Biology subjects

Krizhanovsky, V.

Publications and source records attributed to Krizhanovsky, V..

8 recordsLinked to original sources

bioRxiv2025

Systemic administration of PD-L1 blocking antibodies leads to removal of senescent microglia

Senescent microglia develop during aging and Alzheimers disease (AD), driving chronic neuroinflammation. Here we hypothesized that the previously observed disease-modifying effects of PD-1/PD-L1 blockade occur through clearance of senescent microglia. Using CyTOF, we found that a single systemic anti-PD-L1 injection leads to rapid elimination of senescent microglia in 5xFAD and aged wild-type mice, independently of Fc effector function, while increasing homeostatic microglia. These findings suggest that immune rejuvenation via PD-L1 blockade promotes disease modification in AD through senescent-microglial elimination.

neuroscience↗

bioRxiv2025

Cell surface ATP6V1B2 marks a subset of persistent senescent cells with increased resistance to apoptosis

Accumulation of senescent cells promotes ageing and age-related diseases. While senescent cells are heterogenous and increasingly persistent in vivo with age, the mechanisms underlying their heterogeneity, resistance to apoptosis, and tissue accumulation remain insufficiently understood. Here we report that in response to DNA damage, a subset of senescent cells upregulates the v-type ATPase subunit, ATP6V1B2 (V1B2) on the cell surface. This upregulation is associated with altered lysosomal activity and changes in intracellular pH. Heterogeneity of senescent cells marked by cell surface V1B2 (csV1B2) is present in naturally occurring senescent cells within both ageing and fibrotic lungs. Senescent cells expressing csV1B2 show an age-independent transcriptional signature associated with DNA repair and resistance to apoptosis. Consistent with this, we show that csV1B2 expression correlates with senescent cell resistance to ABT-737-induced apoptosis in culture. Our study identifies a subset of senescent cells, marked by csV1B2, with a distinct signature of apoptosis resistance. Understanding the functional heterogeneity of senescent cells and the mechanisms accountable for persistence of specific subpopulations in tissues may facilitate the development of improved senotherapeutic strategies for age-related diseases.

cell biology↗

bioRxiv2025

Single-cell quantification of senescence burden reveals cell type-specific ageing dynamics across organs

Cellular senescence, a hallmark of ageing, drives tissue dysfunction by promoting inflammation and fuelling disease. Yet, the dynamics of senescent cell accumulation across tissues and their cell type identity remain poorly understood. Here, we introduce the first, single-cell, protein-level approach, combining multiple senescence markers for the identification and quantification of senescent cells across multiple tissues in mice and in human PBMCs. Applying this method, we reveal widespread but heterogeneous changes in senescence marker expression across cell types and tissues. The cells we identify as senescent displayed transcriptomic senescence signatures, providing a direct molecular link between protein- and mRNA-level detection of senescence. Importantly, senescence accumulation was strongly coordinated within organs but showed little correlation across them, supporting the idea of a tissue specific progression of ageing. These findings refine our understanding of the tissue-specific dynamics of senescence accumulation with age, and provide a framework for evaluating diverse therapeutic interventions.

cell biology↗

bioRxiv2024

CD4 T Cells Acquire Cytotoxic Properties to Modulate Cellular Senescence and Aging

Aging is characterized by the progressive deterioration of tissue structure and function, leading to increased vulnerability to diseases and, eventually, death. One prominent process in aging is the accumulation of senescent cells. Although the immune system has been recognized as crucial for the elimination of senescent cells, the associated mechanisms remain incompletely understood. Here we show that CD4 T cells differentiate into cytotoxic T lymphocytes (CTLs) in a senescent cell-rich environment and that a reduction in the senescent cell load, achieved using chemical senolytic drugs, was sufficient to halt this differentiation. We further demonstrate that eliminating CD4 CTLs in the context of late aging by selectively deleting the Eomes transcription factor in CD4 T cells resulted in the increased accumulation of senescent cells, profound physical deterioration, and a decreased life span. In liver cirrhosis, a model of localized chronic inflammation, CD4 CTL elimination increased the senescent load and worsened the disease. Collectively, our findings demonstrate the fundamental role of CD4 CTLs in modulating tissue senescence and unveil a new aspect of age-related T-cell biology implicated in disease susceptibility and longevity.

immunology↗

bioRxiv2023

TREM2-dependent senescent microglia conserved in aging and Alzheimer's disease

Dementia in general, and Alzheimers disease (AD) in particular, are age-related diseases1,2. AD is associated with multiple causative factors3,4, among which local brain inflammation plays a significant role5. Microglia, the brain-resident immune cells6,7, are activated along the disease course7. Yet, their contribution to the disease progression is still controversial. Here, using high-throughput mass cytometry for microglial immuno-phenotyping, we identified accumulation of senescent microglia in several pathologies associated with cognitive decline. These senescent microglia have a unique profile conserved across the multiple conditions investigated, including aging, mouse models of amyloidosis, and tauopathy. Moreover, we found that the expression of markers of senescence correlates with levels of TREM2, whose polymorphism was identified by GWAS as an AD risk factor8,9. A TREM2-null AD mouse model showed lower levels of senescent microglia, relative to TREM2-intact AD mice. Senolysis using the drug ABT-73710,11 in an AD mouse model reduced the abundance of TREM2-senescent microglia without affecting levels of TREM2-dependent activated microglia, ameliorated cognitive deficits, and reduced brain inflammation. These results reveal the unexpected contribution of TREM2 to accumulation of senescent microglia in AD pathology, an effect that must be considered when targeting TREM2 as a therapeutic approach.

neuroscience↗

bioRxiv2023

p16-dependent upregulation of PD-L1 impairs immunosurveillance of senescent cells

The accumulation of senescent cells promotes aging, but a molecular mechanism that senescent cells use to evade immune clearance and accumulate remains to be elucidated. Here, we report that p16-positive senescent cells upregulate the immune checkpoint protein programmed death-ligand 1 (PD-L1) to accumulate in aging and chronic inflammation. p16-mediated inhibition of CDK4/6 promotes PD-L1 stability in senescent cells via the downregulation of ubiquitin-dependent degradation. p16 expression in infiltrating macrophages induces an immunosuppressive environment that can contribute to an increased burden of senescent cells. Treatment with immunostimulatory anti-PD-L1 antibody enhances the cytotoxic T cell activity and leads to the elimination of p16, PD-L1-positive cells. Our study uncovers a molecular mechanism of p16-dependent regulation of PD-L1 protein stability in senescent cells and reveals the potential of PD-L1 as a target for treating senescence-mediated age-associated diseases.

cell biology↗

bioRxiv2019

Pan-cancer single cell RNA-seq uncovers recurring programs of cellular heterogeneity

Cultured cell lines are the workhorse of cancer research, but it is unclear to what extent they recapitulate the cellular heterogeneity observed among malignant cells in tumors, given the absence of a native tumor microenvironment. Here, we used multiplexed single cell RNA-seq to profile ~200 cancer cell lines. We uncovered expression programs that are recurrently heterogeneous within many cancer cell lines and are largely independent of observed genetic diversity. These programs of heterogeneity are associated with diverse biological processes, including cell cycle, senescence, stress and interferon responses, epithelial-to-mesenchymal transition, and protein maturation and degradation. Notably, some of these recurrent programs recapitulate those seen in human tumors, suggesting a prominent role of intrinsic plasticity in generating intra-tumoral heterogeneity. Moreover, the data allowed us to prioritize specific cell lines as model systems of cellular plasticity. We used two such models to demonstrate the dynamics, regulation and drug sensitivities associated with a cancer senescence program also observed in human tumors. Our work describes the landscape of cellular heterogeneity in diverse cancer cell lines, and identifies recurrent patterns of expression heterogeneity that are shared between tumors and specific cell lines and can thus be further explored in follow up studies.

cancer biology↗

bioRxiv2018

Senescent cells and the dynamics of aging

Genetically-identical organisms age at different rates, but the reason for this is unclear. The rate of aging is due to the accumulation of damage, such as senescent cells (SnC) which are a major driver of aging in mammals, but the accumulation dynamics of SnC are unknown. Here, we combine theory and experiments in mice and find that SnC are rapidly produced and removed with a half-life of days in young mice. In old mice SnC half-life grows to weeks, because SnC saturate their own removal process. This saturation leads to persistent fluctuations known as critical-slowing-down: fluctuations are amplified to long-lasting differences in SnC between individuals at old ages. Rapid turnover with saturating removal is a general framework that may apply to any aging-related form of damage, and can quantitatively explain the demographic laws of mortality in worms, flies, mice and humans.

systems biology↗