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Incidence of colorectal cancer (CRC) is increasing likely due to different mechanisms driving initiation and progression. The initial model proposed by Fearon and Vogelstein posits it as a multi-hit neoplasia, originating from adenomatous-polyps induced by WNT activation, ultimately progressing to aggressiveness through p53 loss. Integrating human data with mouse genetics, we redefine this paradigm, highlighting pivotal roles of MYC, oncogenic URI and p53 degradation to initiate CRC. Early APC...

The large variety of inflorescence architectures evolved in grasses depends on shape, longevity and determinacy of meristems directing growth of the main and lateral axes. The CLAVATA pathway is known to regulate meristem size and inflorescence architecture in grasses. However, how individual meristem activities are determined and integrated to generate specific inflorescences is not yet understood. We found that activity of distinct meristems in the barley inflorescence is controlled by a...

CONCLUSIONS: A valid and reliable 17-item community-level indicator was developed, aligning with the WHO framework and incorporating dementia-friendly elements. This indicator is a valuable tool for monitoring, evaluation, and inter-community comparisons, aiding the development of AFCs and DFCs in aging societies like Japan. Additionally, this indicator can be adapted for other high-income countries with similar socioeconomic backgrounds, healthcare systems, and community structures, providing a...

Age-related skeletal muscle atrophy, known as sarcopenia, is characterized by loss of muscle mass, strength, endurance, and oxidative capacity. Although exercise has been shown to mitigate sarcopenia, the underlying governing mechanisms are poorly understood. Mitochondrial dysfunction is implicated in aging and sarcopenia; however, few studies explore how mitochondrial structure contributes to this dysfunction. In this study, we sought to understand how aging impacts mitochondrial...

Aging induces significant alterations in the immune system, with immunosenescence contributing to age-related diseases. Peripheral blood mononuclear cells (PBMCs) offer a convenient and comprehensive snapshot of the body's immune status. In this study, we performed an integrated analysis of PBMCs using both bulk-cell and single-cell RNA-seq data, spanning from children to frail elderlies, to investigate age-related changes. We observed dynamic changes in the PBMC transcriptome during healthy...

CONCLUSIONS: The findings reaffirm the interplay and interdependence of oral health and mental health among older adults. Comprehensive strategies that integrate social engagement opportunities are imperative for developing interventions targeting older adults with compromised oral health.

Lysosomes maintain an acidic pH of 4.5-5.0, optimal for macromolecular degradation. Whereas proton influx is produced by a V-type H^(+) ATPase, proton efflux is mediated by a fast H^(+) leak through TMEM175 channels, as well as an unidentified slow pathway. A candidate screen on an orphan lysosome membrane protein (OLMP) library enabled us to discover that SLC7A11, the protein target of the ferroptosis-inducing compound erastin, mediates a slow lysosomal H^(+) leak through downward flux of...

Cells change their metabolic profiles in response to underlying gene regulatory networks, but how can alterations in metabolism encode specific transcriptional instructions? Here, we show that forcing a metabolic change in embryonic stem cells (ESCs) promotes a developmental identity that better approximates the inner cell mass (ICM) of the early mammalian blastocyst in cultures. This shift in cellular identity depends on the inhibition of glycolysis and stimulation of oxidative phosphorylation...

Cancer cells adapt to signals in the tumor microenvironment (TME), but the TME cues that impact metastasis and tropism are still incompletely understood. We show that abundant stromal lipids from young subcutaneous adipocytes, including phosphatidylcholines, are taken up by melanoma cells, where they upregulate melanoma PI3K-AKT signaling, fatty acid oxidation, oxidative phosphorylation (OXPHOS) leading to oxidative stress, resulting in decreased metastatic burden. High OXPHOS melanoma cells...

CONCLUSIONS: There is no clear consensus opinion among geriatricians in Europe on the definition of 'cognitive frailty'. While there is some core support for the IANA-IAGG definition, it is not intuitive to those not already familiar with the term. The variance in the current understanding of cognitive frailty among geriatricians suggests the time is right for a meaningful debate on this issue. While there is ongoing, growing research on a shared pathophysiology between physical frailty and...

CONCLUSIONS: The new measure can be useful in a range of quantitative assessments of older people's sexuality and well-being. Furthermore, the concept of successful sexual aging may assist in challenging ageism and in interventions focusing on positive sexual aging.

CONCLUSIONS: In summary, our results indicate that low serum Dyrk1b level is associated with an increased risk of sarcopenia in the elderly, suggesting that Dyrk1b may be valuable as a surrogate biomarker for screening and evaluation of sarcopenia.

CONCLUSION: These findings highlight the significant impact of public LTCI scheme on the growth of the LTC industry, particularly for non-residential care services and enterprise-operated organizations.

CONCLUSIONS: The natural communal setting of assisted living, along with supportive staff, presents a valuable opportunity to promote active aging, which is a complex interplay of social and movement behaviour. Our preliminary findings suggest that in addition to supporting individual behaviour change, a comprehensive approach that addresses the environment, social engagement, and staff engagement is needed in this setting. Future interventions should consider addressing each of these components...

CONCLUSIONS: Proactive end-of-life conversations generated several beneficial outcomes for residents and family members, including those with cognitive decline. The study demonstrated that the conversations may strengthen person-centered care and family support in this context. Based on these findings, proactive end-of-life conversations have the potential for use by residential care home staff.

Recent reports suggest dysregulation of the N6-methyladenosine (m6A) RNA modification may contribute to the pathology of neurodegenerative diseases. Herein, we show the m6A methyltransferase complex including METTL3-the catalytic component of the nuclear-localized complex-is robustly upregulated in human microglia and astrocytes exposed to αSyn(f) and Mn. Subcellular localization studies reveal METTL3 was predominantly cytoplasmic following Mn insult but remained nuclear following αSyn(f)...

Parkinson's disease results from degeneration of dopaminergic neurons in the midbrain, but the underlying mechanisms are unclear. Here, we identify novel crosstalk between depolarization-induced entry of Ca2+ and lysosomal cation release in maintaining dopaminergic neuronal function. The common disease-causing G2019S mutation in LRRK2 selectively exaggerated Ca2+ entry in vitro. Chemical and molecular strategies inhibiting the lysosomal ion channel TPC2 reversed this. Using Drosophila, which...

Vorinostat, a pan histone deacetylases (HDACs) inhibitor clinically approved for cutaneous T-cell lymphoma, exerts therapeutic effects by inducing tumor cell death and cycle arrest. Intriguingly, a previously unrecognized hormetic role of low-dose vorinostat in Caenorhabditis elegans. Subtoxic concentrations of vorinostat (1 μM) significantly extended lifespan, enhanced healthspan, and improved resistance to oxidative and heat stress, while ameliorating Aβ-induced paralysis. qPCR analysis...

Microglia are parenchymal brain macrophages that are established during embryogenesis and form a self-containing cellular compartment that resists seeding with cells derived from adult definitive hematopoiesis. We report that monocyte-derived macrophages (MoMΦs) accumulate in the brain of aging mice with distinct topologies, including the nigrostriatum and medulla but not the frontal cortex. Parenchymal MoMΦs adopt bona fide microglia morphology and expression profiles. Due to their...

Aging is a major risk factor for cardiovascular diseases, and the accumulation of DNA damage significantly contributes to the aging process. This study aimed to identify the underlying molecular mechanisms of vascular aging in DNA-repair-deficient progeroid Ercc1^(Δ/-) mice and to explore the therapeutic effect of dietary restriction (DR). RNA sequencing analysis revealed that DR reversed gene expression of vascular aging processes, including extracellular matrix remodeling, in the Ercc1^(Δ/-)...