Biology subjects

Pirtskhalava, T.

Publications and source records attributed to Pirtskhalava, T..

4 recordsLinked to original sources

bioRxiv2025

The Role of Supraoptic Hypothalamic Arginine Vasopressin Neurons in Aging-Associated Water Balance and Thermoregulatory Deficits

Aging disrupts physiological homeostasis, impairing thermoregulation, metabolism, and water balance, but the underlying neural mechanisms remain unclear. Here, we identify arginine vasopressin (AVP) neurons in the supraoptic nucleus (SON) of the hypothalamus as a critical driver of these changes. Using single-nucleus RNA-sequencing of the anterior hypothalamus in young and aged mice, we found Avp to be one of the most upregulated neuronal transcripts with age. Aged SONAVP neurons displayed enlarged size and heightened excitability, features consistent with hyperactivity. Functionally, chemogenetic activation of SONAVP neurons in young mice reproduced aging-associated phenotypes including hypothermia, reduced energy expenditure, and suppressed water intake. Conversely, knockdown of Avp in the SON of aged mice restored water balance, partially improved thermoregulation and systemic metabolism. Pharmacological inhibition of AVP receptors revealed that neuroendocrine release of AVP drives homeostatic deficits, with distinct roles for V1A and V2 receptors. Senolytic drug treatment improved systemic metabolism and reduced inflammaging but does not rescue hypothalamic AVP dysfunction, underscoring a brain autonomous mechanism of age-related physiological failure. Together, our findings establish SONAVP neuronal hyperactivity as a driver of impaired homeostasis with age and suggest that targeted modulation of neuroendocrine AVP signaling may offer a therapeutic strategy to alleviate age-associated water balance defects.

physiology↗

bioRxiv2025

Senolytic-Resistant Senescent Cells Have a Distinct SASP Profile and Functional Impact: The Path to Developing Senosensitizers

The senescent cell (SC) fate is linked to aging, multiple disorders and diseases, and physical dysfunction. Senolytics, agents that selectively eliminate 30-70% of SCs, act by transiently disabling the senescent cell anti-apoptotic pathways (SCAPs), which defend those SCs that are pro-apoptotic and pro-inflammatory from their own senescence-associated secretory phenotype (SASP). Consistent with this, a JAK/STAT inhibitor, Ruxolitinib, which attenuates the pro-inflammatory SASP of senescent human preadipocytes, caused them to become "senolytic-resistant". Administering senolytics to obese mice selectively decreased abundance of the subset of SCs that is pro-inflammatory. In cell cultures, the 30-70% of human senescent preadipocytes or human umbilical vein endothelial cells (HUVECs) that are senolytic-resistant (to Dasatinib or Quercetin, respectively) had increased p16INK4a, p21CIP1, senescence-associated {beta}-galactosidase (SA{beta}gal), {gamma}H2AX, and proliferative arrest similarly to the total SC population (comprising senolytic-sensitive plus -resistant SCs). However, the SASP of senolytic-resistant SCs entailed less pro-inflammatory/ apoptotic factor production, induced less inflammation in non-senescent cells, and was equivalent or richer in growth/ fibrotic factors. Senolytic-resistant SCs released less mitochondrial DNA (mtDNA) and more highly expressed the anti-inflammatory immune evasion signal, glycoprotein non-melanoma-B (GPNMB). Transplanting senolytic-resistant SCs intraperitoneally into younger mice caused less physical dysfunction than transplanting the total SC population. Because Ruxolitinib attenuates SC release of pro-apoptotic SASP factors, while pathogen-associated molecular pattern factors (PAMPs) can amplify the release of these factors rapidly (acting as "senosensitizers"), senolytic-resistant and senolytic-sensitive SCs appear to be interconvertible.

cell biology↗

bioRxiv2024

Profiling microRNA expression during senescence and aging: mining for a diagnostic tool of senescent-cell burden

In the last decade cellular senescence, a hallmark of aging, has come into focus for pharmacologically targeting aging processes. Senolytics are one of these interventive strategies that have advanced into clinical trials, creating an unmet need for minimally invasive biomarkers of senescent cell load to identify patients at need for senotherapy. We created a landscape of miRNA and mRNA expression in five human cell types induced to senescence in-vitro and provide proof-of-principle evidence that miRNA expression can track senescence burden dynamically in-vivo using transgenic p21high senescent cell clearance in HFD fed mice. Finally, we profiled miRNA expression in seven different tissues, total plasma, and plasma derived EVs of young and 25 months old mice. In a systematic analysis, we identified 22 candidate senomiRs with potential to serve as circulating biomarkers of senescence not only in rodents, but also in upcoming human clinical senolytic trials.

molecular biology↗

bioRxiv2020

Partial inhibition of mitochondrial complex I attenuates neurodegeneration and restores energy homeostasis and synaptic function in a symptomatic Alzheimers mouse model

We demonstrate that mitochondrial respiratory chain complex I is an important small molecule druggable target in Alzheimers Disease (AD). Partial inhibition of complex I triggers the AMP-activated protein kinase-dependent signaling network leading to neuroprotection in symptomatic APP/PS1 mice, a translational model of AD. Treatment of APP/PS1 mice with complex I inhibitor after the onset of AD-like neuropathology improved energy homeostasis, synaptic activity, long-term potentiation, dendritic spine maturation, cognitive function and proteostasis, and reduced oxidative stress and inflammation in brain and periphery, ultimately blocking the ongoing neurodegeneration. Therapeutic efficacy in vivo was monitored using translational biomarkers FDG-PET, 31P NMR, and metabolomics. Cross-validation of the mouse and the human AMP-AD transcriptomic data demonstrated that pathways improved by the treatment in APP/PS1 mice, including the immune system response and neurotransmission, represent mechanisms essential for therapeutic efficacy in AD patients.

neuroscience↗