MCU), rectifying age-related mitochondrial calcium mishandling and insulin secretion defects. Genetic ablation of MCU clearly established the central role of the miR-21-5p/IL-6RA/STAT3/MCU axis in this regulatory cascade. Our findings reveal hAMSC-sEVs as a novel senotherapeutic strategy for age-related diabetes, elucidating the pivotal role of miR-21-5p-driven epigenetic-mitochondrial calcium homeostasis in reversing β-cell dysfunction, establishing a framework for targeting cellular senescence in metabolic disorders.

Skin is both the most visible and most environmentally exposed organ, with apparent aging phenotypes. DNA methylation clocks faithfully capture the progression of aging, but so far have been limited to training on abundant in vitro material or invasively collected samples to generate narrow methylomes using microarray platforms. Here, we demonstrate that skin biological age can be measured directly from a person's face with superior accuracy, using non-invasive tape-stripping. We developed two clocks, MitraSolo, based on single CpGs, and MitraCluster, on regions, trained on the largest enzymatic methyl-sequencing dataset of human epidermis (n = 462). Our models were validated on independent, longitudinal, and external datasets and were compared against established clocks. They predict age accurately, with an error of approximately 4 years, outperforming others on epidermal samples. They maintain high accuracy at low sequencing depths, enabling cost-effective scalability and show intra-individual prediction variation <2 years, highlighting their reproducibility. Their predictive capacity generalised across anatomical sites, conversion and sampling methodologies and on in vitro material. They also successfully captured the rejuvenating effects of Yamanaka factor treatment. MitraSolo and MitraCluster represent a new class of epigenetic clocks optimised for human skin with characteristics that support their use in clinical research, intervention monitoring, and skincare innovation.

During aging and cellular senescence, repetitive elements are frequently transcriptionally derepressed across species and cell types. Among these, the most abundant repeats by copy number in the human genome are Alu retrotransposons. Though Alu elements are often studied for their mutagenic potential, there is increasing appreciation for their contributions to other biological functions, including pro-inflammatory signaling and mitochondrial dysfunction. However, a comprehensive analysis of Alu-driven molecular changes remains to be conducted, and Alu's potential contributions to aging features remain incompletely characterized. Here, we show that overexpression of an AluJb transposon in human primary IMR-90 fibroblasts leads to large-scale alterations across the transcriptome, cellular proteome, and secretome. Functional genomics analyses reveal alterations in aging pathways, broadly, and mitochondrial metabolism, proteostasis, cell cycle, and extracellular matrix pathways, more specifically. Our results demonstrate that Alu transcriptional upregulation is sufficient to drive widespread disruptions to cellular homeostasis that mirror aging-associated alterations.

Organ-specific plasma protein signatures identified via proteomics profiling could be used to quantitatively track organ aging. However, the genetic determinants and molecular mechanisms underlying the organ-specific aging process remain poorly characterized. Here we integrated large-scale plasma proteomic and genomic data from 51,936 UK Biobank participants to uncover the genetic architectures underlying aging across 13 organs. We identified 119 genetic loci associated with organ aging, including 27 shared across multiple organs, and prioritized 554 risk genes involved in organ-relevant biological pathways, such as T cell-mediated immunity in immune aging. Causal inference analyses indicated that accelerated heart and muscle aging increase the risk of heart failure, whereas kidney aging contributes to hypertension. Moreover, smoking initiation was positively linked to the aging of the lung, intestine, kidney, and stomach. These findings establish a genetic foundation for understanding organ-specific aging and provide insights for promoting healthy longevity.

Biological aging clocks capture heterogeneous rates of aging in individuals and transform current medical practice toward translational preventive medicine. Here, we developed a clinical aging clock based on routine blood biochemistry markers from 59,741 healthy samples in a Southeast Asian cohort. We established a novel correction method to address the systematic skew in predictions from first-generation clocks. This correction improved the accuracy of age-acceleration predictions for disease risks and enhanced interpretability for disease-driven and organ-specific aging processes without relying on mortality data. Based on only seven biomarkers, our clock accurately predicts both self-reported and physician-annotated ICD health data, indicating an increased hazard ratio. Importantly, the clock is robust even in the presence of acute infections or transient immune activation. To demonstrate the multi-ethnic generalizability of our biological age clock, we validated our approach using data from both the NHANES and UK Biobank cohorts. Our approach demonstrates the feasibility of a simple, robust, and interpretable clinical aging clock with potential for real-world implementation in personalized health monitoring and preventive care.

Epigenetic age acceleration (EAA) reflects biological aging processes beyond chronological age and is associated with morbidity and mortality. However, the causal gene regulatory mechanisms underlying epigenetic age remain unclear. Here, we integrated single-cell expression quantitative trait loci (sc-eQTL) data across 14 immune cell types with Mendelian randomization (MR) and Bayesian colocalization to identify eGenes whose cell-type-specific expression causally influences four major epigenetic clocks: IEAA, HannumAge, GrimAge, and PhenoAge. We identified 58 unique eGenes with strong evidence of causality, including ATM, ENO1, DDX5, and PSMB9, with effects often confined to specific immune lineages such as CD8 T and NK cells. Functional enrichment analysis revealed that these eGenes are involved in immune regulation, NF-κB signaling, and mitochondrial metabolism. Phenome-wide association studies (PheWAS) further linked top eGenes, particularly ATM and DDX5, to a spectrum of aging-related traits, including metabolic and immune disorders. Our findings highlight the importance of immune-cell-specific gene regulation in shaping biological aging and provide candidate targets for future aging interventions.

Previous studies have developed proteomic aging clocks to estimate biological age and predict mortality and age-related diseases. However, these earlier clocks were based on cross-sectional data, capturing only the cumulative aging burden at a single time point but were unable to reflect the dynamic trajectory of biological aging over time. We constructed a longitudinal proteomic aging index (LPAI) using data from 4684 plasma proteins measured by the SomaScan 5K Array across three visits in the Atherosclerosis Risk in Communities (ARIC) study (ages 67-90 at last visit). Our two-step approach applied functional principal component analysis (FPCA) to capture protein-level change patterns over time, followed by elastic net penalized Cox regression for protein selection. LPAI was constructed in a randomly selected training set of ARIC participants (N = 2954), tested among the remaining ARIC participants (N = 1267), and validated externally in Multi-Ethnic Study of Atherosclerosis (MESA) participants (N = 3726, ages 53-94 at last exam). Using Cox proportional hazards model, higher LPAI was associated with increased all-cause mortality (HR = 2.50, 95% CI: [2.15, 2.92] per SD), CVD mortality (HR = 1.79, 95% CI: [1.34, 2.39] per SD), and cancer mortality (HR = 1.96, 95% CI: [1.45, 2.64] per SD) risk in ARIC, with statistically significant and directionally consistent associations also observed in MESA. Additionally, higher LPAI was associated with increased multimorbidity and frailty. This study demonstrates the feasibility of developing biological aging measures from longitudinal proteomics data and supports LPAI as a biomarker for aging-related health risks.

Sinus node dysfunction, a prevalent arrhythmia in aging populations, is characterized by fibrosis and loss of pacemaker activity, necessitating pacemaker implantation. Current therapies fail to reverse the underlying pathology. Small extracellular vesicles derived from human induced pluripotent stem cells possess regenerative potential but lack targeted delivery. Here, we engineer platelet membrane-fused vesicles that synergistically combine collagen targeting for ischemic injury homing with immune evasion. In a rat model of sinus node dysfunction, these modified vesicles exhibit 3.1-fold higher accumulation in the sinoatrial node compared to unmodified vesicles, resulting in a 63% reduction in fibrosis and significant restoration of heart rate and intrinsic pacemaker function. The vesicles mitigate fibroblast activation and protect cardiomyocytes from oxidative stress. This study establishes a targeted, cell-free nanotherapeutic platform for resolving fibrosis and electrophysiological dysfunction in sinus node disease.

Aging and tissue repair involve multilayered and spatially heterogeneous remodeling across transcriptional, biochemical, and cellular dimensions, yet prevailing definitions rely on isolated molecular markers that obscure how biochemical and transcriptional states co-evolve in tissues. Here we present RamanOmics, a multimodal framework that integrates single-nucleus RNA sequencing (snRNA-seq), spatial transcriptomics, and label-free Raman imaging to map the spatial vibrational-biochemical and molecular architecture of aging and senescence directly in intact tissues. Applied to mouse lung and skin, RamanOmics generates spatially resolved biochemical-molecular maps revealing tissue-specific programs: lung senescent cells are enriched for extracellular matrix (ECM) remodeling and TGF-b; signaling (Serpine1, Dab2, Igfbp7), whereas skin senescence is dominated by keratinization and barrier homeostasis modules (Krt10, Lor, Sbsn). Across tissues, we identify a conserved branched-chain fatty-acid-linked biochemical profile and Raman signature (1131-1135 cm-1) that robustly marks p21+ senescent cells. To unify these layers, we develop a machine learning derived multimodal barcode that quantitatively integrates biochemical and transcriptional features, enabling non-destructive identification of senescence in situ. In a wound-healing model, RamanOmics further reveals coordinated reactivation of barrier-repair programs in senescent cells, marked by upregulation of Krt10, Lor, Sbsn, Sfn, and Dmkn together with matching increases in lipid-associated Raman signatures, confirming biological generalizability beyond steady-state aging. By directly integrating gene programs to spatial vibrational-biochemical states, RamanOmics provides a general framework and resource for scalable, multimodal profiling of cellular states.

The Werner syndrome (WS) is characterized with both premature aging and tumorigenic phenotypes. In this study, we introduced a tumorigenic mutation p53N236S (referred as p53S later), which is found in immortalized WS mouse embryo fibroblasts, back into WS mice to investigate its impact on the telomere dysfunction-induced aging process. Intriguingly, the introduction of p53S rescued the aging phenotypes of WS mice, showing the extension of the lifespan and the delay in organ degeneration. Further studies revealed that the introduction of p53S transcriptionally upregulated the DREAM/MMB pathway and downstream DNA helicases and telomere maintenance proteins, facilitated the recruitment of these proteins to G-quadruplex (G4) DNA structures proximal to DNA replication forks, and promoted the unwinding of G4. By comparing the cellular responses to pyridostatin and hydroxyurea, respectively, we confirmed that p53S specifically regulates G4-related DNA replication stress. Thus, p53S compensates the loss of Wrn and telomerase function, solves the DNA replication, telomere lengthening, and cell proliferation problems in WS cells, and ultimately, rescues the aging phenotypes of WS. Together, our data indicate that certain tumorigenic features can be applied to balance with premature aging, rescuing the aging phenotype without tumor risk. This study suggests a new mechanism in aging regulation and provides the possibility of developing a tumor-free longevity strategy and targeting G4 and DNA replication in aging-related tumor therapy.