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CONCLUSION: This multimodal analysis links PD-related ALFF and ReHo alterations to distinct yet converging transcriptomic, cellular, and neurochemical substrates. The findings suggest that PD-related functional alterations spatially align with glial-neurovascular transcriptional gradients and serotonergic receptor distribution, providing convergent but indirect evidence for their involvement in PD-related network reorganization.

Collinolactone, featuring a 7/10/6 tricyclic core, has been proposed to be biosynthesized via a transannular [6 + 4] cycloaddition reaction. Besides its intriguing architecture, collinolactone holds pharmaceutical promises due to its ability to disrupt amyloid-β (Aβ) and tau aggregation, which are specifically found as disease culprits in the brains of Alzheimer's disease (AD) patients and are key targets in current drug discovery efforts. However, challenges associated with its acquisition from...

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to cognitive decline, dementia, and ultimately death. Recent anatomical and functional discoveries of neuroimmune interactions during the development and progression of AD are beginning to shed light on disease mechanisms and potential precision immunotherapies. Here, we review the current understanding of the contribution of innate and adaptive immunity to AD pathogenesis and progression. We discuss how microglia...

Parkinson's disease (PD) is a complex neurodegenerative disorder with both genetic and environmental contributions. Over the past two and a half decades, advances in genetics, genomics and molecular biology have uncovered several monogenic forms of PD, linked to mutations in a number PD genes (collectively called PARK genes) such as SNCA, LRRK2, PRKN, PINK1, and DJ-1. To date there are 26 PARK genes reported with more than 100 genetic variants that increase the risk of PD. These genetic...

Alzheimer's disease (AD), the leading cause of dementia, is predominantly sporadic and influenced by non-genetic factors, including the gut microbiota. Cohabitation studies have shown microbial transmission between AD transgenic (Tg) and wild-type (WT) mice, leading to cognitive impairment; however, the mechanisms during early-life co-housing exposure remain largely undetermined. Here, one-month-old WT mice were housed with age-matched AD Tg (5XFAD) mice for 3 months. Gut microbiota composition...

Alzheimer's disease (AD) involves proteostasis dysregulation causing protein misfolding, but whether these structural changes manifest as plasma conformational biomarkers remains unclear. We profiled plasma protein structures from 520 participants including individuals with AD, individuals with mild cognitive impairment (MCI) and healthy controls. Using mass spectrometry and machine learning, we systematically characterized the structural proteome changes associated with ApoE variations and...

Age-related macular degeneration (AMD) represents one of the therapeutic challenges of aging eye diseases. Our investigation reveals the stimulator of interferon genes (STING) pathway as an orchestrator of immune-mediated retinal degeneration, exhibiting biphasic, stage-dependent functionality-providing cytoprotection in healthy tissue but driving pathogenic inflammation during early AMD progression. Through immunohistochemical analysis of human eyes, we demonstrate stage-dependent cytoplasmic...

Testosterone production by testicular Leydig cells (LCs) in male mammals is energetically demanding and prone to mitochondrial damage. Despite these challenges, LCs exhibit remarkable longevity and minimal turnover, suggesting the existence of specialized mechanisms that maintain LC mitochondrial homeostasis under such constrains. Here we identify a mitochondrial transfer network between LCs and different testicular macrophage (tMac) subpopulations. Leydig cells release extracellular vesicles...

CONCLUSIONS: Despite gradual increases in the prevalence of impaired physical function during ageing, regular physical activity may help to preserve physical function in older adults.

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Walking is fundamental to human mobility, and slowing gait speed is a widely recognized indicator of aging-related mobility decline. Although mobility decline in older adults has been associated with aging-related neural and morphological changes in muscle, the specific neural and morphological correlates of gait speed remain incompletely characterized. Thus, our primary aim was to quantify how peripheral nerve function, muscle cross-sectional area (MCSA) and intramuscular fat (IMAT) are related...

Age-related macular degeneration (ARMD) is the primary manifestation of permanent vision loss internationally. Different factors that contribute to ARMD involve ageing, genetic predisposition, oxidative stress, immunological imbalances, aberrations in the breakdown of lipids, and persistent inflammation. Gut microbiota has emerged as the significant cause of ARMD by disrupting systemic immune and inflammatory responses and metabolic homeostasis. Age-related changes in gut microbiota (dysbiosis)...

Resting metabolic rate (RMR) accounts for the majority of the total energy expenditure. While RMR is known to decline with advancing age and is recognized to be lower in females compared to males, the mechanisms underlying these differences remain unclear. Changes in body composition are posited to account for age- and sex-related differences in RMR, but to what extent lacks consensus. We characterized 80 healthy adults aged 23-82 years from the San Diego Nathan Shock Center (SD-NSC) clinical...

Comparative biology plays a crucial role in uncovering fundamental biological mechanisms and providing evolutionary models for their variation. This approach is particularly valuable for studying aging, given the remarkable diversity in aging trajectories across the tree of life. Many evolutionary theories of aging were proposed well before the discovery of the molecular mechanisms involved, and they remain largely theoretical. Moreover, the growing number of model organisms and the expanding...

Across our lifespan, cells divide and differentiate to create the functional units of all organs, yet with age and cancer a small number of cellular families (clones) will rule the fate of the organism. Advances in synthetic and natural barcoding methods now enable cellular ancestries to be reconstructed with unprecedented single-cell resolution. These single-cell lineage-tracing studies are leading to a re-evaluation of long-standing paradigms in development, ageing and cancer biology and are...

Natural killer (NK) cells, a type of potent cytotoxic lymphocyte, are particularly promising for the treatment of cancers that lose or downregulate major histocompatibility complex class I (MHC class I) expression to evade T cell-mediated immunotherapy. However, the hostile and immunosuppressive tumor microenvironment (TME) greatly hinders the function of tumor-infiltrating NK cells, thus limiting the therapeutic efficacy. Here, we show a fusion protein of interleukin 21 (IL-21-Fc) that safely...

Whole genome sequencing (WGS) studies in large biobanks provide an unprecedented opportunity to study the rare-variant (RV) effects on the natural history of human diseases by analyzing censored time-to-event (TTE) phenotypes, such as age at disease diagnosis, disease progression, and lifespan. Unlike existing methods developed for continuous and categorical phenotypes, rare-variant association tests (RVATs) for TTE phenotypes in large biobanks face several major challenges, including heavy...

Environmental stressors-induced male infertility has become a major public health issue. Sperm motility is the key to conception. However, the immunological mechanism for environmental stress-induced sperm motility reduction remains unknown. Our experiments find that three classical environmental stressors, including lead, cadmium, and mercury, are the key heavy metals reducing sperm motility. We reveal that environmental stress induces epididymal macrophage senescence, whereas the clearance of...

Glasses have complex energy landscapes and exhibit nonequilibrium aging dynamics. Here, we propose a generalized trap model for activated aging based on a key static property of the energy landscape: the distribution of energy barriers. Our theory predicts that, upon cooling, weak ergodicity breaking (WEB) in quenching dynamics occurs before strong ergodicity breaking in equilibrium dynamics. Furthermore, the theory indicates that the characteristic size of activation clusters can be deduced...