Biology subjects

Hajdarovic, K. H.

Publications and source records attributed to Hajdarovic, K. H..

3 recordsLinked to original sources

bioRxiv2026

Single-cell transcriptomic and epigenomic analysis reveals X-linked sex differences in aging mouse hypothalamus

Sex differences contribute to brain aging, neurodegenerative diseases, and more broadly in determining rates of aging across species. The hypothalamus plays a central role in physiological homeostasis and healthy aging, yet how its cellular and molecular landscape diverges between males and females over the lifespan remains poorly understood. Here, we present a single-nucleus multi-omics analysis of the hypothalamus in young, middle aged, and aged male and female mice. We identified major hypothalamic cell types and characterized their sex- and age-dependent transcriptional and chromatin accessibility profiles. Notably, female-specific changes on the X chromosome (chrX) emerged as a prominent feature of aging, including changes to the X inactivation center and an overall increase in chrX gene expression and accessibility in immune cells and neurons. Pseudotime analysis of immune cells revealed an aging trajectory with sex-specific multi-omic programs, featuring increased inflammation in females compared to males. Delving deeper into the epigenetic signatures associated with these sex differences, we found that H3K27me3 - the repressive histone mark enriched on the inactive X in females - increased in abundance and underwent substantial genome-wide redistribution with age in both sexes, particularly on the inactive chrX in females. Collectively, these findings highlight distinct cell-type-specific aging trajectories in the male and female hypothalamus, identify female aging signatures associated with X-linked epigenetic regulatory programs, and provide a comprehensive resource for understanding the molecular basis of sex differences in brain aging.

genomics↗

bioRxiv2025

HypoAD: volumetric and single-cell analysis reveals changes in the human hypothalamus in aging and Alzheimer's disease

Alterations in metabolism, stress response, sleep, circadian rhythms, and neuroendocrine processes are key features of aging and neurodegeneration. These fundamental processes are regulated by the hypothalamus, yet how its functionally distinct subregions and cell types change during human aging and Alzheimers Disease (AD) remains largely unexplored. Here, we present HypoAD, a comprehensive atlas of the human hypothalamus in aging and AD, integrating high-resolution MRI from 202 individuals with single-nucleus RNA-seq (snRNA-seq) of 614,403 nuclei from young, AD, and age-matched non-dementia controls. Our analysis reveals that hypothalamic subregions governing metabolism, stress, and circadian rhythms are particularly vulnerable, exhibiting significant changes in both volumes and gene expression during aging and AD. At the molecular level, machine learning models identified the inflammatory response and regulators of circadian rhythms as key cellular predictors of AD. These signatures were reflected in specific cell types: microglia transitioned to a pro-inflammatory state, while inhibitory neurons within sleep-and circadian-regulating hypothalamic subregions showed the most profound transcriptional alterations, including disruptions in ligand-receptor interactions and G-protein-coupled receptor signaling. Together, HypoAD provides a high-resolution volumetric map and a comprehensive transcriptomic atlas of the human hypothalamus in aging and AD, linking lifestyle and behavioral changes to their underlying volumetric and molecular pathways. Additionally, HypoAD provides a framework to investigate hypothalamic dysfunction and establishes a roadmap for targeted interventions aimed at mitigating physiological disruptions to potentially slow disease progression.

neuroscience↗

bioRxiv2021

Single cell analysis of the aging hypothalamus

Alterations in metabolism, sleep patterns, body composition, and hormone status are all key features of aging. The hypothalamus is a well-conserved brain region that controls these homeostatic and survival-related behaviors. Despite the importance of this brain region in healthy aging, little is known about the intrinsic features of hypothalamic aging. Here, we utilize single nuclei RNA-sequencing to assess the transcriptomes of 40,064 hypothalamic nuclei from young and aged female mice. We identify cell type-specific signatures of aging in neurons, astrocytes, and microglia, as well as among the diverse collection of neuronal subtypes in this region. We uncover key changes in cell types critical for metabolic regulation and body composition, as well as in an area of the hypothalamus linked to cognition. In addition, our analysis reveals an unexpected female-specific feature of hypothalamic aging. Specifically, we discover that the master regulator of X-inactivation, Xist, is elevated with age, particularly in hypothalamic neurons. Moreover, using machine learning, we show that levels of X-chromosome genes, and Xist itself, are the best predictors of cellular age. Together, this study identifies critical cell-specific changes of the aging hypothalamus in mammals, and uncovers a novel marker of neuronal aging in females.

neuroscience↗