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.
