Longevity Papers

Aging proceeds in a nonuniform spatiotemporal manner across tissues. While metabolic stress and chronic inflammation are implicated, the underlying mechanisms remain elusive. Here, we propose that imperfect wound healing-a failure of full resolution-creates and sustains pathological niches that drive progressive age-related dysfunction. Using the liver as a model system, we deconstruct this 'imperfect repair'. We posit that it is driven by a pro-fibrotic, non-resolving microenvironment sustained by complex crosstalk between functionally heterogeneous senescent cells and non-senescent scar-associated cell (SAC) populations (including macrophages, endothelial cells (ECs), and hepatic stellate cells (HSCs)). This pathological ecosystem is further shaped by the spatial context of hepatic zonation collapse, and the dysregulation of core signaling hubs, like WNT, Transforming Growth Factor (TGF)-β, and YAP and TAZ (YAP/TAZ). Viewing aging through the lens of imperfect repair provides a unifying framework linking senescence, inflammation, and fibrosis. This perspective shifts the therapeutic paradigm from targeting single senescent cells toward engineering the pathological niche itself, and redirects focus from end-stage disease, to the sub-clinical, spatial origins of tissue vulnerability.

Accelerated biological aging (BA) is linked to adverse cardiovascular events, but its role in heart failure with preserved ejection fraction (HFpEF) remains unclear. We analyzed 1,727 HFpEF patients from RED-CARPET Study (ChiCTR2000039901), assessing BA using Klemera-Doubal and PhenoAge methods. During a median 4.9-year follow-up, 321 all-cause and 180 cardiovascular deaths occurred. After full adjustment, per 1-SD increase in BA acceleration showed significantly higher risk of all-cause mortality (KDMAge HR 1.55, 95% CI 1.40-1.72; PhenoAge HR 1.24, 95% CI 1.11-1.40) and cardiovascular mortality (KDMAge HR 1.47, 95% CI 1.28-1.69; PhenoAge HR 1.21, 95% CI 1.04-1.41). BA acceleration was also significantly related to increased left ventricular mass index (LVMI), relative wall thickness, and E/e' ratio. Mediation analysis revealed that both LVMI and the E/e' ratio partially mediated the relationship between BA acceleration and mortality. These findings suggest BA acceleration may serve as a key prognostic marker in patients with HFpEF.

Atrazine (ATR), a widely employed triazine herbicide, poses multiorgan toxicity through environmental bioaccumulation. The potential link between chronic pesticide exposure and cardiovascular aging remains a critical yet underexplored public health concern. Lycopene (LYC), a natural carotenoid with antioxidative properties, demonstrates therapeutic potential against xenobiotic-induced pathologies, although its cardioprotective mechanisms against ATR require systematic elucidation. This study employed a chicken model to investigate cardiac outcomes following chronic ATR exposure with or without LYC intervention. Histopathological assessments revealed that LYC supplementation substantially mitigated the ATR-induced myocardial structural disorganization and interstitial abnormalities. Ultrastructural analysis confirmed the capacity of LYC to reverse the ATR-triggered mitochondrial architecture disruption. Mechanistic investigations identified that ATR exposure induces tricarboxylic acid (TCA) cycle disorder, leading to pathological copper ion accumulation. These metabolic disturbances were associated with elevated cellular senescence biomarkers and disrupted proteostasis. LYC administration demonstrated dual regulatory effects, effectively normalizing copper homeostasis and restoring mitochondrial metabolic flux. The findings establish that chronic ATR exposure promotes cardiac aging through TCA cycle-impaired-mediated cuproptosis, a novel pathway counteracted by LYC via modulation of copper metabolism and mitochondrial functionality. This study enhances our understanding of environmental-toxicant-induced cardiovascular pathogenesis and positions LYC as a promising therapeutic candidate for mitigating pesticide-associated cardiotoxicity.

Aging is accompanied by functional decline and increased senescence of pancreatic {beta}-cells. These changes may be influenced by islet-resident macrophages (iMACs) that remodel tissue in response to environmental cues. To explore the molecular mechanisms underlying {beta}-cell aging and senescence, we profiled small non-coding RNAs (sncRNAs) in FACS-sorted {beta}-cells and iMACs from 3-, 12-, and 22-month-old mouse islets or from senescence-associated {beta}gal (SA-{beta}gal) positive {beta}-cells of 8-month-old mice. Overall, senescent {beta}-cells displayed distinct sncRNA signatures that only partially overlapped with those of aging. However, several miRNAs previously found to be deregulated in obese or diabetic conditions were modulated in both aging and senescent {beta}-cells, including upregulation of miRNAs linked to inflammation. In vitro exposure to pro-inflammatory cytokines partially reproduced these profiles. Aging also reshaped the {beta}-cell tRNA-derived fragment (tRF) pool, enhancing global mitochondrial tRF levels. Interestingly, some changes in miRNAs and tRFs were {beta}-cell specific, whereas others occurred also in other aged metabolic tissues. iMACs also showed age-related sncRNA remodeling, including upregulation of anti-inflammatory miRNAs and mitochondrial tRFs, suggesting adaptive immune reprogramming. Together, these data reveal a profound, coordinated reshaping of the sncRNA landscape in {beta}-cells and iMACs during aging, offering new insights into molecular mechanisms driving age-related islet dysfunction.

Epigenetic clocks estimate chronological and biological age from DNA methylation patterns, but conventional models typically train on hundreds of thousands of CpG sites and large training cohorts. We previously demonstrated that tissue-unique methylation sites change in a predictable manner upon aging and disease. Here, we demonstrate that clocks built from tissue-unique methylation sites enable accurate age prediction in the human colon using a compact feature set and limited training data. We trained a machine learning model on healthy colon tissue, identifying CpG sites that capture both chronological age and anatomical location (proximal vs. distal). This clock maintains high predictive performance (r = 0.978; MAE 3.9 years) while using an order of magnitude fewer sites and samples than traditional approaches. Applying the model to tissues from individuals with HIV infection, inflammatory bowel disease (IBD), and colonic polyps reveals consistent patterns of accelerated aging, while aspirin treatment is associated with partial deceleration. Our findings establish tissue-unique CpGs as a powerful basis for efficient, interpretable clocks and offer new insights into how chronic inflammation and neoplasia shape the aging landscape of the colon.

The growing epidemiological burden of multimorbidity among older adults underscores an urgent need to develop interventions that can address multiple age-related diseases (ARDs) at once. Yet, the biological mechanisms driving their co-occurrence remain poorly understood. In this study, we conducted a multivariate genome-wide association analysis to dissect the shared genetic architecture of five common ARDs: heart attack, high cholesterol, hypertension, stroke, and type 2 diabetes. We defined this shared genetic component as the multivariate age-related disease factor (mvARD) and identified 263 independent variants across 180 genomic loci associated with mvARD. These variants were significantly enriched for associations with extreme human longevity, lending empirical support for the geroscience hypothesis in humans. Integrative gene prioritization using transcriptome-wide association studies, colocalization analysis, and Mendelian randomization identified four high-confidence genes in blood-DCAF16, PHF13, MGA, and GTF2B-with putative causal roles on mvARD. Using two-sample Mendelian randomization, we also found several modifiable lifestyle factors, including body mass index and dietary intake, that causally influenced the risk for multiple ARDs. Together, our findings revealed a shared genetic basis for common ARDs that overlapped with the biology of human aging and pointed to potential molecular and behavioral targets for delaying disease onset and promoting healthy aging.

Background Intrinsic lymphatic contractility is essential for tissue fluid balance, immunity and organ function, yet no FDA-approved pharmacologic treatments specifically restore lymphatic contractility. Lymph is returned to the circulation by ion channel-driven cyclic contractions of collecting lymphatic vessels. Although voltage-gated sodium (NaV) channels drive cardiomyocyte excitability, their role in lymphatic muscle cell (LMC) physiology is not well defined. We identified NaV1.3, a NaV channel historically viewed as developmentally restricted and limited in adult tissues, as unexpectedly and selectively expressed in adult lymphatic muscle but absent from heart, vascular smooth muscle, and mature brain. We tested whether selective NaV1.3 activation restores impaired lymphatic pumping in aging and radiation injury. Methods NaV1.3 expression in LMCs was confirmed through single-cell RNA sequencing analysis and immunostaining of mouse and human lymphatic vessels. Lymphatic contractility was quantified by in vivo fluorescence lymphangiography and interstitial fluid clearance was measured with a new bioluminescence assay. NaV1.3 function was assessed in young, aged, and radiation-injured mice. NaV1.3 knockout (Scn3a-/-) mice established the requirement of NaV1.3 for basal lymphatic excitability and responsiveness to the NaV1.3-specific activator, Tf2. Results In mouse and human lymphatic vessels, NaV1.3 is expressed in adult LMCs. Although dispensable for basal lymphatic contractions, NaV1.3 acted as a pharmacologically recruitable reserve that amplified contractile output. Acute NaV1.3 activation with Tf2 increased lymphangion ejection fraction and accelerated interstitial fluid clearance. Tf2 fully restored lymphatic pumping in aged mice and partially rescued radiation-induced contractile deficits. All Tf2 responses were abolished in Scn3a-/- mice, confirming NaV1.3 dependence. Conclusions NaV1.3 is a selectively druggable ion channel in adult lymphatic muscle that can be recruited to restore lymphatic pump function across aging and injury. Targeted NaV1.3 activation provides a molecular entry point for treating diseases characterized by lymphatic pump failure, a domain with no existing pharmacologic therapies.

Hammerhead ribozymes have found extensive applications in gene expression regulation across diverse biological systems including Escherichia coli, yeast, plants, and mammalian cells. However, their implementation in parasitic nematodes remains unexplored. Strongyloides stercoralis emerges as a particularly valuable model organism for studying developmental transitions in parasitic nematodes due to its unique life cycle alternating between parasitic and free-living stages. To expand the experimental toolkit for investigating developmental, evolutionary, and behavioral processes in this species, we established a conditional gene regulation system through transgenic integration of synthetic ribozyme constructs and demonstrated efficacy in regulating both exogenous (mrfp) and endogenous (unc-22) gene expression through targeted RNA processing mechanisms. Focusing on the insulin/IGF-1 signaling pathway, a critical regulator of parasitic nematode development and longevity, we implemented ribozyme-mediated post-transcriptional control to dissect functional divergence between two isoforms of the insulin receptor homolog Ss-DAF-2. Comparative analysis revealed isoform-specific characteristics: while both isoforms maintain conserved signaling functions, isoform B exhibits specific binding affinity for human insulin and demonstrates significant transcriptional upregulation during parasitic transition phases. This ligand selectivity profile suggests that isoform B may serve as a molecular interface for host-derived insulin signaling coordination during parasitism. This study established a programmable ribozyme tool in S. stercoralis, functionally discriminated the two Ss-DAF-2 isoforms through precision RNA engineering, and identified isoform-specific ligand preferences with implications for host-parasite signaling. Our findings not only validate ribozyme-based approaches for genetic manipulation in parasitic nematodes but also lay the groundwork for future implementation of synthetic RNA switches in helminth research.

The increasing focus on longevity and cellular health has brought into the spotlight two key compounds, urolithin A (UroA) and spermidine, for their promising roles in autophagy and mitophagy. Urolithin A, a natural metabolite derived from ellagitannins, stimulates mitophagy through pathways such as PTEN induced kinase 1 (PINK1)/ Parkin RBR E3 ubiquitin protein ligase (PRKN), leading to improved mitochondrial health and enhanced muscle function. On the other hand, spermidine, a polyamine found in various food sources, induces autophagy by regulating key signaling pathways such as 5' AMP-activated protein kinase (AMPK) and sirtuin 1, thus mitigating age-related cellular decline and promoting cardiovascular and cognitive health. While both UroA and spermidine target cellular maintenance, they affect overlapping as well as distinct signaling pathways. Thus, they do not have completely identical effects, although they overlap in many ways, and offer varying benefits in terms of metabolic function, oxidative stress reduction, and longevity. This review article aims to describe the mechanisms of action of UroA and spermidine not only on the maintenance of cellular health, which is mediated by the induction and maintenance of autophagy and mitophagy, but also on their potential clinical relevance. The analysis presented here suggests that although both compounds are safe and offer substantial health benefits and are involved in both autophagy and mitophagy, the role of UroA in mitophagy places it as a targeted intervention for mitochondrial health, whereas the broader influence of spermidine on autophagy and metabolic regulation may provide more comprehensive anti-aging effects.

The Lansing effect is a transgenerational age effect by which old parents tend to produce less viable descendants. Despite its importance for the evolution of lifespan and parental effects, the transgenerational nature of age effects and the underlying mechanisms are poorly understood. In an experiment using the three-spined stickleback, we test whether the age of mothers (generation P0) at reproduction affects parental traits of the F1 offspring, and whether they subsequently influence the early development and viability of the F2 descendants. Daughters (F1 females) of old (2-year-old) and young (1-year-old) mothers showed comparable body size, spawning rate, clutch size and egg telomere length (TL). However, sons (F1 males) of old mothers had a smaller adult body size and produced sperm with shorter TL than those of younger mothers. Structural equation model analysis revealed that P0 female age influenced embryo TL and hatching success of the F2 descendants through its effect on sperm TL of F1 males. There was also an interacting effect of P0 female age and telomerase reverse transcriptase gene (tert) mRNA level in eggs of the F1 females on the hatching success of the F2 descendants. Our results provide novel evidence that maternal age can have transmissive effects on successive generations through the gamete traits of their offspring, especially sperm TL and egg tert gene transcripts. We conclude that this transmissible age effect on grandoffspring TL and viability can shape the evolution of life histories because TL is related to health, ageing and lifespan.

Background: Telomere length (TL), a biomarker of biological aging, but its association with Alzheimer's disease (AD) remains unclear. Methods: We estimated TL in whole-genome sequencing data from 35014 Alzheimer's Disease Sequencing Project participants using TelSeq, which after quality control yielded a dataset including 6973 persons of European ancestry (EA), 4188 African Americans (AA), 4005 Caribbean Hispanics (CH), and 4170 Native American Hispanics (NAH). TL was log-transformed, adjusted for age and blood cell counts, and z-scaled. Scaled TL was dichotomized into long and short groups according to the median. An AD GWAS for the interaction of TL with variants having a minor allele count >20 was performed in each ancestry group using logistic regression models including SNP and TL main effects and a SNPxTL interaction term. Results: AD risk was associated with shorter TL ({beta} = -0.18, P < 2x10-16). Longer TL was associated with dosages of APOE {epsilon}2 (P<5.08x10-8) and APOE {epsilon}4 (P=2.10x10-2). In the EA group, genome-wide significant (GWS) TLxSNP interactions were identified for variants in SEMA6A (P=1.42x10-8) and LOC105378654 (P=4.17x10-8), between IL15 and INPP4B (P=1.77x10-8) and upstream of RP11-2N5.2 (P=4.60x10-8). In the NAH group, GWS interactions were observed with an intronic variant in BSN (P=3.26x10-8) and missense variant in MST1 (P=3.26x10-8). In the total sample, interactions with variants between CTD-2160D9.1 and EEF1A1P20 (P<1.19x10-8), in TBC1D22A (P=1.06x10-8) and in PLK1 (P=3.28x10-8) were GWS. Conclusion: We identified variants that significantly impact AD risk through their interaction with TL, suggesting that TL maintenance pathways may be central to AD pathogenesis.

Aging is a complex biological process characterized by molecular changes across multiple biological scales. While these alterations have been extensively studied in humans and rodents, the molecular changes associated with aging in dogs remain underexplored despite their relevance as a model for human aging. In this study, we profiled gene expression (n = 16,273 genes) and protein abundance (n = 2041 proteins) in whole blood and blood plasma from 40 laboratory beagles across young (3-5 years old, n = 10), old (8-9 years old, n = 17), and geriatric (10-14 years old, n = 13) life stages. We identified 816 genes and 40 proteins that significantly changed in abundance during aging, converging on pathways involved in DNA repair, collagen processing, and inflammation. Notably, these canine aging signatures overlapped with human age-associated genes, including those tied to the hallmarks of aging, reinforcing the existence of conserved aging mechanisms across species.

The prevalence of cardiovascular disease increases with age, driven by processes of inflammation, oxidative stress, and mitochondrial dysfunction. Delaying the cascade caused by these risk factors will be essential to reducing cardiovascular morbidity and mortality in our aging population. Sirtuins are nicotinamide adenine dinucleotide-dependent deacetylase enzymes involved in metabolic regulation that show promise in attenuating these disease processes and increasing longevity. This review will examine the role of sirtuins at the cellular level in relation to cardiovascular health and discuss their potential as novel therapeutic targets for atherosclerosis, heart failure, and metabolic syndrome.

Aging is characterized by amplified inflammation, including proinflammatory macrophages and increased susceptibility to endotoxemia. Here we uncover a mechanism by which macrophages maintain their inflammatory phenotype through autocrine GDF3-SMAD2/3 signaling, which ultimately exacerbates endotoxemia. We show that inflammatory adipose tissue macrophages display an age-dependent increase in GDF3, a TGFβ-family cytokine. Lifelong systemic or myeloid-specific Gdf3 deletion leads to reduced endotoxic inflammation. Using pharmacological interventions to modulate the GDF3-SMAD2/3 axis, we demonstrate its role in regulating the inflammatory adipose tissue macrophage phenotype and endotoxemia lethality in old mice. Mechanistically, single-cell RNA sequencing and assay for transposase-accessible chromatin with sequencing analyses suggest that GDF3 induces a shift toward an inflammatory state by limiting methylation-dependent chromatin compaction. Leveraging human adipose tissue samples and 11,084 participants from the atherosclerosis risk in communities study, we validate the relevance of GDF3 to aging in humans. These findings position the GDF3-SMAD2/3 axis as a critical driver of age-associated chromatin remodeling and a promising therapeutic target for mitigating macrophage-related inflammation in aging.

Diabetic cardiomyopathy (DCM) is a major complication of diabetes and a leading contributor to heart failure, in which cardiomyocyte senescence plays an increasingly recognized role. However, the underlying mechanisms driving this process remain poorly defined. Here, we identify the (pro)renin receptor (PRR) as a critical mediator of cardiomyocyte senescence in DCM. Using a high-fat diet and streptozotocin (STZ)-induced DCM mouse model, as well as primary cardiomyocytes exposed to high glucose and palmitic acid, we demonstrate that PRR expression is significantly upregulated in diabetic hearts and closely associated with key senescence markers, including SA-β-gal, γ-H2AX, p16, and p21. PRR overexpression exacerbates these senescence phenotypes and promotes the secretion of profibrotic senescence-associated secretory phenotype factors, contributing to increased myocardial fibrosis and cardiac dysfunction. Mechanistically, PRR stabilizes the p53 protein by inhibiting tripartite motif-containing 24 (TRIM24)-mediated ubiquitination and proteasomal degradation, thereby activating the p53-p21 axis. These findings reveal a novel role of the PRR in diabetic myocardial senescence and provide potential therapeutic targets for attenuating DCM progression.

Immunosenescence, particularly the altered ratio of naïve and memory T cells, contributes to a diminished immune reserve and impaired adaptive immunity in aging and frail populations. The role of TGF-β signaling pathway-a critical hallmark of organismal senescence and T-cell exhaustion-in terminally differentiated effector memory T (Temra) cells remains elusive. We devised single-cell and bulk-cell RNA sequencing (RNA-seq) datasets to identify age-group-specific transcriptional regulatory networks in T cells and elucidate the roles of TGF-β signaling constituents associated with immunosenescence in Temra.

Frailty is an age-related geriatric syndrome with largely unknown mechanisms. We conducted a longitudinal study of aging C57BL/6JNIA mice (females; n = 40, male; n = 49), measured frailty index and derived DNA methylation data from PBMCs. We selected frailty-related differentially methylated CpGs and determined differentially methylated regions (DMRs), focusing on both age-independent and -dependent frailty, and using both mixed-sex and sex-stratified subgroups. We propose a joint set of 925 frailty-related DMRs, perform an association study with frailty outcomes, build epigenetic frailty clocks and validate in mice with interventions. Notably, age-independent frailty DMRs are enriched in nervous and endocrine pathways, distinct from signaling and lipid metabolism pathways identified from age-dependent DMRs. We observe hypermethylation in signaling pathways and hypomethylation in lipid metabolism and cytochrome P450 pathways with frailty progression. 36 DMRs show consistent associations in validation. These findings highlight distinct epigenetic signatures underlying frailty and aging, with potential sex-specific mechanisms.

Spinal cord injury (SCI) causes not only intraspinal damage but also systemic organ pathology, with aging as a key determinant of outcomes. The mechanisms by which old age aggravate SCI pathology remain unclear. The voltage-gated proton channel Hv1 plays a key role in regulating immune responses. Hv1 increases with aging and SCI, and Hv1 KO provides neuroprotection in young mice. We hypothesized that age-related Hv1 upregulation worsens spinal cord, spleen, and lung pathology and hinders locomotor recovery after SCI via immune modulation. Using aged Hv1 KO and WT male mice subjected to moderate SCI, we assessed behavioral and molecular outcomes. Transcriptomic analysis revealed that Hv1 mRNA expression was higher in the brains of aged sham mice and further upregulated in injured spinal cord tissues. Spinal cord RNA-seq showed acute innate immune and cytokine activation in both genotypes. Hv1 deletion enhanced chromatin remodeling, epigenetic and Wnt signaling, while suppressing NF-κB-driven inflammation and oxidative stress-induced apoptosis. In the spleen, Hv1 depletion enhanced immune responses while suppressing mitosis. T cell and leukocyte activation increased, whereas lung cytokine signaling decreased. Functional recovery improved with reduced tissue damage. After chronic SCI, Hv1 KO mice showed elevated circadian rhythm and T cell proliferation in the spinal cord, increased mitotic gene expression but reduced adaptive immunity in the spleen, and enhanced immune activation with decreased cilium activity in the lungs. Together, our findings reveal how Hv1 contributes to age-related intraspinal damage and peripheral immune dysfunction after SCI, highlighting a potential therapeutic target for elderly patients.

Virus-induced accelerated aging has emerged as a potential contributor to HIV-associated neurocognitive disorders (HAND), despite widespread implementation of combination antiretroviral therapy (cART). Although evidence of accelerated aging in people living with HIV (PLWH) has been reported, most investigations of acute infection rely on in vitro systems or small animal models, leaving a critical gap in understanding early neuropathological events. To address this, we analyzed formalin-fixed, paraffin-embedded (FFPE) brain tissues from rhesus macaques acutely infected with simian immunodeficiency virus (SIV). We focused on two key aging-related proteins: the cellular senescence marker p16INK4a (p16) and the NAD-dependent deacetylase sirtuin 1 (SIRT1). We hypothesized that accelerated aging phenotypes would be detectable during acute infection, manifesting as increased p16 expression and altered SIRT1 levels, correlating with neurodegeneration. Consistent with this hypothesis, we observed marked upregulation of GFAP and p16, along with evidence of neurodegeneration, across multiple brain regions - including the frontal lobe, caudate, putamen, thalamus, hippocampus, and cerebellum - by 21 days post-infection. These findings suggest that aging-related and senescence pathways are activated almost immediately following HIV infection, highlighting the potential importance of astrocyte- or CNS-specific therapeutic strategies to mitigate early neuropathology.

Aging, the decline in physiological function over time, is marked by the intracellular accumulation of damaged components. It can be attributed to trade-offs between organismal maintenance and the generation of high-quality offspring, where the parent retains damage upon reproduction and produces rejuvenated descendants. This occurs even in bacteria, such as

Age-related sarcopenia, characterized by progressive loss of skeletal muscle mass and strength, impacts metabolic health and quality of life in the elderly. Heat shock factor 1 (HSF1) is a transcription factor that orchestrates cellular responses to various stresses, while its role in sarcopenia remains unknown. Here, HSF1 mRNA expression was decreased in muscles of aged mice and humans, correlating negatively with the atrophic gene and positively with the mitochondrial gene. Aged HSF1 muscle-specific knockout mice exhibited severe muscle atrophy and reduced endurance capacity, partially due to smaller fast fibers and mitochondrial dysfunction in slow fibers, as well as impaired systemic metabolic performance. In contrast, HSF1 overexpression in skeletal muscle improved these functions. Mechanistically, via RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq), it is revealed that HSF1 transcriptionally activated Sirtuin3 (SIRT3) for the deacetylation of both PGC1α1 and PGC1α4 isoforms of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), in skeletal muscle, enhancing mitochondrial function and muscle hypertrophy in vivo and in vitro, and inducing fibronectin type III domain-containing protein 5 (FNDC5)/Irisin for tissue crosstalk. Thus, HSF1 regulates skeletal muscle functions and systemic energy homeostasis via the SIRT3-PGC1α axis, representing a potential therapeutic target for sarcopenia and metabolic disorders.

Brain aging can cause cognitive and motor disabilities which often correlate with changes in dendritic branch, axon collateral, and synapse numbers. However, from invertebrates to mammals, age-related decline is typically restricted to specific neuron types or brain parts, indicating differential vulnerability. The rules to pinpoint the susceptibility of distinct brain elements to aging remain largely unknown. Here, we combine longitudinal studies with neuroanatomical, electrophysiological, and optophysiological analyses in the Drosophila genetic model to identify aging-susceptible and aging-resilient elements in a sensorimotor circuit that underlies escape. Young and mid-aged flies escape predator-like visual stimuli with a jump followed by flight, but behavioral performance declines with age. Mapping the underlying functional decline into the brain shows that most circuit components are robust against aging and remain functional even in old flies that have lost the behavior. By contrast, behavioral decline is caused by the selective decay of synaptic transmission between one specific visual projection neuron type (LC4) and the dendrite of one identified descending neuron (GF). Structurally, presynaptic active zone marker density is reduced whereas postsynaptic marker density remains normal. Other central synapses in this circuit as well as neuromuscular synapses are robust to aging. The synaptic connection susceptible to aging is also the circuit element most vulnerable to starvation or oxidative stress. Moreover, the vulnerable circuit element is also required for habituation, and thus, underlying circuit plasticity. In conjunction with data from mammalian brains our data suggest that a trade-off for functional neural circuit plasticity might be vulnerability to aging.

Previous single-cell and single-nucleus heart atlases, often limited by small sample sizes, lack the statistical power needed for phenotype association analysis, particularly for cardiovascular diseases and cardiac aging. To address this, we integrated data from 436 samples across 12 single-cell studies, harmonized the corresponding sample metadata, and constructed a comprehensive heart atlas comprising 355,762 cells and 1,436,719 nuclei. Consensus annotation identified 10 broad cell types and 54 fine-grained subsets. Associating gene expression patterns and cell type proportions with phenotypic data, we identified NRG1-expressing endocardial cells linked to multiple cardiac diseases and found that interferon (IFN) response signatures mark aging in multiple heart cell types. Importantly, we also developed PopComm, a novel computational method for inferring ligand-receptor (LR) interactions from population-scale single-cell data and quantifying interaction strength for individual samples. Using PopComm, we revealed a close association between the IFN response state and altered cell-cell communication during cardiac aging.

The functional decline of the haematopoietic system during ageing propagates detrimental effects on the whole organism, ultimately eroding life and healthspan. Quantifying haematopoietic ageing holds great scientific and clinical relevance. Alterations in chromatin architecture are a well-established hallmark of ageing that encode rich and informative signatures of the ageing process, yet they remain largely unexplored as quantitative markers. Here, we present an interpretable deep learning approach based on convolutional neural networks, ChromAgeNet, that learns changes in the spatial features of chromatin architecture during natural aging of Hematopoietic Stem Cells (HSCs). We trained our algorithm on 3D microscope images of DAPI-stained HSC nuclei to discriminate between young and aged murine HSCs, achieving and AUROC of 0.77 {+/-} 0.03. This approach outperforms classical machine learning models trained on handcrafted chromatin features from the same dataset. We then applied explainable artificial intelligence techniques, identifying chromatin entropy, peripheral heterochromatin and chromatin condensates as predictive markers. As a proof of concept, we evaluated the potential of our model as a phenotypic screening tool for aged HSCs treated with epigenetic drugs to detect rejuvenation. Altogether, we demonstrate that changes in chromatin organization can be modeled via machine learning to predict cellular ageing in the hematopoietic compartment. Our developed framework, ChromAgeNet, serves as an interpretable algorithm to unravel the intricate relationship between chromatin changes and cellular ageing, and advance high throughput drug screening for rejuvenation therapies.

Background Hutchinson-Gilford progeria syndrome (HGPS) is a devastating premature aging disorder driven by the accumulation of progerin, leading to severe vascular pathology. While epigenetic alterations are implicated, the spatiotemporal reorganization of the higher-order chromatin and its functional impact on vascular smooth muscle cell (VSMC) transcription remain poorly defined. Results Through an integrated multi-omics approach combining in situ high-throughput chromosome conformation capture (Hi-C) and Cleavage Under Targets and Tagmentation (CUT&Tag) profiling of CTCF, SMC1A, H3K27me3, H3K27ac, and H3K36me3 with transcriptomic analyses from control and HGPS iPSC-derived VSMCs, we reveal that global topologically associating domain (TAD) architecture remains largely intact in HGPS. However, the internal chromatin states of TADs undergo dynamic, passage-specific remodeling, characterized by a progressive accumulation of broad H3K27me3-repressed domains. This is accompanied by a loss of A/B compartment segregation, as confirmed by DNA-FISH, indicating a collapse of higher-order chromatin organization in late passage. Crucially, we uncover widespread rewiring of enhancer-promoter (E-P) loops, which is linked to the dysregulation of genes critical for vascular development, extracellular matrix organization, and atherosclerosis. Conclusions Our study demonstrates that spatiotemporal redistribution of repressive histone marks and reorganization of E-P interactions within a structurally resilient TAD framework underpin widespread transcriptional dysregulation in HGPS vascular pathogenesis. This uncovers a critical dissociation between higher-order chromatin architecture and histone modification landscape, providing a mechanistic basis for the failure of vascular homeostasis in progeria.

Aging is a complex process marked by the gradual accumulation of impairments in molecules and tissues, leading to frailty and dysfunction. This decline is a significant risk factor for many debilitating conditions. Recently, gut microbiota dysbiosis has been identified as one of the hallmarks of aging. This review sheds light on the role of gut microbiota dysbiosis in accelerating aging and its relation to age-associated diseases, including neurodegenerative disorders, cardiovascular diseases, cancer and diabetes. Emerging research demonstrates a strong link between the gut microbiome and the aging process, although the underlying mechanisms remain under investigation. Animal studies suggest that targeting the gut microbiome may offer a promising approach to mitigate aging and related diseases. However, further human studies are needed to confirm these findings.

Gene profile studies suggest that neurons may face premature aging in neurodegenerative diseases such as Huntington disease (HD). Cells remodel gene expression to resist molecular damage in aging, but how neurons may engage age-related genes to resist HD remains unknown. Here, we found that transcriptional-aging inversion (TAGI) in the Drd1-expressing striatal neurons (Drd1 SNs) of HD knock-in (Hdh) mice shows discrete patterns in the backdrop of a TAG-like (TAGL) signature, and that TAGI persistence as Hdh mice become strongly symptomatic may better explain disease progression compared to TAGL dynamics. We also found that genes affected by 3prime UTR accumulation in aged mouse Drd1 SNs of aged mice are more likely downregulated in aging and deregulated in Hdh mice. Mapping 3prime UTR data in aging on gene dysregulation networks in the Drd1-SNs of weakly symptomatic Hdh mice highlighted a CAG repeat-dependent network of upregulated genes with compensatory potential as suggested by enrichment in development and maintenance factors such as CTCF. This class noticeably contains Atad-5, a PCNA unloader in the DNA repair complex and a modifier of CAG expansion in the plasma of HD patients. This class also contains CXXC4 (IDAX), an epigenetic regulator and repressor of TET2 activity, for which upregulation is lost in strongly symptomatic Hdh mice. CXXC4 reduces the levels of p16INK4a, a cellular senescence marker, in human iPS cell-derived SNs and restores glutamate excitability in human HD iPS cell-derived SNs. Collectively, these data suggest that the resilience capacity of Drd1 SNs against HD involves discrete patterns of age-related genes, where early intervention based on expressing broad-spectrum genes such as CXXC4 may provide novel therapeutic strategies to restore cortico-striatal homeostasis and function.

The functions of multiple organs decline with the process of aging. Revealing the intrinsic mechanisms governing organ degeneration is a critical pursuit for understanding the aging process and creating interventions for aging-related diseases. Macromolecular damage caused by the generation of reactive oxygen species (ROS) increases with the process of aging. However, excessive ROS generation may only partially account for aging at the individual and organ levels. In contrast, they could serve as important signaling molecules in stress responses. In this review, we focused on the dual role of ROS in the aging processes of several human organ systems. Through this investigation, we aim to reassess the relationship between ROS and aging.

Mitochondria play a central role in metabolism and biosynthesis, but function also as platforms that perceive and communicate environmental and physiological stressors to the nucleus and distal tissues. Systemic mitochondrial signaling is thought to synchronize and amplify stress responses throughout the whole body, but during severe or chronic damage, overactivation of mitochondrial stress pathways may be maladaptive and exacerbate aging and metabolic disorders. Here we uncover a protective micro(mi)RNA response to mtDNA damage in Caenorhabditis elegans that prolongs tissue health and function by interfering with mitochondrial stress signaling. Acting within muscle cells, we show that the miRNA miR-71 is induced during severe mitochondrial damage by the combined activities of DAF-16, HIF-1, and ATFS-1, where it restores sarcomere structure and animal locomotion by directly suppressing the inordinate activation of DVE-1, a key regulator of the mitochondrial unfolded protein response (UPR