The maternal X chromosome affects cognition and brain ageing in female mice.

Female mammalian cells have two X chromosomes, one of maternal origin and one of paternal origin. During development, one X chromosome randomly becomes inactivated. This renders either the maternal X (X) chromosome or the paternal X (X) chromosome inactive, causing X mosaicism that varies between female individuals, with some showing considerable or complete skew of the X chromosome that remains active.

Biological sex matters in brain aging.

Every cell in the body has a biological sex. The expansion of aging research to investigate female- and male-specific biology heralds a major advance for human health. Unraveling and harnessing mechanistic etiologies of sex differences may reveal new diagnostics and therapeutics for the aging brain.

drives sex differences in age- and Alzheimer's disease-related demyelination.

Alzheimer's disease (AD) and other age-related disorders associated with demyelination exhibit sex differences. In this work, we used single-nuclei transcriptomics to dissect the contributions of sex chromosomes and gonads in demyelination and AD. In a mouse model of demyelination, we identified the roles of sex chromosomes and gonads in modifying microglia and oligodendrocyte responses before and after myelin loss.

Amyloid-β positivity is less prevalent in cognitively unimpaired KL-VS heterozygotes.

Background: Klotho, encoded by the gene, is an anti-aging and neuroprotective protein. KL-VS heterozygosity (KL-VS) is hypothesized to be protective against the accumulation of Alzheimer's disease (AD) neuropathological hallmarks (amyloid-β (Aβ) and tau).

Objective: We examine whether being positive for Aβ (A+) or tau (T+), or A/T joint status [positive for Aβ (A + T-), tau (A-T+), both (A + T+) or neither (A-T-)] vary by KL-VS and whether serum klotho protein levels vary based on A+, T+, or A/T status in a cohort enriched for AD risk.

A second X chromosome improves cognition in aging male and female mice.

Women show resilience to cognitive aging, in the absence of dementia, in many populations. To dissect sex differences, we utilized the FCG and XY* mouse models. Female gonads and sex chromosomes improved cognition in aging mice of both sexes.

Sex and gender differences in cognitive resilience to aging and Alzheimer's disease.

Sex and gender-biological and social constructs-significantly impact the prevalence of protective and risk factors, influencing the burden of Alzheimer's disease (AD; amyloid beta and tau) and other pathologies (e.g., cerebrovascular disease) which ultimately shape cognitive trajectories.

Plasma phosphorylated tau-217 exhibits sex-specific prognostication of cognitive decline and brain atrophy in cognitively unimpaired adults.

Introduction: Accumulating evidence indicates disproportionate tau burden and tau-related clinical progression in females. However, sex differences in plasma phosphorylated tau (p-tau)217 prediction of subclinical cognitive and brain changes are unknown.

Methods: We measured baseline plasma p-tau217, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) in 163 participants (85 cognitively unimpaired [CU], 78 mild cognitive impairment [MCI]).

Platelet factors are induced by longevity factor klotho and enhance cognition in young and aging mice.

Platelet factors regulate wound healing and can signal from the blood to the brain. However, whether platelet factors modulate cognition, a highly valued and central manifestation of brain function, is unknown. Here we show that systemic platelet factor 4 (PF4) permeates the brain and enhances cognition.

Associations between klotho and telomere biology in high stress caregivers.

Aging biomarkers may be related to each other through direct co-regulation and/or through being regulated by common processes associated with chronological aging or stress. Klotho is an aging regulator that acts as a circulating hormone with critical involvement in regulating insulin signaling, phosphate homeostasis, oxidative stress, and age-related inflammatory functioning. Both klotho and telomere length are biomarkers of biological aging and decrease with age; however, the relationship between them is not well understood.

Longevity factor klotho enhances cognition in aged nonhuman primates.

Cognitive dysfunction in aging is a major biomedical challenge. Whether treatment with klotho, a longevity factor, could enhance cognition in human-relevant models such as in nonhuman primates is unknown and represents a major knowledge gap in the path to therapeutics. We validated the rhesus form of the klotho protein in mice showing it increased synaptic plasticity and cognition.

The mitochondrial unfolded protein response regulates hippocampal neural stem cell aging.

Aging results in a decline in neural stem cells (NSCs), neurogenesis, and cognitive function, and evidence is emerging to demonstrate disrupted adult neurogenesis in the hippocampus of patients with several neurodegenerative disorders. Here, single-cell RNA sequencing of the dentate gyrus of young and old mice shows that the mitochondrial protein folding stress is prominent in activated NSCs/neural progenitors (NPCs) among the neurogenic niche, and it increases with aging accompanying dysregulated cell cycle and mitochondrial activity in activated NSCs/NPCs in the dentate gyrus. Increasing mitochondrial protein folding stress results in compromised NSC maintenance and reduced neurogenesis in the dentate gyrus, neural hyperactivity, and impaired cognitive function.

X Chromosome Factor Kdm6a Enhances Cognition Independent of Its Demethylase Function in the Aging XY Male Brain.

Males exhibit shorter life span and more cognitive deficits, in the absence of dementia, in aging human populations. In mammals, the X chromosome is enriched for neural genes and is a major source of biologic sex difference, in part, because males show decreased expression of select X factors (XY). While each sex (XX and XY) harbors one active X due to X chromosome inactivation in females, some genes, such as Kdm6a, transcriptionally escape silencing in females-resulting in lower transcript levels in males.

AD-associated CSF biomolecular changes are attenuated in KL-VS heterozygotes.

Introduction: Dementia as an inevitable aging consequence has been challenged and underscores the need for investigations of the factors that confer resilience. We examine whether the functionally advantageous KL-VS variant of the putative aging suppressor gene attenuates age-related cognitive decline and deleterious biomolecular changes.

Methods: Trajectories of change in memory and executive function ( = 360; 2-12 visits) and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers-amyloid beta (Aβ)42, total tau (t-tau), phosphorylated tau (p-tau) ( = 112; 2-4 samplings)-were compared between KL-VS non-carriers and heterozygotes in middle-aged and older adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center studies.

Circulating Klotho Is Higher in Cerebrospinal Fluid than Serum and Elevated Among KLOTHO Heterozygotes in a Cohort with Risk for Alzheimer's Disease.

Background: Klotho is a longevity and neuroprotective hormone encoded by the KLOTHO gene, and heterozygosity for the KL-VS variant confers a protective effect against neurodegenerative disease.

Objective: Test whether klotho concentrations in serum or cerebrospinal fluid (CSF) vary as a function of KLOTHO KL-VS genotype, determine whether circulating klotho concentrations from serum and CSF differ from one another, and evaluate whether klotho levels are associated with Alzheimer's disease risk factors.

Methods: Circulating klotho was measured in serum (n = 1,116) and CSF (n = 183) of cognitively intact participants (aged 62.

An Integrated Analysis of Clinical, Genomic, and Imaging Features Reveals Predictors of Neurocognitive Outcomes in a Longitudinal Cohort of Pediatric Cancer Survivors, Enriched with CNS Tumors (Rad ART Pro).

Background: Neurocognitive deficits in pediatric cancer survivors occur frequently; however, individual outcomes are unpredictable. We investigate clinical, genetic, and imaging predictors of neurocognition in pediatric cancer survivors, with a focus on survivors of central nervous system (CNS) tumors exposed to radiation.

Methods: One hundred eighteen patients with benign or malignant cancers (median diagnosis age: 7; 32% embryonal CNS tumors) were selected from an existing multi-institutional cohort (RadART Pro) if they had: 1) neurocognitive evaluation; 2) available DNA; 3) standard imaging.

KL1 Domain of Longevity Factor Klotho Mimics the Metabolome of Cognitive Stimulation and Enhances Cognition in Young and Aging Mice.

Cognitive deficits are a major biomedical challenge-and engagement of the brain in stimulating tasks improves cognition in aged individuals (Wilson et al., 2002; Gates et al., 2011) and rodents (Aidil-Carvalho et al.

KIBRA, MTNR1B, and FKBP5 genotypes are associated with decreased odds of incident delirium in elderly post-surgical patients.

Despite the association between cognitive impairment and delirium, little is known about whether genetic differences that confer cognitive resilience also confer resistance to delirium. To investigate whether older adults without postoperative delirium, compared with those with postoperative delirium, are more likely to have specific single nucleotide polymorphisms (SNPs) in the FKBP5, KIBRA, KLOTHO, MTNR1B, and SIRT1 genes known to be associated with cognition or delirium. This prospective nested matched exploratory case-control study included 94 older adults who underwent orthopedic surgery and screened for postoperative delirium.

Effects of Aerobic Exercise Training on Systemic Biomarkers and Cognition in Late Middle-Aged Adults at Risk for Alzheimer's Disease.

Increasing evidence indicates that physical activity and exercise training may delay or prevent the onset of Alzheimer's disease (AD). However, systemic biomarkers that can measure exercise effects on brain function and that link to relevant metabolic responses are lacking. To begin to address this issue, we utilized blood samples of 23 asymptomatic late middle-aged adults, with familial and genetic risk for AD (mean age 65 years old, 50% female) who underwent 26 weeks of supervised treadmill training.

Sugar sweetened beverage consumption is positively associated with Klotho levels at two years of age in LatinX youth.

Background: Klotho is an anti-aging protein mainly expressed in the kidneys with a smaller amount expressed in adipose tissue. Klotho effects include roles in reducing oxidative stress, insulin signaling, adipogenesis and glucose metabolism. Few studies have investigated the role of dietary factors such as sugar sweetened beverages (SSBs) on serum α-klotho levels in young children.

Age-Related Tau Burden and Cognitive Deficits Are Attenuated in KLOTHO KL-VS Heterozygotes.

Background: Identification of new genetic variants that modify Alzheimer's disease (AD) risk will elucidate novel targets for curbing the disease progression or delaying symptom onset.

Objective: To examine whether the functionally advantageous KLOTHO gene KL-VS variant attenuates age-related alteration in cerebrospinal fluid (CSF) biomarkers or cognitive function in middle-aged and older adults enriched for AD risk.

Methods: Sample included non-demented adults (N = 225, mean age = 63±8, 68% women) from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center who were genotyped for KL-VS, underwent CSF sampling and had neuropsychological testing data available proximal to CSF draw.