Biology subjects

Eremenko, E.

Publications and source records attributed to Eremenko, E..

4 recordsLinked to original sources

bioRxiv2026

Aging in Fast-Forward: An Inducible SIRT6 Deficiency model as a Lens on Brain Aging and Neurodegeneration

Aging and neurodegeneration occur gradually, making in vitro modeling challenging and costly. We generated a time-resolved, reversible neuron-like aging model by gradually depleting SIRT6. Within three weeks, their transcriptomes recapitulated brain-aging signatures and hallmarks. RNA-seq revealed clusters of nonlinear changes and predicted oscillatory DNA-damage and apoptotic programs, allowing stress response and adaptation. SIRT6 loss led to nuclear envelope breakdown and micronuclei accumulation, resembling accelerated-aging phenotypes. Some defects could be rescued by re-expressing SIRT6. As a tool for discovery, we uncovered disrupted nucleocytoplasmic transport as an aging pathway shared with neurodegenerative disorders. When SIRT6 depletion reached 30 days, transcriptional changes correlated with those in Alzheimers patients, but reversed after SIRT6 re-expression. Pathways associated with shSIRT6 and healthy aging became anticorrelated with AD, pointing to critical signatures. Our affordable and easy-to-use model captures key molecular features of aging, distinguishes physiological from disease-linked changes, and accelerates mechanistic discovery in a controllable, neuron-based system. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/705977v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@181c9d1org.highwire.dtl.DTLVardef@1e8be3dorg.highwire.dtl.DTLVardef@121d345org.highwire.dtl.DTLVardef@1b5589e_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO A Novel Reversible Cellular Model of Gradual SIRT6 Decline Reveals Transcriptomic Transitions from Aging to Neurodegeneration. (1) We developed a neuron-like cellular system with gradual, inducible SIRT6 depletion to mimic the aging process. The model enables: (2) Recapitulation of hallmark features of aging, including genomic instability, cellular stress, and nuclear integrity loss. (3) Identification of novel SIRT6-regulated pathways, including impaired nucleocytoplasmic transport. (4) Clustering of dynamic, non-linear gene expression trajectories. (5) Distinction between reversible and irreversible changes following SIRT6 re-expression. (6) Transcriptomic comparison with human brain aging and AD revealing divergence points between healthy and pathological aging. C_FIG

molecular biology↗

bioRxiv2025

The Divergent 3D Genome Landscapes of Aging and Neurodegenerative mouse models

Chromatin structure is essential for gene regulation and genome stability, and neurons must preserve their 3D genome organization throughout life. This structure gradually deteriorates with aging and is further disrupted in neurodegenerative diseases. To investigate whether aging and neurodegeneration share early chromatin changes or diverge, we performed Hi-C on cortical neurons from adult, aged, and brain-specific SIRT6-knockout (S6-KO) mice, and compared them to the CK-p25 Alzheimers disease model results stratified by {gamma}H2AX levels. All models showed early features such as weakened interactions between chromosomes in expanded nuclei, A-to-B compartment shifts, and loss of architectural loops. However, aged neurons retained TAD prominence, short-range interactions, and enhancer-promoter loops, while pathological models showed reduced TAD prominence, shorter loops, and disorganized A-B mixing. These changes correlate with increased DNA damage. Our findings suggest that aging represents a "primed" state, where chromatin regulation begins to erode, but further stressors like DNA damage are associated with progression toward neurodegenerative breakdown.

molecular 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↗

bioRxiv2020

Molecular Mechanism of Nuclear Tau Accumulation and its Role in Protein Synthesis.

Several neurodegenerative diseases present Tau accumulation as the main pathological marker. Tau post-translational modifications such as phosphorylation and acetylation are increased in neurodegenerative patients. Here, we show that Tau hyper-acetylation at residue 174 increases its own nuclear presence and is the result of DNA damage signaling or the lack of SIRT6, both causative of neurodegeneration. Tau-K174ac is deacetylated in the nucleus by SIRT6. However, lack of SIRT6 or chronic DNA damage result in nuclear Tau-K174ac accumulation. Once there, it induces global changes in gene expression affecting protein translation, synthesis and energy production. Tau-K174Q expressing cells showed changes in the nucleolus increasing their intensity and number, as well as in rRNA synthesis leading to an increase in protein translation and ATP reduction. Concomitantly, AD patients showed increased Nucleolin and a decrease in SIRT6 levels. AD patients present increased levels of nuclear Tau, particularly Tau-K174ac. Our results suggest that increased Tau-K174ac in AD patients is the result of DNA damage signaling and SIRT6 depletion. We propose that Tau-K174ac toxicity is due to its increased stability, nuclear accumulation and nucleolar dysfunction.

molecular biology↗