Biology subjects

Burnaevskiy, N.

Publications and source records attributed to Burnaevskiy, N..

3 recordsLinked to original sources

bioRxiv2026

Overmaturation as a major trajectory of naive CD4 T cell aging

Aging is associated with progressive changes of cellular functional states, but whether these changes arise from novel programs or from distortion of normal developmental trajectories often remains unclear. Here, we investigate this question in the context of human immune aging by analyzing age-associated changes in CD4 T cells at single-cell resolution. We show that CD4 T cell subsets accumulate senescence-associated features at different rates and that the naive CD4 T cell compartment is highly heterogeneous with respect to senescence markers. Strikingly, transcriptional changes associated with aging of naive CD4 T cells parallel those observed during normal post-thymic maturation from recent thymic emigrants (RTE) to mature naive cells. This similarity defines a transcriptional aging trajectory that we term overmaturation, characterized by exaggerated execution of a physiological maturation program. This overmaturation is consequential for T cell function, as we demonstrate through perturbation of transcription factor TOX, which is predominantly expressed in RTE and whose expression decreases with age. Together, our findings identify transcriptional overmaturation as a major trajectory of naive CD4 T cell aging and suggest that aging-associated distortion of developmental programs can strongly contribute to immunosenescence.

cell biology↗

bioRxiv2022

Oxidative Stress Induced Senescence Gives Rise to Transcriptionally Distinct Physiological States

As people age, the risk of cardiovascular disease, diabetes, cancer, and Alzheimers disease increases, making age itself the greatest risk factor for many human diseases. Thus, understanding the aging process can have profound consequences for human health. One striking feature of the aging process is the accumulation of senescent cells with age. When cells become damaged, they can enter a state of senescence which is a permanent cell cycle exit associated with the secretion of inflammatory cytokines. In mouse models of aging, the destruction of senescent cells with senolytic drugs delays age-associated decline and extends healthy lifespan. Yet, despite the wealth of accumulated knowledge, we do not entirely understand the biology of senescent cells. Prior work has shown that senescence is associated with increased variation in gene expression, suggesting that there may exist distinct transcriptional signatures of senescence. Understanding the different transcriptional physiological states of senescent cells would allow us to better treat them with cell-type-specific senolytic drugs. Here, we performed large-scale single-cell RNA-sequencing time series experiments to understand the development of transcriptional heterogeneity among senescent cell types. Our approach allowed us to observe and classify different transcriptional signatures of senescent cells as they emerged through time. We found that upon entering oxidative stress-induced senescence, separate subpopulations of cells were reproducibly adopting two distinct transcriptional states, one of which was associated with stress response and the second one with tissue remodeling. Our data suggest that a combination of senolytic drugs may be needed to more effectively eliminate senescent cells by targeting physiologically distinct sub-populations.

cell biology↗

bioRxiv2018

Differences in protein dosage underlie nongenetic differences in traits

Phenotypic expression of many traits varies among isogenic individuals in homogeneous environments. Intrinsic variation in the protein chaperone system affects a wide variety of traits in diverse biological systems. In C. elegans, expression of hsp-16.2 chaperone biomarkers predicts the penetrance of mutations and lifespan after heat shock. But the physiological mechanisms by which cells express different amounts of the biomarker were unknown. Here, we used an in vivo microscopy approach to dissect the mechanisms of cell-to-cell variation in hsp-16.2 biomarker expression, focusing on the intestines, which generate most signal. We found both intrinsic noise and signaling noise are low. The major axis of cell-to-cell variation in gene expression is composed of general differences in protein dosage. Thus, hsp-16.2 biomarkers reveal states of high or low effective dosages for many genes. It is possible that natural variation in protein dosage or chaperone activity may account for missing heritability of some traits.

systems biology↗