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Recent research has established a strong link between metabolic abnormalities and an increased risk of dementia. In parallel, there is growing epidemiological evidence supporting the neuroprotective effects of antidiabetic medications against cognitive impairments. Among these, sodium-glucose co-transporter (SGLT2) inhibitors have emerged as pharmacological candidates with promising potential in alleviating the burden of age-related diseases, particularly neurodegenerative diseases (NDD). SGLT2...

Lipid dyshomeostasis and tau pathology are present in frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). However, the relationship between lipid dyshomeostasis and tau pathology remains unclear. We report that GRAM Domain Containing 1B (GRAMD1B), a nonvesicular cholesterol transporter, is increased in excitatory neurons of human neural organoids (HNOs) with the MAPT R406W mutation. Human FTLD, AD cases, and PS19 tau mice also have increased GRAMD1B expression. We show that...

Microglia are the resident immune cells in the brain and have pivotal roles in neurodevelopment and neuroinflammation^(1,2). This study investigates the function of the immune-checkpoint molecule TIM-3 (encoded by HAVCR2) in microglia. TIM-3 was recently identified as a genetic risk factor for late-onset Alzheimer's disease³, and it can induce T cell exhaustion⁴. However, its specific function in brain microglia remains unclear. We demonstrate in mouse models that TGFβ signalling induces TIM-3...

Global implementation of blood tests for Alzheimer's disease (AD) would be facilitated by easily scalable, cost-effective and accurate tests. In the present study, we evaluated plasma phospho-tau217 (p-tau217) using predefined biomarker cutoffs. The study included 1,767 participants with cognitive symptoms from 4 independent secondary care cohorts in Malmö (Sweden, n = 337), Gothenburg (Sweden, n = 165), Barcelona (Spain, n = 487) and Brescia (Italy, n = 230), and a primary care cohort in Sweden...

Bone fractures and related complications are a significant concern for older adults, particularly with the growing aging population. Therapeutic interventions that promote bone tissue regeneration are attractive for geriatric fracture repair. Extracellular adenosine plays a key role in bone homeostasis and regeneration. Herein, we examined the changes in extracellular adenosine with aging and the potential of local delivery of adenosine to promote fracture healing using aged mice. Extracellular...

The mitochondrial unfolded protein response (UPR^(mt)), a mitochondria-to-nucleus retrograde pathway that promotes the maintenance of mitochondrial function in response to stress, plays an important role in promoting lifespan extension in Caenorhabditis elegans^(1,2). However, its role in mammals, including its contributions to development or cell fate decisions, remains largely unexplored. Here, we show that transient UPR^(mt) activation occurs during somatic reprogramming in mouse embryonic...

Neuroimaging studies have shown age-related alterations in brain structure and function supporting semantic knowledge, although the significance of these is not fully understood. Herein, we report novel temporal, spectral, and spatial information on age-related changes from the largest dynamic functional mapping study of semantic processing. Participants (N = 130, age range 21-87 years, M(age) = 51.05, SD = 14.73, 68 females) performed a semantic judgement task during magnetoencephalography...

Mitochondrial dysfunction is a hallmark of cellular senescence. Here, we investigated whether senescent cells release mitochondrial (mt)DNA into the extracellular space and its impact on innate immunity. We found that both primary senescent cells and tumor cells undergoing therapy-induced senescence actively released mtDNA into the extracellular environment. mtDNA released by senescent cells was packaged within extracellular vesicles and selectively transferred to polymorphonuclear...

To maintain tissue homeostasis, many cells reside in a quiescent state until prompted to divide. The reactivation of quiescent cells is perturbed with aging and may underlie declining tissue homeostasis and resiliency. The unfolded protein response regulators IRE-1 and XBP-1 are required for the reactivation of quiescent cells in developmentally L1-arrested C. elegans. Utilizing a forward genetic screen in C. elegans, we discovered that macroautophagy targets protein aggregates to lysosomes in...

Ceria nanoparticles supported on alumina are widely used in various catalytic reactions, particularly in conjunction with platinum group metals (PGMs)^(1-9). Here we found that treating these catalysts at temperatures between 750 and about 1,000 °C in the presence of CO and NO in steam (reactive treatment under reducing atmosphere) leads to the dispersion of ceria nanoparticles into high-density 2D (roughly one atomic layer thin) Ce(x)O(y) domains, as confirmed by microscopy, X-ray photoelectron...

Core body temperature (T(b)) is a long-established determinant of longevity across species. In this Perspective, we first summarize evidence demonstrating that reducing T(b) increases lifespan and that lowered T(b) contributes to the antiaging effects of calorie restriction. Next, we discuss recent data that diverge from prior hypotheses on the mechanisms by which T(b) affects longevity, suggesting these are limited neither to the thermodynamics of nonenzymatic chemical reactions, nor reduced...

Peripheral arterial disease (PAD) is more prevalent in individuals with type 2 diabetes mellitus (T2DM). The most severe complication of PAD is chronic limb-threatening ischemia (CLTI), which is associated with major adverse cardiovascular events (MACE) and major adverse limb events (MALE) following lower limb revascularization (LER). This study investigates the relationship between baseline levels of Klotho and FGF23 and the risk of cardiovascular and limb-related outcomes after LER in a...

Although an increased risk of the skin cancer melanoma in people with Parkinson's disease (PD) has been shown in multiple studies, the mechanisms involved are poorly understood, but increased expression of the PD-associated protein alpha-synuclein (αSyn) in melanoma cells may be important. Our previous work suggests that αSyn can facilitate DNA double-strand break (DSB) repair, promoting genomic stability. We now show that αSyn is preferentially enriched within the nucleolus in melanoma, where...

This book chapter will focus on modifications to chromatin itself, how chromatin modifications are regulated, and how these modifications are deciphered by the cell to impact aging. In this chapter, we will review how chromatin modifications change with age, examine how chromatin-modifying enzymes have been shown to regulate aging and healthspan, discuss how some of these epigenetic changes are triggered and how they can regulate the lifespan of the individual and its naïve descendants, and...

Dietary restriction (DR) is a well-established method for extending lifespan across various species, including C. elegans. Among the different DR regimens, axenic dietary restriction (ADR), in which worms are grown in a nutrient-rich sterile liquid medium, yields the most powerful lifespan extension. However, the molecular mechanisms underlying this longevity phenotype remain largely unexplored. Through a pilot screen of candidate genes, we identified the proprotein convertase BLI-4 as a crucial...

CONCLUSION: These findings suggested a substantial link between elevated B2M levels and cognitive decline among U.S. older adults, partly mediated through the faster pace of aging. This correlation highlights the potential of B2M as a biomarker for early detection and therapeutic intervention of aging-related cognitive decline.

The influence of gut microbes on aging has been reported in several studies, but the mediating pathways of gut microbiota, whether there is a causal relationship between the two, and biomarker screening and validation have not been fully discussed. In this study, Mendelian Randomization (MR) and Linkage Disequilibrium Score Regression (LDSC) are used to systematically investigate the associations between gut microbiota, three aging indicators, and 14 age-related diseases. Additionally, this...

Cognitive decline has been postulated to predispose to presbyphagia but the neurophysiological basis of this interaction is unclear. To investigate the role of cognition for compensatory resource allocation within the swallowing network and behavioral swallowing performance in dual-task cognitive and motor interference in ageing, volunteers ≥ 70 years of age without preexisting diseases causing dysphagia were investigated using Flexible Endoscopic Evaluation of Swallowing (FEES) including a...