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Japan has one of the world's longest life expectancies, yet biomarkers associated with disability and mortality in very old adults remain uncertain. The goal of this study was to identify plasma proteins associated with incident disability and mortality in community-dwelling octogenarians. Two prospective cohorts were analyzed: the Kawasaki Aging Well-being Project (KAWP; 2017-2018; 4.5-year follow-up) as discovery and Invecchiare in Chianti (InCHIANTI; 1998-2000; 15-year follow-up) for external...

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,...

The battle between butter and margarine comes down to chemistry. Butter’s naturally occurring fats create rich flavors, golden browning, and flaky baked goods, while margarine’s modified plant oils offer consistency and a longer shelf life. Although both contain mostly fat, their different structures influence how they behave in recipes. Understanding those differences can help you choose the right one for cooking, baking, or health goals.

A new study found that fructose and glucose may look the same on a nutrition label, but the brain treats them very differently. In mice, glucose strongly reduced activity in hunger-promoting brain cells, while fructose had a much weaker effect. High-fructose corn syrup triggered a stronger response and was preferred by the animals. The findings suggest that the type of sugar—not just the calories—can influence appetite and food preferences.

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...

Growth/differentiation factor-15 (GDF15) is a secreted cytokine strongly associated with dementia risk. However, the extent to which GDF15 represents a biomarker and driver of dementia risk remains unclear. Across multiple cohorts, we demonstrated that plasma GDF15 is associated with greater dementia risk over 15- to 25-year follow-up periods when measured in midlife, with stronger associations observed for vascular, compared to Alzheimer's disease (AD), dementia. Two-sample Mendelian...

Lysophosphatidylinositol (LPI) is an endogenous GPR55 agonist, yet its role in Alzheimer's disease (AD) remains unclear. Here, we performed serum metabolomic profiling in 5xFAD mice and observed a reduction in multiple LPI species prior to the onset of overt Aβ pathology, and this decrease was further corroborated in human cohort samples. Exogenous LPI treatment reduced cerebral Aβ deposition, improved performance in learning and memory behavioral tasks, reduced pathological microglial...

Alzheimer's disease (AD) commences with the preclinical stage where individuals remain cognitively unimpaired but already have AD pathology. As fluid and neuroimaging biomarker research progresses, AD has become defined biologically rather than based on traditional clinical symptoms. While the diagnosis of AD has been conceptually advanced by the AT(N) classification framework according to core biomarker profiles of amyloid-β (A), tau (T) and neurodegeneration (N), solely relying on biological...

The gut microbiome modulates metabolic and neurovascular processes implicated in Alzheimer's disease and related dementias (ADRD), but the underlying mechanisms remain unclear. Here, we identify the bacterial metabolite imidazole propionate (ImP) as a modifier of ADRD pathology. In a cohort of 1196 cognitively unimpaired adults, higher plasma ImP levels were associated with lower preclinical cognitive scores and biomarkers of ADRD, both cross-sectionally and longitudinally. Fecal metagenomic...

Cognitive flexibility declines early in Alzheimer's disease, yet the underlying circuit mechanisms remain unknown. Here, we report that young 5xFAD mice exhibit deficits in instrumental reversal learning prior to spatial memory impairment. This behavioral inflexibility is associated with abnormal neuronal reactivation in the medial prefrontal cortex and dorsomedial striatum. Electrophysiological recordings reveal that medial prefrontal cortex neurons are hyperexcitable and receive increased...

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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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