Biology subjects

Mamde, S.

Publications and source records attributed to Mamde, S..

7 recordsLinked to original sources

bioRxiv2026

A Manifold-Based Measure of Transcriptional Entropy for Quantifying Aging in Single Cells

Aging reshapes tissues through changes in cellular composition, coordinated transcriptional reprogramming, and loss of transcriptional coordination. Whereas the first two have been characterized across aging tissues, the third remains difficult to quantify. We introduce an unsupervised, first-principles framework for measuring transcriptional dyscoordination in single cells as deviation from a learned, predictable structure accounting for technical noise. Orthogonal validation links transcriptional dyscoordination to classical intrinsic noise and distinguishes it from coordinated change. In controlled perturbations, dyscoordination rises after genotoxic injury and senescence induction, then falls following senolytic depletion. Across mouse, rat, and human tissues, dyscoordination increases with chronological age, especially in regenerative compartments. In human T cells, dyscoordination increases with clonal expansion and effector function yet declines within persisting clones after checkpoint blockade. Cross-modal analyses further link dyscoordination to chromatin-based mitotic age and genome instability. These results identify loss of transcriptional coordination as a distinct and dynamic feature of cellular aging.

genomics↗

bioRxiv2025

Aging-induced hepatocyte CD44 drives IL6/STAT3 signaling and associates with impaired neighboring T cell function.

Liver cancer incidences increase dramatically beyond 55 years of age, suggesting that age-associated changes contribute critically to tumor initiation. However, the mechanisms linking liver aging and cancer initiation are not well defined. This study investigates the role of CD44, a marker of liver tumor-initiating cells (TIC), in age-associated liver pathophysiology. Aged livers showed accumulation of CD44-expressing hepatocytes exhibiting enrichment of immune modulatory genes and activation of the immunosuppressive IL6/JAK/STAT3 pathway. Indeed, in adoptive transfer assays, antigen-exposed CD8+ T cells mounted a lower IFN-{gamma} response in aged livers than in young livers, indicating an immunosuppressive aged milieu. Concordantly, spatial analyses showed that the proximal neighbourhoods of Cd44-expressing hepatocytes are enriched in T cells exhibiting reduced cytokine and chemokine gene expression. Finally, hepatocyte-specific knock out of Cd44 mitigated the IL6/JAK/STAT3 gene signature in aged livers. Overall, these findings suggest that CD44 expression in aged hepatocytes promotes activation of the immunosuppressive IL6/JAK/STAT3 pathway and this is associated with impaired T cell effector function.

cell biology↗

bioRxiv2025

Aging alters tumor cell - T cell crosstalk to promote breast cancer progression

Age is a dominant risk factor for all major breast cancer subtypes. However, the mechanisms by which aging influences tumor development remain unclear. Using a novel mouse model whereby breast cancer is induced in situ in young and old wild-type mice via intraductal delivery of a lentivirus encoding the HER2/neu oncogene, we found that old mice exhibited a higher oncogene-induced tumor burden than young mice. Old tumor cells showed reduced expression of interferon-related genes, particularly the T cell-recruiting chemokines Cxcl9 and Cxcl10, linked to their altered chromatin accessibility. CXCL9/10 expression also declined with age in human HER2+ tumors. Correspondingly, old tumors exhibited fewer T cells within tumor lesions. Targeted interventions showed that decreased expression of Cxcl9/10 is responsible for reduced T cell infiltration and weakened anti-tumor immunity. These results show how aged tumor cells are impaired in their recruitment of immune cells, leading to a defective anti-tumor immune response.

cancer biology↗

bioRxiv2025

Targeting CyclinD1-CDK6 to Mitigate Senescence-Driven Inflammation and Age-Associated Functional Decline

Cellular senescence contributes to aging and age-related diseases by driving chronic inflammation through the Senescence Associated Secretory Phenotype (SASP) and interferon-stimulated genes (ISGs). Cyclin D1 (CCND1), a key cell cycle regulator, is paradoxically upregulated in these non-proliferating cells. We show that CCND1 and its kinase partner CDK6 drive SASP and ISG expression in senescent cells by promoting DNA damage accumulation. This leads to the formation of cytoplasmic chromatin fragments (CCFs) that activate pro-inflammatory CGAS-STING signaling. The tumor suppressor p53 (TP53) and its target p21 (CDKN2A) antagonize this CCND1-CDK6-dependent DNA damage accumulation pathway to suppress the SASP. In aged mouse livers, senescent hepatocytes show increased Ccnd1 expression. Hepatocyte-specific Ccnd1 knockout or treatment with the Cdk4/6 inhibitor Palbociclib reduces DNA damage and ISGs in aged mouse liver. Notably, Palbociclib also suppresses frailty and improves physical performance of aged mice. These findings reveal a novel role for CCND1/CDK6 in regulating DNA damage and inflammation in senescence and aging, highlighting it as a promising therapeutic target.

cell biology↗

bioRxiv2025

Single-Cell Epigenomics Uncovers Heterochromatin Instability and Transcription Factor Dysfunction during Mouse Brain Aging

The mechanisms regulating transcriptional changes in brain aging remain poorly understood. Here, we use single-cell epigenomics to profile chromatin accessibility and gene expression across eight brain regions in the mouse brain at 2, 9, and 18 months of age. In addition to a significant decline in progenitor cell populations involved in neurogenesis and myelination, we observed widespread and concordant changes of transcription and chromatin accessibility during aging in glial and neuronal cell types. These alterations are accompanied by dysregulation of master transcription factors and a shift toward stress-responsive programs driven by AP-1, indicating a progressive loss of cell identity with aging. We also identify region- and cell-type-specific heterochromatin decay, characterized by increased accessibility at H3K9me3-marked domains, activation of transposable elements, and upregulation of long non-coding RNAs, particularly in glutamatergic neurons. Together, these results reveal age-related disruption of heterochromatin maintenance and transcriptional programs, identify vulnerable brain regions and cell types, and pinpoint key molecular pathways altered in brain aging. HighlightsO_LISingle-cell multimodal profiling across eight brain regions reveals coordinated chromatin and transcriptional shifts during aging C_LIO_LIAge-related depletion of progenitor cells coincides with dysregulation of key developmental transcription factors C_LIO_LICell identity maintenance is compromised with the decline of master transcription factors C_LIO_LIHeterochromatin destabilization accompanied by activation of AP-1, transposable elements, pseudogene families, and long non-coding RNAs C_LI

genomics↗

bioRxiv2025

Genetic risk in endolysosomal network genes correlates with endolysosomal dysfunction across neural cell types in Alzheimer's disease

Late-onset Alzheimer disease (LOAD) has a complex genomic architecture. LOAD risk variants suggest multiple pathways, including the endolysosomal network (ELN), contribute to the pathobiology of Alzheimer disease (AD). Whether genetic risk in specific pathways correlates with corresponding biological dysfunction remains largely unknown. We developed an endolysosomal pathway-specific polygenic risk score (ePRS) using 14 well-established AD risk alleles implicating ELN genes. We investigated the association between ePRS and AD neuropathology, then examined cell-specific endolysosomal morphology and transcriptomic profiles in post-mortem dorsolateral prefrontal cortex samples from donors stratified by ePRS burden. We found that the ePRS was significantly associated with AD diagnosis and neuropathological measures, comparable to a pathway-agnostic PRS despite representing far fewer loci. High ePRS correlated with increased neuronal endosome volume, number and perinuclear aggregation independent of AD pathology. Single-nucleus RNA sequencing revealed cell type-specific transcriptomic changes associated with ePRS status, influencing glutamatergic signaling, protein homeostasis, responses to DNA damage and immune function. Neurons, astrocytes, oligodendrocytes, and microglia each showed varied gene expression patterns associated with ePRS burden. Together, these results provide evidence that AD genetic risk variants harboring ELN genes correlate with endolysosomal dysfunction in human brain tissue. These findings suggest that pathway-specific genetic risk contributes to corresponding cellular pathology in AD and nominates candidate mechanisms by which ELN AD variants contribute to pathogenesis.

neuroscience↗

bioRxiv2024

Epigenetic and 3D genome reprogramming during the aging of human hippocampus

Age-related cognitive decline is associated with altered physiology of the hippocampus. While changes in gene expression have been observed in aging brain, the regulatory mechanisms underlying these changes remain underexplored. We generated single-nucleus gene expression, chromatin accessibility, DNA methylation, and 3D genome data from 40 human hippocampal tissues spanning adult lifespan. We observed a striking loss of astrocytes, OPC, and endothelial cells during aging, including astrocytes that play a role in regulating synapses. Microglia undergo a dramatic switch from a homeostatic state to a primed inflammatory state through DNA methylome and 3D genome reprogramming. Aged cells experience erosion of their 3D genome architecture. Our study identifies age-associated changes in cell types/states and gene regulatory features that provide insight into cognitive decline during human aging.

genomics↗