Ageing Research Reviews最新文献

Transposable elements (TEs) are essential components of eukaryotic genomes and subject to stringent regulatory mechanisms to avoid their potentially deleterious effects. However, numerous studies have verified the resurrection of TEs, particularly long interspersed nuclear element-1 (LINE-1), during preimplantation development, aging, cancer, and other age-related diseases. The LINE-1 family has also been implicated in several aging-related processes, including genomic instability, loss of heterochromatin, DNA methylation, and the senescence-associated secretory phenotype (SASP). Additionally, the role of the LINE-1 family in cancer development has also been substantiated. Research in this field has offered valuable insights into the functional mechanisms underlying LINE-1 activity, enhancing our understanding of aging regulation. This review provides a comprehensive summary of current findings on LINE-1 and their roles in aging and age-related diseases.

Neurodegenerative diseases like Alzheimer's and Parkinson's disease (AD and PD) are well-known, yet their underlying causes remain unclear. Recent studies have suggested that disruption of ion channels contribute to their pathogenesis. Among these channels, the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, encoded by HCN1–4 genes, are of particular interest due to their role in generating hyperpolarization-activated current (Ih), which is crucial in various neural activities impacting memory and motor functions. A growing body of evidence underscores the pivotal role of HCN in Aβ generation, glial cell function, and ischemia-induced dementia; while HCN is expressed in various regions of the basal ganglia, modulating their functions and influencing motor disorders in PD; neuroinflammation triggered by microglial activation represents a shared pathological mechanism in both AD and PD, in which HCN also plays a significant part. This review delves into the neuronal functions governed by HCN, its roles in the aforementioned pathogenesis, its expression patterns in AD and PD, and discusses potential therapeutic drugs targeting HCN for the treatment of these diseases, aiming to offer a novel perspective and inspire future research endeavors.

Macroautophagy/autophagy is primarily accountable for the degradation of damaged organelles and toxic macromolecules in the cells. Regarding the essential function of autophagy for preserving cellular homeostasis, changes in, or dysfunction of, autophagy flux can lead to disease development. In the current paper, the complicated function of autophagy in aging-associated pathologies and cancer is evaluated, highlighting the underlying molecular mechanisms that can affect longevity and disease pathogenesis. As a natural biological process, a reduction in autophagy is observed with aging, resulting in an accumulation of cell damage and the development of different diseases, including neurological disorders, cardiovascular diseases, and cancer. The MTOR, AMPK, and ATG proteins demonstrate changes during aging, and they are promising therapeutic targets. Insulin/IGF1, TOR, PKA, AKT/PKB, caloric restriction and mitochondrial respiration are vital for lifespan regulation and can modulate or have an interaction with autophagy. The specific types of autophagy, such as mitophagy that degrades mitochondria, can regulate aging by affecting these organelles and eliminating those mitochondria with genomic mutations. Autophagy and its specific types contribute to the regulation of carcinogenesis and they are able to dually enhance or decrease cancer progression. Cancer hallmarks, including proliferation, metastasis, therapy resistance and immune reactions, are tightly regulated by autophagy, supporting the conclusion that autophagy is a promising target in cancer therapy.

Background

Alcohol use is associated with a wide spectrum of neurological disorders, including cognitive dysfunction and dementia. Likewise, the high prevalence of cognitive dysfunction and dementia specifies the urgent need to identify modifiable risk factors. Because findings on alcohol and cognitive dysfunction and dementia have been inconsistent, the present dose-response meta-analysis of cohort and case control studies was conducted to evaluate the available evidence.

Method and materials

A systematic search was conducted on PubMed/MEDLINE, Scopus, Embase, and PsychInfo databases and Google Scholar up to April, 2023. In the dose-response meta-analysis, a restricted cubic spline regression model was conducted to evaluate a possible non-linear relation between alcohol intake and the outcomes. Random-effects model was used to perform the meta-analysis and evaluate heterogeneity. Egger’s test and a funnel plot were used to assess small study effects. Subgroup analyses were carried out to explore possible sources of heterogeneity.

Results

Seventeen eligible studies comprising 80,680 total persons with 4929 cases for dementia and 13,530 total persons with 1579 cases for cognitive dysfunction were included for dose-response analysis. When compared to the reference group of 0 g/day of alcohol intake, the dose-response meta-analysis revealed a significant non-linear (J-shaped) association between alcohol intake and the risk of each of cognitive dysfunction, (lower dose range: 1–30.5 g/day, RR: 0.97; 95 % CI 0.95–0.99; higher dose range: >30.5 g/day, RR: 1.07; 95 % CI 1.01–1.15) and dementia (lower dose range: 1–17.5 g/day, RR: 0.92; 95 % CI 0.88–0.96, higher dose range: >17.5 g/day, RR: 1.23; 95 % CI 1.09–1.35). The lowest risk was achieved at approximately 30 g/day of alcohol for cognitive dysfunction and 15 g/day for dementia. The J-shape association remained with subgroups defined by age (≤65; >65 years) or study duration (<10; ≥10 years) for dementia, and within age >65 and duration <10 years for cognitive dysfunction.

Conclusion

We observed a J-shape association between alcohol consumption and both cognitive dysfunction and dementia, with light-to-moderate alcohol intake being associated with a reduced risk in adults. Further studies are needed to clarify more specifically the association between alcohol consumption and six domains of cognitive dysfunction based on diagnostic and statistical manual of mental disorders (DSM) criteria.

RNA-binding proteins (RBPs) are evolutionarily conserved across most forms of life, with an estimated 1500 RBPs in humans. Traditionally associated with post-transcriptional gene regulation, RBPs contribute to nearly every known aspect of RNA biology, including RNA splicing, transport, and decay. In recent years, an increasing subset of RBPs have been recognized for their DNA binding properties and involvement in DNA transactions. We refer to these RBPs with well-characterized DNA binding activity as RNA/DNA binding proteins (RDBPs), many of which are linked to neurological diseases. RDBPs are associated with both nuclear and mitochondrial DNA repair. Furthermore, the presence of intrinsically disordered domains in RDBPs appears to be critical for regulating their diverse interactions and plays a key role in controlling protein aggregation, which is implicated in neurodegeneration. In this review, we discuss the emerging roles of common RDBPs from the heterogeneous nuclear ribonucleoprotein (hnRNP) family, such as TAR DNA binding protein-43 (TDP43) and fused in sarcoma (FUS) in controlling DNA damage response (DDR). We also explore the implications of RDBP pathology in aging and neurodegenerative diseases and provide a prospective on the therapeutic potential of targeting RDBP pathology mediated DDR defects for motor neuron diseases and aging.

Introduction

Neuropsychiatric symptoms may impact prognosis in individuals with mild cognitive impairment (MCI); however, data on frequency of psychotic symptoms are sparse.

Methods

We searched MEDLINE, EMBASE, PsychoINFO from inception to June 2023. We included studies reporting patients with MCI prevalence of (delusions and/or hallucinations. Random effects model were performed to estimate the prevalence, and subgroup and meta-regression analyses were performed to explore heterogeneity.

Results

Of 3145 records identified, 36 studies were included, enrolling 20,426 patients. Overall prevalence of hallucinations was 1.78 % (95 % CI, 1.17 – 2.71) and delusions 3.84 % (95 % CI, 2.71 – 5.42), both with significant heterogeneity (/² = 90 %). Prevalence of hallucinations and delusions were lower when measured by NPI scales and in population-based samples.

Discussion

Delusions and hallucinations occur in MCI patients at low rates. Prevalence can be partially explained by the assessment method, sample source and study heterogeneity.

Brain aging is characterized by several structural, biochemical and molecular changes which can vary among different individuals and can be influenced by genetic, environmental and lifestyle factors. Accumulation of protein aggregates, altered neurotransmitter composition, low-grade chronic inflammation and prolonged oxidative stress have been shown to contribute to brain tissue damage. Among key metabolic byproducts, advanced glycation end products (AGEs), formed endogenously through non-enzymatic reactions or acquired directly from the diet or other exogenous sources, have been detected to accumulate in brain tissue, exerting detrimental effects on cellular structure and function, contributing to neurodegeneration and cognitive decline. Upon binding to signal transduction receptor RAGE, AGEs can initiate pro-inflammatory pathways, exacerbate oxidative stress and neuroinflammation, thus impairing neuronal function and cognition. AGE-RAGE signaling induces programmed cell death, disrupts the blood-brain barrier and promotes protein aggregation, further compromising brain health. In this review, we investigate the intricate relationship between the AGE-RAGE pathway and brain aging in order to detect affected molecules and potential targets for intervention. Reduction of AGE deposition in brain tissue either through novel pharmacological therapeutics, dietary modifications, and lifestyle changes, shows a great promise in mitigating cognitive decline associated with brain aging.

Human skin ageing is closely related to the ageing of the whole organism, and it's a continuous multisided process that is influenced not only by genetic and physiological factors but also by the cumulative impact of environmental factors. Currently, there is a scientific community need for developing skin models representing ageing processes to (i) enhance understanding on the mechanisms of ageing, (ii) discover new drugs for the treatment of age-related diseases, and (iii) develop effective dermo-cosmetics. Bioengineers worldwide are trying to reproduce skin ageing in the laboratory aiming to better comprehend and mitigate the senescence process. This review provides details on the main ageing molecular mechanisms and procedures to obtain in vitro aged skin models.

It is imperative to optimise health and healthspan across the lifespan. The accumulation of reactive oxygen species (ROS) has been implicated in the hallmarks of ageing and inhibiting ROS production can potentially delay ageing whilst increasing healthy longevity. Lipids and lipid mediators (derivatives of lipids) are becoming increasingly recognized as central molecule in tissue and cellular function and are susceptible to peroxidation; hence linked with ageing. Lipid classes implicated in the ageing process include sterols, glycerophospholipids, sphingolipids and the oxidation products of polyunsaturated fatty acids but these are not yet translated into the clinic. Further mechanistic studies are required for the understanding of lipid classes in the ageing process. Lipidomics, the system level characterisation of lipid species with respect to metabolism and function, might provide a significant and useful biological age profiling tool through longitudinal studies. Lipid profiles in different ages among healthy individuals could be harnessed as lipid biomarkers of healthy ageing with potential integration for the development of lipid-based ageing clock (lipid clock). The potential of a lipid clock includes the prediction of future morbidity or mortality, which will promote precision and healthy longevity medicine.

Background

Frailty, an age-related state of reduced physiological reserve, is often associated with lower socio-economic position (SEP). This systematic review synthesised observational studies assessing (i) the association between SEP and frailty prevalence; (ii) how changes in frailty status over time vary by SEP; and (iii) whether the association between frailty and clinical outcomes is modified by SEP.

Methods

We searched three electronic databases from 2001 to 2023. We included observational studies measuring early-, mid-, and late-life indicators of SEP (education, income, wealth, housing, occupation, and area-based measures of multiple deprivation) and frailty (assessed using any validated measure). Screening and extraction were performed in duplicate. Findings were synthesised using narrative synthesis.

Results

We included 383 studies reporting findings from 265 independent samples/cohorts across 64 countries. Lower SEP was associated with higher frailty prevalence across all indicators (childhood deprivation 7/8 studies, education 227/248, occupation 28/32, housing 8/9, income 98/108, wealth 39/44 and area-based deprivation 32/34). Lower SEP was also associated with higher frailty incidence (27/30), with greater odds of transitioning towards a more severe frailty state (35/43), lower odds of frailty reversion (7/11), and (in some studies) with more rapid accumulation of deficits (7/15). The relationship between frailty and mortality was not modified by SEP.

Interpretation

Preventative measures across multiple levels of individual and structural inequality are likely to be required to reduce the rising levels of frailty. Resourcing of interventions and services to support people living with frailty should be proportionate to needs in the population to avoid widening existing health inequalities.