GeroScience最新文献

In Alzheimer’s disease (AD), the accumulation of neuropathological markers such as amyloid-β plaques, neurofibrillary tangles, and cortical neurodegeneration occurs over many years before overt manifestation of cognitive impairment. There is thus a need for neuropsychological markers that are indicative of pathological changes in the early stages of the disease. Intra-individual cognitive variability (IICV), defined as the variation of an individual’s performance across cognitive domains, is a promising neuropsychological marker measuring heterogeneous changes in cognition that may reflect these early pathological changes. In this study, we comprehensively evaluated the global and regional associations of IICV with positron emission tomography (PET) and magnetic resonance imaging (MRI) measures of AD biomarkers in cognitively normal (CN) and mild cognitive impairment (MCI) participants. We found that higher IICV was robustly associated with increased Aβ, increased tau, decreased brain glucose metabolism, and reduced cortical thickness. Higher IICV was also associated with tau (OR = 2.53, P < .001) and fluorodeoxyglucose (OR = 1.34, P < .001) positivity but not Aβ positivity (OR = 1.15, P = .107). In regional analyses, IICV showed widespread associations with AD biomarkers, with the strongest Aβ and tau effects in the frontal and temporal regions, respectively. The strongest regional cortical thickness effects were found in the entorhinal and parahippocampal cortices. Our findings suggest that IICV may be a useful neuropsychological marker for increased Aβ, and especially increased tau and neurodegeneration that are reflective of emerging AD pathology in individuals without dementia.

Biological brain age is a brain-predicted age using machine learning to indicate brain health and its associated conditions. The presence of an older predicted brain age relative to the actual chronological age is indicative of accelerated aging processes. Consequently, the disparity between the brain’s chronological age and its predicted age (brain-age gap) and the factors influencing this disparity provide critical insights into cerebral health dynamics during aging. In this study, we employed a Lasso regression model and analyzed multimodal imaging data from 124 participants aged 53 to 76 to formulate and predict brain age. Additionally, we conducted partial correlation analyses to explore the complex relationship between the brain-age gap and network metrics, cognitive assessments, and emotional evaluations, while controlling for chronological age, gender, and education. Our findings highlight psychological resilience as a significant mitigating factor against premature brain aging. It is established that psychological resilience significantly influences the modulation of the brain-age gap. Moreover, psychological resilience and the brain-age gap exhibit a high accuracy (above 0.72) in segregating Montreal Cognitive Assessment score–based cohorts. This observation underscores significant insight into the potential of utilizing the brain-age gap as a diagnostic tool for the early detection of accelerated aging. It advocates for the timely application of interventions, including the development of programs aimed at bolstering psychological resilience.

Inflammaging, a state of chronic low-grade inflammation associated with aging, has been linked to the development and progression of various disorders. Cellular senescence, a state of irreversible growth arrest, is another characteristic of aging that contributes to the pathogenesis of cardiovascular pathology. Senescent cells accumulate in tissues over time and secrete many inflammatory mediators, further exacerbating the inflammatory environment. This senescence-associated secretory phenotype can promote tissue dysfunction and remodeling, ultimately leading to the development of age-related cardiovascular pathologies, such as mitral valve myxomatous degeneration. The species-specific form of canine myxomatous mitral valve disease (MMVD) provides a unique opportunity to investigate the early causes of induction of ECM remodeling in mitral valve leaflets in the human form of MMVD. Studies have shown that in both humans and dogs, the microenvironment of the altered leaflets is inflammatory. More recently, the focus has been on the mechanisms leading to the transformation of resting VICs (qVICs) to myofibroblast-like VICs (aVICs). Cells affected by stress fall into a state of cell cycle arrest and become senescent cells. aVICs, under the influence of TGF-β signaling pathways and the mTOR complex, enhance ECM alteration and accumulation of systemic inflammation. This review aims to create a fresh new view of the complex interaction between aging, inflammation, immunosenescence, and MMVD in a canine model, as the domestic dog is a promising model of human aging and age-related diseases.

Background

Superagers, older adults with exceptional cognitive abilities, show preserved brain structure compared to typical older adults. We investigated whether superagers have biologically younger brains based on their structural integrity.

Methods

A cohort of 153 older adults (aged 61-93) was recruited, with 63 classified as superagers based on superior episodic memory and 90 as typical older adults, of whom 64 were followed up after two years. A deep learning model for brain age prediction, trained on 899 diverse-aged adults (aged 31-100), was adapted to the older adult cohort via transfer learning. Brain age gap (BAG), a metric based on brain structural patterns, defined as the difference between predicted and chronological age, and its annual rate of change were calculated to assess brain aging status and speed, respectively, and compared among subgroups.

Results

Lower BAGs correlated with more favorable cognitive status in memory and general cognitive function. Superagers exhibited a lower BAG than typical older adults at both baseline and follow-up. Individuals who maintained or attained superager status at follow-up showed a slower annual rate of change in BAG compared to those who remained or became typical older adults.

Conclusions

Superaging brains manifested maintained neurobiological youthfulness in terms of a more youthful brain aging status and a reduced speed of brain aging. These findings suggest that cognitive resilience, and potentially broader functional resilience, exhibited by superagers during the aging process may be attributable to their younger brains.

Existing epidemiological studies have ignored the effect of depressive duration on cognitive decline despite the presence of biological cues and understudied the depression-cognition association in Asian countries in the context of increasing cognitive burden worldwide. We aimed to comprehensively characterize the effects of depressive duration and intensity on cognitive decline at the population level. A total of 6406 individuals from the Korean Longitudinal Study of Aging (KLoSA) from 2010 to 2018 were included to generate four datasets with durations of 2, 4, 6, and 8 years. Depressive intensity was categorized as no, mild, and major depression according to the Center for Epidemiological Studies Depression scale (CES-D10), and duration was measured by the span of consecutive interviews. Cognitive function was assessed using the Korean Mini-Mental Status Examination (K-MMSE). Multiple linear regressions and meta-regressions were used to estimate the effects of depressive intensity and duration on global cognition and seven cognitive subdomains. Stratified analyses were performed to explore effect differences between subpopulations of different sexes and ages. The potential bias in the effect of depressive intensity on cognitive decline when ignoring duration was also explored. On average, a 1-year longer duration decreased the global cognitive scores by 0.44 (95% CI 0.36, 0.51) across intensities and major depression decreased the scores by an additional 0.82 (95% CI 0.59, 1.04) points than mild depression across durations. Similar trends held for seven cognitive subdomains except for visual construction. Older adults suffered more cognitive decline from major depression than middle-aged adults did. More severe and longer-duration depression lead to greater cognitive decline. Ignoring depressive duration can lead to an overestimated effect of depressive intensity on cognitive decline. The depressive effects and susceptible populations clarified in our study have important implications for the preservation of cognitive health in Asian region.

About one out of two diabetic patients develop diabetic neuropathy (DN), of these 20% experience neuropathic pain (NP) leading to individual, social, and health-economic burden. Risk factors for NP are largely unknown; however, premature aging was recently associated with several chronic pain disorders. DNA methylation-based biological age (DNAm) is associated with disease risk, morbidity, and mortality in different clinical settings. The purpose of this work was to study, for the first time, whether biological age is involved in pain development in a huge cohort of DN patients with neuropathy assessed by anatomopathological assay (99 painful (PDN), 132 painless (PLDN) patients, 84 controls (CTRL)). Six subsets of DNAm biomarkers were calculated to evaluate NP-associated changes in epigenetic aging, telomere shortening, blood cell count estimates, and plasma protein surrogates. We observed pain-related acceleration of epigenetic age (DNAmAgeHannum, DNAmGrimAgeBasedOnPredictedAge, DNAmAgeSkinBloodClock), pace of aging (DunedinPoAm), and shortening of telomeres between PDN and PLDN patients. PDN showed decreased predicted counts of B lymphocytes, naive and absolute CD8 T cells, and increased granulocyte counts. Several surrogates of plasma proteins were significantly different (GHR, MMP1, THBS2, PAPPA, TGF-α, GDF8, EDA, MPL, CCL21) in PDNs compared to PLDNs. These results provide the first evidence of an acceleration of biological aging in patients with painful compared to painless DN. This achievement has been possible thanks to the state of the art clinical phenotyping of the enrolled patients. Our findings indicate that the aging process may be directly involved in the PDN progression and in general health degeneration in the T2DM patients. Therefore, it is possible to hypothesize that the administration of effective antiaging drugs could slow down or even block the disease advancement.

Cellular senescence is a phenotypic state that contributes to the progression of age-related disease through secretion of pro-inflammatory factors known as the senescence-associated secretory phenotype (SASP). Understanding the process by which healthy cells become senescent and develop SASP factors is critical for improving the identification of senescent cells and, ultimately, understanding tissue dysfunction. Here, we reveal how the duration of cellular stress modulates the SASP in distinct subpopulations of senescent cells. We used multiplex, single-cell imaging to build a proteomic map of senescence induction in human epithelial cells induced to senescence over the course of 31 days. We map how the expression of SASP proteins increases alongside other known senescence markers such as p53, p21, and p16^INK4a. The aggregated population of cells responded to etoposide with an accumulation of stress response factors over the first 11 days, followed by a plateau in most proteins. At the single-cell level, however, we identified two distinct senescence cell populations, one defined primarily by larger nuclear area and the second by higher protein concentrations. Trajectory inference suggested that cells took one of two discrete molecular paths from unperturbed healthy cells, through a common transitional subpopulation, and ending at the discrete terminal senescence phenotypes. Our results underscore the importance of using single-cell proteomics to identify the mechanistic pathways governing the transition from senescence induction to a mature state of senescence characterized by the SASP.

Alzheimer’s disease (AD) is a neurodegenerative disorder that affects more than 6.2 million Americans aged 65 and older, particularly women. Along with AD’s main hallmarks (formation of β-amyloid plaques and tau neurofibrillary tangles), there are vascular alterations that occurs in AD pathology. Adenosine A2 receptor (A_2AR) is one of the key factors of brain vascular autoregulation and is overexpressed in AD patients. Our previous findings suggest that protein arginine methyltransferase 4 (PRMT4) is overexpressed in AD, which leads to decrease in cerebral blood flow in aged female 3xTg mice. We aimed to investigate the mechanism behind A_2AR signaling in the regulation of brain perfusion and blood–brain barrier integrity in age and sex-dependent 3xTg mice, and if it is related to PRMT4. Istradefylline, a highly selective A_2AR antagonist, was used to modulate A_2AR signaling. Aged female 3xTg and C57BL/6 J mice were evaluated for brain perfusion (via laser speckle) and cognitive function (via open field, T-maze and novel object recognition). Our results suggest that modulation of A_2AR signaling in aged female 3xTg increased cerebral perfusion by decreasing PRMT4 expression, restored the levels of APP and tau, maintained blood–brain barrier integrity by maintaining the expression of tight junction proteins, and preserved functional learning/memory.

Aging phenotype is characterized by musculoskeletal impairment that leads to diminished mobility and physical function. This study investigated whether circulating miRNAs and metabolic and inflammatory biomarkers may reflect the walking performance of the elderly. Elderly hospitalized for an acute condition and recruited from the ReportAge Biobank were grouped, based on their walking performance, in active subjects (n = 23, age: 83.0 ± 4.3), able to walk ≥ 1 km and who performed more than 1 h activity, and inactive subjects (n = 23, age: 85.0 ± 6.0), able to walk < 100 m and who performed < 1 h activity in the 3 days prior hospitalization. Plasma levels of 754 miRNAs were evaluated using OpenArray® platform, and miRNAs whose level was ± 2.5 fold (p < 0.05) were validated by qPCR. Target prediction for validated miRNAs was performed on MirWalk 3.0, Gene Ontology and pathway enrichment on Panther 19.0. Cytokines and metabolites associated with bone, muscle, and inflammation were evaluated from plasma samples using Luminex and ELISA. Among the 7 miRNAs found differentially expressed in active compared to inactive elderly after the initial screening, 4 miRNAs were validated: hsa-let7g-5p, hsa-miR-27a-3p, hsa-miR-361-5p, hsa-miR-574-3p, all upregulated in the active group. Gene Ontology and pathway enrichment analysis revealed the identified miRNAs potentially involved in muscle and bone metabolism during aging. Among cytokines, gp130 and IL-10 significantly differed between the two groups. This study suggests the potential association of specific circulating biomarkers with walking performance in elderly and their potential involvement in the molecular mechanism underlying age-associated musculoskeletal impairment.

β-Secretase-1 (BACE1) plays a key role in the regulation of cerebral amyloid-β homeostasis, being involved in amyloidogenic and, as recently found, amyloidolytic pathways. Growing evidence indicates that increased serum BACE1 (sBACE1) activity might represent an early biomarker for Alzheimer’s disease. Here, we tested the hypothesis that an increase in sBACE1 activity may already occur in individuals with subjective cognitive decline (SCD). We found that sBACE1 activity was significantly higher in individuals with SCD (n 118) compared to cognitively normal subjects (controls, n 137) (p < 0.001). Moreover, compared with SCD, sBACE1 activity was even higher in patients affected by amnestic (n 179) or non-amnestic mild cognitive impairment (MCI) (n 99) (p < 0.001 and p 0.02, respectively). In all cases, the respective increase in sBACE1 activity was significant after adjustment for possible confounders including age, sex, and comorbidities. We also found a significant sexual dimorphism, with women affected by either type of MCI, but not by SCD, having higher levels of serum BACE1 activity compared to men. These results provide evidence supporting the potential use of sBACE1 activity as tool for blood-based screening of cognitively healthy individuals at clinical risk of MCI and dementia.