Aging, Lifespan & Longevity

Tau (MAPT) drives neuronal dysfunction in Alzheimer disease (AD) and other tauopathies. To dissect the underlying mechanisms, we combined an engineered ascorbic acid peroxidase (APEX) approach with quantitative affinity purification mass spectrometry (AP-MS) followed by proximity ligation assay (PLA) to characterize Tau interactomes modified by neuronal activity and mutations that cause frontotemporal dementia (FTD) in human induced pluripotent stem cell (iPSC)-derived neurons. We established...

The signs of aging in humans can often be detected through a decrease in bone mass density (BMD). The decrease in BMD as a risk of osteoporosis is often only seen in women, but not in men, even though men also have a risk of osteoporosis which can affect their well-being. We conducted study searches through databases such as PubMed, EBSCO, ProQuest, Willey Online, Science Direct, and SAGE. We performed analysis on four types of Vitamin D receptor polymorphisms: BsmI, ApaI, FokI, and TaqI from 14...

Loss of Klotho, an anti-aging protein, plays a critical role in the pathogenesis of chronic kidney diseases. As Klotho is a large transmembrane protein, it is challenging to harness it as a therapeutic remedy. Here we report the discovery of a Klotho-derived peptide 1 (KP1) protecting kidneys by targeting TGF-β signaling. By screening a series of peptides derived from human Klotho protein, we identified KP1 that repressed fibroblast activation by binding to TGF-β receptor 2 (TβR2) and disrupting...

In the last years, many studies were able to identify associations between common genetic variants and complex diseases. However, the mechanistic biological links explaining these associations are still mostly unknown. Common variants are usually associated with a relatively small effect size, suggesting that interactions among multiple variants might be a major genetic component of complex diseases. Hence, elucidating the presence of functional relations among variants may be fundamental to...

Microglia play a role in the emergence and preservation of a healthy brain microenvironment. Dysfunction of microglia has been associated with neurodevelopmental and neurodegenerative disorders. Investigating the function of human microglia in health and disease has been challenging due to the limited models of the human brain available. Here, we develop a method to generate functional microglia in human cortical organoids (hCOs) from human embryonic stem cells (hESCs). We apply this system to...

Growth differentiation factor 15 (GDF15) is recently emerging not only as a stress-related mitokine, but also as a key player in the aging process, being the most up-regulated protein with age and associated with a variety of age-related diseases (ARDs). Many data indicate that GDF15 has protective roles in several tissues during different stress and aging, thus playing a beneficial role in apparent contrast with the observed association with many ARDs. A possible detrimental role for this...

Macromolecules damaged by covalent modifications produced by chemically reactive metabolites accumulate in the slowly renewable components of living bodies and compromise their functions. Among such metabolites, catecholamines (CA) are unique, compared with the ubiquitous oxygen, ROS, glucose and methylglyoxal, in that their high chemical reactivity is confined to a limited set of cell types, including the dopaminergic and noradrenergic neurons and their direct targets, which suffer from CA...

Aging and age-related neurodegenerative diseases have become one of the major concerns in modern times as cognitive abilities tend to decline when we get older. It is well known that the main cause of this age-related cognitive deficit is due to aberrant changes in cellular, molecular circuitry and signaling pathways underlying synaptic plasticity and neuronal connections. The p75 neurotrophin receptor (p75^(NTR)) is one of the important mediators regulating the fate of the neurons in the...

CONCLUSION: Among initially well-functioning older adults, worse muscle mitochondrial function predicts mobility decline, and part of this longitudinal association is explained by decline in muscle strength and mass. Our findings suggest that worse mitochondrial function contributes to mobility decline with aging. These findings need to be verified in studies correlating longitudinal changes in mitochondrial function, muscle, and mobility performance.

Age-related loss of cellular function and increased cell death are characteristic hallmarks of aging. While defects in gene expression and RNA metabolism have been linked with age-associated human neuropathies, it is not clear how the changes that occur in aging neurons contribute to loss of gene expression homeostasis. R-loops are RNA-DNA hybrids that typically form co-transcriptionally via annealing of the nascent RNA to the template DNA strand, displacing the non-template DNA strand....

Cells are continuously exposed to potentially dangerous compounds. Progressive accumulation of damage is suspected to contribute to neurodegenerative diseases and aging, but the molecular identity of the damage remains largely unknown. Here we report that PARK7, an enzyme mutated in hereditary Parkinson's disease, prevents damage of proteins and metabolites caused by a metabolite of glycolysis. We found that the glycolytic metabolite 1,3-bisphosphoglycerate (1,3-BPG) spontaneously forms a novel...

The fate of hematopoietic stem cells (HSCs) can be directed by microenvironmental factors including extracellular calcium ion concentration ([Ca^(2+)](e)), but the local [Ca^(2+)](e) around individual HSCs in vivo remains unknown. Here we develop intravital ratiometric analyses to quantify the absolute pH and [Ca^(2+)](e) in the mouse calvarial bone marrow, taking into account the pH sensitivity of the calcium probe and the wavelength-dependent optical loss through bone. Unexpectedly, the mean...

Ageing is accompanied by a decline in cellular proteostasis, which underlies many age-related protein misfolding diseases^(1,2). Yet, how ageing impairs proteostasis remains unclear. As nascent polypeptides represent a substantial burden on the proteostasis network³, we hypothesized that altered translational efficiency during ageing could help to drive the collapse of proteostasis. Here we show that ageing alters the kinetics of translation elongation in both Caenorhabditis elegans and...

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