Aging & Longevity

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. Here we performed genome-wide association studies meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of...

The dysfunction of the ubiquitin-proteasome system (UPS) facilitates the malignant progression of hepatocellular carcinoma (HCC). While targeting the UPS for HCC therapy has been proposed, identifying effective targets has been challenging. In this study, we conducted a focused screen of siRNA libraries targeting UPS-related WD40 repeat (WDR) proteins and found that silencing WDR20, a deubiquitinating enzyme activating factor, selectively inhibited the proliferation of HCC cells without...

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Genome-wide association studies have advanced our understanding of complex traits, but studying how a GWAS variant can affect a specific trait in the human population remains challenging due to environmental variability. Drosophila melanogaster is in this regard an excellent model organism for studying the relationship between genetic and phenotypic variation due to its simple handling, standardized growth conditions, low cost, and short lifespan. The Drosophila Genetic Reference Panel (DGRP) in...

Breast cancer is a leading cause of cancer-related mortality among women worldwide, particularly affecting those in their later years. As the incidence of breast cancer increases with age, understanding the biological mechanisms that link aging and cancer becomes crucial. Cellular senescence, a hallmark of aging, plays a dual role in cancer by inhibiting tumorigenesis while also contributing to tumor progression through the senescence-associated secretory phenotype (SASP). This study aims to...

Biomarkers of biological aging predict health outcomes more accurately than chronological age. This study examines the relationship between aging biomarkers, immune function, and kidney health using the Future of Families and Child Wellbeing Study Biomarker Dataset. Using Wave 5 (year 9) and Wave 6 (year 15), we examined biomarker data from a total of 4898 individuals. The panel of aging biomarkers, comprised of epigenetic clocks (GrimAge, Horvath), immune function markers (CD8 + T cells,...

Dual-functional stability (DFS) in cognitive and physical abilities is important for successful aging. This study examines the brain topology profiles that underpin high DFS in older adults by testing two hypotheses: (1) older adults with high DFS would exhibit a unique brain organization that preserves their physical and cognitive functions across various tasks, and (2) any individuals with this distinct brain topology would consistently show high DFS. We analyzed two cohorts of cognitively and...

Mitophagy is the intracellular recycling system that disposes damaged/inefficient mitochondria and allows biogenesis of new organelles to ensure mitochondrial quality is optimized. Dysfunctional mitophagy has been implicated in human aging and diseases. Multiple evolutionarily selected, redundant mechanisms of mitophagy have been identified, but their specific roles in human health and their potential exploitation as therapeutic targets are unclear. Recently, the characterization of the...

Sarcopenia is a common musculoskeletal disorder characterized by degenerative processes and is strongly linked to an increased susceptibility to falls, fractures, physical limitations, and mortality. Several models have been used to explore therapeutic and preventative measures as well as to gain insight into the molecular mechanisms behind sarcopenia. With novel experimental methodologies emerging to design foods or novel versions of conventional foods, understanding the impact of nutrition on...

Aging is a universal biological process characterized by a progressive, cumulative decline in homeostatic capabilities and physiological functions, which inevitably increases vulnerability to diseases. A number of molecular pathomechanisms and hallmarks of aging have been recognized, yet we miss a thorough understanding of their complex interconnectedness. This review explores the molecular and cellular mechanisms underlying human aging, with a focus on the multiple roles of high mobility group...

Cancer is caused by an accumulation of somatic mutations and copy number alterations (CNAs). Besides mutations, these copy number changes are key characteristics of cancer development. Nonetheless, some tumors show hardly any CNAs, a remarkable phenomenon in oncogenesis. Head and neck squamous cell carcinomas (HNSCCs) arise by either exposure to carcinogens, or infection with the human papillomavirus (HPV). HPV-negative HNSCCs are generally characterized by many CNAs and frequent mutations in...

Yamanaka factors (YFs) can reverse some aging features in mammalian tissues, but their effects on the brain remain largely unexplored. Here, we induced YFs in the mouse brain in a controlled spatiotemporal manner in two different scenarios: brain development and adult stages in the context of neurodegeneration. Embryonic induction of YFs perturbed cell identity of both progenitors and neurons, but transient and low-level expression is tolerated by these cells. Under these conditions, YF...

CONCLUSIONS AND IMPLICATIONS: This study highlighted the importance of eHealth literacy and self-efficacy in improving HRQoL among older adults, supporting the development of tailored interventions to promote their HRQoL.

Morphogens play a critical role in coordinating stress adaptation and aging across tissues, yet their involvement in neuronal mitochondrial stress responses and systemic effects remains unclear. In this study, we reveal that the transforming growth factor beta (TGF-β) DAF-7 is pivotal in mediating the intestinal mitochondrial unfolded protein response (UPR^(mt)) in Caenorhabditis elegans under neuronal mitochondrial stress. Two ASI sensory neurons produce DAF-7, which targets DAF-1/TGF-β...

The potential use of pro-senescence therapies, known as TIS (Therapy-Induced Senescence), for the treatment of colorectal cancer (CRC) generated significant interest since they require lower doses compared to those required for inducing apoptosis. However, the senescent cell cycle-arrested cancer cells are long-lived, and studies have revealed escape mechanisms contributing to tumor recurrence. To deepen our understanding of the survival pathways used by senescent cancer cells, we delved into...

CONCLUSIONS: Cognitive functions explained gait speed and step length during normal walking, as well as the decrease of gait speed while performing a concurrent cognitive task. The results suggest that different cognitive processes are important for different postural control aspects. Postural sway in quiet stance, step time and gait variability seem to depend more on physical and automatic processes rather than higher cognitive functions among physically active older people. The relationships...

CONCLUSIONS: The empirical evidence generated by this study posits that the impact of physical activity on MCI is partially mediated through physical performance in an aging population with T2DM residing in rural environments. Consequently, interventional strategies aimed at ameliorating physical performance may serve as a viable approach to mitigate the progression of cognitive decline.

Stimulator of interferon genes (STING) is activated in many pathophysiological conditions, leading to TBK1-dependent interferon production in higher organisms. However, primordial functions of STING independent of TBK1 are poorly understood. Here, through proteomics and bioinformatics approaches, we identify lysosomal biogenesis as an unexpected function of STING. Transcription factor EB (TFEB), an evolutionarily conserved regulator of lysosomal biogenesis and host defense, is activated by STING...

In a Science paper, Park et al. identified interleukin (IL)-1α as a key driver of positive feedback in inflammaging, linking aging-associated downregulation of DNMT3A to increased IL-1α production in lung myeloid cells. This triggers emergency myelopoiesis in the bone marrow, amplifying myeloid-mediated intratumoral immunosuppression for tumor progression in aged mice.

Epigenetic clocks provide an accurate molecular readout of epigenetic age and epigenetic age acceleration (EAA) derived from DNA methylation data have shown promise as biomarkers of ageing. This systematic review synthesised research on associations between EAA measures and various physiological, cognitive, social, and environmental factors. A comprehensive search strategy identified 299 publications reporting 1050 unique EAA-factor associations based on 53 methylation clocks. Random-effects...