Wiley: Aging Cell: Table of Contents

Personalized‐Context‐Aware Age Gap: A New Multi‐Omics Measurement Based on Age‐Enhanced Model AOE‐Net for Aging Acceleration and Chronic Disease Risk Prediction

Thu, 28 May 2026 23:22:07 -0700

Addressing systemic biases in traditional aging clocks, we introduce PAAG, a context-aware multi-omics metric derived from the pre-trained AOE-Net. PAAG accurately captures localized aging acceleration, demonstrating superior predictive power for chronic disease risks and clinical outcomes across diverse aging populations.

ABSTRACT

Aging is a global issue that affects human health and increases disease risk. The traditional concept of the “age gap (AG),” defined as the difference between estimated biological age and an individual's chronological age, has been used for self-monitoring the risk of age-related diseases. However, the current AG does not account for the stratified aging patterns across different stages of chronological age, which may lead to biased or paradoxical interpretations of aging acceleration. To address these limitations, we propose Personalized-context-Aware Age Gap (PAAG), a robust metric to estimate aging acceleration, based on our new pre-training model AOE-Net (Age Order Enhanced Network). AOE-Net employs age-order enhanced contrastive learning on multi-omics data from healthy populations to learn latent representations that accurately reconstruct aging trajectories by capturing biological deviation rather than technical deviation in omics data. We demonstrate that PAAG, generated via fine-tuning AOE-Net, significantly outperforms AG of conventional first- and second-generation aging clocks in predicting clinical outcomes. This superior predictive power was validated across diverse age-related diseases and phenotypes: pan-cancer (overall survival), subclinical atherosclerosis (PESA score), and osteoporosis (bone mineral density). Crucially, PAAG serves as a context-aware metric that may improve the clinical outcome prediction of existing aging clocks. Furthermore, interpretive analysis of PAAG's molecular drivers revealed a strong functional enrichment for immune-response pathways, providing a shared mechanistic link between accelerated aging and disease. Collectively, PAAG could serve as a stable indicator of aging acceleration for clinically assessing age-related diseases, and AOE-Net provides an effective pre-training model for aging study and PAAG evaluation.

Ligand‐Independent Activation of Notch1 by Cathepsin L Induces CUX1/p16INK4a‐Dependent Endothelial Senescence Associated With Atherosclerosis

Thu, 28 May 2026 23:20:48 -0700

CTSL activates Notch1/RBPJ in a ligand-independent fashion, inducing CUX1/p16^INK4a-dependent endothelial senescence associated with atherosclerosis.

ABSTRACT

Our post-GWAS functional analysis revealed that cathepsin L (CTSL) is an upstream regulator of CUX1, and it induces p16^INK4a-dependent and atherosclerosis-associated senescence by indirectly activating CUX1 transcription in a process that requires its proteolytic activity. This suggests an unidentified transcription regulator between CTSL and CUX1, and CTSL-mediated cleavage of this regulator could transcribe CUX1, inducing senescence. Here, in search of this transcriptional regulator, we discovered that Notch1 is a substrate of CTSL, and CTSL can proteolytically activate Notch1 in a ligand-independent fashion, liberating NICD. NICD, after complexing with RBPJ in the nuclei, induces CUX1/p16^INK4a-dependent senescence. Consistently, an upregulation of both CTSL and NICD, along with elevated cellular senescence in the plaques isolated from patients with atherosclerosis, was observed. In addition, we showed that endothelial deletion of CUX1 in the atherosclerosis-prone ApoE^−/− mice blocks high-fat diet-induced senescence throughout the entire plaques, and these ApoE^−/− mice exhibit similar phenotypes as the atherosclerosis-prone models with CTSL and Notch1/RBPJ inactivation including attenuated atherosclerotic lesion, intact and well-organized elastin fibers, and reduced macrophage content of plaque. This further supports our findings that both CTSL and Notch1/RBPJ are upstream regulators of CUX1, regulating senescence. Thus, while our studies identify a non-canonical Notch1 pathway that can be activated by CTSL in a ligand-independent fashion to induce senescence, our findings also reveal a role of senescence in the development of atherosclerosis. This provides new insight into developing drugs aimed to target cellular senescence for atherosclerosis.

Blm10/PA200‐Activated 20S Proteasomes Promote α‐Synuclein Degradation and Bypass Proteasome Inhibition in Parkinson's Disease Models

Thu, 28 May 2026 06:39:11 -0700

This study demonstrates that α-synuclein expression stabilizes the proteasome activator Blm10, thereby linking α-synuclein stress to changes in proteasome composition. Blm10/PA200-capped 20S proteasomes efficiently degrade both monomeric and oligomeric α-synuclein and remain resistant to α-synuclein-induced inhibition. Our findings reveal a proteasome configuration that maintains proteolytic activity under proteotoxic stress.

ABSTRACT

Protein homeostasis is essential for maintaining normal cellular function. However, protein homeostasis efficiency declines with age, leading to the accumulation of aberrant protein structures associated with neurodegenerative diseases such as Parkinson's disease (PD). PD is characterized by the aggregation of alpha-synuclein (αSyn) into cytoplasmic inclusions. This process is accompanied by elevated phosphorylation at serine 129 (S129). The accumulation of αSyn into aggregates and their propagation disrupts key proteostasis pathways, including the ubiquitin–proteasome system (UPS) or autophagy, contributing to cellular dysfunction and neuronal death. This study identified the proteasome activator Blm10 and its human ortholog PA200 as modulators of αSyn degradation and toxicity. The conserved Blm10/PA200 protein plays a key role in regulating proteasome activity and assembly. The αSyn expression increases Blm10 protein stability through autophagy inhibition, in a manner dependent on αSyn phosphorylation at S129 in yeast. Overexpression of BLM10 or PA200 reduces αSyn aggregation and enhances αSyn turnover via activation of the 20S proteasome in yeast and mammalian cells. Blm10 and PA200-capped 20S proteasomes efficiently degrade both monomeric as well as oligomeric αSyn in vitro. Notably, capped proteasomes retain proteolytic activities in the presence of αSyn, indicating resistance to αSyn-induced inhibition, in contrast to 20S or 26S proteasomes. These results reveal a distinct proteasome subtype that bypasses UPS impairment and restores proteolytic capacity under proteotoxic stress. Our findings establish Blm10/PA200 as critical regulators of αSyn proteostasis and highlight its protective role in maintaining protein homeostasis and cell viability under conditions of αSyn toxicity.

Correction to “The Variant Senescence‐Associated Secretory Phenotype Induced by Centrosome Amplification Constitutes a Pathway That Activates Hypoxia‐Inducible Factor‐1α”

Wed, 27 May 2026 19:43:38 -0700

Aging Cell, Volume 25, Issue 6, June 2026.

Loss of Brain‐Derived Estrogen Is Associated With Sex‐ and Age‐Dependent Alterations in Memory, Affective Behavior, and Hippocampal Extracellular Matrix Gene Expression

Tue, 26 May 2026 02:42:23 -0700

Age, sex, and estrogen loss are widely recognized risk factors for Alzheimer's disease. Here, we show that brain-specific aromatase knockout (bArKO) and the resulting estrogen loss lead to memory impairment, reduced social interaction, and extracellular environment dysregulation selectively in aged female mice, but not in young female or male mice.

ABSTRACT

Nearly two-thirds of Americans with Alzheimer's disease (AD) are women. Prior research suggested that women with AD have lower brain estrogen levels than those without AD. However, how estrogen deficiency modulates this sex-based difference in AD vulnerability is not well understood. Aromatase, the key enzyme for estrogen biosynthesis, is expressed in both neurons and astrocytes of the brain, including the hippocampus. This study aims to assess the mechanistic link between brain-selective aromatase deficiency and sex-specific AD vulnerability. To achieve this goal, we used brain-specific aromatase knockout (bArKO) and whole-body total aromatase knockout (tArKO) mice of both sexes at young (6- to 8-month-old) and old (> 19-month-old) ages. We found that aromatase deletion decreased brain estrogen levels in bArKO mice and circulating and brain estrogen levels in tArKO mice. Impairment in spatial working memory and social interaction behavior was observed only in old female bArKO and tArKO mice. Both young and old female, but not male, tArKO mice displayed depression-like behavior. Bulk RNA-seq analysis of hippocampal tissues from young and old bArKO mice of both sexes revealed enrichment of extracellular matrix-related pathways and upregulated mRNA and/or protein expression of extracellular matrix-associated genes (e.g., Col1a1, Ccn2, Dcn, and Ogn) in old female bArKO mice compared to littermate control mice. These findings point to a novel link between local brain estrogen deficiency and sex- and age-specific extracellular matrix changes in the hippocampus of old bArKO female mice accompanied by AD-related memory and behavioral impairments.

Tubular Omega‐3 Fatty Acid Receptor FFAR4 Deficiency Aggravated Renal Aging and Chronic Kidney Disease

Sat, 23 May 2026 07:34:19 -0700

This study illustrates that omega-3 PUFAs with their receptor FFAR4 alleviate tubular senescence and fibrosis in aged and fibrotic kidneys. Furthermore, we indicate that tubular FFAR4 improves renal senescence via 15d-PGJ2-PPARγ-Klotho signaling, and suppresses kidney fibrosis by senescent tubular cell-driven fibroblast activation. Here, we propose a therapeutic strategy of omega-3 PUFAs, but also highlight that tubular FFAR4 is a potential target against renal aging and CKD.

ABSTRACT

Aging leads to renal function decline and increases the risk of chronic kidney disease (CKD). Omega-3 polyunsaturated fatty acids (PUFAs) are essential fatty acids for humans, exerting their functions via free fatty acid receptor 4 (FFAR4). Clinical studies indicate that omega-3 PUFAs supplementation shows benefits for the elderly population and CKD patients, but these results remain controversial. Herein, we found that omega-3 PUFAs alleviated renal fibrosis and tubular senescence in aged mice, adenine diet-induced CKD mice, and unilateral ureteral obstruction (UUO) mice. Meanwhile, omega-3 fatty acid receptor FFAR4 expression in tubular epithelial cells (TECs) were down-regulated in the old population and CKD patients, positively correlated with renal dysfunction. Systemic or TEC-specific knockout of FFAR4 aggravated renal aging and CKD in mice. Mechanically, FFAR4 agonism increases the production of endogenous PPARγ activator 15-deoxy-∆12,14-Prostaglandin J2 (15d-PGJ2), and improves PPARγ-dependent tubular epithelial cell senescence, which was indicated by anti-aging marker Klotho expression, senescence-associated β-galactosidase (SA-β-gal) activity, and profibrotic factor TGF-β1 secretion. The study demonstrated a novel role of FFAR4 from senescent TECs on fibroblast activation via paracrine effects and highlighted the therapeutic effects of omega-3 PUFAs with their receptor FFAR4 as an attractive drug target against renal aging and CKD.

Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study

Fri, 22 May 2026 00:36:43 -0700

Can we boost vaccine responses in older adults? In a double-blind, randomised, placebo-controlled pilot study (n = 40, > 65 years), spermidine supplementation (6 mg/day, 13 weeks) was safe and significantly improved immune responses following a 3rd SARS-CoV-2 vaccine dose. Vaccine non-responders showed hallmarks of immune senescence—↑ p16, mTOR signalling, in lymphocytes. Remarkably, spermidine reversed these senescence signatures, restored autophagic flux, and selectively enhanced spike-specific IgG, memory B-cell recall, and neutralising antibodies in non-responders. Takeaway: Targeting immune senescence with spermidine rescues vaccine failure in ageing populations, and senescence markers could help predict poor vaccine responsiveness.

ABSTRACT

Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders. Single-cell RNA-seq after treatment revealed increased expression of TFEB targets and autophagy-related genes in B cells, in line with elevated autophagic flux. These findings suggest that targeting immune cell senescence with Spermidine may improve vaccine responsiveness in older adults and highlight immune-senescence markers as potential predictors of vaccine failure in ageing populations.

Immunosenescence and Vaccine Efficacy in Aging: Dynamic Interplay of Gut Microbiota and mTOR Signaling Pathways

Jiaxuan Li, Yuhong Zhang, Daijun Yu, Jianhua Li, Keda Chen, Lisheng Chu — Fri, 22 May 2026 00:35:03 -0700

Aging impairs vaccine efficacy through gut microbiota dysbiosis and mTOR hyperactivation, which together drive inflammaging and weaken immune memory. This review highlights the bidirectional microbiota–mTOR axis and proposes that combining mTOR inhibitors with microbiota modulation offers a promising strategy to enhance vaccine responses in older adults.

ABSTRACT

Aging significantly impairs vaccine efficacy in older adults, driven by immunosenescence, inflammaging, and disruptions in the gut microbiota-mTOR-immune axis. This review synthesizes current evidence on how aging alters vaccine-induced immune responses through the interplay of gut microbiota dysbiosis and dysregulated mTOR signaling. Age-related microbial diversity declines and reduced short-chain fatty acid (SCFA) production exacerbate inflammation, while heightened mTOR activity suppresses autophagy, promotes pro-inflammatory states, and impairs T/B cell function, collectively diminishing antibody production and immune memory formation. We highlight the bidirectional interaction between SCFAs and mTOR, where SCFAs mitigate mTOR overactivation to enhance immune regulation, and mTOR dysregulation further aggravates microbial dysbiosis, forming a vicious cycle. Critically, this review systematically stratifies the evidence, distinguishing preclinical mechanistic insights from correlative human data. Animal and human studies suggest that targeting this axis—via mTOR inhibitors, probiotics, or dietary interventions—holds promise for improving vaccine responses in the elderly. We propose future research directions, including personalized vaccine strategies leveraging microbiota profiling and mTOR modulation, to address the challenges of infection in aging populations and advance precision medicine for healthy aging.

Supplements and Drugs Are Associated With Biological Age in a Cohort of Exceptionally Healthy Individuals

Thu, 21 May 2026 13:23:33 -0700

Supplement users have lower epigenetic biological age than non-users. Several supplements or supplement classes are associated with some benefit on epigenetic age in either cross-sectional or longitudinal analyses.

ABSTRACT

In this cross-sectional cohort we analyzed data from 4260 “health enthusiasts” who purchased at least one saliva-based DNA epigenetic test between 2020 and 2025 and completed detailed lifestyle and supplement questionnaires. A proprietary 9-CpG clock with a mean absolute error of 5.4 years served as the primary biomarker of biological age. High prevalence (71%) of supplement use in this cohort increased our power to study the effects of supplements compared to earlier studies that focused on the general population. We tested the association between 84 commonly used supplements and biological age measured as Age Residual. In our cross-sectional analysis, a commercially available, delayed-release calcium-alpha-ketoglutarate (dAKG) + vitamin supplement (“Rejuvant”) was associated with an average 1.8-year lower Age Residual. The difference remained significant in models adjusted for age, sex, smoking, health status and additional covariates. In contrast, participants who reported taking regular AKG showed a much smaller and statistically insignificant benefit. Among medications, there was a non-significant benefit of antihistamine use, although the analysis was sample-size limited. In a longitudinal subset, intake of coenzyme Q10 (CoQ10) and dAKG was associated with increased odds of a lower Age Residual, but the results were not significant after multivariate correction. In conclusion, this study underscores the utility of an inexpensive saliva-based epigenetic test for population-level aging research and the benefits of health enthusiast cohorts. It highlights AKG and CoQ10, among others, as promising supplements warranting further investigation. Limitations like healthy user and recruitment bias remain and will require future controlled trials to fully address.

Methionine Restriction Extends Yeast Lifespan by Activating Non‐Nitrogen‐Starvation‐Induced Autophagy Through Limiting Methylation of Protein Phosphatase 2A

Wed, 20 May 2026 13:45:22 -0700

Methionine restriction extends yeast replicative and chronological lifespan as a consequence of depletion of S-adenosylmethionine (SAM). SAM depletion leads to demethylation of PP2A and increased phosphorylation of Npr2 which activates non-nitrogen-starvation (NNS) induced autophagy; early methionine restriction is sufficient to activate persistent autophagy and lifespan extension, implicating an epigenetic memory.

ABSTRACT

Methionine restriction (MR) extends the lifespan and healthspan of numerous eukaryotic organisms, but the molecular mechanisms at play are unclear. Here we find that the ability of MR to extend the budding yeast chronological and replicative lifespans is the consequence of reduced methionine conversion to the methyl donor S-adenosylmethionine (SAM). Mechanistically, the key antiaging event downregulated by MR is the methylation of protein phosphatase 2A (PP2A). In chronological aging cells under MR, unmethylated PP2A no longer dephosphorylates Npr2, a component of the SEACIT complex, resulting in activation of non-nitrogen-starvation (NNS)-induced autophagy. Deletion of genes encoding components of SEACIT or ATG1 (encoding a central player in the initiation of autophagy) blocked the ability of MR to extend lifespan, showing the critical role of the NNS-induced autophagy pathway in lifespan extension by MR. We identify the relevant Npr2 site dephosphorylated by PP2A as serine 362 and show that Npr2 phosphomimetic mutants are sufficient to extend chronological and replicative lifespan. Finally, we discover that MR only during the early stages of chronological aging is sufficient to prolong autophagy and extend lifespan. In addition to elucidating the molecular mechanism of MR-mediated lifespan extension, this study highlights potential therapeutic targets to achieve lifespan and healthspan extension in humans without the challenging long-term dietary changes required to achieve MR.

RORA Targeting PRNP Modulates Age‐Related Cataract via Activation Oxidative Injury‐Induced Cellular Senescence and Apoptosis of Lens Epithelial Cells

Wed, 20 May 2026 13:34:32 -0700

The molecular mechanisms of RORA targeting PRNP activate oxidative injury-induced cellular senescence and apoptosis of lens epithelial cells. Current research confirms that the transcription factor RORA targets PRNP, exacerbating cellular senescence and apoptosis of LECs (Figure 7). The RORA-PRNP-p53/p21/Bax axis may offer an innovative framework for identifying potent therapeutic targets for ARC and other age-related ocular diseases. All these molecular mechanisms were created with BioGDP.com.

ABSTRACT

Age-related cataract (ARC) is a severe vision-impairing disorder primarily caused by oxidative stress-induced senescence and apoptosis of lens epithelial cells (LECs). In this study, a sodium selenite-induced oxidative stress cataract model in neonatal rats was established to simulate the pathological progression of ARC. We found that retinoic acid receptor-related orphan receptor α (RORA) exacerbates cellular senescence and oxidative damage by targeting prion protein (PRNP), and its small-molecule inhibitor SR3335 exhibits therapeutic potential in regulating ARC progression. In vitro experiments showed that inhibiting RORA significantly alleviated cellular senescence, enhanced the anti-apoptotic capacity of LECs, and improved their resistance to oxidative stress, whereas activating RORA exerted opposite effects. In vivo, intravitreal injection of recombinant PRNP protein was demonstrated to abrogate the protective effect of RORA silencing, thereby exacerbating the progression of ARC. Mechanistically, RNA sequencing and dual-luciferase reporter assay revealed that RORA binds to its downstream target PRNP. RORA targets PRNP to regulate the p53/p21/Bax signaling pathway, thereby suppressing both cellular senescence and apoptosis. These findings highlight the critical role of the transcription factor RORA in ARC development by modulating oxidative stress injury, apoptosis, and senescence in LECs. The identification of PRNP as a downstream target of RORA may provide a novel dual-target strategy for ARC treatment.