Cell-to-cell transmitted alpha-synuclein recapitulates experimental Parkinson's disease.

Parkinson's disease is characterized by a progressive accumulation of alpha-Synuclein (αSyn) neuronal inclusions called Lewy bodies in the nervous system. Lewy bodies can arise from the cell-to-cell propagation of αSyn, which can occur via sequential steps of secretion and uptake. Here, by fusing a removable short signal peptide to the N-terminus of αSyn, we developed a novel mouse model with enhanced αSyn secretion and cell-to-cell transmission.

Klotho increases antioxidant defenses in astrocytes and ubiquitin-proteasome activity in neurons.

Klotho is an antiaging protein, and its levels decline with age and chronic stress. The exogenous administration of Klotho can enhance cognitive performance in mice and negatively modulate the Insulin/IGF1/PI3K/AKT pathway in terms of metabolism. In humans, insulin sensitivity is a hallmark of healthy longevity.

Impact of balance on the energetic cost of walking and gait speed.

Background: Examine the relationship between balance test performance and the energetic cost of walking (ECW) and gait speed.

Methods: Cross-sectional and longitudinal analyses of data from the Baltimore Longitudinal Study of Aging. Men (48%) and women aged 60-96 years enrolled in the BLSA between 2007 and 2020 (n = 1132).

Lethal eosinophilic crystalline pneumonia in mice expressing a stabilized Csf2 mRNA.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that stimulates the proliferation and differentiation of granulocyte and macrophage precursors. The mouse gene-encoding GM-CSF, Csf2, is regulated at both transcriptional and post-transcriptional levels. An adenine-uridine-rich element (ARE) within the 3'-untranslated region of Csf2 mRNA was shown in cell transfection studies to confer instability on this transcript.

Apolipoprotein E gene variants shape the association between dietary fibre intake and cognitive decline risk in community-dwelling older adults.

Background: healthy dietary patterns have been associated with lower risk for age-related cognitive decline. However, little is known about the specific role of dietary fibre on cognitive decline in older adults.

Objective: this study aimed to examine the association between dietary fibre and cognitive decline in older adults and to assess the influence of genetic, lifestyle and clinical characteristics in this association.

Does diet influence aging? Evidence from animal studies.

Nutrition profoundly influences the risk for many age-related diseases. Whether nutrition influences human aging biology directly is less clear. Studies in different animal species indicate that reducing food intake ("caloric restriction" [CR]) can increase lifespan and delay the onset of diseases and the biological hallmarks of aging.

Unraveling the complex interplay between genes, environment, and climate in ALS.

Various genetic and environmental risk factors have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Despite this, the cause of most ALS cases remains obscure. In this review, we describe the current evidence implicating genetic and environmental factors in motor neuron degeneration.

Diet Inflammatory Index and Dementia Incidence: A Population-Based Study.

Background And Objectives: Aging is characterized by a functional shift of the immune system toward a proinflammatory phenotype. This derangement has been associated with cognitive decline and has been implicated in the pathogenesis of dementia. Diet can modulate systemic inflammation; thus, it may be a valuable tool to counteract the associated risk for cognitive impairment and dementia.

BMI and Allostatic Load Are Directly Associated with Longitudinal Increase in Plasma Neurofilament Light among Urban Middle-Aged Adults.

Background: Plasma neurofilament light chain (NfL) is a novel biomarker for age-related neurodegenerative disease. We tested whether NfL may be linked to cardiometabolic risk factors, including BMI, the allostatic load (AL) total score (ALtotal), and related AL continuous components (ALcomp). We also tested whether these relations may differ by sex or by race.

Differences in molecular phenotype in mouse and human hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is characterized by phenotypic heterogeneity. We investigated the molecular basis of the cardiac phenotype in two mouse models at established disease stage (mouse-HCM), and human myectomy tissue (human-HCM). We analyzed the transcriptome in 2 mouse models with non-obstructive HCM (R403Q-MyHC, R92W-TnT)/littermate-control hearts at 24 weeks of age, and in myectomy tissue of patients with obstructive HCM/control hearts (GSE36961, GSE36946).

Sex Differences in Longitudinal Determinants of Carotid Intima Medial Thickening With Aging in a Community-Dwelling Population: The Baltimore Longitudinal Study on Aging.

Background Common carotid intima medial thickness (IMT) increases with aging. However, the longitudinal association between IMT and other age-associated hemodynamic alterations in men and in women are not fully explored. Methods and Results We analyzed repeated measures of IMT, blood pressure, and carotid-femoral pulse wave velocity over a 20-year period in 1067 men and women of the Baltimore Longitudinal Study on Aging; participants were ages 20 to 92 years at entry and free of overt cardiovascular disease.

The Polygenic and Monogenic Basis of Blood Traits and Diseases.

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics.

Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations.

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro.

Plasma proteomic signatures predict dementia and cognitive impairment.

Introduction: Biomarker discovery of dementia and cognitive impairment is important to gather insight into mechanisms underlying the pathogenesis of these conditions.

Methods: In 997 adults from the InCHIANTI study, we assessed the association of 1301 plasma proteins with dementia and cognitive impairment. Validation was conducted in two Alzheimer's disease (AD) case-control studies as well as endophenotypes of AD including cognitive decline, brain amyloid burden, and brain volume.

Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing of a cohort of 1118 Caucasian DLB patients, and focused on genes causative of monogenic neurodegenerative diseases.

Monoclonal Antibody to Marinobufagenin Downregulates TGFβ Profibrotic Signaling in Left Ventricle and Kidney and Reduces Tissue Remodeling in Salt-Sensitive Hypertension.

Background Elevated levels of an endogenous Na/K-ATPase inhibitor marinobufagenin accompany salt-sensitive hypertension and are implicated in cardiac fibrosis. Immunoneutralization of marinobufagenin reduces blood pressure in Dahl salt-sensitive (Dahl-S) rats. The effect of the anti-marinobufagenin monoclonal antibody on blood pressure, left ventricular (LV) and renal remodeling, and gene expression were investigated in hypertensive Dahl-S rats.

Could changing the course of Alzheimer's disease pathology with immunotherapy prevent dementia?

This scientific commentary refers to ‘Persistent neuropathological effects 14 years following amyloid-β immunization in Alzheimer’s disease’ by Nicoll (doi:10.1093/brain/awz142).

Artificial Intelligence Based Approaches to Identify Molecular Determinants of Exceptional Health and Life Span-An Interdisciplinary Workshop at the National Institute on Aging.

Artificial intelligence (AI) has emerged as a powerful approach for integrated analysis of the rapidly growing volume of multi-omics data, including many research and clinical tasks such as prediction of disease risk and identification of potential therapeutic targets. However, the potential for AI to facilitate the identification of factors contributing to human exceptional health and life span and their translation into novel interventions for enhancing health and life span has not yet been realized. As researchers on aging acquire large scale data both in human cohorts and model organisms, emerging opportunities exist for the application of AI approaches to untangle the complex physiologic process(es) that modulate health and life span.

Remembering Robert D. Terry at a Time of Change in the World of Alzheimer's Disease.

Dr. Robert Terry (January 14, 1924-May 20, 2017) studied normal aging and Alzheimer's disease for more than five decades. He was at a visionary neuropathologist who trained generations of researchers in the field of neurodegenerative disorders and was always at the cutting edge of incorporating ever advancing technology into the fields of neuroscience and neuropathology.

Transcriptional Regulation in the Immune System: One Cell at a Time.

Transcriptional regulation of cells in the immune system must be strictly controlled at multiple levels to ensure that a proper immune response is elicited only when required. Analysis in bulk, or ensemble of cells, provides a wealth of important information leading to a better understanding of the various molecular steps and mechanisms involved in regulating gene expression in immune cells. However, given the substantial heterogeneity of these cells, it is imperative now to decipher these mechanisms at a single cell level.

Pathogenesis of age-related HIV neurodegeneration.

People over the age of 50 are the fastest growing segment of the HIV-infected population in the USA. Although antiretroviral therapy has remarkable success controlling the systemic HIV infection, HIV-associated neurocognitive disorder (HAND) prevalence has increased or remained the same among this group, and cognitive deficits appear more severe in aged patients with HIV. The mechanisms of HAND in the aged population are not completely understood; a leading hypothesis is that aged individuals with HIV might be at higher risk of developing Alzheimer's disease (AD) or one of the AD-related dementias (ADRD).

The Parkinson's progression markers initiative (PPMI) - establishing a PD biomarker cohort.

Objective: The Parkinson's Progression Markers Initiative (PPMI) is an observational, international study designed to establish biomarker-defined cohorts and identify clinical, imaging, genetic, and biospecimen Parkinson's disease (PD) progression markers to accelerate disease-modifying therapeutic trials.

Methods: A total of 423 untreated PD, 196 Healthy Control (HC) and 64 SWEDD (scans without evidence of dopaminergic deficit) subjects were enrolled at 24 sites. To enroll PD subjects as early as possible following diagnosis, subjects were eligible with only asymmetric bradykinesia or tremor plus a dopamine transporter (DAT) binding deficit on SPECT imaging.

Metabolic remodelling of glucose, fatty acid and redox pathways in the heart of type 2 diabetic mice.

Key Points: Hearts from type 2 diabetic animals display perturbations in excitation-contraction coupling, impairing myocyte contractility and delaying relaxation, along with altered substrate consumption patterns. Under high glucose and β-adrenergic stimulation conditions, palmitate can, at least in part, offset left ventricle (LV) dysfunction in hearts from diabetic mice, improving contractility and relaxation while restoring coronary perfusion pressure. Fluxome calculations of central catabolism in diabetic hearts show that, in the presence of palmitate, there is a metabolic remodelling involving tricarboxylic acid cycle, polyol and pentose phosphate pathways, leading to improved redox balance in cytoplasmic and mitochondrial compartments.