Aging is the primary risk factor for synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), and independently contributes to motor dysfunction. This review summarizes motor system degeneration in aging and disease, focusing on the primary motor cortex (M1), its white matter tracts, and the nigrostriatal system. In healthy aging, M1 exhibits cortical thinning, myelin loss, reduced perfusion, and iron deposition. The motor cortex-derived corticospinal and corticostriatal pathways undergo microstructural decline, often linked to vascular factors. The substantia nigra (SN) demonstrates selective neuronal loss, oxidative stress, iron deposition, and synaptic reduction, contributing to motor impairment. In synucleinopathies, these age-related vulnerabilities are exacerbated by disease-specific pathology. In PD, progressive dopaminergic neuron loss in the SN is a core feature, detectable with advanced magnetic resonance imaging (MRI) markers of iron, neuromelanin, and microstructure. PD pathophysiology extends beyond the nigrostriatal system, involving M1 dysfunction and widespread white matter abnormalities linked to motor deficits and cognitive impairment. DLB is characterized by widespread involvement of cortex (especially posterior), limbic, basal ganglia, brainstem, and cholinergic system, accounting for its early cognitive impairment, neuropsychiatric, motor, and autonomic symptoms. In contrast, MSA is characterized by oligodendroglial α-synuclein inclusions, causing multi-system degeneration, with characteristic atrophy and microstructural disruption in the putamen, pons, and cerebellum that aid differential diagnosis. Multiparametric MRI offers in vivo insights into structural, microstructural, hemodynamic, metabolic, and pathological changes underlying motor dysfunction in aging and neurodegenerative disorders. Understanding the convergence of age-related motor neuron degeneration and disease-specific pathology is essential for elucidating disease mechanisms, identifying early biomarkers, and developing targeted therapies in synucleinopathies.
Altered lipid metabolism is increasingly recognized as a feature of aging and age-related disease, including cancer. Here, we present a lipid-based biological aging clock developed from serum lipidomics data of 443 patients with pancreatic ductal adenocarcinoma (PDAC). Using penalized Cox proportional hazards models, we derived a risk-equivalent Lipid Age and Lipid Age Acceleration (LAA) metric and evaluated its relationship to survival, healthy aging, and pancreatitis. Despite being trained exclusively on a pathological PDAC cohort, the lipid clock predicted chronological age in healthy individuals with high accuracy (Pearson r=0.86; median absolute error = 3.46 years), indicating that pathological cohorts can retain biologically meaningful aging signals. Both PDAC patients and, in exploratory analyses, pancreatitis patients exhibited accelerated lipid aging relative to healthy individuals, with mean LAA values of 5.57 and 2.71 years, respectively. Increased continuous LAA was significantly associated with worse overall and progression-free survival and remained predictive of overall mortality even after adjusting for standard clinical cancer measures, staging, and the conventional tumor marker CA19-9 (HR=1.09 per 1-year increase, p<0.005). Specific individual lipid species, particularly sphingolipids, carried independent prognostic value. Lipid age acceleration was associated with pancreatic disease and with lipidomic patterns consistent with systemic aging-associated and inflammatory remodeling independent of traditional oncological risk parameters. Because the model was developed and evaluated within a single parent dataset and analytical platform, external validation in independent cohorts will be needed to establish broader generalizability.
Chronic kidney disease (CKD) and cerebral small vessel disease (cSVD) share major cardiometabolic risk factors, including hypertension, diabetes, and obesity. The immune system may play a key role in kidney-brain interactions and disease development. However, whether circulating inflammatory mediators reflect similar immune responses in the kidney and brain remains unclear. We therefore characterized circulating, renal and cortical cerebral responses in a rat model of metabolic syndrome. Lean and Obese ZSF1 rats were studied at 8-9, 22-23, and 34-35 weeks of age. Systemic inflammation was assessed using multiplex plasma cytokine/chemokine analysis and flow cytometry of circulating immune cells. Kidney injury was evaluated by histopathology and expression of injury markers. Renal and cerebral blood flow were measured by Laser Speckle Contrast Imaging. Renal macrophage accumulation and cortical cerebral immune cell readouts were assessed by immunohistochemistry. Progression of metabolic syndrome in Obese ZSF1 rats was associated with elevated circulating inflammatory mediators, including IP-10, MCP-1, and RANTES, together with increased classical monocytes from 8-9 weeks and non-classical monocytes from 22-23 weeks onward. Kidney pathology was further characterized by progressive macrophage accumulation and reduced renal blood flow. In contrast, cortical cerebral analyses showed no evidence of macrophage infiltration, while CD68 positivity was reduced in Iba1+ microglia in Obese rats at 34-35 weeks. Despite marked systemic inflammation and renal immune activation, the cerebral cortex displayed a distinct immune response with no macrophage infiltration and altered microglial activity. Rather than indicating a uniform inflammatory response across organs, these descriptive findings provide insight into kidney-brain immune divergence during metabolic syndrome.
Advanced age is associated with larger infarct volumes and poorer functional recovery after acute ischemic stroke (AIS). Carotid stenosis is also a common comorbidity in older individuals and often predicts subsequent AIS. However, no age-specific therapy is currently available to protect the aging brain from aggravated ischemic injury. Here, we investigated whether a senolytic approach could improve cerebrovascular status and reduce ischemic brain injury in a comorbid aging model of AIS. Unilateral common carotid artery occlusion was induced in young and aged rats and served as a diagnostic trigger for chronic senolytic therapy with dasatinib plus quercetin (D+Q). Two weeks later, the distal middle cerebral artery was occluded for 60 min. Compared with vehicle-treated animals, infarct size was measured, spreading depolarizations (SDs) were recorded electrophysiologically, cerebral blood flow (CBF) dynamics were monitored by laser speckle contrast imaging, and cerebrovascular senescent cell burden was assessed by immunocytochemistry. Cerebral angiogenesis, central and systemic inflammatory markers, and metabolic status were evaluated using protein arrays and blood glucose measurements. Aged rats developed larger infarcts than young controls, and this age-related increase was attenuated by D+Q treatment. D+Q reduced the higher frequency of SDs observed in the aged ischemic brain. Increased cerebrovascular senescence in aged animals was diminished by D+Q, accompanied by enhanced angiogenesis, although CBF responses to SDs and reperfusion were unchanged. In addition, D+Q modulated central and systemic inflammatory profiles and counteracted age-related metabolic impairment. Senolytic D+Q therapy administered after carotid artery occlusion confers multifaceted protection against subsequent AIS in the aged brain. By targeting fundamental aging mechanisms that exacerbate brain vulnerability to AIS, D+Q enhanced the resilience of the aging neurovascular niche. Long-term neurological outcomes were not assessed in the present study; therefore, the results provide a rationale for further investigation of senolytic strategies in age-related stroke vulnerability.
The discovery of the glymphatic system and of meningeal lymphatic vessels has substantially revised our understanding of how the central nervous system clears waste and maintains neuroimmune homeostasis. Acting in series, these two pathways remove interstitial solutes, metabolic by-products, and neurotoxic proteins such as tau and amyloid-β from the brain parenchyma and deliver them to the peripheral lymphatic system. Converging experimental and clinical evidence indicates that both pathways decline with age, and that impaired clearance contributes to the onset and progression of Alzheimer's disease, Parkinson's disease, and stroke, although the direction of causality in these associations is not yet fully resolved. In this review, we summarize current knowledge of the anatomy and physiology of the glymphatic and meningeal lymphatic systems; examine the molecular and cellular mechanisms by which their function deteriorates with age; appraise the imaging modalities and fluid biomarkers used to assess them; and evaluate the therapeutic strategies being developed to restore them. A clearer understanding of this clearance pathways may open new avenues for the treatment of age-related neurodegenerative disease.
Late-life depression is associated with reduced treatment efficacy and age-related impairments in synaptic plasticity and stress responsiveness. Myo-inositol, an endogenous regulator of phosphoinositide signalling, has been proposed as candidate treatment for mood disorders, but its effects in age-related mood disorders remain unclear. Here, we investigated the impact of chronic myo-inositol supplementation on depressive behaviour and synaptic markers in aged male and female mice. Aged mice displayed reduced self-care behaviour in the sucrose splash test compared to young adults. Myo-inositol supplementation restored grooming behaviour in both sexes, an effect maintained following exposure to unpredictable chronic mild stress and independent of locomotor activity. Molecular analyses revealed sex-specific synaptic adaptations, with myo-inositol enhancing postsynaptic density protein 95 (PSD-95) levels in aged males, while increasing phosphorylation of the AMPA receptor subunit GluA1 at serine 845 and TARP expression in females. These findings demonstrate that myo-inositol dampens age-related apathetic alterations and is associated with sex-specific synaptic mechanisms, supporting its potential as a therapeutic strategy for late-life depression.
Sarcopenia, the age-related skeletal muscle disorder characterized by declines in muscle mass, strength, and physical performance, has significant health consequences and represents a major global public health challenge. Age-related endocrine and peripheral anabolic-catabolic dysregulation plays a central role in sarcopenia development, and lifestyle factors interact with hormonal regulation to influence skeletal muscle homeostasis. In older adults, reduced hormone secretion capacity, receptor responsiveness, and peripheral metabolism impair hormonal systems, including the somatotropic, gonadal, adrenal, and thyroid axes, as well as insulin and peripheral mediators, such as adipokines, myokines, and inflammatory cytokines. These alterations promote anabolic resistance, a catabolic environment, and metabolic dysfunction, contributing to sarcopenia. Age-related changes in appetite, nutrient utilization, and food choice impair anabolic efficiency and metabolic homeostasis. Declines in physical activity and neuromuscular efficiency disrupt multiple signaling pathways required to maintain muscle mass, and psychosocial factors may increase the risk of a vicious cycle of inactivity. Alterations in the suprachiasmatic nucleus (SCN) and inconsistent behavioral zeitgebers disrupt physiological rhythms. These lifestyle domains influence skeletal muscle homeostasis independently and interact bidirectionally through shared endocrine pathways. Current pharmacological approaches remain adjunctive, limited to confirmed endocrine deficiencies. The coordinated optimization of nutrition, exercise, and circadian health, with attention to regularity and timing, may offer complementary benefits exceeding single-domain interventions. A stage-specific and individually tailored approach supported by multidimensional monitoring and digital technologies is recommended for effective sarcopenia prevention and management.
Cellular senescence is an irreversible growth arrest state and a hallmark of organismal aging. While induction of cellular senescence in healthy organs is undesirable, senescence of specific cell types can be beneficial in certain pathological milieus. For instance, the senescence of activated myofibroblasts helps to limit excessive collagen deposition and preserving tissue homeostasis. Senescent cells express signature gene products, including cell cycle regulators and senescence-associated secretory phenotype (SASP), which includes proinflammatory cytokines, growth factors, and protease inhibitors. Among the senescence regulators, the tumor suppressor p53 plays a pivotal role in suppression of fibrogenesis by dual action: through transcriptional repression of matrix protein genes, and through activation of the cellular senescence pathway in matrix-producing myofibroblasts. Because p53 activation suppresses collagen synthesis, it offers a promising treatment for most fibrotic diseases. However, sustained activation of p53 stress-response in healthy cells may accelerate cellular senescence and aging by promoting the release of SASP. Therefore, the magnitude and timing of p53 activation are critical factors that determine whether its effects are beneficial or detrimental in a given pathological milieu. Here, we discuss the fascinating dual trajectory of p53: its role in driving cellular senescence that contributes to aging, and its capacity to limit the progression of fibrogenesis, a major driver of age-related morbidity and mortality worldwide.
Cancer is largely a disease of older adults, yet the framework used to explain how tumors evade immunity was built almost entirely on young, specific-pathogen-free mouse models and on clinical trials that under-enroll older adults. This review examines whether that framework holds when the host is old. Rather than surveying cancer immunology and aging comprehensively, it focuses on one question: whether the four host capacities the standard account of immunoediting and checkpoint blockade assumes still hold in the aged host. These are a naive T-cell repertoire wide enough to generate tumor-specific clones, a stromal environment that does not suppress priming, functional natural killer [NK] cell surveillance, and an immune baseline free of chronic inflammation. Aging alters all four, but not uniformly. Thymic involution and NK cell decline result in the immune system operating at reduced capacity, representing a shift in severity rather than a fundamental change in mechanism. The NK cell axis is disproportionately significant, as no approved therapies currently restore its function. In contrast, aged stromal senescence and inflammaging represent qualitative changes: the tissue environment becomes suppressive prior to tumor development, rather than as a consequence of tumor presence. The clinical evidence neither confirms nor refutes this interpretation. Older and younger patients gain similar benefit from checkpoint blockade, which is easily read as age being immunologically irrelevant. We argue instead that chronological age bundles aging changes acting on response in opposite directions. What predicts response is more accurately captured by immunological age than by chronological age. This reframing has a clear translational consequence. Therapeutic approaches should not only target the release of suppressed immune responses but also address the correction of the aged microenvironment. This hypothesis is currently being evaluated by senolytic strategies, which have been tested in an initial clinical trial and are supported by converging preclinical evidence.
Cardiovascular aging, characterized by endothelial dysfunction, arterial stiffening, and myocardial remodeling, is a major contributor to the development of age-related cardiovascular disease. Metformin, a first-line therapy for type 2 diabetes, has attracted interest as a promising geroprotective agent due to its ability to target several fundamental aging pathways. Mechanism: Beyond glucose-lowering effects, metformin may confer cardiovascular benefits through activation of AMP-activated protein kinase and inhibition of mitochondrial complex I. Preclinical work suggests these pathways enhance mitochondrial biogenesis, reduce oxidative stress, promote autophagy, and suppress chronic inflammation. Furthermore, metformin has been reported to modulate epigenetic clocks and support genomic stability, potentially mitigating several hallmarks of aging. Clinical Evidence: Although preclinical evidence is substantial, clinical findings remain heterogeneous. Observational studies and trials like UKPDS suggest cardiovascular benefits, whereas randomized controlled trials (RCTs) such as TAYSIDE, GIPS-III, REMOVAL and GOMET yielded inconsistent results for both clinical and surrogate cardiovascular endpoints. Result interpretations are often limited by relatively small sample sizes and short follow-up durations. Sex Differences and Limitations: Emerging evidence suggests sexual dimorphism in metformin responses, potentially influenced by hormonal status and pharmacokinetics. Additional challenges include the hormetic dose-response, the heterogeneity and frailty of older populations, and the absence of validated aging-specific cardiovascular endpoints. Metformin remains a promising candidate to mitigate cardiovascular aging. However, definitive conclusions regarding its efficacy in non-diabetic older adults will require large-scale, long-term RCTs incorporating aging-related biomarkers and stratification according to sex and metabolic status.
The Dual-Pathway Neuroprotection Hypothesis, recently proposed by Badea and colleagues, distinguishes voluntary from enforced exercise and links each to distinct neural pathways, moving beyond the unitary view of exercise as a homogeneous intervention. However, the hypothesis does not consider sex as a biological variable. Given that AD is a sex-biased disease affecting approximately 65-70% women, and that the neuroprotective effects of exercise are sexually dimorphic, we argue that sex may function as a critical moderator of this framework. We propose three testable predictions: (1) voluntary exercise's cortico-limbic effects may be potentiated in females through estrogen-BDNF signaling, but this effect may be constrained by menopausal status; (2) structured/supervised exercise may yield sex-divergent outcomes-with preliminary observations suggesting Aβ clearance in females versus neurotrophic upregulation in males-though evidence remains preliminary and derives from a limited number of heterogeneous studies; and (3) stress burden may reduce the net benefit of enforced exercise, but this will require direct testing. These predictions converge on a formal revision in which sex is not a confounder to be controlled for, but a core biological moderator that may moderate modality-specific neuroprotection. This extended model provides a hypothesis-generating framework for designing future sex-aware exercise studies in AD, but does not yet support sex-stratified clinical prescriptions. This framework is predominantly based on preclinical and indirect evidence from heterogeneous models, necessitating cautious interpretation and rigorous validation.
Age is the greatest risk factor for cardiovascular diseases, including heart failure (HF), which is a leading cause of morbidity and mortality. While left ventricular fibrosis, hypertrophy and decreased contractility are associated with cardiac aging, age is not sufficient for HF development. Despite diminished cardiomyocyte (CM) function being central to cardiac pathology, whether factors predisposing the aged CM to disease are the same or distinct from those underlying disease are not determined. To address this, we integrated our own and published single-nucleus RNA-Seq data of different cardiomyopathies and from young and old human samples and probed for unique and overlapping features. To test the utility of rodents for modelling human aging and disease, we compared human data with data from deeply phenotyped relevant rat models. We identified diverse CM substates, which were significantly altered in proportion with pathology in human and in both pathology and age in rat. In human and rat, CM exhibited substantial transcriptomic changes with age and pathology. In addition to established hallmarks of cardiomyopathy and aging, we detected etiology/age-specific differentially expressed genes/pathways and identified candidate nodal regulators underlying these changes. In human and rat, CM exhibited greater cellular and transcriptional heterogeneity in pathology and age. While rats showed substantial differences to humans, overlapping features, including increased CM heterogeneity and altered expression of genes related to epigenetic, fibrotic and hypertrophic remodelling, were also detected. Although some pathways, differentially expressed genes and trajectories are shared between age and pathology, unique aspects support age and pathology as distinct entities.
Global trajectories of brain aging are well-characterized thanks to many large MRI datasets in the general population. However, regional patterns that may reflect individual differences in brain aging remain less well understood. In this study, we aim to identify differences in brain aging in a longitudinal study of healthy older individuals using a clustering approach and test predictors of cluster membership. Cortical thickness (CTh) is an important biomarker of cortical macrostructure, relevant both in normal aging processes and in many pathologies. CTh was assessed in 176 healthy individuals aged 68-85 years at two time points (mean time interval: 5 ± 1 years) using T1-weighted magnetic resonance imaging (MRI). Regional cortical atrophy was identified based on the annualized percent change (APC) of CTh. Different aging clusters were then classified using hierarchical cluster analysis based on APC values. Two clusters emerged: one with minimal atrophy and the other with more pronounced atrophy of CTh, particularly in left prefrontal and central regions. There were no significant group differences in age or sex between the two clusters. The cluster with more pronounced atrophy was significantly associated with education in the univariate analysis and at borderline significance in the adjusted analysis and showed a non-significant trend of association with cognitive decline. Our results indicate different rates of cortical aging within the context of healthy aging processes.
The glymphatic system, a brain-wide perivascular network mediating cerebrospinal fluid-interstitial fluid exchange, has emerged as a candidate determinant of cognitive health through its role in clearing metabolic waste, neurotoxic proteins, and neuroactive metabolites. The diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index provides a non-invasive means to assess glymphatic activity in vivo, yet no synthesis has consolidated what this marker captures, how reliably it predicts cognitive outcomes, and what pathways may account for observed associations. This narrative review, informed by selected principles from the PRISMA 2020 framework but not constituting a formal systematic review, synthesizes evidence linking DTI-ALPS to domain-specific cognitive performance in healthy aging and neurological disease, encompassing the Alzheimer's disease continuum, cerebral small vessel disease, Parkinson's disease, multiple sclerosis, stroke, and HIV-associated neurocognitive disorder. Lower DTI-ALPS values were consistently associated with worse cognitive performance. The strongest associations were observed for memory and global cognition, followed by executive functions and processing speed; evidence for language and visuospatial abilities was less consistent. Longitudinal data indicate that DTI-ALPS decline may precede detectable amyloid pathology, positioning this index as a candidate early prognostic marker. Three mechanistic pathways are discussed: disruption of sleep-dependent waste clearance; compromise of gray matter integrity through neurotoxic metabolite accumulation; and facilitation of amyloid-β and tau pathology via impaired perivascular protein clearance. Limitations include the indirect nature of DTI-ALPS as a clearance measure, predominance of cross-sectional designs, small samples, and absence of sex-stratified analyses despite known hormonal modulation of glymphatic function. Longitudinal studies, randomized trials of glymphatic-targeting interventions, and acquisition protocol standardization represent priority directions for future research.
Type 2 diabetes mellitus (T2DM) is an aging-related disease with greater incidence in older African Americans (AAs) than whites, but studies on racial disparity in epigenetic aging pathways are scarce; specifically, socio-biological aging processes are not well characterized. We investigated biological aging acceleration (aging accel) with development of T2DM and additionally, insulin resistance (IR) of nondiabetic women at baseline in cross-section. We estimated the extent to which social adversity explained AAs' greater aging accel and, together with accelerated aging, mediated their greater burden of glucometabolic outcomes. Clinical and social determinants of health (SDOH) variables and genome-wide DNA methylation data were extracted from the Women's Health Initiative with > 1,500 postmenopausal non-diabetic women. Diabetic outcome was followed for a mean of 19 years, and baseline IR was measured using fasting serum samples. Aging accel metrics were calculated with Levine's clock, and mediation effects of SDOH and aging accel was estimated via Multiple Mediation analyses. Greater aging accel was observed in T2DM, albeit with only univariate significance and IR and in AAs rather than whites. SDOH was associated with greater aging accel, but its impact on greater accelerated aging in AAs varied and in combination, was minimal. Although aging accel has greater influence than SDOH on the racial difference in glucometabolic outcomes, these parameters jointly mediated to only a limited extent T2DM/IR pathways by race. Our mediation findings are exploratory and hypothesis-generating and thus, our results warrant validation studies to better understand socio-glucometabolic pathways shared by epigenetic aging processes and to inform early risk stratification among at-risk older women for disease prevention and reduced racial health inequity.
Sarcopenia is an age-related progressive degenerative disorder of skeletal muscle characterized by declining muscle mass, strength, and function. Increasing evidence indicates that chronic low-grade inflammation plays an important contributory role in its pathogenesis. The inflammatory microenvironment contributes to sarcopenia through complex interactions involving cellular senescence, mitochondrial dysfunction, and sustained inflammatory signaling, forming a self-reinforcing pathological cycle within skeletal muscle. This review synthesizes current evidence on the molecular mechanisms underlying inflammation-driven sarcopenia, with particular emphasis on how inflammatory signaling disrupts protein turnover and satellite cell metabolism. In addition, exercise is examined as a precision "hormone-like" intervention tailored to different sarcopenia phenotypes, highlighting the distinct mechanisms through which resistance training, aerobic exercise, and combined training modulate the senescence-associated phenotype and inflammatory responses. The review further evaluates anti-inflammatory therapeutic strategies, including nutritional interventions, pharmacotherapy, and acupuncture. These approaches improve muscle health by restoring immune balance, enhancing mitochondrial function, modulating the gut-muscle axis, reducing oxidative stress, and promoting the clearance of senescent cells. Finally, emerging precision medicine frameworks and multi-omics strategies that may support individualized sarcopenia management are discussed. Overall, this review provides an integrated perspective on inflammatory signaling in sarcopenia and outlines potential therapeutic strategies targeting the inflammatory microenvironment, offering insights for future research and clinical management.
Regulation of the endocrine and immune system is pivotal for bodily homeostasis and healthy physiology, and these processes deteriorate as life progresses from adulthood to senescence. Aging, progressively weakening the structural and functional efficacies of the hypothalamic-pituitary-thyroid-adrenal-gonadal autoregulating axis, results in endocrino-immuno-senescence (EIS) that modulates a variety of complications and diseases. Both endocrine and immune responses are compromised during aging, along with impaired tissue regeneration, weakened pathogen detection, and decreased immune surveillance, and these events increase the susceptibility to infection, autoimmunity, cancers, and chronic disorders. Nonetheless, while immunosenescence modulates systemic inflammation and overall host defense, inflammaging accelerates tissue deterioration and intensifies diverse pathologies. Dysregulation of hormonal, genetic, and epigenetic machineries dampens the immune system, elevates pro-inflammatory activity, and fails to defend an organism against foreign pathogens, representing a link between cellular dysfunction and EIS. To mitigate these events, immunomodulation is an important therapeutic strategy that helps renew endocrine and immune dysregulation and simultaneously diminish age health disparities. Moreover, preservation of hormonal stability, involving immune response, emerges as a central determinant and could serve as a preventive medicine for the health and well-being of aged populations. This review provides a comprehensive understanding of the mechanisms by which EIS is coordinately associated with a variety of pathological processes and delineates new insights into immunomodulatory strategies ameliorating age-related diseases for healthy aging and quality living.
TP53-mutated acute myeloid leukemia (AML) is associated with an extremely poor prognosis and is refractory to conventional chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT). We identified high expression of lysine demethylase 4C (KDM4C) in AML, particularly in TP53-mutated AML. Pharmacological inhibition of KDM4C with QC6352 predominantly induced apoptosis in TP53-wild-type AML cells, whereas it caused limited apoptosis but pronounced senescence and growth arrest in TP53-mutated AML cells. In TP53-mutated AML cells, QC6352 induced senescence-associated cytosolic DNA accumulation and activated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, leading to the upregulation of NK cell-activating ligands and enhancing NK cell-mediated cytotoxicity. In vivo, QC6352 effectively attenuated AML progression, and its combination with NK cell therapy further reduced leukemic burden and prolonged survival in mice. Collectively, these findings demonstrate that pharmacological KDM4C inhibition with QC6352 induces cellular senescence and enhances the intrinsic immunogenicity of TP53-mutated AML cells through activation of the cGAS-STING pathway. The study supports KDM4C inhibition as a potential therapeutic strategy for TP53-mutated AML, particularly in patients receiving NK cell-based immunotherapy or undergoing allo-HSCT.
Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder with a higher incidence among older adults. Aging per se alters platelet characteristics, including reduced reactivity and increased caspase activity, changes also observed in ITP. The aim of this study was to assess the impact of aging on the hemostatic characteristics of patients with ITP and its potential contribution to the increased burden of the disease. Additionally, the study sought to identify characteristics of the disease itself, independent of age. Patients with ITP over 65 years of age (ITP>65) and patients aged 65 or under (ITP≤65) were included, as well as age-matched healthy controls (HC). Basal P-selectin exposure was higher in the ITP≤65 than in the HC≤65 group but no difference was observed between the ITP>65 and HC>65 groups. This may be due to the synergistic effect of disease and aging, because P-selectin exposure was higher in the HC>65 group than in the HC≤65 group. The ITP>65 patients exhibited reduced platelet responsiveness to agonists and increased caspase-3/7 activity compared with the ITP≤65 patients. Their clots were more resistant to lysis, likely due to elevated plasma levels of circulating cell-free DNA (cfDNA) and plasminogen activator inhibitor-1 (PAI-1). Comparisons between the ITP≤65 and HC≤65 groups as well as the ITP>65 and HC>65 groups revealed ITP-specific features, such as reduced sialic acid residues due to elevated neuraminidase-1 (NEU1) exposure. These findings showed that age-related changes in haemostasis can overlap with disease-specific features, highlighting the need for age-stratified approaches.
Studies of short-chain fatty acids (SCFAs) in Alzheimer's disease (AD) report protective, neutral, and adverse findings, but the same class label often conceals non-equivalent exposures and endpoints. We propose an AD-specific interpretive framework that organizes this heterogeneity as a causal sequence: source or intervention → SCFA species, dose, and route → absorption and metabolic filtering → target-compartment exposure → host and disease state → responding cell type → endpoint. Seven interdependent axes-SCFA species, dose, route, compartment, exposure context, disease stage, and responding cell type-identify the coordinates needed to compare studies. This organization separates administered dose from achieved exposure, direct entry into the central nervous system from blood-brain barrier or peripheral gut-brain signaling, and stage-related disease biology from evidence of stage-specific treatment efficacy. It also requires symmetric interpretation of null findings according to exposure verification, target engagement, power, cellular resolution, and endpoint specificity. The framework integrates rather than replaces established microbiome, pharmacological, and neuroimmune principles and has not been validated as a predictor of effect direction. Its explanatory value can be tested by prespecified meta-regression, variance partitioning, interaction analysis, matched-exposure replication, and causal mediation. Persistent opposite effects under matched coordinates would indicate missing dimensions or failure of the framework. This Perspective therefore supports mechanism-linked, biomarker-informed research rather than nonspecific SCFA supplementation in unselected patients.
