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G protein-coupled receptor 3 (GPR3) is a class A orphan receptor characterized by high constitutive activity in the G(s) signaling pathway. GPR3 has been implicated in Alzheimer's disease and the regulation of thermogenesis in human adipocytes, yet the molecular mechanisms underlying its self-activation and potential endogenous modulators remain unclear. In this study, we present cryo-electron microscopy (cryo-EM) structures of GPR3 in different oligomerization states, both in the absence and...

Targeting proteins to their final cellular destination requires transport mechanisms and nearly all lysosomal enzymes reach the lysosome via the mannose-6-phosphate receptor pathway. One of the few known exceptions is the enzyme β-glucocerebrosidase (GCase) that requires the lysosomal integral membrane protein type-2 (LIMP-2) as a proprietary lysosomal transporter. Genetic variations in the GCase encoding gene GBA1 cause Gaucher's disease (GD) and present the highest genetic risk factor to...

Cellular senescence is a stress-inducible state switch relevant in aging, tumorigenesis and cancer therapy. Beyond a lasting arrest, senescent cells are characterized by profound chromatin remodeling and transcriptional reprogramming. We show here myeloid-skewed aberrant lineage plasticity and its immunological ramifications in therapy-induced senescence (TIS) of primary human and murine B-cell lymphoma. We find myeloid transcription factor (TF) networks, specifically AP-1-, C/EBPβ- and...

Although ovarian reserve remains sufficient, ovarian function declines in mid-age, leading to reduced fertility around age 35, with the causes remaining unclear. Recent studies highlight vascular aging as a key factor in this decline, with age-related reductions in ovarian vascular remodeling disrupting oocyte development. Salidroside, a natural compound that reverses ovarian vascular aging and promotes ovarian angiogenesis, presents a promising strategy to rejuvenate ovarian health and enhance...

Neuroimaging of blood-brain barrier permeability has been instrumental in identifying its broad involvement in neurological and systemic diseases. However, current methods evaluate the blood-brain barrier mainly as a structural barrier. Here we developed a non-invasive positron emission tomography method in humans to measure the blood-brain barrier permeability of molecular radiotracers that cross the blood-brain barrier through its molecule-specific transport mechanism. Our method uses...

Skeletal muscle weakness is a major component of age-associated frailty, but the underlying mechanisms are not completely understood. Drosophila has emerged as a useful model for studying skeletal muscle aging. In this organism, previous lab-based selection established strains with increased longevity and reduced age-associated muscle functional decline compared to a parental strain. Here, we have applied a computational pipeline (JUMPptm) for retrieving information on 8 post-translational...

Aging is a complex process that affects human health and lifespan. While chronological age (CA) is a significant risk factor for many diseases, it does not fully capture biological changes that influence health span. This study explores cognitive measures using the Seoul Neuropsychological Screening Battery and body composition profiles as potential biological age (BA) markers in the older population. Multiple linear regression, principal component analysis (PCA), and the Klemera-Doubal (KDM)...

Skin aging is influenced by both intrinsic and extrinsic factors. The gradual manifestation of changes in telomere length and telomerase activity, as crucial indicators of aging, elucidates the underlying mechanism of skin aging. This review aims to comprehensively analyze the association between telomeres and aging, along with their impact on skin biological function. Firstly, we summarize the structure and function of telomeres and their role in cell division. Subsequently, we discuss the...

Nicotinic acetylcholine receptors (nAChRs) are important regulators of brain and immune function that play critical roles in the neuropathology and progression of Alzheimer's disease and related dementias (ADRD). However, quantifying nAChRs in the brain remains elusive, and little is known about peripheral measures of nAChR in older adults or their relationship to cognition. Here, we examined associations between nAChR expression and immunoregulatory function in peripheral blood monocytes and...

As men get older, they often develop benign prostatic hyperplasia (BPH), an enlarged prostate that is not cancerous or dangerous. Although the etiology of BPH is unknown, increasing evidence indicates that the TGF-β signaling pathway might be a key player in its pathogenesis. TGF-β is a pleiotropic cytokine involved in proliferation, differentiation, and extracellular matrix re-modeling, which are all dysregulated in BPH. Cellular senescence is primarily initiated by TGF-β--induced, irreversible...

In particular, oxidative stress, generated by excessive reactive oxygen species (ROS), plays a major role in the neurodegenerative component of Parkinson's disease (PD) in aged neurons. DJ-1 (PARK7) is a key factor for maintaining redox homeostasis and modulation of mitochondrial function to preserve the cellular survival pathways. DJ-1 also plays a role in redox signaling independently of its antioxidant capacity by preventing the redox chain disulfide formation and stabilizing the master...

Ageing is a scientifically fascinating and complex biological occurrence characterised by morphological and functional changes due to accumulated molecular and cellular damage impairing tissue and organ function. Ageing is often accompanied by cognitive decline but is also the biggest known risk factor for Alzheimer's disease, the most common form of dementia. Emerging evidence suggests that sedentary and unhealthy lifestyles accelerate brain ageing, while regular physical activity, high...

Mitochondria play a crucial role in brain homeostasis and changes in mitochondrial bioenergetics are linked to age-related neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. We investigated changes in the activities of the electron transport chain (ETC) complexes in normally aging baboon brains and determined how these changes relate to donor sex, morning cortisol levels, and walking speed. We assessed mitochondrial bioenergetics from archived prefrontal cortex...

Aging affects reproductive capabilities in males through physiological and behavioral alterations, including endocrine changes and decreased libido. In this study, we investigated the influence of intermittent fasting (IF) on these aging-related declines, using male C57BL/6J mice. Our findings revealed that IF significantly preserved reproductive success in aged mice, not by improving traditional reproductive metrics such as sperm quality or endocrine functions but by enhancing mating behavior....

Ageing is a scientifically fascinating and complex biological occurrence characterised by morphological and functional changes due to accumulated molecular and cellular damage impairing tissue and organ function. Ageing is often accompanied by cognitive decline but is also the biggest known risk factor for Alzheimer's disease, the most common form of dementia. Emerging evidence suggests that sedentary and unhealthy lifestyles accelerate brain ageing, while regular physical activity, high...

CONCLUSION: Our findings demonstrate that, regardless of age, sex, education level, stature, and fall incidence, PFF assessments remain critical for identifying older adults at risk for PFS. The study highlights the predictive strength of key variables, such as PAL, MGS, and the Tinetti-POMA components, offering novel insights into the role of these tests in improving PFS screening accuracy. These results underscore the importance of integrating PFF assessments into routine clinical and...

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Chemical exposures may affect human metabolism and contribute to the etiology of neurodegenerative disorders such as Alzheimer's disease. Identifying these small metabolites involves matching experimental spectra to reference spectra in databases. However, environmental chemicals or physiologically active metabolites are usually present at low concentrations in human specimens. The presence of noise ions can substantially degrade spectral quality, leading to false negatives and reduced...

Plasma p-tau217 and tau positron emission tomography (PET) are strong prognostic biomarkers in Alzheimer's disease (AD), but their relative performance in predicting future cognitive decline among cognitively unimpaired (CU) individuals is unclear. In a head-to-head comparison study including nine cohorts and 1,474 individuals, we show that plasma p-tau217 and medial temporal lobe tau-PET signal display similar associations with cognitive decline on a global cognitive composite test (R²(PET) =...

Senescent hepatocytes accumulate in metabolic dysfunction-associated steatotic liver disease (MASLD) and are linked to worse clinical outcomes. However, their heterogeneity and lack of specific markers have made them difficult to target therapeutically. Here, we define a senescent hepatocyte gene signature (SHGS) using in vitro and in vivo models and show that it tracks with MASLD progression/regression across mouse models and large human cohorts. Single-nucleus RNA-sequencing and functional...