Aging & Longevity

Mitochondrial DNA (mtDNA) mutations are hallmarks of aging. mtDNA in all opisthokonts is replicated exclusively by DNA Polymerase γ (Pol γ; encoded by POLG). PolgD257A/D257A mice, lacking Pol γ exonuclease proofreading (exo-), exhibit premature aging and higher mtDNA mutation rates than Polgwt/wt (exo+) mice. Using short-read sequencing and the ultra-sensitive LostArc indel-junction detection pipeline, we analyzed mtDNA from exo- and exo+ mice across 10 tissues. Indel-junction frequency,...

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Accurate identification and quantification of senescence-modulating compounds require screening platforms that can distinguish between phenotypically distinct drug response profiles. Conventional approaches relying on single-parameter measurements-either cell viability or senescence markers alone-cannot differentiate senolytic-like or anti-aging-like response profiles from non-specific cytotoxicity or proliferative effects. Here, we present the quantitative Cellular AGing Evaluation system...

The NLRP3 inflammasome has been implicated in a wide range of human diseases, including cardiovascular, metabolic, neurodegenerative (such as Alzheimer's disease), and other age-related conditions. This has positioned NLRP3 as a promising pharmacological target. Numerous studies have shown that complete NLRP3 ablation can prevent or mitigate these diseases. However, total elimination of NLRP3 is not a feasible therapeutic strategy for the millions of patients affected by these degenerative...

Aging tissues lose function in part because stem cells change in number and behavior, but how age-related changes in the stem cell niche drive these processes is not well understood. Using the fruit fly testis, we asked how aging of the niche microenvironment influences stem cell maintenance and competition. We show that levels of niche cell-derived bone morphogenetic protein (BMP) signals decline with age, leading to increased expression of the transcriptional corepressor Hairless in germline...

The ability to continuously adjust hand movements using visual information is critical for success in many everyday tasks. To further characterize the age-related decline in visuomotor processes, here we investigated a task in which participants had to track with the hand, by means of a joystick, a visual target whose position was updated at different rates on a screen (from 1.5 to 240 Hz). This procedure was selected to grade the necessity for online control. As the target refresh rate...

Polyamines are ancient metabolites that support growth, translation, and autophagy. Zabala-Letona et al. reveal a new mode of action-'metabolic shielding'-in which polyamines protect phosphorylation motifs in spliceosomal factors. This work links polyamines, for the first time, to alternative splicing, raising new questions for cancer, aging, and beyond.

Vascular aging is characterized by endothelial senescence and vascular smooth muscle cell (VSMC) phenotypic switching, yet the role of endothelial extracellular vesicles (EVs) in these processes remains unclear. We show that EVs from non-senescent endothelial cells prevent PDGF-BB-induced VSMC dedifferentiation, preserving contractile markers and limiting migration. In endothelial cells, EVs protected against TNF-α-induced eNOS downregulation but failed to reverse inflammatory and mitochondrial...

Glycosylation is an important post-translational modification, and glycan alterations reflect physiological and pathological states. However, whether common age-associated glycan changes occur across organs remains unclear. Here, we analyzed protein-bound N-glycans in serum, brain, lung, heart, liver, skeletal muscle, and kidney to identify aging-related alterations shared across tissues. Although glycan profiles were strongly organ-specific, age-dependent changes were observed in each organ....

Multimorbidity, the co-occurrence of multiple chronic conditions in individuals, complicates clinical management, increases healthcare use, and reduces life quality. This study investigates the association between socioeconomic position and multimorbidity, restricted to co-occurrence of two or more conditions among type 2 diabetes, cardiovascular diseases, selected cancers as a single category, chronic obstructive pulmonary disease, and depression, in a population-based cohort in Piedmont,...

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Mitochondria have evolved a specialized mitochondrial unfolded protein response (UPR^(mt)) to maintain proteostasis and promote recovery under stress. Studies in simple organisms have shown that UPR^(mt) activation in glial cells supports proteostasis through beneficial non-cell-autonomous communication with neurons. However, the role of mitochondrial stress responses in the human brain remains unclear. To address this gap, we investigated the cell-type-specific effects of mitochondrial...

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Despite the thousands of genes implicated in age-related phenotypes, effective interventions for aging remain elusive, due to the multifactorial nature of longevity and the interconnectedness of molecular components involved. Here we introduce a network medicine framework to map 2,358 longevity-associated genes onto the human interactome to identify drug-repurposing candidates capable of modulating specific hallmarks of aging. We find that genes associated with each hallmark form a connected...

Epigenetic changes, in particular DNA methylation, accumulate with age across different tissues, but whether these changes follow consistent patterns across different organs remains poorly understood. Here we show, through a meta-analysis of more than 15,000 human methylation profiles spanning 17 tissues, that aging produces both conserved and tissue-specific epigenetic signatures. We identify systemic shifts in methylation levels, increases in methylation variability, and growing molecular...

CONCLUSION: Plasma p-tau217 and Aβ42/40 were associated with neurostructural and cognitive impairment in PD and older adults, supporting the potential utility of AD-related plasma biomarkers-particularly p-tau217-for the clinical-biological characterization of cognitive decline in PD.

Genomic instability drivers of senescence and carcinogenesis. The ribosomal RNA gene (rDNA) locus in budding yeast provides an excellent model to study these processes. Because of its highly repetitive structure and the gene amplification system that maintains its copy number, rDNA represents one of the most unstable regions in the genome. Here, we demonstrate that the integrity of rDNA transcription is essential for maintaining genomic stability and lifespan. Loss of Paf1, an elongation factor...

CONCLUSION: Primary same-day TJA can be safely and effectively performed in selected octogenarian patients when guided by comprehensive preoperative assessment and multidisciplinary perioperative care. This case series reinforces growing evidence that age alone should not preclude surgical intervention. Our findings contribute to an evolving understanding of evidence-based, age-inclusive arthroplasty practices.

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