Biogerontology最新文献

{"title":"Inflammation-linked aging signals in frozen single-cell foundation models: donor-aware detection and robustness testing.","authors":"Ihor Kendiukhov","doi":"10.1007/s10522-026-10471-8","DOIUrl":"10.1007/s10522-026-10471-8","url":null,"abstract":"<p><p>Single-cell foundation models such as scGPT and Geneformer are large neural networks trained on human single-cell RNA-seq data. They were never shown chronological age during training. Do their internal representations nevertheless encode aging biology in a way that can be interpreted, and how should we test whether an apparent aging signal is real biology rather than an artifact of which donors and cell types happened to be sampled?. We applied a nine-step evaluation pipeline to two foundation models (frozen, no fine-tuning) and five PBMC datasets containing 4 to 5 million cells from <math><mo>∼</mo></math> 2,000 donors with chronological age. Each step is one specific test: can we read age out of the model's representation; does the representation place age along a clean axis; do sparse-feature decompositions surface aging-related programs; do the two models agree at the pathway level; do targeted perturbations of those features change predicted age in the expected direction; and finally, does the signal survive when we resample cells so that young and old donors have matched cell-type composition (removing the most obvious confound). (1) The foundation models encode age but do not predict it better than a 50-component PCA of gene expression: in all five cohorts the PCA baseline matches or exceeds the best foundation-model probe. What they add is a complementary interpretability mode-sparse-feature decomposition and activation-level intervention-rather than predictive power; a PCA of gene expression is itself interpretable through its loadings, so the contribution here is the evaluation framework that adjudicates such signals, not a claim that foundation models predict age better. Randomly reinitialising Geneformer's weights destroys most of its age signal ( <math><mrow><mo>-</mo> <mn>0.107</mn></mrow> </math> balanced-accuracy points), while doing the same to scGPT's layer 9 changes essentially nothing-so the two models encode age asymmetrically. (2) Sparse autoencoders surface 132 robust aging-related features across the two models, of which 193 cross-model pairs match each other at pathway level, concentrated in inflammation. The shared inflammation signal resolves into specific submodules: TNF / NF- <math><mi>κ</mi></math> B classical and type-II IFN- <math><mi>γ</mi></math> (both models agree), complement (scGPT-specific). (3) The strongest aging signal is Geneformer's NF- <math><mi>κ</mi></math> B program in the AIDA phase 1 v2 cohort. Pushing those features in the \"older\" direction increases predicted age by 0.15 expected-age units; pushing them the opposite way decreases it; pushing along random unrelated directions does neither-a three-way directional check we call the \"strict gate\". When cells are resampled so that the age groups have matched cell-type composition (the strictest control), the directional effect shrinks <math><mo>∼</mo></math> 3 <math><mo>×</mo></math> but 7 of 8 resampling seeds still pass the strict gate. One i","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":"27 4","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13407579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148598544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AGGF1 delays endothelial cellular senescence through the TGFB3-TAK1-AMPK signaling axis.","authors":"Xiaojuan Zhong, Weixin Lv, Xueer Li, Limei Wang, Minhong Zhang, Kang Liu, Jiayi Dong, Qiang Yuan, Shilin Zhang, Andong Wu, Xueting Gong, Jiankun Liu, Bingbing Zhou, Shihui Ye, Qiquan Wang, Yang Xiang, Xiao-Li Tian","doi":"10.1007/s10522-026-10474-5","DOIUrl":"10.1007/s10522-026-10474-5","url":null,"abstract":"<p><p>Endothelial senescence is a critical contributor to vascular aging and age-related vasculopathies. Our previous work identified AGGF1 as a regulator of cell cycle progression and anti-inflammatory signaling. However, whether AGGF1 modulates endothelial senescence remains unclear. Here, we demonstrate that AGGF1 is downregulated in both replicative and DOX-induced senescent HUVECs. AGGF1 knockdown accelerated cellular senescence as evidenced by senescence markers, including increased SA-β-gal activity, enhanced formation of γH2AX foci, elevated IL-6 levels, and impaired proliferation, whereas AGGF1 overexpression prevented DOX- and MMC-induced senescence using adenovirus and lentivirus-mediated gene manipulation. To investigate the underlying mechanisms, we performed RNA sequencing, small-molecule drug intervention, transmission electron microscopy (TEM), and other imaging techniques in subsequent experiments. Transcriptomic and functional analyses revealed that AGGF1 transcriptionally upregulates TGFB3, which is associated with TAK1 activation and AMPK phosphorylation, ultimately inhibiting excessive mitochondrial fragmentation and suppressing cellular senescence. This signaling module reduced DRP1 expression and attenuated its activating phosphorylation at Ser616. TEM results further confirmed that AGGF1 overexpression significantly reduced mitochondrial fragmentation in cells. Additionally, this proposed association was supported by pharmacological inhibition (Takinib, Compound C) and TGFB3 knockdown, which abrogated AGGF1-mediated protection. Collectively, we identified that AGGF1 is critical for regulating a proposed TGFB3-TAK1-AMPK regulatory module, which delays endothelial senescence partially through maintenance of mitochondrial morphology. Our study provides evidence that AGGF1 plays an important role in metabolic control and cellular senescence.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":"27 4","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13415593/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148598425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic landscape of human cardiac aging: identification of cardioselective age-associated genes and predictive modeling.","authors":"Sheena Yi-Hsin Cheng, Yi-Chiung Hsu","doi":"10.1007/s10522-026-10479-0","DOIUrl":"10.1007/s10522-026-10479-0","url":null,"abstract":"<p><p>Age is a major risk factor for cardiovascular disease, yet the molecular mechanisms underlying human cardiac aging are not fully understood. Using bulk RNA sequencing data from the Genotype-Tissue Expression (GTEx) project, we identified cardiac age-associated genes by intersecting transcripts significantly correlated with age in both the atrial appendage and left ventricle, while excluding those similarly altered in skeletal muscle. Among these, 131 genes were positively correlated with age, and 262 were negatively correlated. Functional enrichment and gene set enrichment analyses revealed several recurring biological themes. Pathways positively enriched with age included the P53 pathway, replicative senescence, extracellular matrix organization, transient receptor potential channel activity, and cardiac epithelial-mesenchymal transition. Conversely, negatively enriched pathways involved fatty acid oxidation, oxidative phosphorylation, mitochondrial biogenesis, membrane repolarization, cardiac conduction, and NOS1 signaling. Immune deconvolution indicated an age-dependent increase in neutrophil fractions and a decrease in monocyte abundance. Finally, an ordinal elastic net regression model, trained on these cardiac age-associated genes, demonstrated acceptable internal performance, achieving a quadratic weighted kappa of 0.797 and an ordinal concordance index of 0.901. External validation on two independent microarray cohorts showed modest predictive capability, with R² values of 0.20 and 0.38. These findings provide a transcriptomic landscape of cardiac aging based on human tissue, with potential implications for biomarker development and therapeutic strategies.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":"27 4","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148589504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-apoptotic role of caspase enzymes in satellite cells from human skeletal muscle.","authors":"Roberta Di Pietro, Rosa Mancinelli, Gianna Impicciatore, Gianmarco Stati, Stefania Fulle, Silvia Sancilio","doi":"10.1007/s10522-026-10478-1","DOIUrl":"10.1007/s10522-026-10478-1","url":null,"abstract":"<p><p>Satellite cells (SCs) are essential for skeletal muscle regeneration, but their function declines with aging, often associated with increased pro-apoptotic signaling. This study investigated the impact of in vitro serum starvation-as a model of acute microenvironmental and nutrient stress-on the apoptosis and differentiation potential of human SCs from young and aged donors. SCs were isolated from the Vastus Lateralis of young and aged subjects and cultured in serum-free medium for up to 72 h. We assessed apoptosis through Annexin V/PI staining, TUNEL assays, and caspase activity measurements, while transcriptional profiles were analyzed via RT-PCR. Aged SCs displayed a significantly higher susceptibility to stress-induced apoptosis compared to young controls, marked by the early upregulation of CASP9 and FOXO1. While typical nucleosomal DNA fragmentation was absent, we observed the activation of caspase-3 after 72 h of starvation. In aged cells, activated caspase-3 co-localized with myogenin and extranuclear DNA at sites of nuclear remodeling. Notably, treatment with a pan-caspase inhibitor (z-VAD-fmk) prevented the formation of micronuclei and myotubes, further highlighting a non-apoptotic role for these enzymes. Aged SCs also showed a distinct cell cycle profile characterized by an enlarged G0/G1 phase and altered expression of CDK and CCNB1 genes. Our findings suggest that in human aged SCs, caspase enzymes serve a dual role: mediating a heightened stress response and facilitating the nuclear remodeling necessary for myogenic differentiation. These results clarify how intrinsic aging shapes the response of muscle stem cells under severe environmental and metabolic resource deprivation.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":"27 4","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13401550/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148590416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular senescence and inflammageing: from mechanisms to senotherapeutic interventions.","authors":"Piotr Paweł Chmielewski","doi":"10.1007/s10522-026-10477-2","DOIUrl":"10.1007/s10522-026-10477-2","url":null,"abstract":"<p><p>Cellular senescence is a context-dependent cellular state characterised by persistent cell-cycle arrest, epigenetic remodelling, metabolic reprogramming and acquisition of a senescence-associated secretory phenotype. Transient senescence contributes to embryogenesis, tissue repair and tumour suppression, whereas persistent senescent cell populations accumulate with advancing age across multiple tissues, in part owing to declining immune-mediated clearance and intrinsic resistance to apoptosis, thereby promoting chronic systemic inflammation, tissue fibrosis, stem-cell dysfunction and propagation of secondary senescence. Experimental genetic and pharmacological evidence supports a contributory and in several contexts causal role for senescent cells in cardiovascular, metabolic, musculoskeletal, fibrotic and neurodegenerative disorders. These findings have accelerated the development of senotherapeutic strategies, including senolytics, senomorphics and immune-mediated clearance approaches, with early clinical studies showing preliminary evidence of functional benefit in idiopathic pulmonary fibrosis and diabetic kidney disease. However, clinical translation remains constrained by senescence heterogeneity, limited biomarker specificity and unresolved long-term safety concerns. Improved molecular, spatial and functional resolution of senescent states will be essential for developing biomarker-guided and tissue-specific interventions that preserve the beneficial functions of transient senescence while limiting its chronic deleterious effects.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":"27 4","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13396041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A machine learning approach to identify key epigenetic transcripts for ageing research in human blood (Epitage).","authors":"Thiago Benazzi Maia, Ulrich Pfeffer","doi":"10.1007/s10522-026-10473-6","DOIUrl":"10.1007/s10522-026-10473-6","url":null,"abstract":"<p><p>DNA methylation is an established biomarker of human ageing and is used by a variety of tools to identify meaningful epigenetic signals. We investigated whether analysing CpGs grouped by transcript as functional units could generate a ranked list of transcripts most correlated with age that might otherwise be overlooked in genome-wide CpG-based studies. Here we present Epitage ( https://github.com/a00s/epitage ), a continuously updated ranked list of transcripts built from the GSE87571 dataset (714 whole-blood samples, ages 14-94 years) through intensive testing with machine-learning models. To support reproducible analyses, we developed ugPlot ( https://github.com/a00s/ugplot ), an open-source R/Shiny tool with a graphical user interface that automates model training, testing, and comparison. Initially, we identified 48 transcripts across 13 genes, with some transcripts from the genes OBSCN, PRRT1, and SPTBN4 showing better predictive performance when multiple associated CpGs were analysed together rather than individually. In contrast, for the majority of transcripts, a dominant individual CpG still showed a higher Spearman correlation with age, as seen in established ageing genes such as ELOVL2, FHL2, and TRIM59. Epitage is a transcript-ranking list based on the methylation patterns observed in the analysed dataset. It provides a reproducible framework for prioritising transcripts associated with human ageing and for guiding future epigenetic studies.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":"27 4","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148547601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From matrix to nucleus: CD44 as a central regulator of inflammaging, autophagy, and tissue homeostasis.","authors":"Syeda Ayesha Ali, Pengfei Qiang, Xiaojun Zhou, Xiaoting Yang, Shang Li, Yunpeng Shen, Zhiqiang Chen, Lu Zhang","doi":"10.1007/s10522-026-10476-3","DOIUrl":"10.1007/s10522-026-10476-3","url":null,"abstract":"<p><p>Aging is characterized by a progressive decline in cellular and tissue function, shaped in part by disruptions in communication between the extracellular matrix (ECM) and intracellular signaling networks. The cell surface receptor CD44 functions as a molecular hub, integrating signals from a remodeled ECM to regulate core aging programs including senescence, inflammation, and metabolic balance. This review synthesizes evidence that CD44, through its structural domains, isoform diversity, and proteolytic processing, integrates extracellular cues to modulate key pathways such as STAT3, NF-κB, and the class III PI3K complex. Mechanistically, HA-fragment engagement of CD44 activates the CD44-STAT3 axis in vascular tissue, suppressing autophagic flux and promoting endothelial senescence. Concurrently, ECM-derived ligand binding to CD44 drives NF-κB signaling that amplifies chronic inflammation in a tissue and context-dependent manner, contributing to inflammaging. Functional outcomes are context-dependent, shaped by isoform switching and γ-secretase-mediated release of CD44-ICD, which may drive degeneration or support repair and proteostasis. Emerging single-cell and spatial transcriptomics reveal spatiotemporal CD44 dysregulation across vasculature, brain, adipose tissue, kidney, and liver. This review establishes CD44 as a mechanistic link connecting ECM remodeling to nuclear responses in aging and outlines therapeutic strategies including ligand competition, antibody blockade, and γ-secretase modulation to mitigate age-related pathology and extend health span. These insights provide a coherent framework for understanding aging biology and guiding future translational interventions targeting CD44 signaling pathways effectively.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":"27 4","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148547603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic evidence links hypertension to accelerated brain aging.","authors":"Xiaoyang Zhu, Shuaiqi Zhang, Zhiyuan Liu, Ben Nie","doi":"10.1007/s10522-026-10475-4","DOIUrl":"10.1007/s10522-026-10475-4","url":null,"abstract":"<p><p>Hypertension affects one-third of adults and is a major comorbidity of neurocognitive disorders. The causal relationship, shared genetic architecture, and upstream mechanisms linking hypertension to brain aging remain unclear. Hypertension GWAS datasets from MVP and FinnGen R12 were meta-analyzed as the exposure, and a European-ancestry brain age gap (BAG) GWAS derived from the UK Biobank and LIFE-Adult cohorts was used as the outcome. MR and GSMR assessed causality. LDSC, HDL, and S-LDSC estimated genetic correlation. Four TWAS methods (MAGMA, FUSION, JTI-PrediXcan, FOCUS) mapped associations to genes, followed by SMR for causal validation and PoPS for prioritization. GSMAP with spatial transcriptomics characterized regional and cell-type enrichment. Hypertension and brain aging were genetically correlated, and MR and GSMR analyses suggested a causal effect of hypertension on increased brain age gap. TWAS identified 15 shared Hypertension-BAG genes, 10 supported by SMR. PoPS prioritized TRIM47 as the core gene. Shared signals were enriched in meninges, fiber tracts, cortical layer 1, and CA1 stratum lacunosum/radiatum, with cell-type enrichment in meninges, smooth muscle cells, oligodendrocytes, and astrocyte subtypes. Hypertension is genetically correlated with, and shows evidence of a causal effect on, accelerated brain aging. TRIM47 is a core gene bridging hypertension and BAG. GSMAP-based spatial enrichment provides a hypothesis-generating framework for understanding vascular, meningeal, and myelin-related pathways linking hypertension to increased brain age gap.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":"27 4","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148468740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Silymarin attenuates senescence-exacerbated amyloidogenesis, neuroinflammation, and oxidative stress in lipopolysaccharide-induced memory impairment in aging mice.","authors":"Bienose S Chijioke, Benneth Ben-Azu, Daniel T Esuku, Miracle K Nekabari, Saviour G Usin, Faith B Friday, Prosper Iwhiwhu, Ayereoghene S Moses, Emmanuel O Chidebe, Samuel Nwawuba","doi":"10.1007/s10522-026-10465-6","DOIUrl":"10.1007/s10522-026-10465-6","url":null,"abstract":"<p><p>Accelerated cellular perturbations such as cellular senescence, neuroinflammation and oxidative stress are hallmarks of Alzheimer's disease, a neurodegenerative disease associated with memory decline. However, the senolytic effects of silymarin, a flavonolignan with known antioxidant and anti-inflammatory properties, on memory decline remain unknown. Hence, we investigated the effect of silymarin on doxycycline-mediated senescence and exacerbated neuroinflammation in lipopolysaccharide-induced memory-impaired mice. Five groups of adult Swiss female mice (n = 10) were exposed to doxycycline-induced accelerated senescence for 21 days, followed by lipopolysaccharide-induced neuroinflammation from days 15-21, and silymarin (50 and 100 mg/kg, p.o.) or donepezil (1 mg/kg, p.o.) treatments. Spatial and non-spatial memory, and social and motor function tests in mice were assessed. Biochemical assays were performed on the prefrontal cortex and hippocampus to assess senescence-associated secretory phenotypes (SASPs), including SA-β-galactosidase activity, cytokines (TNF-α, IL-6, IL-10), amyloid-beta levels, acetylcholinesterase activity, oxidative stress markers, and molybdoenzymes. Doxycycline-lipopolysaccharide-exacerbated memory impairments were reversed by silymarin, accompanied by reduced molybdoenzymes, malondialdehyde, nitrite, and elevated antioxidants (glutathione, superoxide-dismutase, catalase) in the prefrontal cortex and hippocampus. Additionally, silymarin reverses doxycycline-exacerbated lipopolysaccharide-induced increases in IL-6 and TNF-α release and myeloperoxidase activity while also reducing IL-10 levels. Similar to donepezil, silymarin reduced heightened acetylcholinesterase activity associated with doxycycline-enhanced lipopolysaccharide-induced accumulation of cortical SA-β-galactosidase and amyloid-β levels, relative to the doxycycline-lipopolysaccharide group. These findings suggest that silymarin ameliorates doxycycline-lipopolysaccharide-exacerbated memory impairment and modulates senescence and neuroinflammation by reducing oxidative stress, SASP marker levels, and amyloid-beta concentrations in the prefrontal cortex and hippocampus of mouse brains.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":"27 4","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148429791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endosymbiotic theory of aging revisited: Age-related leakage of mitochondrial dsDNA/RNA stimulates cytosolic nucleic acid sensors which remodel the immune network and promote the aging process.","authors":"Antero Salminen, Kai Kaarniranta, Anu Kauppinen","doi":"10.1007/s10522-026-10470-9","DOIUrl":"10.1007/s10522-026-10470-9","url":null,"abstract":"<p><p>About 1.5-2 billion years ago, an endosymbiosis between aerobic α-proteobacteria and anaerobic archaeal cells generated mitochondria, i.e., organelles capable of producing oxidative energy. The bacterial genome was fundamentally reduced and a circular mitochondrial genome evolved containing mainly the genes coding for the subunits of the electron transport chain. Before the symbiotic event, there existed a virus-host co-evolution which involved the development of sensors for detecting dangerous viral DNA/RNA molecules. Endosymbiosis supplied eukaryotic cells not only with an oxidative powerhouse to allow the evolution of more complex multicellular organisms but it also meant that cells now housed an organelle which was able to generate reactive oxygen species (ROS) and to leak mitochondrial DNA (mtDNA) and double-stranded RNA (dsRNA) into the cytoplasm. There is now abundant evidence that during aging and age-related diseases mitochondria are prone to release both mtDNA and dsRNA. In the cytoplasm, mtDNA/dsRNA molecules activate a number of cytosolic nucleic acid sensors leading to the secretion of type-1 interferons (IFN) and many other cytokines which promote an age-related proinflammatory state. Currently, it is known that mtDNA can activate the cGAS-STING pathway, AIM2 inflammasomes, IFI16 receptors, and ZBP1 sensors and in addition mitochondrial dsRNA stimulates RIG-1/MDA5 signaling. Interestingly, there is abundant evidence that all these receptors are drivers of cellular senescence and inflammaging. For decades, there has been mounting evidence that mitochondria have a crucial role in the aging process. We will examine this question from the perspective of evolution and propose that mitochondrial evolution created an endogenic source for the leakage of dangerous mtDNA/dsRNA which subsequently stimulated cytosolic DNA/RNA sensors, an evolutionarily conserved viral defence mechanism. It seems that these two evolutionary events provided not only the basis for the inevitable process of aging but also ensuring the death of parental organisms.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":"27 4","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13341910/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148395802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}