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Cellular 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. [ABSTRACT FROM AUTHOR]

The conserved serine residues S866 and S870 are the major phosphorylation sites essential for the processing of p100 to p52 in cells. Keywords: Common Variable Immunodeficiency (CVID); NFKB2; novel pathogenic gene variants; lym1 mice; hypogammaglobulinaemia; autoimmunity EN Common Variable Immunodeficiency (CVID) NFKB2 novel pathogenic gene variants lym1 mice hypogammaglobulinaemia autoimmunity 1159 1164 6 07/20/23 20230801 NES 230801 Kruthika Sundaram and Micol Ferro contributed equally to this work. The reduction of p100 processing was linked to a markedly less increased phosphorylation of p100 in Patient 1 compared to the controls - which is likely caused by the absence of S870 in the p100 truncated form (p.Tyr868*). The two major phospho-serines (S866 & S870) create a binding site for -TrCP, the receptor subunit of the E3 ubiquitin ligase -TrCP SP SCF sp , which mediates p100 ubiquitination and its proteasomal-dependent processing to p52 employing the p100 ubiquitin acceptor site lysine 855 [[3]]. [Extracted from the article]

Senescent cells drive tissue dysfunction through the senescence-associated secretory phenotype (SASP). We uncovered a central role for mitochondria in the epigenetic regulation of the SASP, where mitochondrial-derived metabolites, specifically citrate and acetyl-CoA, fuel histone acetylation at SASP gene loci, promoting their expression. We identified the mitochondrial citrate carrier (SLC25A1) and ATP-citrate lyase (ACLY) as critical for this process. Inhibiting these pathways selectively suppresses SASP without affecting cell cycle arrest, highlighting their potential as therapeutic targets for age-related inflammation. Notably, SLC25A1 inhibition reduces systemic inflammation and extends healthspan in aged mice, establishing mitochondrial metabolism as pivotal to the epigenetic control of aging., Competing Interests: Competing interests All authors declare no competing interests. Additional Declarations: There is NO Competing Interest.

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.