Ageing Research Reviews最新文献

Targeting senescent cells has recently emerged as a promising strategy for treating age-related diseases, such as atherosclerosis, which significantly contributes to global cardiovascular morbidity and mortality. This review elucidates the role of senescent cells in the development of atherosclerosis, including persistently damaging DNA, inducing oxidative stress and secreting pro-inflammatory factors known as the senescence-associated secretory phenotype. Therapeutic approaches targeting senescent cells to mitigate atherosclerosis are summarized in this review, which include the development of senotherapeutics and immunotherapies. These therapies are designed to either remove these cells or suppress their deleterious effects. These emerging therapies hold potential to decelerate or even alleviate the progression of AS, paving the way for new avenues in cardiovascular research and treatment.

Background

Motoric cognitive risk syndrome (MCR) is defined as the presence of slow gait-speed and subjective cognitive decline in older individuals without mobility disability or dementia. While some studies suggest that MCR is a pre-dementia syndrome and may help predict the risk of cognitive impairment and dementia, not all studies concur. The objective of this study is to comprehensively summarize and synthesize evidence to assess the association between MCR and cognitive impairment and dementia.

Methods

Following a pre-specified protocol, two authors systematically searched PubMed, Embase, and The Cochrane Library from inception to 19 August 2024 for observational or randomized studies pertaining to the association between MCR and cognitive impairment and dementia. We favoured maximally adjusted hazards and odds ratios to determine the longitudinal and cross-sectional risk of cognitive impairment and dementia. We investigated for potential sources of heterogeneity and also conducted sensitivity and subgroup analyses by continent and the type of cognitive outcome. The quality of evidence was assessed using the Newcastle-Ottawa Scale (NOS) and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework.

Results

We included 20 studies comprising a combined cohort of 1206,782 participants, of which 17 studies were included in the quantitative analysis. The pooled analysis outlined that individuals with MCR exhibited 2.20-fold higher risk of cognitive impairment and dementia, compared to controls (RR=2.20; 95 %CI=1.91–2.53). These findings remained robust across all subgroup analyses, sensitivity analyses and assessments of publication bias.

Conclusion

MCR may be considered a predictive factor for long-term cognitive impairment and dementia. This should be taken into consideration when clinically evaluating the risk of cognitive impairment and dementia but further research is required to lend greater clarity to this association.

Background

Subjective cognitive decline (SCD) is considered a pre-symptomatic stage of dementia characterized by cognitive complaints. The ability of education to reduce the risk of dementia is well known. Our objective is to investigate the influence of education on the risk of progression from SCD to MCI or dementia.

Methods

Prospective longitudinal studies of adults (≥50 years) with SCD evaluating progression to objective cognitive decline, MCI, or dementia were selected. Pooled estimates (random effects model) and 95 % confidence intervals were calculated, exploring heterogeneity. Standardized education differences, Odds Ratio, or Hazard Ratio between converters and non-converters were estimated.

Results

The systematic review carried out showed that high education, as well as other cognitive reserve proxies, delays cognitive decline. The first meta-analysis showed a significant association of SCD with conversion in both high and low education strata. A second meta-analysis considering education as a continuous variable found that SCD converters showed two years less education than non-converters.

Conclusions

Our results suggest that education has a delaying effect against cognitive decline progression. The presumed improvement in accurately detecting cognitive decline associated with better metacognitive skills in higher-educated SCD participants does not seem to neutralize the incremental risk of objective cognitive decline associated with lower educational attainment.

Metal ions play a pivotal role in maintaining optimal brain function within the human body. Nevertheless, the accumulation of these ions can result in irregularities that lead to brain damage and dysfunction. Disruptions of metal ion homeostasis can result in various pathologies, including inflammation, redox dysregulation, and blood-brain barrier disruption. While research on metal ions has chiefly focused on neurodegenerative diseases, little attention has been given to their involvement in the onset and progression of stroke. Recent studies have identified cuproptosis and confirmed ferroptosis as significant factors in stroke pathology, underscoring the importance of metal ions in stroke pathology, including abnormal ion transport, neurotoxicity, blood-brain barrier damage, and cell death. Additionally, it provides an overview of contemporary metal ion chelators and detection techniques, which may offer novel approaches to stroke treatment.

Recently included in the 2024 new revised diagnostic criteria of Alzheimer’s disease (AD), glial fibrillary acidic protein (GFAP) has garnered significant attention. A systematic review and meta-analysis were performed to comprehensively evaluate the diagnostic, differential diagnostic, and prospective diagnostic performance of GFAP in cerebrospinal fluid (CSF) and blood for AD continuum. A literature search using common electronic databases, important websites and historical search way was performed from inception to the beginning of March 2023. The inclusion criteria was studies evaluating the diagnostic accuracy of GFAP in CSF and/or blood for the AD continuum patients, utilizing PET scans, CSF biomarkers and/or clinical criteria. The systematic review and meta-analysis were conducted referring to the Cochrane Handbook. In total, 34 articles were eventually included in the meta-analysis, 29 of which were published within the past three years. Blood GFAP exhibited good diagnostic accuracy across various AD continuum patients, and the summary area under curve for distinguishing PET positive and negative individuals, CSF biomarkers defined positive and negative individuals, clinically diagnosed AD and cognitive unimpaired controls, AD and/or mild cognitive impairment and other neurological diseases, and prospective cases and controls was 0.85[0.81–0.88], 0.77[0.73–0.81], 0.92[0.90–0.94], 0.80[0.77–0.84], and 0.79[0.75–0.82], respectively. Only several studies were recognized to evaluate the diagnostic accuracy of CSF GFAP, which was not as good as that of blood GFAP (paired mixed data: AUC = 0.86 vs. AUC = 0.77), but its accuracy remarkably increased to AUC = 0.91 when combined with other factors like sex, age, and ApoE genotype. In summary, GFAP, particularly in blood, shown good diagnostic, differential diagnostic, and prospective diagnostic accuracy for AD continuum patients, with improved accuracy when used alongside other basic indexes.

An autosomal dominant neurodegenerative disease called Huntington's disease (HD) is characterized by motor dysfunction, cognitive decline, and a variety of psychiatric symptoms due to the expansion of polyglutamine in the Huntingtin gene. The disease primarily affects the striatal neurons within the basal ganglia, leading to significant neuronal loss and associated symptoms such as chorea and dystonia. Current therapeutic approaches focus on symptom management without altering the disease's progression, highlighting a pressing need for novel treatment strategies. Recent studies have identified imidazoline receptors (IRs) as promising targets for neuroprotective and disease-modifying interventions in HD. IRs, particularly the I1 and I2 subtypes, are involved in critical physiological processes such as neurotransmission, neuronal excitability, and cell survival. Activation of these receptors has been shown to modulate neurotransmitter release and provide neuroprotective effects in preclinical models of neurodegeneration. This review discusses the potential of IR-targeted therapies to not only alleviate multiple symptoms of HD but also possibly slow the progression of the disease. We emphasize the necessity for ongoing research to further elucidate the role of IRs in HD and develop selective ligands that could lead to effective and safe treatments, thereby significantly improving patient outcomes and quality of life.

Alzheimer's disease (AD) is the most common cause of dementia and accounts for 60–70 % of all cases. It affects millions of people worldwide. AD poses a substantial economic burden on societies and healthcare systems. AD is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impaired daily functioning. As the prevalence of AD continues to increase, understanding its pathogenesis, improving diagnostic methods, and developing effective therapeutics have become paramount. This comprehensive review delves into the intricate mechanisms underlying AD, explores the current state of diagnostic techniques, and examines emerging therapeutic strategies. By revealing the complexities of AD, this review aims to contribute to the growing body of knowledge surrounding this devastating disease.

Alzheimer's Disease (AD), a multifaceted neurodegenerative disorder, is increasingly understood through the regulatory lens of microRNAs (miRNAs). This review comprehensively examines the pivotal roles of miRNAs in AD pathogenesis, shedding light on their influence across various pathways. We delve into the biogenesis and mechanisms of miRNAs, emphasizing their significant roles in brain function and regulation. The review then navigates the complex landscape of AD pathogenesis, identifying key genetic, environmental, and molecular factors, with a focus on hallmark pathological features like amyloid-beta accumulation and tau protein hyperphosphorylation. Central to our discussion is the intricate involvement of miRNAs in these processes, highlighting their altered expression patterns in AD and subsequent functional implications, from amyloid-beta metabolism to tau pathology, neuroinflammation, oxidative stress, and synaptic dysfunction. The predictive analysis of miRNA targets using computational methods, complemented by experimental validations, forms a crucial part of our discourse, unraveling the contributions of specific miRNAs to AD. Moreover, we explore the therapeutic potential of miRNAs as biomarkers and in miRNA-based interventions, while addressing the challenges in translating these findings into clinical practice. This review aims to enhance understanding of miRNAs in AD, offering a foundation for future research directions and novel therapeutic strategies.

Mitochondria functionally degrade as neurons age. Degenerative changes cause inefficient oxidative phosphorylation (OXPHOS) and elevated electron leakage from the electron transport chain (ETC) promoting increased intramitochondrial generation of damaging reactive oxygen and reactive nitrogen species (ROS and RNS). The associated progressive accumulation of molecular damage causes an increasingly rapid decline in mitochondrial physiology contributing to aging. Melatonin, a multifunctional free radical scavenger and indirect antioxidant, is synthesized in the mitochondrial matrix of neurons. Melatonin reduces electron leakage from the ETC and elevates ATP production; it also detoxifies ROS/RNS and via the SIRT3/FOXO pathway it upregulates activities of superoxide dismutase 2 and glutathione peroxidase. Melatonin also influences glucose processing by neurons. In neurogenerative diseases, neurons often adopt Warburg-type metabolism which excludes pyruvate from the mitochondria causing reduced intramitochondrial acetyl coenzyme A production. Acetyl coenzyme A supports the citric acid cycle and OXPHOS. Additionally, acetyl coenzyme A is a required co-substrate for arylalkylamine-N-acetyl transferase, which rate limits melatonin synthesis; therefore, melatonin production is diminished in cells that experience Warburg-type metabolism making mitochondria more vulnerable to oxidative stress. Moreover, endogenously produced melatonin diminishes during aging, further increasing oxidative damage to mitochondrial components. More normal mitochondrial physiology is preserved in aging neurons with melatonin supplementation.

Neuroinflammation is an innate and adaptive immune response initiated by the release of inflammatory mediators from various immune cells in response to harmful stimuli. While initially beneficial and protective, prolonged or excessive neuroinflammation has been identified in clinical and experimental studies as a key pathological driver of numerous neurological diseases and an accelerant of the aging process. Glycolysis, the metabolic process that converts glucose to pyruvate or lactate to produce adenosine 5′-triphosphate (ATP), is often dysregulated in many neuroinflammatory disorders and in the affected nerve cells. Enhancing glucose availability and uptake, as well as increasing glycolytic flux through pharmacological or genetic manipulation of glycolytic enzymes, has shown potential protective effects in several animal models of neuroinflammatory diseases. Modulating the glycolytic pathway to improve glucose metabolism and ATP production may help alleviate energy deficiencies associated with these conditions. In this review, we examine six neuroinflammatory diseases—stroke, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and depression—and provide evidence supporting the role of glycolysis in their treatment. We also explore the potential link between inflammation-induced aging and glycolysis. Additionally, we briefly discuss the critical role of glycolysis in three types of neuronal cells—neurons, microglia, and astrocytes—within physiological processes. This review highlights the significance of glycolysis in the pathology of neuroinflammatory diseases and its relevance to the aging process.