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Alzheimer's disease (AD) is a progressive neurodegenerative disorder traditionally defined by amyloid-β plaques and tau tangles. However, growing evidence indicates that deeper disruptions in cellular homeostasis contribute to disease onset and progression. Among these, impaired communication between mitochondria and the nucleus has emerged as a central yet underrecognized pathological feature. Mitochondrial-nuclear (mito-nuclear) crosstalk regulates energy metabolism, stress responses, and...

There is increasing evidence of microglia participation in Alzheimer's disease (AD), which incentives their modulation to intercept the disease. Here, we describe a new mechanism by which the recently AD-associated Peptidase M20 Domain Containing 1 (PM20D1) instructs microglia to tackle AD. We show that the PM20D1-derived N-oleoyl-Leucine (OLE) improves AD pathologies in two animal models of AD. OLE induces microglia association with amyloid beta (Aβ) plaques, reduce their size, number and...

Aging is driven in part by progressive deterioration of proteostasis and antioxidant defense, leading to cellular dysfunction and age-associated disease. The naturally occurring methylated inositol D-pinitol (DP) was reported to present metabolic, antioxidant, and anti-inflammatory effects, as well as to extend the lifespan of D. melanogaster and C. elegans through the insulin/IGF-1 signaling pathway. But the mechanism of DP on delay aging remains poorly understand. Here, we showed that 200 μM...

Alzheimer's disease (AD) is a progressive neurodegenerative disorder traditionally defined by amyloid-β plaques and tau tangles. However, growing evidence indicates that deeper disruptions in cellular homeostasis contribute to disease onset and progression. Among these, impaired communication between mitochondria and the nucleus has emerged as a central yet underrecognized pathological feature. Mitochondrial-nuclear (mito-nuclear) crosstalk regulates energy metabolism, stress responses, and...

Sarcopenia is an age-related condition characterized by loss of skeletal muscle mass and strength and is associated with increased cancer incidence and mortality, yet how muscle decline promotes tumorigenesis remains unclear. Here, we show that skeletal muscle functions as an anti-tumor organ by secreting extracellular vesicles (EVs) that suppress tumor growth. Using Drosophila melanogaster and mouse cancer models, we demonstrate that muscle-derived EVs inhibit tumorigenesis. In contrast,...

Amyloid assembly in vivo occurs in complex environments where multiple aggregation-prone species coexist. Aβ and medin are prevalent amyloids in ageing humans that co-localize in cerebral amyloid angiopathy (CAA), yet their structural interactions remain poorly understood. Here, using cryo-electron microscopy, we determine high-resolution fibril structures from in vitro mixtures of Aβ40 and medin. From the same reaction, we resolve three distinct fibril populations: (i) a previously...

Aging is driven in part by progressive deterioration of proteostasis and antioxidant defense, leading to cellular dysfunction and age-associated disease. The naturally occurring methylated inositol D-pinitol (DP) was reported to present metabolic, antioxidant, and anti-inflammatory effects, as well as to extend the lifespan of D. melanogaster and C. elegans through the insulin/IGF-1 signaling pathway. But the mechanism of DP on delay aging remains poorly understand. Here, we showed that 200 μM...

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Retinal ganglion cell (RGC) axons form the optic nerve (ON). Numerous age-related ON diseases, including glaucoma, the second most common cause of worldwide blindness, result from multiple RGC stressors. Nearly all ON astrocytes in the optic nerve head (ONH): the junctional region between the ON and the retina in young-adult rodents expresses the homeodomain only (Hopx) protein. Hopx(+) ONH astrocytes are depleted during aging. ONH primary cultures which include Hopx(+) astrocytes secrete...

The focus of this study is to investigate the role of diffusion tensor imaging along the perivascular space (DTI-ALPS) index in brain aging. To address this, we first examined the association of DTI-ALPS with aging hallmarks among 40,488 UK Biobank (UKB) participants. Next, we developed normative brain age models incorporating the DTI-ALPS index from 12,401 healthy UKB adults and validated in UKB-ADNI and UKB-TALENT datasets. Finally, we explored the relationship between brain age gap (BAG) with...

Ageing is a complex process influenced by modifiable factors such as diet, which may accelerate or decelerate physiological decline. While chronological age increases uniformly, biological ageing varies between individuals, reflecting differences in health status and the resilience of biological systems. The Klemera-Doubal Method (KDM), a composite biomarker-based index often used as an estimate of biological age, has been associated with morbidity and mortality in large cohorts. This study...

This study examined the extent to which processing speed moderates the relationship between age and crystallized intelligence and influences the indirect effect of age on verbal working memory in 233 healthy middle and older adults aged 51-94 years. Participants were screened for cognitive impairment and depressive symptoms before completing a battery of cognitive tests. Data were analyzed using moderated mediation models with bootstrapping. Correlational analyses revealed significant negative...

Pink1 (PTEN-induced kinase 1) is a key guardian of mitochondrial quality via mitophagy; its mutations are tightly linked to early-onset PD. This review synthesizes how aging, exercise, and high-fat diet (HFD) modulate Pink1 activity and thereby PD risk. Aging down-regulates Pink1, impairing clearance of damaged mitochondria and promoting α-synuclein aggregation. Exercise up-regulates Pink1-Parkin signaling, enhances PGC-1α and brain-derived neurotrophic factor (BDNF), and protects dopaminergic...

BACKGROUND: Chronic kidney disease (CKD) and cognitive frailty frequently co-occur in older adults, compounding adverse health outcomes and placing substantial strain on healthcare systems.

INTRODUCTION: Aplysia californica has been a useful model system for studies of the neural basis of behavior, learning, and aging. While the latter topic has been explored with respect to several of its simple reflex behaviors, this study represents the first examination of how one of Aplysia's more complex behaviors, escape locomotion, is affected in animals nearing the end of their natural lifespan.

INTRODUCTION: Sleep disruption and metabolic decline are key contributors to cognitive aging and dementia risk. While cerebral glucose utilization declines with age, ketone metabolism remains relatively preserved, suggesting that ketogenic interventions may enhance brain energetics, sleep quality, and cognition in older individuals. Therefore, we investigated the effects of a ketogenic diet (KD) and β-hydroxybutyrate ester (KE) supplementation on sleep-wake architecture and novel spatial memory...

Humans have evolved adaptive mechanisms that enable survival even with zero calories for periods of months or longer. Intermittent 'low-dose' exposure to the metabolic stress of fasting may also activate pathways that promote metabolic health and longevity, although such benefits have not been proven in humans. Here we present our perspective of the current rationale and evidence base to support fasting for gain in metabolic health. In the absence of individual level risk factors for potential...

Several studies suggest that higher skeletal muscle mass (SMM) may be associated with a lower risk of adverse cardiometabolic outcomes. However, the relationship between SMM and cardiometabolic multimorbidity (CMM) has not been evaluated. We investigated the prospective association between height-indexed SMM and CMM risk in an older population. Data were analyzed from 3348 participants (mean age 64 years; 45.1% men) in the English Longitudinal Study of Ageing who were free of hypertension,...