Ageing Research Reviews最新文献

MicroRNAs are small non-coding RNAs evolutionary conserved molecules. They regulate cellular processes, including RNA silencing, post-translational gene expression and neurodegeneration. MicroRNAs are involved with human diseases such as cancer, Alzheimer’s disease (AD) and others. Interestingly, cerebrospinal fluids (CSF) and the blood of AD patients have altered expressions of many RNAs, which may serve as potential peripheral biomarkers. The intensive investigation from our lab revealed that microRNA-455–3 P (miR-455–3p) is a strong candidate as a potential biomarker and therapeutic target for AD. Several genes implicated in the pathogenesis of AD are directly targeted by miR-455–3p. Several years of our lab research revealed that miR-455–3p regulates important physiological processes associated with AD, such as the processing of the amyloid precursor protein (APP), TGF-β signaling, the regulation of oxidative stress, mitochondrial biogenesis, and synaptic damages. The expression of miR-455–3p in mild cognitive impaired subjects and AD patients pointed out its involvement in AD progression. Recently, our lab generated both transgenic and knockout mice for miR-455–3p. Interestingly miR-455–3p transgenic mice showed superior cognitive learning, improved memory and extended lifespan compared to age matched wild-type mice, whereas miR-455–3-p knockout mice showed cognitive decline and reduced lifespan. Information derived from mouse models further demonstrated the advantageous impact of miR-455–3p on dendritic growth, synaptogenesis, and mitochondrial biogenesis in preventing the onset and progression of AD. The identification of miR-455–3p as a biomarker was suggested by its presence in postmortem AD brains, B-lymphocytes, and fibroblasts. Our hypothesis that miR-455–3p could be a peripheral biomarker and therapeutic target for AD.

Cognitive decline is a natural consequence of aging, but several genetic, environmental, and psychological factors can influence its trajectories. Among the most enduring factors, the Big Five personality traits – defined as relatively stable tendencies to think, behave, and react to the environment – can influence both directly (e.g., by physiological correlates) and indirectly (e.g., healthy or risky behaviors) the risk of developing dementia and mild cognitive impairment (MCI) – a preclinical form of cognitive decline. Despite the great amount of studies focusing on the relationship between personality and cognitive decline, an updated systematic synthesis of the results including a broader range of study designs is still lacking. This systematic review aims to summarize the findings of studies investigating: (i) differences in personality traits between groups of healthy individuals and those with MCI, (ii) the impact of personality traits on the risk for both MCI and dementia, and (iii) changes in personality traits among individuals progressing from normal cognition to MCI. Neuroticism emerged as a significant risk factor for MCI and dementia; Conscientiousness and Openness appear to offer protection against dementia and moderate cognitive decline. Overall, these findings suggest a pivotal role of personality structure in shaping cognitive outcomes on the long run.

Understanding mechanisms of ageing remains a complex challenge for biogerontologists, but recent adaptations of evolutionary ageing theories offer a compelling lens in which to view both age-related molecular and physiological deterioration. Ageing is commonly associated with progressive declines in biochemical and molecular processes resulting from damage accumulation, yet the role of continued developmental gene activation is less appreciated. Natural selection pressures are at their highest in youthful periods to modify gene expression towards maximising reproductive capacity. After sexual maturation, selective pressure diminishes, subjecting individuals to maladaptive pleiotropic gene functions that were once beneficial for developmental growth but become pathogenic later in life. Due to this selective ‘shadowing’ in ageing, mechanisms to counter such hyper/hypofunctional genes are unlikely to evolve. Interventions aimed at targeting gene hyper/hypofunction during ageing might, therefore, represent an attractive therapeutic strategy. The nematode Caenorhabditis elegans offers a strong model for post-reproductive mechanistic and therapeutic investigations, yet studies examining the mechanisms of, and countermeasures against, ageing decline largely intervene from larval stages onwards. Importantly, however, lifespan extending conditions frequently impair early-life fitness and fail to correspondingly increase healthspan. Here, we consolidate multiple evolutionary theories of ageing and discuss data supporting hyper/hypofunctional changes at a global molecular and functional level in C. elegans, and how classical lifespan-extension mutations alter these dynamics. The relevance of such mutant models for exploring mechanisms of ageing are discussed, highlighting that post-reproductive gene optimisation represents a more translatable approach for C. elegans research that is not constrained by evolutionary trade-offs. Where some genetic mutations in C. elegans that promote late-life health map accordingly with healthy ageing in humans, other widely used genetic mutations that extend worm lifespan are associated with life-limiting pathologies in people. Lifespan has also become the gold standard for quantifying ‘ageing’, but we argue that gerospan compression (i.e., ‘healthier’ ageing) is an appropriate goal for anti-ageing research, the mechanisms of which appear distinct from those regulating lifespan alone. There is, therefore, an evident need to re-evaluate experimental approaches to study the role of hyper/hypofunctional genes in ageing in C. elegans.

Alzheimer's disease (AD) is a multifaceted neurodegenerative condition marked by gradual cognitive deterioration and the loss of neurons. While conventional bulk RNA sequencing techniques have shed light on AD pathology, they frequently obscure the cellular diversity within brain tissues. The advent of single-cell RNA sequencing (scRNA-seq) has transformed our capability to analyze the cellular composition of AD, allowing for the detection of unique cell populations, rare cell types, and gene expression alterations at an individual cell level. This review examines the use of scRNA-seq in AD research, focusing on its contributions to understanding cellular diversity, disease progression, and potential therapeutic targets. We discuss key technological innovations, data analysis techniques, and challenges associated with scRNA-seq in studying AD. Furthermore, we highlight recent studies that have utilized scRNA-seq to identify novel biomarkers, uncover disease-associated pathways, and elucidate the role of non-neuronal cells, such as microglia and astrocytes, in AD pathogenesis. By providing a comprehensive overview of advancements in scRNA-seq for unraveling cellular heterogeneity in AD, this review highlights the transformative impact of scRNA-seq on our comprehension of disease mechanisms and the creation of targeted treatments.

Diabetic encephalopathy (DE), a significant micro-complication of diabetes, manifests as neurochemical, structural, behavioral, and cognitive alterations. This condition is especially dangerous for the elderly because aging raises the risk of neurodegenerative disorders and cognitive impairment, both of which can be made worse by diabetes. Despite its severity, diagnosis of this disease is challenging, and there is a paucity of information on its pathogenesis. The pivotal roles of various cellular pathways, activated or influenced by hyperglycemia, insulin sensitivity, amyloid accumulation, tau hyperphosphorylation, brain vasculopathy, neuroinflammation, and oxidative stress, are widely recognized for contributing to the potential causes of diabetic encephalopathy. We also reviewed current pharmacological strategies for DE encompassing a comprehensive approach targeting metabolic dysregulations and neurological manifestations. Antioxidant-based therapies hold promise in mitigating oxidative stress-induced neuronal damage, while anti-diabetic drugs offer neuroprotective effects through diverse mechanisms, including modulation of insulin signaling pathways and neuroinflammation. Additionally, tissue engineering and nanomedicine-based approaches present innovative strategies for targeted drug delivery and regenerative therapies for DE. Despite significant progress, challenges remain in translating these therapeutic interventions into clinical practice, including long-term safety, scalability, and regulatory approval. Further research is warranted to optimize these approaches and address remaining gaps in the management of DE and associated neurodegenerative disorders.

Gut dysbiosis has been recently recognized as a hallmark of ageing. At this stage of life, gut microbiota becomes depleted from bacteria involved in the production of short-chain fatty acids (SCFA), indole and its derivative indole-3-propionic acid (IPA), metabolites shown to improve host glycemic control as well as insulin sensitivity and secretion. Moreover, gut microbiota becomes enriched in pathobiont bacteria involved in the production of imidazole propionate, phenols and trimethylamine, metabolites that promote host insulin resistance and atherosclerosis. The magnitude of these changes is much more pronounced in unhealthy than in healthy ageing. On the other hand, a distinct gut microbiota signature is displayed during longevity, the most prominent being an enrichment in both SCFA and IPA bacterial producers. This short Review discusses, in an innovative and integrative way, cutting-edge research on the composition of gut microorganisms and profile of metabolites secreted by them, that are associated with a healthy and unhealthy ageing pattern and with longevity. A detailed description of the positive or detrimental metabolic effects, in the ageing host, of diet-derived gut microbial metabolites is provided. Finally, microbiota-targeted interventions that counteract gut dysbiosis associated with ageing, are briefly outlined.

Dementia is a global health concern with increasing numbers of people living long enough to develop dementia. People with dementia (PwD) may be particularly vulnerable to suicidality. However, suicide in PwD has not been thoroughly explored. The objective of this review was to determine the prevalence and risk factors of suicide in PwD. Five databases were searched from inception to July 2023. Peer-reviewed publications reporting prevalence, risk factors or quantitative summary data for suicide outcomes in PwD were included. Random effects models were used to calculate the pooled prevalence and effect sizes. 54 studies met inclusion criteria. In PwD, the point prevalence of suicidal ideation was 10 % (95 %CI=6 %;16 %), 2-year period prevalence of suicide attempts was 0.8 % (95 %CI=0.3 %;2 %), 10-year period prevalence of suicide attempts was 8.7 % (95 %CI=6.0 %%;12.7 %) and the incidence of death by suicide 0.1 % (95 %CI=0.1 %;0.2 %). Compared to not having dementia, a diagnosis of dementia increased risk of suicidal ideation (OR=1.62[95 %CI=1.17;2.24]) but not risk of suicide attempt (OR=1.77 [95 %CI=0.85;3.69]) or death by suicide (OR=1.30 [95 %CI=0.81;2.10]). People with moderate dementia had significantly increased risk of suicidal ideation than those with mild dementia (OR=1.59[95 %CI=1.11;2.28]), younger PwD were at increased risk of dying by suicide (OR=2.82[95 %CI=2.16;3.68]) and men with dementia were more likely to attempt (OR=1.28[95 %CI=1.25;1.31]) and die by suicide (OR=2.88[95 %CI=1.54;5.39]) than women with dementia. This review emphasises the need for mental health support and suicide prevention in dementia care, emphasising tailored approaches based on age, symptoms, and being male.

Lactate, a byproduct of glycolysis, was considered as a metabolic waste until identified by studies on the Warburg effect. Increasing evidence elucidates that lactate functions as energy fuel, signaling molecule, and donor for protein lactylation. Altered lactate utilization is a common metabolic feature of the onset and progression of neurodegenerative diseases, such as Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease and Huntington's disease. This review offers an overview of lactate metabolism from the perspective of production, transportation and clearance, and the role of lactate in neurodegenerative progression, as well as a summary of protein lactylation and the signaling function of lactate in neurodegenerative diseases. Besides, this review delves into the dual roles of changed lactate metabolism during neurodegeneration and explores prospective therapeutic methods targeting lactate. We propose that elucidating the correlation between lactate and neurodegeneration is pivotal for exploring innovative therapeutic interventions for neurodegenerative diseases.

Olfactory functioning involves multiple cognitive processes and the coordinated actions of various neural systems. Any disruption at any stage of this process may result in olfactory dysfunction, which is consequently widely used to predict the onset and progression of diseases, such as Alzheimer’s Disease (AD). Although the underlying mechanisms have not yet been fully unraveled, apparent changes were observed in olfactory brain areas form patients who suffer from AD by means of medical imaging and electroencephalography (EEG). Olfactory dysfunction holds significant promise in detecting AD during the preclinical stage preceding mild cognitive impairment (MCI). Owing to the strong specificity, olfactory tests are prevalently applied for screening in community cohorts. And combining olfactory tests with other biomarkers may further establish an optimal model for AD prediction in studies of specific olfactory dysfunctions and improve the sensitivity and specificity of early AD diagnosis.

Background

Cognitive impairment can be caused by infections with various pathogens, including SARS-CoV-2. Research has yet to determine the true incidence and course of cognitive impairment in older adults following COVID-19. Furthermore, research has theorised that COVID-19 is associated with dementia progression and diagnosis but this association has yet to be fully described.

Methods

A systematic review was registered in Prospero and conducted on the databases PubMed, Embase, Ovid, CENTRAL and Cochrane Library. Studies reporting cognitive impairment and dementia outcomes in post-acute and post-COVID-19 patients aged ≥65 years, and which included control data, were included in this review.

Results

15,124 articles were identified by the search strategy. After eliminating duplicate titles and completing title, abstracts and full-text review, 18 studies were included comprising of 412,957 patients with COVID-19 (46.63 % male) and 411,929 patients without COVID-19 (46.59 % male). The overall mean Montreal Cognitive Assessment (MoCA) score in COVID-19 patients was 23.34 out of 30 (95 % CI [22.24, 24.43]). indicating cognitive impairment. The overall proportion of patients identified as having new onset cognitive impairment was 65 % (95 % CI [44,81]). Subgroup analyses indicated that time since infection significantly improves overall MoCA score and reduces proportion of patients with cognitive impairment.

Conclusion

This study indicates that cognitive impairment may be an important sequela of COVID-19. Further research with adequate sample sizes is warranted regarding COVID-19’s association with new-onset dementia and dementia progression, and the effect of repeat infections. There is a need for development of diagnostic and management protocols for COVID-19 patients with cognitive impairment.