Citations 2
Senescent cell transplantation into the skin induces age‐related peripheral dysfunction and cognitive decline
Franco, Ana Catarina , Martini, Hélène , Victorelli, Stella , Lagnado, Anthony B. , Wyles, Saranya P. , Pirius, Nicholas, Woo, Seung‐Hwa , Costa, Daniela G. , Chaib, Selim , Tullius, Stefan G., Kirkland, James L. , Jurk, Diana , Cavadas, Cláudia , Passos, João F. , Rowsey, Jennifer L. , Chaib, Selim , Khosla, Sundeep , Jurk, Diana , Cavadas, Claudia , Passos, João F , Tullius, Stefan G. , Tchkonia, Tamar , Khosla, Sundeep
Aging Cell | October 7, 2024 | Volume: 24 | Issue: 1 | Pages: No page available
AbstractCellular senescence is an established cause of cell and tissue aging. Senescent cells have been shown to increase in multiple organs during aging, including the skin. Here we hypothesized that senescent cells residing in the skin can spread senescence to distant organs, thereby accelerating systemic aging processes. To explore this hypothesis, we initially observed an increase in several markers of senescence in the skin of aging mice. Subsequently, we conducted experiments wherein senescent fibroblasts were transplanted into the dermis of young mice and assessed various age‐associated parameters. Our findings reveal that the presence of senescent cells in the dermal layer of young mice leads to increased senescence in both proximal and distal host tissues, alongside increased frailty, and impaired musculoskeletal function. Additionally, there was a significant decline in cognitive function, concomitant with increased expression of senescence‐associated markers within the hippocampus brain area. These results support the concept that the accumulation of senescent cells in the skin can exert remote effects on other organs including the brain, potentially explaining links between skin and brain disorders and diseases and, contributing to physical and cognitive decline associated with aging.
Mitochondrial RNA cytosolic leakage drives the SASP
Victorelli, Stella , Eppard, Madeline, Woo, Seung‐Hwa , Everts, Stacia , Martini, Hélène , Pirius, Nicholas, Franco, Ana Catarina , Han, Yeaeun , Saul, Dominik , Splinter, Patrick L., O’Hara, Steven P. , Valenzuela-Pérez, Lucía , Lee, Hyun Se Kim , Jurk, Diana , Everts, Stacia P A, LaRusso, Nicholas F , Hirsova, Petra , Passos, João F , Jurk, Diana , Kim Lee, Hyun Se , Saul, Dominik , Lee, Gung , Han, Nuan , Liang, Eugene Y., Nóvoa, Eva , Nogueiras, Rubén , Morgenthaler, Olivia , LaRusso, Nicholas F. , Passos, João F.
No container title available | August 26, 2024 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Senescent cells secrete proinflammatory factors known as the senescence-associated secretory phenotype (SASP), contributing to tissue dysfunction and aging. Mitochondrial dysfunction is a key feature of senescence, influencing SASP via mitochondrial DNA (mtDNA) release and cGAS/STING pathway activation. Here, we demonstrate that mitochondrial RNA (mtRNA) also accumulates in the cytosol of senescent cells, activating RNA sensors RIG-I and MDA5, leading to MAVS aggregation and SASP induction. Inhibition of these RNA sensors significantly reduces SASP factors. Furthermore, BAX and BAK plays a key role in mtRNA leakage during senescence, and their deletion diminishes SASP expression in vitro and in a mouse model of Metabolic Dysfunction Associated Steatohepatitis (MASH). These findings highlight mtRNA's role in SASP regulation and its potential as a therapeutic target for mitigating age-related inflammation.