Longevity Papers

Pathogenic or null mutations in WRN helicase is a cause of premature aging disease Werner syndrome (WS). WRN is known to protect somatic cells including adult stem cells from premature senescence. Loss of WRN in mesenchymal stem cells (MSCs) not only drives the cells to premature senescence but also significantly impairs the function of the stem cells in tissue repair or regeneration.

Cellular senescence precipitates a decline in physiological activities and metabolic functions, often accompanied by heightened inflammatory responses, diminished immune function, and impaired tissue and organ performance. Despite extensive research, the mechanisms underpinning cellular senescence remain incompletely elucidated. Emerging evidence implicates circadian rhythm and hypoxia as pivotal factors in cellular senescence. Circadian proteins are central to the molecular mechanism governing circadian rhythm, which regulates homeostasis throughout the body. These proteins mediate responses to hypoxic stress and influence the progression of cellular senescence, with protein Brain and muscle arnt-like 1 (BMAL1 or Arntl) playing a prominent role. Hypoxia-inducible factor-1α (HIF-1α), a key regulator of oxygen homeostasis within the cellular microenvironment, orchestrates the transcription of genes involved in various physiological processes. HIF-1α not only impacts normal circadian rhythm functions but also can induce or inhibit cellular senescence. Notably, HIF-1α may aberrantly interact with BMAL1, forming the HIF-1α-BMAL1 heterodimer, which can instigate multiple physiological dysfunctions. This heterodimer is hypothesized to modulate cellular senescence by affecting the molecular mechanism of circadian rhythm and hypoxia signaling pathways. In this review, we elucidate the intricate relationships among circadian rhythm, hypoxia, and cellular senescence. We synthesize diverse evidence to discuss their underlying mechanisms and identify novel therapeutic targets to address cellular senescence. Additionally, we discuss current challenges and suggest potential directions for future research. This work aims to deepen our understanding of the interplay between circadian rhythm, hypoxia, and cellular senescence, ultimately facilitating the development of therapeutic strategies for aging and related diseases.

Objective and subjective aging indicators reflect diverse biological and psychosocial processes, yet their combined association with premature mortality remains underexplored. This study aimed to investigate the association between a multidomain framework of aging indicators and premature mortality, addressing gaps in understanding cumulative effects. We included 369,741 UK Biobank participants initially free of cardiovascular disease (CVD) and cancer, followed until December 31, 2022. Four indicators, hearing loss, tooth loss, falls and subjective aging, were counted, and their joint associations with all-cause and cause-specific premature mortality were analyzed using the Cox proportional hazard models. During a median follow-up of 13.74 years, we documented 22,934 premature mortality. Participants with all indicators had an 81% (95%CI: 59-107%), 96% (47-160%), 55% (26-91%), and 114% (73-165%) higher risk of all-cause, CVD, cancer, and other-cause premature mortality, respectively, compared to those without indicators. The associations were particularly elevated among younger participants, those with unhealthy lifestyles, and those of lower socioeconomic status (P for interactions <0.05). Additive interaction with frailty contributed an additional 16.08% (7.91-24.25%) risk of premature mortality. Findings were replicated in the Health and Retirement Study, supporting the robustness of the multidomain aging framework. This study highlights the potential of integrating objective and subjective aging indicators to refine risk assessments and inform interventions targeting aging-related diseases.

Oocyte aging is closely related to a decline in female fertility, accompanied by increased reactive oxygen species levels and changes in protein posttranslational modifications. However, the role of protein palmitoylation in oocyte aging has not been investigated. In the present study, a new association between redox and palmitoylation in aging oocytes was found. We found that the protein level of palmitoyl-protein thioesterase 1 (PPT1), a depalmitoylation enzyme, was increased in maternally aged mice oocytes and follicular fluid of aged (age >35 years) patients with decreased ovarian reserve (DOR). Elevated PPT1 led to decreased S-palmitoylation levels in oocytes, which impaired oocyte maturation and spindle formation. Tubulin was identified as a critical palmitoylated protein regulated by PPT1, whose palmitoylation was also decreased by advanced age, accompanied by abnormalities in membrane localization and microtubule polymerization. Melatonin was found to down-regulate excessive PPT1 and rescue PPT1-induced damage in mouse oocytes, not only by regulating oxidative stress, but also by binding with PPT1 to regulate its lysosomal degradation. In summary, our data demonstrate that PPT1 participates in oocyte aging by regulating tubulin palmitoylation, providing evidence that oxidative stress regulates protein palmitoylation and revealing a novel mechanism of oocyte aging.

Cognitive and physical stress have significant effects on brain health, particularly through their influence on the central executive network (CEN). The CEN, which includes regions such as the dorsolateral prefrontal cortex, anterior cingulate cortex and inferior parietal lobe, is central to managing the demands of cognitively challenging motor tasks. Acute stress can temporarily reduce connectivity within the CEN, leading to impaired cognitive function and emotional states. However a rebound in these states often follows, driven by motivational signals through the mesocortical and mesolimbic pathways, which help sustain inhibitory control and task execution. Chronic exposure to physical and cognitive challenges leads to long-term improvements in CEN functionality. These changes are supported by neurochemical, structural and systemic adaptations, including mechanisms of tissue crosstalk. Myokines, adipokines, anti-inflammatory cytokines and gut-derived metabolites contribute to a biochemical environment that enhances neuroplasticity, reduces neuroinflammation and supports neurotransmitters such as serotonin and dopamine. These processes strengthen CEN connectivity, improve self-regulation and enable individuals to adopt and sustain health-optimizing behaviours. Long-term physical activity not only enhances inhibitory control but also reduces the risk of age-related cognitive decline and neurodegenerative diseases. This review highlights the role of progressive physical stress through exercise as a practical approach to strengthening the CEN and promoting brain health, offering a strategy to improve cognitive resilience and emotional well-being across the lifespan.

Lung adenocarcinoma (LUAD), the most common histological subtype of lung cancer(1, 2), is a disease of the elderly, with an average age of diagnosis of about 70 years of age(3). Older age is associated with an increased incidence of KRAS-driven LUAD(4), a particularly deadly type of LUAD characterized by treatment resistance and relapse. Despite this, our understanding of how old age shapes KRAS-driven LUAD evolution remains incomplete. While the age-related increase in cancer risk was previously ascribed to the accumulation of mutations over time, we are now beginning to consider the role of host biology as an independent factor influencing cancer. Here, we use single-cell RNA-Sequencing of KP (KrasG12D/+;Trp53flox/flox) LUAD transplanted into young and old mice to define how old age affects LUAD evolution and map the changes that old age imposes onto LUAD microenvironment. Our data demonstrates that the aged lung environment steers LUAD evolution towards a primitive stem-like state that is associated with poor prognosis. We ascribe this differential evolution, at least in part, to a population of rare and highly secretory damage-associated alveolar differentiation intermediate (ADI) cells that accumulate in the aged tumor microenvironment (TME) and that dominate the niche signaling received by LUAD cells. Overall, our data puts aging center stage in coordinating LUAD evolution, highlighting the need to model LUAD in its most common context and creating a framework to tailor future cancer therapeutic strategies to the age of the patient to improve outcomes in the largest and most vulnerable LUAD patient population, the elderly.

Cellular senescence is understood to be a biological process that is defined as irreversible growth arrest and was originally recognized as a tumor-suppressive mechanism that prevents further propagation of damaged cells. More recently, cellular senescence has been shown to have a dual role in prevention and tumor promotion. Senescent cells carry a senescence-associated secretory phenotype (SASP), which is altered by secretory factors including pro-inflammatory cytokines, chemokines, and other proteases, leading to the alteration of the tissue microenvironment. Though senescence would eventually halt the growth of cancerous potential cells, SASP contributes to the tumor environment by promoting inflammation, matrix remodeling, and tumor cell invasion. The paradox of tumor prevention/promotion is particularly relevant to the bone niche tumor microenvironment, where longer-lasting, chronic inflammation promotes tumor formation. Insights into a mechanistic understanding of cellular senescence and SASP provide the basis for targeted therapies, such as senolytics, which aim to eliminate senescent cells, or SASP inhibitors, which would eliminate the tumor-promoting effects of senescence. These therapeutic interventions offer significant clinical implications for treating cancer and healthy aging.

Cellular senescence is a phenotypic state that contributes to the progression of age-related disease through secretion of pro-inflammatory factors known as the senescence-associated secretory phenotype (SASP). Understanding the process by which healthy cells become senescent and develop SASP factors is critical for improving the identification of senescent cells and, ultimately, understanding tissue dysfunction. Here, we reveal how the duration of cellular stress modulates the SASP in distinct subpopulations of senescent cells. We used multiplex, single-cell imaging to build a proteomic map of senescence induction in human epithelial cells induced to senescence over the course of 31 days. We map how the expression of SASP proteins increases alongside other known senescence markers such as p53, p21, and p16

Cistanche deserticola Ma (CD), an edible and medicinal plant native to Xinjiang, Inner Mongolia, and Gansu in China, is rich in bioactive polysaccharides known for their health-promoting properties. The polysaccharides of C. deserticola (CDPs) have been shown to possess a range of beneficial activities, including immunomodulatory, anti-aging, antioxidant, and anti-osteoporosis effects.

Small molecules (SMs) are integral to biological processes, influencing metabolism, homeostasis, and regulatory networks. Despite their importance, a significant knowledge gap exists regarding their downstream effects on biological pathways and gene expression, largely due to differences in scale, variability, and noise between untargeted metabolomics and sequencing-based technologies. To address these challenges, we developed a multi-omics framework comprising a machine learning-based protocol for data processing, a semi-supervised network inference approach, and network-guided analysis of complex traits. The ML protocol harmonized metabolomic, lipidomic, and transcriptomic data through batch correction, principal component analysis, and regression-based adjustments, enabling unbiased and effective integration. Building on this, we proposed a semi-supervised method to construct transcriptome-SM interaction networks (TSI-Nets) by selectively integrating SM profiles into gene-level networks using a meta-analytic approach that accounts for scale differences and missing data across omics layers. Benchmarking against three conventional unsupervised methods demonstrated the superiority of our approach in generating diverse, biologically relevant, and robust networks. While single-omics analyses identified 18 significant genes and 3 significant SMs associated with insulin sensitivity (IS), network-guided analysis revealed novel connections between these markers. The top-ranked module highlighted a cross-talk between fiber-degrading gut microbiota and immune regulatory pathways, inferred by the interaction of the protective SM, N-acetylglycine (NAG), with immune genes (FCER1A, HDC, MS4A2, and CPA3), linked to improved IS and reduced obesity and inflammation. Together, this framework offers a robust and scalable solution for multi-modal network inference and analysis, advancing SM pathway discovery and their implications for human health. Leveraging data from a population of thousands of individuals with extended longevity, the inferred TSI-Nets demonstrate generalizability across diverse conditions and complex traits. These networks are publicly available as a resource for the research community.

Chromatin is a highly dynamic entity of the eukaryotic cell nucleus. New evidence is emerging in support of the notion that chromatin can locally and globally rearrange itself to adapt with the cellular microenvironmental changes. Such changes include oxidative stress such as supraphysiological oxygen level, found in hyperoxia. Although it is known that hyperoxia can result in DNA damage and alterations in cell function, it is not well understood how the chromatin architecture changes under such a condition and what the functional significance of such change entails. In this work we developed an imaging-based technique to visualize and characterize nanoscale chromatin remodeling under hyperoxia, created via hydrogen peroxide treatment. We found high spatiotemporal variability of remodeling in different chromatin domains such as the euchromatin, heterochromatin and interchromatin. Chromatin remodeling was hindered by the GSK126 mediated inhibition of methyltransferase EZH2, which regulates the chromatin compaction. Epigenetic modifications and DNA damage under hyperoxia was investigated, which was found affected by the pretreatment of GSK126. The developed techniques and findings inform us with new mechanistic insights of chromatin remodeling which might lead to new intervention strategies to target genotoxic hyper-oxidative stress, which is common in degenerative diseases and aging, and for cell therapy in regenerative medicine.

Human mitochondrial DNA (mtDNA) harbors essential mutations linked to aging, neurodegenerative diseases, and complex muscle disorders. Due to its uniparental and haploid inheritance, mtDNA captures matrilineal evolutionary trajectories, playing a crucial role in population and medical genetics. However, critical questions about the genomic diversity patterns, inheritance models, and evolutionary and medical functions of mtDNA remain unresolved or underexplored, particularly in the transition from traditional genotyping to large-scale genomic analyses. This review summarizes recent advancements in data-driven genomic research and technological innovations that address these questions and clarify the biological impact of nuclear-mitochondrial segments (NUMTs) and mtDNA variants on human health, disease, and evolution. We propose a streamlined pipeline to comprehensively identify mtDNA and NUMT genomic diversity using advanced sequencing and computational technologies. Haplotype-resolved mtDNA sequencing and assembly can distinguish authentic mtDNA variants from NUMTs, reduce diagnostic inaccuracies, and provide clearer insights into heteroplasmy patterns and the authenticity of paternal inheritance. This review emphasizes the need for integrative multi-omics approaches and emerging long-read sequencing technologies to gain new insights into mutation mechanisms, the influence of heteroplasmy and paternal inheritance on mtDNA diversity and disease susceptibility, and the detailed functions of NUMTs.

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

\"Brain age delta\" is the difference between age estimated from brain imaging data and actual age. Positive delta in adults is normally interpreted as implying that an individual is aging (or has aged) faster than the population norm, an indicator of unhealthy aging. Unfortunately, from cross-sectional (single timepoint) imaging data, it is impossible to know whether a single individual\'s positive delta reflects a state of faster ongoing aging, or an unvarying trait (in other words, a \"historical baseline effect\" in the context of the population being studied). However, for a cross-sectional dataset comprising many individuals, one could attempt to disambiguate the overall relative contributions of varying aging rates vs. fixed baseline effects. We present a method for doing this, and show that for the most common approaches, which estimate a single delta per subject, baseline effects are likely to dominate. If instead one estimates multiple biologically distinct modes of brain aging, we find that some modes do reflect aging rates varying strongly across subjects. We demonstrate this, and verify our modelling, using longitudinal (two timepoint) data from 4,400 participants in UK Biobank. In addition, whereas previous work found incompatibility between cross-sectional and longitudinal brain aging, we show that careful data processing does show consistency between cross-sectional and longitudinal results.

Fast twitch, type II muscle fibers are particularly prone to degradation in skeletal muscle pathologies, such as sarcopenia and muscular dystrophies. We previously showed that endogenous activation of the exercise-induced long noncoding RNA CYTOR promotes fast-twitch myogenesis. In the present study, we identify an independent pro-myogenic element within human CYTOR and optimize its RNA delivery. In human primary myoblasts exogenous, vector-based CYTORexon 2 recapitulates the effect of full-length CYTOR by enhancing fast-twitch myogenic differentiation. Furthermore, chemically modified CYTORexon 2 RNA (N1-me-PseudoU, 7-methyl guanosine 5 prime Cap, polyA tail) enhanced RNA stability and reduced the immunogenic response to CYTOR exon 2 RNA. We demonstrate that viral- or chemically optimized RNA-mediated CYTOR exon 2 administration enhances the commitment towards myogenic maturation in Duchenne muscular dystrophy-derived primary myoblasts, induced myogenic progenitor cells and mouse embryonic stem cells. Furthermore, chemically optimized CYTOR exon 2 improves key disease characteristics in dystrophic myotubes, including calcium handling and mitochondrial bioenergetics. In summary, our findings identify CYTOR exon 2 as the pro-myogenic domain of CYTOR that can be delivered in a disease context using chemical modifications. This is of particular importance given the susceptibility of type II muscle fibers in different muscle pathologies such as aging and dystrophies, and the reported oncogenic effect of CYTOR exon 1. Our study, therefore, highlights the potential of identifying functional domains in noncoding RNAs. Delivery, or targeting of such RNA domains could constitute next-generation RNA therapeutics.

Aging leads to the decline of immunity, rendering the elderly susceptible to infection and disease. In the CD8+ T cell compartment, aging leads to a substantial increase of cells with high levels of senescence-associated beta-galactosidase activity (SA-BGal) and other senescence characteristics, including a pro-inflammatory transcriptome and impaired proliferative potential. Using senescent cell isolation coupled with multiomic profiling, here we characterized the epigenetic mechanisms regulating CD8+ T cell senescence in a cohort of younger and older donors. High levels of SA-BGal activity defined changes to global transcriptomes and chromatin accessibility landscapes, with a minor effect of age. Widespread enhancer remodeling was required for the repression of functional CD8+ T cell genes and upregulation of inflammatory and secretory pathway genes. Mechanistically, the senescence program in CD8+ T cells was controlled by chromatin state-specific transcription factor (TF) networks whose composition was largely insensitive to donor age. Pharmacological inhibition of TF network nodes AP1, KLF5, and RUNX2 modulated the transcriptional output, demonstrating the feasibility of TF network perturbation as an approach to modulate CD8+ T cell senescence. Further, CD8+ T cell senescence gene signatures faithfully predicted refractoriness to chimeric antigen receptor (CAR) T-cell therapy in a cohort of diffuse large B cell lymphomas and were highly enriched in the transcriptomes of peripheral CD8+ T cells of individuals with active systemic lupus erythematosus. Collectively, our findings demonstrate the potential of multiomic profiling in identifying key regulators of senescence across cell types and suggest a critical role of senescent CD8+ T cells in disease progression.

Myelodysplastic syndromes (MDS) are age-related diseases characterized by bone marrow (BM) dysfunction and an increased risk of developing acute leukemia. While there is growing evidence highlighting the crucial role of the BM microenvironment (BMME) in MDS, the specific influence of inflammation on BMME changes, as well as the potential benefits of targeting cytokines therapeutically, remain to be elucidated. We previously found interleukin-1 (IL-1) to be a driver of aging phenotypes of BMME and hematopoietic stem and progenitor cells (HSPCs). In the current study, BM samples from patients with MDS demonstrated upregulated levels of IL-1 family cytokines including IL-18. Utilizing highly purified primary BM-derived mesenchymal stromal cells (MSCs), both interleukin-1b (IL-1b) and IL-18 were found to exert direct effects on MSCs, thus influencing their ability to support HSPCs as well as erythroid progenitors. This confirms the significant involvement of both these IL-1 family cytokines in regulating the BM niche. Furthermore, targeting IL-1 receptor type I (IL-1R1) mitigated these aging phenotypes in elderly mice. We subsequently employed an age-appropriate murine model of MDS by transplanting NUP98-HOXD13 transgenic mice (NHD13Tg) cells into aged wild-type mice. Treatment with inhibitors targeting interleukin-1 receptor-associated kinase 4 (IRAK4) and NLR family pyrin domain containing 3 (NLRP3) reversed the proliferation of dysfunctional MSCs and enhanced their functionality. Additionally, IRAK4 inhibition selectively suppressed MDS clonal cells while sparing non-MDS cells in the BM. These findings suggest that targeting IL-1 signaling holds promise for MDS treatment by addressing the underlying myeloid malignancy and restoring the altered BMME via BM-MSCs.

The decline in mitochondrial function has been identified as one of the central pathological mechanisms underlying a variety of aging-related diseases. Nanozymes are nanomaterials with intrinsic enzyme-like properties and are important alternatives to natural enzymes. As emerging biocatalysts, nanozymes exhibit significant potential in mimicking the activity of natural enzymes, enhancing mitochondrial function, and offering novel therapeutic strategies for aging-related conditions. This review provides an overview of various approaches to modulate the catalytic activity of nanozymes, considering factors such as particle size, shape, surface modifications, and constituent elements. It then examines the role of nanozymes in mitigating aging-related diseases by preserving mitochondrial health, with a particular focus on their ability to regulate three critical aspects: mitochondrial energy metabolism, quality control, and antioxidant capacity. By improving mitochondrial energy generation, supporting mitochondrial integrity, and eliminating excess reactive oxygen species (ROS), nanozymes offer new therapeutic possibilities for neurodegenerative diseases, bone-related disorders, and diabetes. Finally, this article discusses the major challenges faced in this field, including issues such as the scalability, biocompatibility, and targeting ability of nanozymes. It also emphasizes that future research should focus on enhancing clinical translation to ensure that nanozymes can play an effective role in practical therapeutic applications.

The pace of biological aging varies between people independently of chronological age and mitochondria dysfunction is a key hallmark of biological aging. We hypothesized that higher functional impact (FI) score of mitochondrial DNA (mtDNA) variants might contribute to premature aging and tested the relationships between a novel FI score of mtDNA variants and epigenetic and biological aging in young adulthood. A total of 81 participants from the European Longitudinal Study of Pregnancy and Childhood (ELSPAC) prenatal birth cohort had good quality genetic data as well as blood-based markers to estimate biological aging in the late 20. A subset of these participants (n = 69) also had epigenetic data to estimate epigenetic aging in the early 20s using Horvath's epigenetic clock. The novel FI score was calculated based on 7 potentially pathogenic mtDNA variants. Greater FI score of mtDNA variants was associated with older epigenetic age in the early 20s and older biological age in the late 20s. These medium to large effects were independent of sex, current BMI, cigarette smoking, cannabis, and alcohol use. These findings suggest that elevated FI score of mtDNA variants might contribute to premature aging in young adulthood.

Telomeres are hypersensitive to the formation of the common oxidative lesion 8-oxoguanine (8oxoG), which impacts telomere stability and function. OGG1 and MUTYH glycosylases initiate base excision repair (BER) to remove 8oxoG or prevent mutation. Here, we show OGG1 loss or inhibition, or MUTYH loss, partially rescues telomeric 8oxoG-induced premature senescence and associated proinflammatory responses, while loss of both glycosylases causes a near complete rescue in human fibroblasts. Glycosylase deficiency also suppresses 8oxoG-induced telomere fragility and dysfunction, indicating that downstream single-stranded break (SSB) repair intermediates impair telomere replication. Preventing BER initiation suppresses PARylation and confers resistance to the synergistic effects of PARP inhibitors on 8oxoG-induced senescence. However, OGG1 activity is essential for preserving cell growth after chronic telomeric 8oxoG formation, whereas MUTYH promotes senescence to prevent chromosomal instability from unrepaired damage. Our studies reveal that inefficient completion of 8oxoG BER at telomeres triggers cellular senescence via SSB intermediates which disrupt telomere function.

Aging is an inevitable physiological process in organisms, and the development of tumors is closely associated with cellular senescence. This article initially examines the role of cellular senescence in tumorigenesis, emphasizing the correlation between telomere length-a marker of cellular senescence-and tumor risk. Concurrently, the study explores the expression levels of senescence-associated markers, such as p16, p53, and mTOR, in the context of tumor development. Additionally, the study investigates the impact of tumors on cellular and organismal senescence, including the effects on immune system function and metabolic processes. Ultimately, the discussion explores the potential application of anti-aging strategies in tumor therapy and considers the possibility of utilizing senescence mechanisms as a novel therapeutic approach for tumors. This research provides novel insights into the complex interplay between senescence and tumor development, suggesting potential strategies for future preventative measures and therapeutic interventions.

Skeletal muscle function relies on mitochondria for energy and for mediating its unique adaptive plasticity. The NLRP3 inflammasome complex is an innate immune mechanism that responds to mitochondrial damage-associated molecular patterns (DAMPS), however its activity relative to mitochondrial dysfunction in muscle requires exploration. The purpose of this study was to characterize immune signaling and mitochondrial function in muscle during aging, endurance training, and disuse induced by denervation. Denervation led to decreases in muscle mass, mitochondrial content, and impaired respiration. Protein analyses revealed increases in NF-{kappa}B p65 and downstream inflammatory markers including NLRP3, caspase-1, GSDMD-N, STING and IL-1{beta}, along with pro-apoptotic BAX and AIF. When assessing potential DAMPS, denervation led to increased ROS production but no changes in cytosolic mtDNA levels, relative to total mtDNA. Since we hypothesized that inflammasome activation would be increased with age, we studied young (6-8 months) and aged (21-22 months) mice that remained sedentary or underwent a 6-week voluntary running protocol. Aging resulted in marked increases in the expression of multiple pro-inflammatory and pro-apoptotic proteins. Remarkably, training uniformly attenuated age-related increases in BAX, NLRP3, caspase-1, STING, and GSDMD protein expression, and reduced the elevated level of cytosolic mtDNA evident in aged muscle. Training adaptations were evident also in the aged animals by the preservation of muscle mass and improvements in oxygen consumption and endurance performance and were achieved despite a lower training distances than in young animals. Our results strongly implicate endurance training as a promising therapeutic for combatting disuse and age-related inflammation in skeletal muscle.

Senescent cells are involved in age-related disorders in different organs and are therapeutic targets for fibrotic and chronic pathologies. Immune-modulating agents, able to enhance senescent cell detection and elimination by endogenous immune cells, have emerged as pharmacological strategies. We report herein a nanoparticle for immune cell-mediated senolytic therapy designed to recruit immune cells in response to specific enzymatic matrix metalloproteinase-3 (MMP-3) activity in the senescence-associated secretory phenotype. For this, mesoporous silica nanoparticles (MSNs) are coated with a peptide substrate of the metalloproteinase MMP-3, and the peptide is decorated with chemokine CXCL12 that enhances immune cell recruitment (NPs@CXCL12). Controlled release studies confirmed the progressive and specific release of CXCL12 in the presence of MMP-3. The ability of immune cell recruitment in response to a senescent microenvironment (senescent WI-38 fibroblasts) is confirmed by Transwell migration assays with green fluorescent Jurkat T-cells, showing NPs@CXCL12 has an enhanced chemotaxis effect toward senescent cells compared to free CXCL12 (2-fold). Moreover, the cytotoxic capacity of human primary natural killer (NK) cells over senescent WI-38 is also confirmed, and their migration trajectories in response to NPs@CXCL12 or free CXCL12 are monitored by using a microfluidic device. Results confirm the ability of NPs@CXCL12 to generate a chemotactic gradient able to attract NK cells. When compared with free CXCL12, the NPs@CXCL12 system showed a reduction of up to 15.56% in the population of NK cells migrating toward free CXCL12 under competitive conditions. This study demonstrates the potential of designing nanoparticles to recruit immune cells under specific responses to eliminate senescent cells. Results confirm that NPs@CXCL12 can effectively establish a chemotactic gradient to attract NK cells.

Skeletal and cardiac muscle mitochondria exist in a dynamic reticulum that is maintained by a balance of mitochondrial biogenesis, fusion, fission, and mitophagy. This balance is crucial for adequate ATP production, and alterations in skeletal muscle mitochondria have been implicated in aging-associated declines in mitochondrial function. We sought to determine whether age and biological sex affect mitochondrial content [Complex IV (CIV)], biogenesis (PGC-1[a]), fusion (MFN2, OPA1), fission (DRP1, FIS1), and mitophagy (Parkin, Pink1) markers in skeletal and cardiac muscle by assessing protein expression in tibialis anterior (TA) and ventricular tissue from 16 young ([≤]6 months) and 16 old ([≥]20 months) male and female Sprague-Dawley rats. In the TA, CIV expression was 40% lower in old vs. young rats (p<0.001), indicating lower mitochondrial content, and coincided with higher expression of Parkin (+4-fold, p<0.001). Further, MFN2 expression was higher (+2-fold, p<0.005) and Parkin was lower (-40%, p=0.014) in older rats. In cardiac muscle, mitochondrial content was maintained in old vs. young rats, and this occurred concomitantly with higher expression of both PGC-1[a] and Parkin. MFN2 and OPA1 expression were also 1.2-5-fold higher in older rats (p<0.05 for all). Largely, protein expression did not differ between male and female rats, with the exception of Pink1 and FIS1 expression in the TA. Collectively, older skeletal and cardiac muscle demonstrated higher expression of fusion and mitophagy proteins, which indicates age alters the balance of biogenesis, fission, fusion, and mitophagy. This may, in turn, affect the ability to provide ATP to these metabolically active tissues.

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

The American Heart Association's (AHA) Life's Essential 8 (LE8) metrics provide a framework for assessing cardiovascular health (CVH). This study evaluates the relationship between CVH levels from LE8 and mortality risk, considering biological aging's role. Using data from the NHANES non-CVD adult population, CVH scores were categorized as low (< 50), moderate (50-79), and high (≥ 80) per AHA guidelines. Cox regression model assessed the impact of CVH levels on all-cause and cardiovascular mortality, while examining four aging indicators as mediators. RCS explored the relationships between CVH scores and mortality risk. The model's performance was evaluated using nine machine learning algorithms, with SHAP analysis on the best model to determine CVH score components' importance. Cox regression showed that all-cause mortality rates decreased by 35% for moderate and 54% for high CVH groups compared to low CVH. The high CVH group had a 59% lower cardiovascular mortality rate. Each unit increase in CVH score reduced all-cause and cardiovascular mortality to 0.98 times. RCS analysis revealed a nonlinear trend between CVH scores and mortality risk. Biological aging indicators significantly mediated the CVH-mortality relationship, with PhenoAge (21.57%) and KDM-Age (20.33%) showing the largest effects. The XGBoost model outperformed others, with SHAP analysis ranking CVH components: physical activity, nicotine, blood pressure, BMI, lipids, healthy eating index, blood glucose, and sleep. Higher CVH levels correlate with reduced all-cause and cardiovascular mortality risk, with biological aging mediating these effects. Adhering to AHA's LE8 metrics is recommended to enhance life expectancy in the non-CVD population.

Neuroinflammation, a significant contributor to various neurodegenerative diseases, is strongly associated with the aging process; however, to date, no efficacious treatments for neuroinflammation have been developed. In aged mouse brains, the number of infiltrating immune cells increases, and the key transcription factor associated with increased chemokine levels is nuclear factor kappa B (NF-κB). Exosomes are potent therapeutics or drug delivery vehicles for various materials, including proteins and regulatory genes, to target cells. In the present study, we evaluated the therapeutic efficacy of exosomes loaded with a nondegradable form of IκB (Exo-srIκB), which inhibits the nuclear translocation of NF-κB to suppress age-related neuroinflammation. Single-cell RNA sequencing revealed that these anti-inflammatory exosomes targeted macrophages and microglia, reducing the expression of inflammation-related genes. Treatment with Exo-srIκB also suppressed the interactions between macrophages/microglia and T and B cells in the aged brain. We demonstrated that Exo-srIκB successfully alleviates neuroinflammation by primarily targeting activated macrophages and partially modulating the functions of age-related interferon-responsive microglia in the brain. Thus, our findings highlight Exo-srIκB as a potential therapeutic agent for treating age-related neuroinflammation.

Reactive oxygen species (ROS) are highly reactive oxygen containing molecules that are generated by normal metabolism. While ROS can cause damage to the building blocks that make up cells, these molecules can also act as intracellular signals that promote longevity. The levels of ROS within the cell can be regulated by antioxidant enzymes, such as superoxide dismutase (SOD), which converts superoxide to hydrogen peroxide. Interestingly, our previous work has shown that disruption of the mitochondrial SOD gene sod-2 results in increased lifespan, suggesting that elevating levels of mitochondrial superoxide can promote longevity. To explore the molecular mechanisms involved, we determined the tissues in which disruption of sod-2 is necessary for lifespan extension and the tissues in which disruption of sod-2 is sufficient to extend lifespan. We found that tissue-specific restoration of SOD-2 expression in worms lacking SOD-2 could partially revert changes in fertility, embryonic lethality and resistance to stress, but did not inhibit the effects of sod-2 deletion on lifespan. Knocking down sod-2 expression using RNA interference specifically in the intestine, but not other tissues, was sufficient to extend longevity. Intestine-specific knockdown of sod-2 also increased resistance to heat stress while decreasing resistance to oxidative stress. Combined, these results indicate that disruption of sod-2 in neurons, intestine, germline, or muscle is not required for lifespan extension, but that decreasing sod-2 expression in just the intestine extends lifespan. This work defines the conditions required for disruption of mitochondrial superoxide dismutase to increase longevity.

The nucleus is a highly specialized organelle that houses the cell's genetic material and regulates key cellular activities, including growth, metabolism, protein synthesis, and cell division. Its structure and function are tightly regulated by multiple mechanisms to ensure cellular integrity and genomic stability. Increasing evidence suggests that nucleophagy, a selective form of autophagy that targets nuclear components, plays a critical role in preserving nuclear integrity by clearing dysfunctional nuclear materials such as nuclear proteins (lamins, SIRT1, and histones), DNA-protein crosslinks, micronuclei, and chromatin fragments. Impaired nucleophagy has been implicated in aging and various pathological conditions, including cancer, neurodegeneration, autoimmune disorders, and neurological injury. In this review, we focus on nucleophagy in mammalian cells, discussing its mechanisms, regulation, and cargo selection, as well as evaluating its therapeutic potential in promoting human health and mitigating disease.

Many cancers use an alternative lengthening of telomeres (ALT) pathway for telomere maintenance. ALT telomeric DNA synthesis occurs in ALT telomere-associated PML bodies (APBs). However, the mechanisms by which APBs form are not well understood. Here, we monitored the formation of APBs with time-lapse imaging employing CRISPR knock-in to track the promyelocytic leukemia (PML) protein at endogenous levels. We found APBs form via two pathways: telomeres recruit PML proteins to nucleate PML bodies de novo, or telomeres fuse with preformed PML bodies. Both nucleation and fusion of APBs require interactions between SUMO and SUMO interaction motifs (SIMs). Moreover, APB nucleation is associated with higher levels of SUMOs and SUMO-mediated recruitment of DNA helicase BLM, resulting in more robust telomeric DNA synthesis. Finally, further boosting SUMO levels at telomeres enhances APB nucleation, BLM enrichment, and telomeric DNA synthesis. Thus, high SUMO levels at telomeres promote APB formation via nucleation, resulting in stronger ALT activity.

Gentianella acuta (GA) is a folk medicine used by Ewenki people in Inner Mongolia to treat heart disease. Transcriptional inhibition caused by the increase of DNMT1/3A/3B levels inhibited Nrf2, an anti-aging factor with antioxidant effect in aging myocardia, and the level of Nrf2 decreased with the increase of age. The main chemical component of GA, xanthones, can reverse this inhibition. In this study, D-gal was injected subcutaneously to establish an aging mouse model, and echocardiography was helpful to evaluate myocardial damage. Myocardial histological changes were detected by haematoxylin eosin and Masson's trichrome staining. The activities of catalase (CAT) and total superoxide dismutase (T-SOD) and the content of malondialdehyde (MDA) in serum of mice were detected to investigate the relationship between GA and oxidative stress. The serum levels of tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) were determined to investigate the effects of GA on aging mice. Results showed that Xanthones could alleviate myocardial damage and fibrosis, significantly improve diastolic dysfunction, gradually decrease MDA content, gradually increase T-SOD and CAT activities, and decrease serum TNF-α, IL-6 and IL-1β contents in aging mice. Reduce cardiac structural disorders, reduce inflammatory infiltration. In addition, GA reduces inflammation by promoting Nrf2 expression, inhibiting DNMT1/3A/3B levels, and activating the p53/p21 signaling pathway. This study suggests that GA has a protective effect on D-gal-induced cardiac aging, which may be related to the activation of p53/p21 signaling pathway and epigenetic regulation of Nrf2 level.