Aging and Disease最新文献

Glutathione (GSH) is a crucial redox scavenger, essential for maintaining cellular redox balance. This study explores the long-term effects of chronic GSH deficiency on lifespan, motor function, cognitive performance, redox status and inflammation. GCLM^-/- mice, with a 70-90% reduction in GSH levels, were compared to GCLM^+/+ controls across their lifespan (5, 10 and 20 months). We assessed lifespan, motor performance using balance and coordination tests, cognitive function through anxiety and memory tests, redox markers, and inflammation markers, particularly TNF-α and IL-6. Biochemical analyses of GSH levels in peripheral tissues and brain regions were conducted to evaluate redox state changes. GCLM^-/- mice displayed extended lifespans and improved motor function at young and adult stages, with a delayed onset of motor decline with age. Cognitive function remains largely unaffected, although there are reductions in anxiety-related behaviors and minor deficits in fear-associated memory. Age-related increases in TNF-α, an inflammatory marker, are observed in both genotypes, with GCLM^-/- mice showing a less pronounced increase, particularly in females. There were significant GSH reductions in peripheral tissues, with sporadic changes in brain regions. This stress likely triggers compensatory antioxidant responses, modulating inflammation and redox-sensitive pathways. The data suggests that lifelong GSH deficiency provides protective effects against inflammation and motor decline in younger animals but exacerbates these issues in older mice. The study offers insights into potential therapeutic strategies that leverage mild oxidative stress to promote healthy aging, emphasizing the importance of redox state and antioxidant defenses in the aging process.

Idiopathic intracranial hypertension (IIH) is a disease characterized by increased intracranial pressure (ICP) without identifiable secondary causes. While the increased ICP is a critical diagnostic feature, the underlying pathophysiological mechanisms remain unclear. Previous theories have suggested cerebrospinal fluid (CSF) overproduction, impaired reabsorption, or circulatory obstruction as potential causes. Emerging evidence indicates that IIH may not be solely a central nervous system disorder but also a systemic metabolic disorder. Metabolic and hormonal dysregulation features, including hyperleptinemia, adipocyte leptin hypersecretion, increased insulin resistance, and androgen excess, have been noted in IIH. Furthermore, the targeted blockade of the cortisol-producing enzyme 11β-hydroxysteroid dehydrogenase type 1 has demonstrated therapeutic potential in treating IIH. Consequently, the role of metabolic dysfunction and hormonal imbalance in IIH warrants consideration. This review aims to provide a comprehensive update on current theories regarding the mechanisms of metabolic dysfunction in IIH.

Aging is a key risk factor for numerous diseases, including cardiac diseases. High energy demands of the heart require precise cellular energy sensing to prevent metabolic stress. AMPK and sirtuins are key intracellular metabolic sensors regulating numerous cell functions, like mitochondrial function and biogenesis, autophagy, and redox balance. However, their function is impaired during the aging process leading to mitochondrial dysfunction, oxidative stress, and inflammation culminating in cardiovascular diseases. The underlying molecular mechanisms leading to dysfunction of metabolic sensing in the aging heart are complex and comprise both intracellular and systemic age-related alterations. In this study, we overview the current knowledge on the impact of aging on cardiac metabolic sensing, with a focus on AMPK and sirtuins, while mTOR pathway was only marginally considered. A particular focus was given to systemic factors, e.g., inflammation, vascular diseases, and microbiome.

As a key member of the neurotrophin family in the central nervous system, brain-derived neurotrophic factor (BDNF) plays a critical role in the maintenance and plasticity of the nervous system. Its innate neuroprotective advantage can also be shared with the brain when normal aging-dependent processes challenge neural circuits. The intricate relationship between BDNF and resilience during the aging process signifies the molecular mechanisms that underlie the maintenance and protection of brain function, such as cognition, movement and psychological well-being. As BDNF is crucial for neuronal growth and survival, it can also promote resilience against age-related functional decline and frailty, even if it fails to entirely prevent aging-related functional decline. In the present review, we discuss BDNF function from a neuroprotective perspective and how it may promote resilience in aging. We emphasize briefly the principal, well-known cellular hallmarks of brain aging and how BDNF may restrict such disabling molecular dynamics and enhance overall functional resilience in aging. Insight into the molecular pathways through which BDNF reduces age-related brain dysfunctions and/or improves resilience, provides a foundation for developing targeted interventions to promote mental well-being in an aging population.

Path integration (PI), which supports navigation without external spatial cues, is facilitated by grid cells in the entorhinal cortex. These cells are often impaired in individuals at risk for Alzheimer's disease (AD). However, other brain systems can compensate for this impairment, especially when spatial cues are available. From a graph-theoretical perspective, this compensatory mechanism might manifest through changes in network segregation, indicating shifts in distinct functional roles among specialized brain regions. This study explored whether similar compensatory mechanisms are active in APOE ε4 carriers and individuals with elevated insulin resistance, both susceptible to entorhinal cortex dysfunction. We applied a graph-theoretical segregation index to resting-state fMRI data from two cohorts (aged 50-75) to assess PI performance across virtual environments. Although insulin resistance did not directly impair PI performance, individuals with higher insulin resistance demonstrated better PI with less segregated brain networks, regardless of spatial cue availability. In contrast, the APOE effect was cue-dependent: ε4 heterozygotes outperformed ε3 homozygotes in the presence of local landmarks, linked to increased sensorimotor network segregation. When spatial cues were absent, ε4 carriers exhibited reduced PI performance due to lower segregation in the secondary visual network. Controlling cortical thickness and intracortical myelin variability mitigated these APOE effects on PI, with no similar adjustment made for insulin resistance. Our findings suggest that ε4 carriers depend on cortical integrity and spatial landmarks for successful navigation, while insulin-resistant individuals may rely on less efficient neural mechanisms for processing PI. These results highlight the importance of targeting insulin resistance to prevent cognitive decline, particularly in aging navigation and spatial cognition.

Cirrhosis incidence is significantly increased with age and frequently complicated with neurocognitive dysfunction. We have evaluated the contribution of aging to neuroinflammation in the liver-brain axis in advanced chronic liver disease. Young (6-week-old) and old (9-month-old) mice were included in a 12-week protocol of CCl₄-induced cirrhosis. Liver damage, neuromotor and cognitive capacities, blood brain barrier integrity and function, liver and brain T cell subpopulations and ammonia levels were evaluated. Timp1 and Acta2 gene expression was upregulated in old cirrhotic mice. Increased liver damage was confirmed histologically by Sirius red staining, expression of alpha-SMA, collagen 1-alpha1 and vimentin in aged CCl₄-treated mice. Aging further compromised the neuromotor and cognition capabilities in cirrhotic animals. Stress axis components Crh and its receptor Nr3c1 gene expression levels were upregulated in the paraventricular nucleus and hippocampus of old cirrhotic mice. CCl₄-damage significantly increased ammonia levels in the liver, brain and serum of cirrhotic mice. Circulating ammonia was significantly higher in old cirrhotic mice. Significant correlations were established between brain ammonia, neuromotor capabilities and results on the object recognition tests. A decreased integrity of blood brain barrier was accompanied by astrocyte activation and increased apoptosis-linked cleaved Caspase 3 in old cirrhotic mice. Liver resident CD4⁺ T-cell subpopulations were contracted in cirrhosis, although they showed a pro-inflammatory Th17 profile. Liver and brain resident CD8⁺ T-cell subpopulations were expanded in old cirrhotic animals, along with reduced tissue cytolytic activity. CD8⁺ T cell expansion and reduced perforin levels in the brain correlated with neuromotor and cognitive dysfunction. In conclusion, aging aggravates liver fibrosis, worsens neuromotor and cognitive functions and shifts liver and brain adaptive T cell profiles compromising the BBB integrity in experimental advanced chronic liver disease. Results strengthen the impact of aging in the liver-brain axis and neuroinflammation in cirrhosis.

Alzheimer's disease (AD) is an insidious, progressive, and irreversible neurodegenerative disease characterized by the deposition of extracellular amyloid β-protein (Aβ) to form senile plaques and abnormal phosphorylation of intracellular tau protein to form neuronal fiber tangles. The pathogenesis of AD is complex, and there are several hypotheses, primarily including the Aβ cascade hypothesis, the neurofibrillary tangle hypothesis, the inflammatory hypothesis, and the cholinergic hypothesis. It has been suggested that the dysregulation of multiple energy metabolic pathways, especially mitochondria metabolism, may be related to the severity of AD pathology and disease symptoms in the brain. The modification of histone (lysine) methylation, an actively regulated and reversible process, is closely related to energy metabolism and plays a crucial role in AD development. In summary, histone methylation, energy metabolism, and AD restricted and regulated each other. Here, we review the advances in the correlation between histone methylation, energy metabolism, and AD. This can provide further insights into the mechanisms underlying AD pathogenesis and its control.

Osteoarthritis (OA), a prevalent age-related disease, is increasingly recognized as a multifactorial condition. This comprehensive review provides a multifaceted perspective on the organ-joint crosstalk contributing to OA, transcending the traditional focus on local joint pathology. Based on current research, we discussed the brain-joint, gut-joint, muscle-joint interactions in the etiology and progression of OA. In brain-joint axis, the neuroendocrine regulation, circadian rhythms, and leptin signaling influence joint tissues. We also discussed the role of prostaglandin E2 in skeletal interoception and its potential as a therapeutic target. The gut-joint axis is underscored by the impact of gut microbiota dysbiosis on systemic inflammation and metabolic disorders, both of which are implicated in OA pathogenesis. Furthermore, age-related sarcopenia, characterized by muscle mass and strength loss, is identified as a significant risk factor. Sarcopenia may contribute to OA progression through compromised mechanical support, systemic inflammation, and muscle-derived myokines. Finally, we synthesize the evidence supporting the modulation of circadian rhythm, skeletal interoception, gut microbiome, and muscle mass as innovative strategies for OA management. The organ-joint crosstalk is integral to the complex pathogenesis of OA, highlighting the multifactorial nature of OA and the potential for targeted therapeutic interventions. By integrating these multidimensional perspectives, we aim to enhance our understanding of OA pathogenesis and explore potential pharmacological targets.

Although age-related deterioration of the cardiac function is a well-studied area of research, the interventions and their molecular pathways have not yet been fully identified. Since physical activity is a powerful preventive measure against cardiac aging, our study compared the effects of long-term voluntary and forced physical activity with a sedentary group, utilizing an aging rat model characterized by mitochondrial dysfunction that contributes to age-related cardiovascular diseases. Four experimental groups were created: (I) young controls (12-week-old); (II) 18-month-old aged sedentary rats; (III) aged group with free access to running wheels for 6 months; (IV) aged rats subjected to forced physical activity for 6 months. At the endpoint of the study, the aged animals were two years old. The aged sedentary rats exhibited increased Tei-index, LA/Ao and E/e' ratios as well as decreased e'/a' ratio and lengthened DecT and IVRT, higher perivascular fibrosis ratio and reduced myocardial PKG, STAT3 and Opa1 protein expression, along with decreased ATP synthase (ATPS) activity in comparison to the young controls. In terms of echocardiographic parameters and perivascular fibrosis, the forced running provided more substantial benefits than the voluntary activity demonstrated by decreased Tei-index, E/e' ratio, increased e'/a' ratio and reduced DecT and IVRT. Forced exercise was strongly associated with elevated myocardial expression of PKG, STAT3 and Opa1 proteins and, moreover, the ATPS activity was restored only in the forced running rats. In conclusion, forced but not voluntary exercise has significant protective effects on age-associated diastolic dysfunction by upregulating PKG-STAT3-Opa1 axis and thereby enhancing ATPS activity.