Speakers - CARWC2025

Abstract

Cellular senescence refers to a permanent cessation of cell division triggered by different forms of cellular stress. As individuals age, these senescent cells progressively build up within various tissues, contributing to organ dysfunction and the onset of age-associated disorders. Eliminating senescent cells has been shown to markedly alleviate pathological states and promote longevity. Epigenetic dysregulation not only serves as a fundamental mechanism underlying the aging process but also represents a potentially reversible target for therapeutic intervention. Age-related changes in DNA methylation patterns, histone modification profiles, chromatin organization, and non-coding RNA regulation constitute a common framework that connects genomic instability, aberrant gene expression, stem cell depletion, mitochondrial dysfunction, and the development of chronic age-associated disorders. Moreover, the aging phenotype arises from a complex interplay among genetic factors, epigenetic regulation, and environmental influences. In this context, advances in tissue engineering, regenerative medicine, and CRISPR/Cas9-based genetic screening provide powerful tools to investigate regulatory networks, counteract age-related functional decline, and restore stem cell activity. To explore and summarize current genetic and regenerative strategies aimed at mitigating cellular senescence and restoring stem cell function, thereby providing insights into potential interventions for age-related disorders.

By utilizing a CRISPR/Cas9-mediated loss-of-function screen targeting ribosome-associated genes involved in the regulation of human mesenchymal progenitor cells (MPC) senescence, it was demonstrated that the nucleolus-localized RPL22 acts as a heterochromatin destabilizer, enhancing rRNA transcription and thereby promoting cellular senescence. In contrast, decreasing RPL22 expression was shown to alleviate cellular senescence across multiple biological contexts, highlighting a critical role for RPL22 in driving senescence, at least in human MPCs and vascular endothelial cells.

Knockout of the insulin-responsive glucose transporter GLUT4 emerged as a top hit in both in vitro and in vivo screens, resulting in a twofold increase in neurogenesis in aged mice. Aged qNSCs displayed elevated glucose uptake, approximately twice that of young cells. Reversing this increase, either through genetic manipulation or glucose restriction, enhanced the activation capacity of aged, but not young, NSCs. The prominent role of GLUT4 among glucose transporters in regulating NSC aging may stem from its modest age-related upregulation and its insulin dependency. These findings suggest that targeting the increased glucose uptake in aged cells, via GLUT4 knockout or glucose limitation, could represent a broader strategy to mitigate aging-related decline.

Recent evidence suggests that modulation of the H2AZ1-PTN axis may represent a promising avenue to alleviate cellular senescence and age-associated pathologies. Studies employing CRISPR/Cas9-based screening have identified H2AZ1 as a key histone variant involved in regulating human stem cell aging, thereby expanding the current understanding of chromatin dynamics in senescence. These findings highlight H2AZ1 as a potential molecular target for future therapeutic interventions aimed at delaying or reversing age-related functional decline.

Overall, these studies highlight the potential of leveraging advanced genetic and regenerative approaches to counteract cellular senescence and restore stem cell function. By systematically uncovering mechanisms driving aging, such strategies offer promising avenues for mitigating age-related functional decline and developing effective interventions against aging-associated disorders.