Aging and Disease最新文献

Throughout the course of evolution, organisms and cells have evolved a suite of mechanisms to manage persistent stimuli, thereby preserving cellular and organismal homeostasis. Upon detecting stress signals, cells activate a transcriptional response termed the mitochondrial unfolded protein response (UPR^mt). This response is crucial for maintaining protein homeostasis, facilitating mitochondrial function recovery, promoting cell survival, and ultimately influencing lifespan. Striated muscles play a pivotal role in oxygen supply, movement, and metabolism. The aging of these muscles can lead to heart failure, arrhythmias, and sarcopenia, significantly impacting quality of life and lifespan. Given the intimate connection between UPR^mt and striated muscle aging, UPR^mt emerges as a potential therapeutic target for mitigating the effects of striated muscle aging. In this review, we delve into the role of UPR^mt in striated muscle aging, drawing upon the extant molecular regulatory mechanisms of UPR^mt. This exploration may enhance our understanding of the underlying mechanisms of striated muscle aging and aid in the identification of potential drug targets.

Hutchison-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by a mutation in LMNA, the gene encoding A-type lamins, leading to premature aging with severely reduced life span. HGPS is characterized by growth deficiency, subcutaneous fat and muscle issue, wrinkled skin, alopecia, and atherosclerosis. Patients also develop a bone phenotype with reduced bone mineral density, osteolysis and striking demineralization of long bones. To further clarify the tissue modifications in HGPS, we characterized bone mineralization in the Lmna^G609G/G609G progeria mouse model. Femurs from 8-week-old mice and humeri from 15-week-old mice were analyzed using quantitative backscattered electron imaging to assess bone mineralization density distribution, osteocyte lacunae sections and structural bone histomorphometry. Tissue sections were stained with Giemsa and Goldner trichrome for histologic evaluation. Bone tissue from Lmna^+/+ and Lmna^G609G/G609G mice had similar mineral content at 3 different bone sites with specific tissue ages. The osteocyte lacunae features were not statistically different, but more empty lacunae were found in Lmna^G609G/G609G at both animal ages. Bone histomorphometry and histology demonstrated decreased bone volume per tissue volume in primary (8W: -23%, p=0.001; 15W: -38%, p=0.002) and secondary spongiosa (8W: -36%, p=0.001; 15W: -49 %, ns), as well as growth plate dysplasia with thinner unmineralized resting and proliferative zones in the Lmna^G609G/G609G mice versus controls (8W: -18%, p=0.006; 15W: -25%, p=0.001). Overall, the Lmna^G609G/G609G mouse develops chondrodysplasia with reduced trabecular bone volume. Mineral content findings at several tissue sites and ages suggest that bone dysplasia results from impaired bone formation with normal bone turnover.

With the progression of global aging, neurological diseases in elderly individuals have aroused widespread interest among researchers. Imbalances in the homeostasis of neuronal microenvironments, including neural progenitor cells and microglia, are the leading cause of worsening neurodegenerative diseases. The aging of various glial cells can further lead to abnormal functions in the central nervous system (CNS). Recent studies have shown that aging plays a vital role in a variety of degenerative diseases, including Huntington's disease (HD). In this manuscript, we describe the molecular mechanisms of aging, the cellular constitution of the neural microenvironment and the progression of aging in various neurodegenerative diseases, providing new targets and perspectives for the clinical treatment of various neurodegenerative diseases.

Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) are neurodegenerative disorders characterized by the pathological deposition of amyloid-beta (Aβ) in the brain. Although both conditions share common pathogenic pathways, they exhibit distinct cellular manifestations and disease progression. This study focused on the differential expression and role of astrocytic colony-stimulating factor 1 (CSF1) in these diseases. Through transcriptomic analysis of 248 brain tissue samples from the hippocampal-entorhinal system of 50 individuals, we identified a significant increase in CSF1 expression in the CA4 subfield of AD patients, contrasting with a marked decrease in CAA. Functional investigations revealed that astrocytes with elevated CSF1 levels displayed neurotoxicity associated with AD-like pathology, while reduced CSF1 expression in astrocytes was linked to vascular damage characteristic of CAA. These findings suggest that CSF1 plays divergent roles in AD and CAA, contributing to their distinct pathological profiles. Our study highlights the potential of targeting astrocytic CSF1 expression as both a differential diagnostic marker and a therapeutic approach in managing these overlapping yet distinct neurological conditions.

Neurodegenerative diseases, particularly Alzheimer's disease and other dementias as well as Parkinson's disease, are emerging as profoundly significant challenges and burdens to global health, a trend highlighted by the most recent Global Burden of Disease (GBD) 2021 studies. This growing impact is closely linked to the demographic shift toward an aging population and the potential long-term repercussions of the COVID-19 pandemic, both of which have intensified the prevalence and severity of these conditions. In this review, we explore several critical aspects of this complex issue, including the increasing global burden of neurodegenerative diseases, unmet medical and social needs within current care systems, the unique and amplified challenges posed by the COVID-19 pandemic, and potential strategies for enhancing healthcare policy and practice. We underscore the urgent need for cohesive, multidisciplinary approaches across medical, research, and policy domains to effectively address the increasing burden of neurodegenerative diseases, thereby improving the quality of life for patients and their caregivers.

The relationship between key energy metabolites and brain health is not well understood. We investigated the association between circulating ketone bodies, pyruvate, and citrate with cognitive decline, structural brain characteristics, and risk of dementia. We measured ketone bodies (acetoacetate, β-hydroxybutyrate, and acetone), pyruvate, and citrate species using NMR in plasma samples from 1,850 older adults in the Cardiovascular Health Study collected in 1989-90 or 1992-93. Cognitive decline was assessed using the modified Mini-Mental State Examination and the Digit Symbol Substitution Test. Dementia was adjudicated by a committee of experts through comprehensive evaluations including cognitive tests, medical records, and interviews with the next of kin. Dementia-related mortality was confirmed by a committee using death certificates and other clinical data from hospitalization. Multivariable linear mixed models were used to assess 9-year cognitive decline, while multivariable Cox regression models evaluated 6-year dementia incidence and 22-year dementia-related mortality. White matter lesions and ventricular size were measured using MRI in 1992-94 and were analyzed using multivariable linear regression models. Higher plasma levels of ketones, particularly β-hydroxybutyrate, were associated with faster cognitive decline (β, -0.10; 95% CI, -0.15 to -0.05; P_adj&;lt.001) and dementia-related mortality (HR per SD, 1.29; 95% CI, 1.07 to 1.56; P_adj=0.023). Higher pyruvate concentrations were associated with slower cognitive decline, smaller ventricular size, lower dementia risk (HR per SD, 0.87; 95% CI, 0.77 to 0.97; P=0.013; P_adj=0.073), and lower dementia mortality. Higher citrate levels were associated with less cognitive decline and lower dementia risk. In adults aged 65 years and older, circulating ketone bodies are associated with faster cognitive decline and higher dementia mortality, while pyruvate and citrate are associated with lower dementia risk.

Plasma biomarkers represent promising tools for the screening and diagnosis of patients with neurodegenerative conditions. However, it is crucial to account for the effects of aging on biomarker profiles, especially in the oldest segments of the population. Additionally, biomarkers in this sample can offer in vivo insights into the physiological mechanisms underlying brain aging while concomitantly supporting cognitive preservation. In this study we analyzed plasma Alzheimer's disease (AD) core biomarkers, neurofilament light chain (NfL), and glial fibrillary acid protein (GFAP) using the Single Molecule Array (SIMOA) platform in 75 cognitively preserved nonagenarians, and compared with baseline samples of 153 volunteers who were cognitively unimpaired (CU) during six years (classified in ≤ 70, and 71 to 85 years of age), and with 108 AD patients. Nonagenarians almost lack the APOEε4 allele, and had significantly higher Aß40, Aß42, p-tau181, NfL, and GFAP, along with a significantly lower Aß42/40 ratio (P&;lt0.001) compared with the two CU groups. NfL and GFAP tripled concentrations in nonagenarians. No differences were noted in any plasma biomarker between the younger and older CU groups. Biomarkers correlated strongly with age only when analyzing together CU controls and nonagenarians. Compared with AD cases, nonagenarians showed lower p-tau181 (P=0.001), higher total tau (P=0.02), and much higher Aß40, Aß42 and NfL levels (P&;lt0.001). The levels of GFAP in nonagenarians were similar to those observed in AD patients. In conclusion, cognitively preserved nonagenarians do not develop the AD biomarker signature and exhibit higher levels of Aß42. However, their threefold increase in NfL and GFAP supports their aging brains are somehow resilient to neurodegeneration. These data support caution in the prognosis of clinical dementia based on NfL and GFAP values. Overall, plasma biomarkers in CU individuals remained quite stable till the eighties.

Alzheimer's disease (AD) is a neurodegenerative disorder condition linked to various systemic comorbidities. Numerous studies have shown bidirectional crosstalk between the heart and the brain, but the specifics of how these interactions occur in AD are poorly understood. This narrative review summarizes the clinical evidence for a firm link between AD and cardiovascular health and discusses the bidirectional roles of AD and the cardiovascular system. AD pathogenic proteins, AD risk genes, neurohormones, the autonomic nervous system, and neurotransmitters may affect cardiovascular health, and cardiac-derived proteins, neurohormones, vascular function, inflammation, and other potential specific molecules or neural pathways may also influence AD pathology and cognitive function. Additionally, we propose potential AD intervention strategies based on the heart-brain axis to provide novel insights into AD prevention and treatment.

Macrophages, a critical subset of innate immune cells, play a pivotal role in cytokine production during disease progression, tissue injury, and pathogen invasion. Their intricate involvement in the manifestation of chronic low-grade inflammation associated with the aging process is widely acknowledged. Notably, in aged tissues, macrophages exhibit an altered phenotype characterized by an augmented synthesis of pro-inflammatory cytokines and chemokines, a profile intimately associated with a phenomenon known as inflammaging. Macrophages possess the capacity to undergo cellular senescence, a state of permanent growth arrest, in response to diverse stressors, including aging. Senescent macrophages secrete an array of pro-inflammatory molecules, growth factors, and matrix metalloproteinases, collectively referred to as the Senescence-Associated Secretory Phenotype (SASP). The SASP exacerbates the state of chronic inflammation observed in aging tissues. Thus, disruptions in macrophage function and signaling pathways due to aging result in escalated production of inflammatory mediators, perpetuating inflammaging. Recent research has uncovered novel mechanisms centred around innate immune signaling and mitochondrial dysfunction in macrophages, highlighting their crucial role in the development of inflammaging and associated pathological conditions. This review delves into the latest scientific findings on these emerging mechanisms in macrophage senescence related to aging and explores the prospects of targeting macrophages to address age- associated conditions effectively.