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Cognitive aging, a pivotal domain at the intersection of neuroscience and psychology, exhibits a strong association with neurodegenerative disorders; however, its comprehensive underlying mechanisms remain incompletely elucidated. This review aims to provide a thorough synthesis of recent advancements in the investigation of cognitive aging in the brain, highlighting multidimensional assessment techniques, neurobiological foundations, molecular regulatory pathways, systemic changes,...

Many models of aging assume that processes such as cellular senescence or epigenetic alteration occur under sterile conditions. However, humans sustain infection with viral, bacterial, fungal, and parasite pathogens across the course of a lifetime, many of which are capable of long-term persistence in host tissue and nerves. These pathogens-especially members of the human virome like herpesviruses, as well as intracellular bacteria and parasites-express proteins and metabolites capable of...

Mutations in the genes encoding APP, Presenilin-1 (PSEN1), and PSEN2 result in early-onset Alzheimer's disease (AD). Previous studies, using iPSC-derived neurons and/or knock-in mice, elucidated the characteristics of neurons expressing familial AD (fAD) mutations. Here, we employ biochemical and state-of-the-art fluorescence imaging assays and report the discovery of a unique subpopulation of wild-type neurons strikingly recapitulating key phenotypes previously identified in the fAD neurons,...

Mutations that disrupt the clearance of damaged mitochondria via mitophagy are causative for neurological disorders including Parkinson's. Here, we identify a Mitophagic Stress Response (MitoSR) activated by mitochondrial damage in neurons and operating in parallel to canonical Pink1/Parkin-dependent mitophagy. Increasing levels of mitochondrial stress trigger a graded response that induces the concerted degradation of negative regulators of autophagy including Myotubularin-related phosphatase...

Parkinson's disease (PD) is characterized by the accumulation and spread of pathological α-synuclein (α-syn) fibrils, which contribute to neuroinflammation and neurodegeneration. Here we show that two immunoglobulin-like (Ig-like) domains derived from α-syn receptors, the D1 domain of lymphocyte-activation gene 3 (L3D1) and the V domain of advanced glycation end-products (vRAGE), effectively block cell surface binding of α-syn fibrils, suppress fibrils-induced neuronal α-syn aggregation, and...

Both aging and systemic inflammation are major risk factors for cardiovascular disease. This review summarizes the interrelationship of aging and inflammation-known as inflammaging-and the consequences for cardiovascular health. We discuss mechanisms including epigenetic modification, mitochondrial dysfunction, cellular senescence, and gut dysbiosis, many of which are themselves interrelated. Increasing understanding of inflammaging provides an array of biomarkers, some of which are now...

Many models of aging assume that processes such as cellular senescence or epigenetic alteration occur under sterile conditions. However, humans sustain infection with viral, bacterial, fungal, and parasite pathogens across the course of a lifetime, many of which are capable of long-term persistence in host tissue and nerves. These pathogens-especially members of the human virome like herpesviruses, as well as intracellular bacteria and parasites-express proteins and metabolites capable of...

CONCLUSION: A substantial proportion of aging individuals maintain cognitive function over time, which may be supported by protective strategies like cognitive/physical engagement, healthy sleep, social connection, and disease management. The adverse outcomes linked to decline trajectories underscore the need for future research on modifiable factors. Comparing predictors across subgroups provides insights into cognitive resilience and proactive protection. Further exploration of biological...

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Circadian freerunning periods change across the lifespan, yet most computational models do not reproduce these shifts without assuming additional mechanisms. Although the maturation and later deterioration of the suprachiasmatic nucleus (SCN) shape behavioral and humoral rhythms, the underlying driver of period change is more general. We show that it arises from an inherent property of a positively skewed frequency distribution, which naturally follows from a symmetric Gaussian distribution of...

Peptide-based supramolecular nanostructures offer a versatile platform with substantial promise for clinical translation in regenerative medicine. These systems allow for the incorporation of biologically active sequences and can be engineered to modulate tissue-specific parameters such as stiffness, diffusivity, and biodegradability. We developed here a bioactive supramolecular nanostructure containing a peptide designed based on glial cell-derived neurotrophic factor. These nanostructures form...

Clusterin (apolipoprotein J), a conserved glycoprotein abundant in blood and cerebrospinal fluid, functions as a molecular chaperone and apolipoprotein. Dysregulation of clusterin is linked to late-onset Alzheimer disease. Despite its prominent role in extracellular proteostasis, the mechanism of clusterin function remained unclear. Here, we present crystal structures of human clusterin, revealing a discontinuous three-domain architecture. Structure-based mutational analysis demonstrated that...

While clonal hematopoiesis (CH) is associated with protection from Alzheimer's disease (AD), a limited understanding of the mechanisms by which this occurs has been a barrier to therapeutic intervention. In a new study, Matatall et al.¹ discover protective mechanisms by which TET2-mutant, but not DNMT3A-mutant, CH impacts dementia pathology and cognition.

Alzheimer's disease (AD) often begins with non-cognitive symptoms such as olfactory deficits, which can predict later cognitive decline, though the mechanisms remain unclear. Pathologically, the brainstem locus coeruleus (LC), the main source of the neurotransmitter noradrenalin (NA) modulating olfactory information processing is affected early. Here we show early and distinct loss of noradrenergic input to the olfactory bulb (OB) coinciding with impaired olfaction in an AD mouse model, before...

Senescence-associated secretory phenotype (SASP) in cancer refers to the bioactive secretome produced by senescence cells in the tumor microenvironment, which could be triggered by therapeutics or local stress conditions. Here, we provided a SASP Score in glioblastoma (GBM) with generating a SASP gene panel to identify the potential small molecular candidate targeting SASP in GBM. The effectiveness of this scoring method was firstly interrogated with our in-house GBM cohort and public datasets,...

In aging cells and animal models of premature aging, heterochromatin loss coincides with transcriptional disruption including the activation of normally silenced endogenous retroviruses (ERVs). Here we show that loss of heterochromatin maintenance and de-repression of ERVs result in a chronic inflammatory environment characterized by neurodegeneration and cognitive decline in mice. We identify distinct roles for HP1 proteins to ERV silencing where HP1γ is necessary and sufficient for H4K20me3...

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Aging and cognitive impairment increase the risk for Alzheimer's disease (AD), and growing evidence suggests that transposable elements (TEs) in the genome play a role in aging and AD. The mechanisms of TE dysregulation in this context are unclear, but one possibility is that epigenetic changes, including DNA hypomethylation and/or reduced chromatin structure, underlie age- and AD-related TE activity. Therefore, the purpose of the present study was to generate a resource for studying TE...

The weight-adjusted waist index (WWI) is a novel anthropometric measure designed to better reflect central obesity than traditional indices such as body mass index and waist circumference (WC). This study examined the prospective association between WWI and cardiometabolic multimorbidity (CMM) and evaluated its predictive utility. We included 3,348 participants (mean age 63 years; 45.1% male) from the English Longitudinal Study of Ageing who were free from hypertension, coronary heart disease,...

People with dementia have complex medical, functional, and social needs and experience highly variable care quality and outcomes across the U.S. health care system. Community-based physicians, nurse practitioners, and physician assistants serve critical roles in diagnosing and managing dementia, yet little is known about this workforce and factors contributing to variability in care. The National Dementia Workforce Study (NDWS), sponsored by the National Institute on Aging, is conducting large...