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.

Optical techniques, such as functional near-infrared spectroscopy (fNIRS), contain high potential for the development of non-invasive wearable systems for evaluating cerebral vascular condition in aging, due to their portability and ability to monitor real-time changes in cerebral hemodynamics. In this study, thirty-six healthy adults were measured by single channel fNIRS to explore differences between two age groups using machine learning (ML). The subjects, measured during functional magnetic resonance imaging (fMRI) at Oulu University Hospital, were divided into young (age ≤ 32) and elderly (age ≥ 57) groups. Brain pulses were extracted from fNIRS using a single 830 nm wavelength. Four feature sets were derived from log-normal parameters estimated by pulse decomposition algorithm. ML experiments utilized support vector machines and random forest learners, along with maximum relevance minimum redundancy and principal component analysis for feature selection. Performance with increasing sample size was estimated using learning curve method. The best mean balanced accuracies for each feature set were over 75% (75.9%, 76.4%, 79.3%, 76.9%), indicating the pulse features containing age related information. Learning curves indicated stable classification performance with increasing sample size. The results demonstrate the potential of using single channel fNIRS in the analysis of aging.

Age-related neurodegenerative diseases involve reduced cell numbers and impaired behavioral capacity. Neurodegeneration and behavioral deficits also occur during aging, and notably in the absence of disease. The cerebellum, which modulates movement and cognition, is susceptible to cell loss in both aging and disease. Here, we demonstrate that cerebellar Purkinje cell loss in aged mice is not spatially random but rather occurs in a pattern of parasagittal stripes. We also find that aged mice exhibit impaired motor coordination and more severe tremor compared to younger mice. However, the relationship between patterned Purkinje cell loss and motor dysfunction is not straightforward. Examination of postmortem samples of human cerebella from neurologically typical individuals supports the presence of selective loss of Purkinje cells during aging. These data reveal a spatiotemporal cellular substrate for aging in the cerebellum that may inform about how neuronal vulnerability leads to neurodegeneration and the ensuing deterioration of behavior.

Inflammaging, a state of chronic low-grade inflammation associated with aging, has been linked to the development and progression of various disorders. Cellular senescence, a state of irreversible growth arrest, is another characteristic of aging that contributes to the pathogenesis of cardiovascular pathology. Senescent cells accumulate in tissues over time and secrete many inflammatory mediators, further exacerbating the inflammatory environment. This senescence-associated secretory phenotype can promote tissue dysfunction and remodeling, ultimately leading to the development of age-related cardiovascular pathologies, such as mitral valve myxomatous degeneration. The species-specific form of canine myxomatous mitral valve disease (MMVD) provides a unique opportunity to investigate the early causes of induction of ECM remodeling in mitral valve leaflets in the human form of MMVD. Studies have shown that in both humans and dogs, the microenvironment of the altered leaflets is inflammatory. More recently, the focus has been on the mechanisms leading to the transformation of resting VICs (qVICs) to myofibroblast-like VICs (aVICs). Cells affected by stress fall into a state of cell cycle arrest and become senescent cells. aVICs, under the influence of TGF-β signaling pathways and the mTOR complex, enhance ECM alteration and accumulation of systemic inflammation. This review aims to create a fresh new view of the complex interaction between aging, inflammation, immunosenescence, and MMVD in a canine model, as the domestic dog is a promising model of human aging and age-related diseases.

Telomere length (TL) is considered a biomarker of aging, and short TL in leukocytes is related to age and stress-related health problems. Cumulative lifetime stress exposure has also been associated with shorter TL and age-related health problems, but the mechanisms are not well understood. We tested in 108 individuals whether shorter TL in leukocytes is observed in individuals with the GABRA6 TT genotype, which has been associated with dysregulation of hypothalamic-pituitary-adrenal axis activity (the main biological stress system) compared to the CC genotype. We also investigated if individuals carrying the TT genotype show higher stress-induced and diurnal cortisol secretion and if cortisol explains the interindividual variability in TL. The analysis pipeline of this study was pre-registered, and the results showed that GABRA6 TT carriers had shorter TL in CD8+CD28+ cells (Bonferroni corrected). In contrast to previous studies, no differences between groups in cortisol secretion were observed, and TL and cortisol did not show significant associations. This study shows, for the first time, shorter TL in CD8+CD28+ cells in TT carriers for GABRA6 compared to CC carriers, suggesting accelerated cellular aging. Although this difference could be linked to an increased susceptibility to stress in the TT carriers, this could not be attributed to the direct influence of cortisol, suggesting the involvement of other mechanisms.

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.

Osteoblasts play a critical role in maintaining bone homeostasis. Senescence causes by free radical-mediated oxidative stress may affect the viability and osteogenic differentiation potential of osteoblast during bone formation. To eliminate the impacts of senescent cells by free radical scavenging is an optimal option for bone regeneration in age-related bone disease, such as osteoporosis (OP) and periodontitis. In this study, we fabricated an antioxidant film (CG-ARB) by crosslinking chitosan (C) and gelatin (G) using α-Arbutin (ARB) as a crosslinker. The morphological, physicochemical, and radical scavenging characteristics of the films were investigated. Its antioxidative ability to prevent osteoblast senescence for restoration of osteogenic differentiation was analyzed in vitro. A Sprague- Dawley (SD) rat model with critical size calvarial defect was used to evaluate the bone regeneration and biosafety in vivo. The results demonstrated that CG-ARB formed a dense fiber membrane, allowing for the gradual and sustained release of ARB for at least 10 days. ARB exerted antioxidant effect that prevented osteoblast senescence in vitro and promote bone healing in vivo. Furthermore, CG-ARB did not cause hemolysis or organ toxicity, and was therefore, considered biosafe. These results indicated that CG-ARB film could be an ideal drug delivery system (DDS) for sustained released of ARB in bone defect repair.

Post-maturation oocyte aging (PMOA) is known to significantly impair the developmental potential of oocytes; however, comprehensive studies on ovine PMOA remain limited. In mice, cumulus cells (CCs) accelerate oocyte aging by releasing cytokines, but the roles of CCs and cytokines in PMOA of domestic animals are poorly understood. This study aimed to elucidate the involvement of CCs and tumor necrosis factor (TNF)-α in the PMOA of ovine oocytes. Our findings reveal that PMOA significantly reduced blastocyst rates and the expression of development-promoting genes, while increasing oocyte degeneration and activation rates, along with expression of development-inhibiting genes, compared to newly matured oocytes. These detrimental effects were more pronounced in oocytes aged as cumulus-oocyte complexes than as cumulus-denuded oocytes. Additionally, PMOA led to increased apoptotic rates, TNF-α production, and TNF receptor 1 (TNFR1) expression in CCs, coupled with a significant reduction in the expression of anti-apoptotic genes. Mature oocytes expressed TNFR1, with levels decreasing significantly during PMOA. Importantly, the addition of the TNF-α antagonist Etanercept to the aging medium markedly improved parthenogenetic embryo development and the expression of competence-related genes, while mitigating CC apoptosis during PMOA of COCs. In conclusion, PMOA compromises developmental potential while heightening oocyte degeneration and activation sensitivity in ovine oocytes. Cumulus cells exacerbate PMOA through increased TNF-α signaling activity, highlighting the potential of TNF-α antagonists as therapeutic agents to counteract the deleterious effects of PMOA.

Delirium is a common complication in elderly surgical patients and is associated with an increased risk of dementia. Although advanced age is a major risk factor, the mechanisms underlying postoperative delirium remain poorly understood. The glymphatic system, a brain-wide network of perivascular pathways, facilitates cerebrospinal fluid (CSF) flow and supports the clearance of metabolic waste. Impairments in glymphatic function have been observed in aging brains and various neurodegenerative conditions. Using in vivo two-photon imaging, we examined the effects of surgery (laparotomy) on glymphatic function in adult (6 months) and aged (18 months) mice 24 h post-surgery. In adult mice, CSF tracer entry into the brain parenchyma along periarteriolar spaces occurred rapidly following intracisternal tracer injection, with no significant differences between sham and surgery groups. In contrast, aged mice exhibited delayed tracer influx, with further impairments observed in the surgery group compared to sham controls. This glymphatic dysfunction correlated with poorer T-maze performance in aged mice. These findings suggest that surgery exacerbates glymphatic impairment in aging brains, potentially hindering brain waste clearance and contributing to postoperative delirium.

The present study explored the association between biological aging (BA), healthy eating index-2015 (HEI-2015) and non-alcoholic fatty liver disease (NAFLD) in the general population of the United States.

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.

TFPI2 is known to regulate the proliferation of various cell types and tumor tissues; however, its role in the process of skin aging has not been elucidated. In this study, we identified TFPI2 as a potential antagonist of aging. Our findings indicate that TFPI2 expression is downregulated in aging skin tissues and senescent human dermal fibroblasts and that the depletion of TFPI2 accelerates the senescence of human dermal fibroblasts and skin aging. RNA-sequencing analysis revealed that CDC6, a protein associated with cell cycle, is a downstream target of TFPI2. Further liquid chromatography-mass spectrometry analysis confirmed that TFPI2 interacts with p85β to activate the phosphoinositide 3-kinase/protein kinase B pathway. Subsequent experiments revealed that the activation of the phosphoinositide 3-kinase/protein kinase B pathway alleviates senescence in human dermal fibroblasts by promoting CDC6 expression and facilitating cell cycle progression. Collectively, these findings underscore the crucial role of the TFPI2/phosphoinositide 3-kinase/protein kinase B/CDC6 pathway in skin aging and highlight its potential for the development of antiaging interventions.

The developmental theory of ageing proposes that age-specific decline in the force of natural selection results in suboptimal levels of gene expression in adulthood, leading to functional senescence. This theory explicitly predicts that optimising gene expression in adulthood can ameliorate functional senescence and improve fitness. Reduced insulin/IGF-1 signalling (rIIS) extends the reproductive lifespan of Caenorhabditis elegans at the cost of reduced reproduction. Here, we show that adulthood-only rIIS improves late-life reproduction without any detrimental effects on other life-history traits in both benign and stressful conditions. Remarkably, we show that rIIS additively extends late-life reproduction and lifespan when animals are exposed to a fluctuating food environment-intermittent fasting (IF)-resulting in reduced food intake in early adulthood. Full factorial genome-wide RNA-Seq across the life course demonstrated that IF and rIIS modulate the age-specific expression of pro-longevity genes. IF, rIIS and combined IF + rIIS treatment downregulated genes involved in biosynthesis in early life and differentially regulated immunity genes in later life. Importantly, combined IF + rIIS treatment uniquely regulated a large cluster of genes in mid-life that are associated with immune response. These results suggest that optimising gene expression in adulthood can decelerate reproductive ageing and increase fitness.

Osteoarthritis (OA) is an age-related degenerative joint disease, prominently influenced by the pro-inflammatory cytokine interleukin-6 (IL-6). Although elevated IL-6 levels in joint fluid are well-documented, the uneven cartilage degeneration observed in knee OA patients suggests additional underlying mechanisms. This study investigates the role of interleukin-6 receptor (IL-6R) in mediating IL-6 signaling and its contribution to OA progression. Here, significantly elevated IL-6R expression is identified in degenerated cartilage of OA patients. Further, in vivo experiments reveal that intra-articular injection of recombinant IL-6R protein or activation of gp130 (Y757F mutation) accelerates OA progression. Conversely, knockout of IL-6R or JAK2, as well as treatment with a JAK inhibitor, alleviates OA symptoms. Mechanistically, chondrocytes derived from degenerative cartilage exhibit impaired nuclear localization of SOX9, a key regulator of cartilage homeostasis. JAK inhibition stabilizes SIRT1, reduces SOX9 acetylation, and thereby facilitates SOX9 nuclear localization, promoting cartilage repair. Additionally, the JAK inhibitor-induced apoptosis in p21-positive senescent cells, and their targeted clearance successfully alleviates OA in p21-3MR mice. In conclusion, these findings reveal a novel mechanism by which inhibiting the IL-6R/JAK2 pathway can alleviate OA. Furthermore, this study proposes targeting p21-positive senescent cells as a new therapeutic strategy for OA.

Resistance to senescence in retinal pigment epithelial (RPE) cells can delay the progression of age-related macular degeneration (AMD). However, the mechanisms underlying RPE cell senescence remain inadequately understood, and effective therapeutic strategies are lacking. While astragaloside IV (Ast) has demonstrated anti-aging properties, its specific effects on RPE cell senescence and potential mechanisms are not yet fully clarified.

In Drosophila, like in many other animal species, females tend to live longer than males, a phenomenon known as sex gap in longevity (SGL). One of the possible causes underlying this phenomenon could be related to the high content of transposable elements (TE) in the Y chromosome (toxic Y hypothesis). TE activity is normally repressed by epigenetic mechanisms, but this regulation weakens with age. Since the Y chromosome is rich in TEs, age-related TE activity should be more pronounced in old males than in old females, likely affecting longevity patterns. In this work, we studied the natural variation in SGL in wild-type populations of three different Drosophila species that vary in their TE content: Drosophila melanogaster, Drosophila simulans, and Drosophila suzukii. Transcriptomic data revealed increased copy-specific TE expression in D. melanogaster and D. suzukii older flies. Moreover, we observed a higher number of upregulated TEs in old males compared to old females across all the three species tested. Additionally, we detected an increase in TE-chimeric transcript generation in some aged samples, particularly in D. suzukii males. Finally, the replacement of the Y chromosome between strains with different SGL led to a progressive reduction in male lifespan and increased TE transcriptional release over generations, suggesting a Y chromosome important role in male longevity. Our work contributes to a better understanding of the genomic differences that lead to variation in longevity patterns between sexes in several species, and emphasizes the importance of studying the role of TEs in male longevity.

The senescence of bone marrow mesenchymal stem cells (BMMSCs) is increasingly recognized as a critical factor contributing to the pathophysiology of age-related diseases. Recent studies suggest that small extracellular vesicles (sEVs) derived from the serum of elderly individuals may play a pivotal role in promoting BMMSC senescence. Glycoprotein non-metastatic melanoma protein B (GPNMB), a type I transmembrane glycoprotein, is upregulated during cellular senescence and can regulate stem cell ageing. However, the precise mechanisms by which GPNMB influences BMMSCs senescence remain poorly understood. Understanding this relationship could provide valuable insights into therapeutic strategies for enhancing BMMSCs function and mitigating age-related degeneration.

Benign prostatic hyperplasia (BPH), characterized as a chronic disease with unregulated enlargement of prostatic gland, is commonly observed in elderly men leading to lower urinary tract dysfunction. Sestrin2 plays a role in the maintenance of cellular homeostasis and protects organisms from various stimuli. The exact role of Sestrin2 in the etiology of BPH, a common age-related disease, remains unknown. Here, we explored the regulatory function of Sestrin2 in modulating autophagy and its therapeutic role in spontaneous BPH. In vivo study, the 3-month-old (3 M) and 24-month-old (24 M) mice were used, and the 24 M mice were additionally administered recombinant Sestrin2 protein (rp-Sestrin2) for consecutive 14 days. In vitro, BPH-1 cells were transfected with an empty or Sestrin2 overexpression vector. Sestrin2 expression in mice prostate was gradually declined with age. Administration of rp-Sestrin2 to these mice suppressed prostatic hyperplasia, restored the balance between proliferation and apoptosis, and reduced prostatic fibrosis. Moreover, rp-Sestrin2 treatment enhanced autophagy by activating AMP-activated protein kinase (AMPK)/ mammalian target of rapamycin (mTOR) signaling pathway, as evidenced by increased autophagosome and autolysosome formation, along with a decrease in degradation marker such as p62. Our findings were further supported by in vitro studies, where Sestrin2 overexpression induced autophagy via AMPK/mTOR signaling pathway. These results suggest that Sestrin2 plays a critical role in attenuating spontaneous BPH by regulating autophagy through AMPK/mTOR signaling pathway. This study provides novel insights into the therapeutic potential of Sestrin2 in age-related spontaneous BPH.

The 12-h ultradian rhythm plays a crucial role in metabolic homeostasis, but its role in ovarian aging has not been explored. This study investigates age-related changes in 12-h rhythmic gene expression across various human tissues, with a particular focus on the ovary.

Excessive alcohol consumption poses significant health risks and is closely associated with oxidative damage. The KEAP1-NRF2-ARE signaling pathway serves as the primary antioxidant system. However, current small molecule inhibitors are all covalently bound to KEAP1, meaning that once bound, they are not easily dissociated, while continuous inhibition of KEAP1 exhibits severe side effects. In this study, BLI, CETSA, Pull-down, Co-IP, and HDX-MS assay analysis were conducted to detect the KEAP1 binding behavior of natural product, capsaicin (CAP), both in vitro and in cells. The ethanol-induced acute gastric mucosal damage rat model was also established to evaluate the therapeutic effect of CAP. Our findings demonstrated that CAP mitigated mitochondrial damage, facilitated the nuclear translocation of NRF2, leading to the up-regulation of downstream antioxidant response elements, HMOX1, TXN, GSS, and NQO1 in GES-1 cells. Furthermore, CAP directly bind to KEAP1 and inhibit the interaction between KEAP1 and NRF2. In the KEAP1-knockout 293T cells, CAP failed to activate NRF2 expression. We identified that CAP non-covalently bound to the Kelch domain and allosterically regulated three specific regions of KEAP1: L342-L355, D394-G423, and N482-N495. To improve drug solubility and delivery efficiency, we developed IR-Dye800 modified albumin-coated CAP nanoparticles. The nanoparticles significantly reduced the gastric mucosal inflammation and activated NRF2 downstream genes in vivo. Our hypothesis was further verified our hypothesis in Nrf2-knockout mice. This study provides new insights that CAP is a safe and novel NRF2 agonist by allosterically regulating KEAP1, which may contribute to the development of lead drugs for oxidative stress-related illness, e.g., aging, cancer, neurodegenerative, and cardiovascular diseases.

Hematopoiesis changes to adapt to the physiology of development and aging. Temporal changes in hematopoiesis parallel age-dependent incidences of blood diseases. Several heterochronic regulators of hematopoiesis have been identified, but how the master transcription factor (TF) circuitry of definitive hematopoietic stem cells (HSCs) adapts over the lifespan is unknown. Here, we show that expression of the ETS family TF Erg is adult-biased, and that programmed upregulation of Erg expression during juvenile to adult aging is evolutionarily conserved and required for complete implementation of adult patterns of HSC self-renewal and myeloid, erythroid, and lymphoid differentiation. Erg deficiency maintains fetal transcriptional and epigenetic programs, and persistent juvenile phenotypes in Erg haploinsufficient mice are dependent on deregulation of the fetal-biased TF Hmga2. Finally, Erg haploinsufficiency in the adult results in fetal-like resistance to leukemogenesis. Overall, we identify a mechanism whereby HSC TF networks are rewired to specify stage-specific hematopoiesis, a finding directly relevant to age-biased blood diseases.

About one out of two diabetic patients develop diabetic neuropathy (DN), of these 20% experience neuropathic pain (NP) leading to individual, social, and health-economic burden. Risk factors for NP are largely unknown; however, premature aging was recently associated with several chronic pain disorders. DNA methylation-based biological age (DNAm) is associated with disease risk, morbidity, and mortality in different clinical settings. The purpose of this work was to study, for the first time, whether biological age is involved in pain development in a huge cohort of DN patients with neuropathy assessed by anatomopathological assay (99 painful (PDN), 132 painless (PLDN) patients, 84 controls (CTRL)). Six subsets of DNAm biomarkers were calculated to evaluate NP-associated changes in epigenetic aging, telomere shortening, blood cell count estimates, and plasma protein surrogates. We observed pain-related acceleration of epigenetic age (DNAmAgeHannum, DNAmGrimAgeBasedOnPredictedAge, DNAmAgeSkinBloodClock), pace of aging (DunedinPoAm), and shortening of telomeres between PDN and PLDN patients. PDN showed decreased predicted counts of B lymphocytes, naive and absolute CD8 T cells, and increased granulocyte counts. Several surrogates of plasma proteins were significantly different (GHR, MMP1, THBS2, PAPPA, TGF-α, GDF8, EDA, MPL, CCL21) in PDNs compared to PLDNs. These results provide the first evidence of an acceleration of biological aging in patients with painful compared to painless DN. This achievement has been possible thanks to the state of the art clinical phenotyping of the enrolled patients. Our findings indicate that the aging process may be directly involved in the PDN progression and in general health degeneration in the T2DM patients. Therefore, it is possible to hypothesize that the administration of effective antiaging drugs could slow down or even block the disease advancement.

Osteoarthritis (OA) is a degenerative joint disease with an immense unmet medical need. FGF18 protein is a potential regenerative factor for cartilage repair. However, traditional protein delivery methods have limited efficacy due to the short lifetime and shallow infiltration.

The importance of integrating physical and psychosocial factors in assessing frailty -health outcomes has been increasingly acknowledged, while the related evidence is lacking. We sought to investigate the associations of joint physical-psychosocial frailty with risk of premature mortality and evaluate the relative importance of individual physical and psychosocial factors.

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.

The aging of the body is accompanied by a decline in tissue function, and this decline mainly stems from the aging of tissue stem cells. Therefore, they play a crucial role in the aging of the body.This study explores the biological characteristics of senescent hUCMSCs by establishing a replicative senescence model of hUCMSCs and a rapid senescence model induced by D - galactose (D-Gal), and analyzing the proliferative capacity, cell viability, cell cycle, pluripotency, and reactive oxygen species (ROS) levels of senescent hUCMSCs.

The complex microbial community residing in the human gut has long been understood to regulate gastrointestinal physiology and to participate in digestive diseases, but its extraintestinal actions and influences are increasingly recognized. This article discusses bidirectional interactions between the gut microbiome and athletic performance, metabolism, longevity and the ability of the gut-brain axis to influence cognitive function and mental health.

Oxygen is essential for human life, yet a growing body of preclinical research is demonstrating that chronic continuous hypoxia can be beneficial in models of mitochondrial disease, autoimmunity, ischemia, and aging. This research is revealing exciting new and unexpected facets of oxygen biology, but translating these findings to patients poses major challenges, because hypoxia can be dangerous. Overcoming these barriers will require integrating insights from basic science, high-altitude physiology, clinical medicine, and sports technology. Here, we explore the foundations of this nascent field and outline a path to determine how chronic continuous hypoxia can be safely, effectively, and practically delivered to patients.

Vascular calcification is a detrimental aging pathology markedly accelerated in patients with chronic kidney disease. Prelamin A is a biomarker of vascular smooth muscle cell aging that accelerates calcification however the mechanisms remain undefined.

Adaptation to starvation is a multi-molecular and temporally ordered process, that could be impaired in obesity. To elucidate how the healthy liver regulates various molecules in a temporally ordered manner during starvation and how obesity disrupts this process, we measured time course multiomic data in the liver of wild-type (WT) and leptin-deficient obese (ob/ob) mice during starvation. Using the measured data, we constructed a starvation-responsive metabolic network, that is a transomic network including responsive molecules and their regulatory relationships during starvation, and analyzed the structure of the network. In WT mice, ATP and AMP, the energy indicators, regulated various metabolic reactions in the network as the hub molecules, both of which were not responsive in ob/ob mice. However, the structural properties of the network were maintained in ob/ob mice. In WT mice, the molecules in the network were temporally ordered through metabolic process coordinated by the hub molecules including ATP and AMP and were positively or negatively co-regulated. By contrast, both temporal order and co-regulation were disrupted in ob/ob mice. Taken together, the starvation-responsive metabolic network is structurally robust, but temporally vulnerable by the loss of responsiveness of the hub molecules in obesity. In addition, we proposed a potential therapeutic target to treat the negative effects of obesity on intermittent fasting to extend lifespan.

Senescence is a key driver of age-related kidney dysfunction, including diabetic kidney disease. Oxidative stress activates cellular senescence, induces abnormal glycolysis, and is associated with pyruvate kinase muscle isoform 2 (PKM2) dysfunction; however, the mechanisms linking PK activation to cellular senescence have not been elucidated. We hypothesized that PKM2 activation by TEPP-46 could suppress oxidative stress-induced renal tubular cell injury and cellular senescence.

Aortic stenosis (AS) remains a prevalent and serious global health concern, exacerbated by an aging population worldwide. This valvular disease, when symptomatic and without appropriate intervention, severe AS can drastically reduce life expectancy. In our systematic review and

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.

The human gut microbiome changes considerably over time. Previous studies have shown that gut microbiome profiles correlate with multiple metabolic traits. As disease development is likely a lifelong process, evidence gathered at different life stages would help gain a better understanding of this correlation. Therefore, we aim to investigate how the association of the gut microbiome and metabolic traits change over the lifespan.

Sarcopenia is an age-related muscle atrophy syndrome characterized by the loss of muscle strength and mass. Although many agents have been used to treat sarcopenia, there are no successful treatments to date. In this study, we identified Danshensu sodium salt (DSS) as a substantial suppressive agent of muscle atrophy. We used a D-galactose (DG)-induced aging-acceleration model, both in vivo and in vitro, to confirm the effect of DSS on sarcopenia. DSS inhibits the expression of muscle atrophy-related factors (MuRF1, MAFbx, myostatin, and FoxO3a) in DG-induced mouse C2C12 and human skeletal muscle cells. Additionally, DSS restored the diameter of reduced C2C12 myotubes. Next, we demonstrated that DSS stimulates AMPK and PGC1α through CaMKII. DSS inhibits the translocation of FoxO3a into the nucleus, thus inhibiting muscle atrophy in a calcium-dependent manner. DSS initiated the protein-protein interaction between FoxO3a and PGC1α. The reduction of the PGC1α-FoxO3a interaction by DG was restored by DSS. Also, DSS suppressed increased intracellular reactive oxygen species (ROS) by DG. In animal models, DSS administration improved mouse muscle mass and physical performance (grip strength and hanging test) under DG-induced accelerated aging conditions. These findings demonstrated that DSS attenuates muscle atrophy by inhibiting the expression of muscle atrophy-related factors. Therefore, DSS may be a potential therapeutic agent for the treatment of sarcopenia.

BACKGROUND: High levels of sedentary behavior among older adults highlight the importance of walking football (WF) in promoting physical activity for healthy aging. This study examines the external and internal load profiles of male and female participants during a WF tournament, addressing a gap in research on game demands and induced load. METHODS: The study involved 176 players aged 50+ participating in a 40-min, 5v5 WF tournament with unlimited substitutions. External load (total and categorized distances) was measured using Global Positioning System (GPS), while heart rate (HR) monitors assessed internal load, including absolute HR and intensity zones based on %HRmax. RESULTS: The proportion of male participants (n=123; 70.3%) was higher than females (n=52; 29.7%), p<.001. They were similar in age (61.6{+/-}8.6 and 60.8{+/-}6.9, respectively). Males covered a higher distance per minute than females, with sex showing a moderate effect (63.3{+/-}10.7 m/min vs. 54.7{+/-}15.8 m/min; p < .001; Cohens dunbiased = 0.69 [0.36; 1.03]), especially in fast walking (41.7{+/-}12.2 m/min vs. 32.6{+/-}16.7 m/min; p < .001; Cohens dunbiased = 0.66 [0.33; 1.00]). Males played more time than females (22:26{+/-}09:47 min:ss vs. 15:41{+/-}07:46 min:ss; p<.001), with moderate effect (Cohens dunbiased = 0.73 [0.40; 1.06]). However, no differences between sexes were identified in the internal load variables, such that the female average %HRmax was 80{+/-}11% and the male was 82{+/-}8% during the practice. CONCLUSIONS: Overall, while males generally exhibit higher external loads in WF, both sexes experience similar internal load demands, highlighting WFs potential as a scalable, health-promoting intervention for aging populations.

To examine the effect of DBS of the lateral hypothalamic area (LHA) on age-related memory changes, neuronal firing from CA1, oxidative stress, and the expression of Hsp70, BDNF, and synaptophysin. 72 male rats were randomly allocated into 6 equal groups: a) normal young group (8 W), b) sham young group, c) DBS young group, d) normal old group (24 months), e) sham old group and f) DBS old group. Memory tests (passive avoidance and Y maze), oxidative stress markers (MDA, catalase, and GSH) and expression of Nrf2, HO-1, Hsp70, BDNF, and synaptophysin were measured by the end of the experiment. Also, in vivo recording of the neuronal firing of the CA1 region in the hippocampus was done. Old rats show significant decline in memories, antioxidant genes (Nrf2 and HO-1), antioxidants (GSH and catalase), Hsp70, BDNF, and synaptophysin with significant increase in MDA in hippocampus (p < 0.05) and DBS for LHA caused a significant improvement in memories in old rats, with significant rise in fast gamma and theta waves in CA1 region in old rats (p < 0.05). This was associated with a significant increase in antioxidants (GSH and CAT), antioxidant genes (Nrf2, HO-1), Hsp70, BDNF, and synaptophysin with significant reduction in MDA in hippocampus (p < 0.05). DBS for LHA ameliorates the age-induced memory decline. This might be due to increase in fast gamma in CA1, attenuation of oxidative stress, upregulation of Nrf2, HO-1, Hsp70, BDNF, and synaptophysin in the hippocampus.

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.

The body temperature of Drosophila melanogaster depends on the extrinsic temperature. Numerous studies in fruit flies have shown that environmental temperature has an effect on metabolism, lifespan and starvation resilience. We have previously shown that Chameau (Chm), a MYST-domain acetyltransferase, promotes aging but also increases starvation resilience. As starvation resilience is highly temperature dependent, we explored the effect of temperature on starvation resilience in fruit flies with reduced chm expression. Strikingly, we found that an increase of 2oC was sufficient to restore starvation resilience in chm mutants. The increase in temperature rescued the dampened expression of genes involved in insulin, hormone and starvation response as well as a reduced rate of weight loss and misregulation of trehalose, we observed in chm mutants at 23oC. Our data show that whereas Chm has an important role in regulating starvation at 23oC and below, it becomes obsolete at higher temperatures. Our finding that a gene plays an important role only under specific environmental conditions has important implications in light of the recent global change of climate conditions.

Brain aging is an inevitable process in adulthood, yet there is a lack of objective measures to accurately assess its extent. This study aims to develop brain age prediction model using magnetic resonance imaging (MRI), which includes structural information of gray matter and integrity information of white matter microstructure. Multiparameter MRI was performed on two population cohorts. We collected structural MRI data from T1- and T2-sequences, including gray matter volume, surface area, and thickness in different areas. For diffusion tensor imaging (DTI), we derived four white matter parameters: fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity. To achieve reliable brain age prediction based on structure and white matter integrity, we employed LASSO regression. We successfully constructed a brain age prediction model based on multiparameter brain MRI (Mean absolute error of 3.87). Using structural and diffusion metrics, we identified and visualized which brain areas were notably involved in brain aging. Simultaneously, we discovered that lateralization during brain aging is a significant factor in brain aging models. We have successfully developed a brain age estimation model utilizing white matter and gray matter metrics, which exhibits minimal errors and is suitable for adults.

Spermatogenesis is finely regulated by histone methylation, which is crucial for regulating gene expression and chromatin remodeling. Functional studies have demonstrated that the histone lysine methyltransferases (KMTs) SETD1B, CFP1, SETDB1, G9A, and SETD2 play pivotal roles in spermatogenesis through establishing the key histone methylation marks, H3K4me3, H3K9me2, H3K9me3, and H3K36me3, respectively. This study aimed to evaluate the spatiotemporal expression of these KMTs and methylation marks as well as senescence-associated β-galactosidase (β-GAL), transcriptional activity, and apoptosis rates in mouse testes during biological aging. In accordance with these purposes, the following groups of Balb/C mice were created: young (1- and 2-week-old), prepubertal (3- and 4-week-old), pubertal (5- and 6-week-old), postpubertal (16-, 18-, and 20-week-old), and aged (48-, 50-, and 52-week-old). The β-GAL staining gradually increased from the young to the aged groups (P < 0.01). The SETD1B, G9A, SETDB1, and SETD2 protein levels increased in spermatogonia, early and pachytene spermatocytes, and Sertoli cells of the aged group (P < 0.05). In contrast, CFP1 protein level decreased in spermatogonia, pachytene spermatocytes, round spermatids, and Sertoli cells towards the older ages (P < 0.05). Moreover, H3K4me3, H3K9me2, H3K9me3, and H3K36me3 levels increased in the aged group (P < 0.05). There was also a significant reduction in apoptosis rates in seminiferous tubules of the pubertal, postpubertal, and aged groups (P < 0.01). Consequently, accumulation of histone methylation marks due to increased expression of KMTs in spermatogenic and Sertoli cells during testicular aging may alter chromatin reprogramming and gene expression, contributing to age-related fertility loss.

The growing prevalence of age-related cardiovascular diseases (CVDs) poses significant health challenges, necessitating the formulation of novel treatment approaches. GATA4, a vital transcription factor identified for modulating cardiovascular biology and cellular senescence, is recognized for its critical involvement in CVD pathogenesis. This review collected relevant studies from PubMed, Google Scholar, and Science Direct using search terms like 'GATA4,' 'cellular senescence,' 'coronary artery diseases,' 'hypertension,' 'heart failure,' 'arrhythmias,' 'congenital heart diseases,' 'cardiomyopathy,' and 'cardiovascular disease.' Additionally, studies investigating the molecular mechanisms underlying GATA4-mediated regulation of GATA4 and senescence in CVDs were analyzed to provide comprehensive insights into this critical aspect of potential treatment targeting. Dysregulation of GATA4 is involved in a variety of CVDs, as demonstrated by both experimental and clinical research, comprising CAD, hypertension, congenital heart diseases, cardiomyopathy, arrhythmias, and cardiac insufficiency. Furthermore, cellular senescence enhances the advancement of age-related CVDs. These observations suggested that therapies targeting GATA4, senescence pathways, or both as necessary may be an effective intervention in CVD progression and prognosis. Addressing age-related CVDs by targeting GATA4 and senescence is a broad mechanism approach. It implies further investigation of the molecular nature of these processes and elaboration of an effective therapeutic strategy. This review highlights the importance of GATA4 and senescence in CVD pathogenesis, emphasizing their potential as therapeutic targets for age-related CVDs.

Aging women experience a significant decline of ovarian hormones, particularly estrogen, following menopause, and become susceptible to cognitive and psychomotor deficits. Although the effects of estrogen depletion had been documented in the prefrontal and somatosensory cortices, its impact on somatomotor cortex, a region crucial for motor and cognitive functions, remains unclear. To explore this, we ovariectomized young adult female rats and fed subsequently with phytoestrogen-free diet and studied the effects of estrogen depletion on the somato-sensory and motor cortices. Low serum estrogen was confirmed prior to biochemical and morphological analyses. Results revealed that estrogen depletion differentially affected the two cortical areas: all three estrogen receptors were downregulated in the somatosensory cortex, whereas in the somatomotor cortex, G-protein-coupled estrogen receptor 30 was upregulated, estrogen receptor α decreased, and estrogen receptor β remained unaffected. Intracellular dye injections revealed decreased dendritic spines on layer III and V pyramidal neurons of the somato-sensory cortex but increased in those of the motor cortex. These were accompanied by decrease and increase of excitatory postsynaptic density protein 95 respectively. Since dendritic spines receive excitatory inputs, these findings suggest that estrogen depletion changes the excitatory connectivity of the somato-sensory and motor cortices in opposite directions. Notably, estradiol replenishment reversed the dendritic spine increase in the somatomotor cortex, confirming the estrogen dependency of this effect. The differential influence of estrogen depletion on these two cortices could have contributed to the cognitive and psychomotor abnormalities in postmenopausal females.