Epigenetic activation of secretory phenotypes in senescence by the FOXQ1-SIRT4-GDH signaling.

Although metabolic reprogramming is characterized as a hallmark of aging, implications of the crucial glutamate dehydrogenase (GDH) in human senescence remain poorly understood. Here, we report that GDH activity is significantly increased in aged mice and senescent human diploid fibroblasts. This enzymatic potentiation is associated with de-repression of GDH from its functionally suppressive ADP-ribosylation modification catalyzed by NAD-dependent ADP-ribosyltransferase/deacetylase SIRT4. A series of transcription analyses led to the identification of FOXQ1, a forkhead family transcription factor (TF), responsible for the maintenance of SIRT4 expression levels in juvenile cells. However, this metabolically balanced FOXQ1-SIRT4-GDH axis, is shifted in senescence with gradually decreasing expressions of FOXQ1 and SIRT4 and elevated GDH activity. Importantly, pharmaceutical inhibition of GDH suppresses the aberrantly activated transcription of IL-6 and IL-8, two major players in senescence-associated secretory phenotype (SASP), and this action is mechanistically associated with erasure of the repressive H3K9me3 (trimethylation of lysine 9 on histone H3) marks at IL-6 and IL-8 promoters, owing to the requirement of α-ketoglutaric acid (α-KG) from GDH-mediated glutamate dehydrogenase reaction as a cofactor for histone demethylation. In supplement with the phenotypic evidence from FOXQ1/SIRT4/GDH manipulations, these data support the integration of metabolism alterations and epigenetic regulation in driving senescence progression and highlight the FOXQ1-SIRT4-GDH axis as a novel druggable target for improving human longevity.

Mobility, independent agency, and cosmopolitan settlement: Evidence from Chinese senior undergraduates.

Cosmopolitan cities share similarities with historical frontiers, including potential opportunities for economic success, high social mobility, weakened traditional conventions, and adventure and novel experiences. Individuals with high independence typically prefer to settle in cosmopolitan cities. However, previous research testing this cosmopolitan settlement hypothesis did not consider the influence of relational mobility and residential mobility. Moreover, the mechanisms that drive people to prefer cosmopolitan cities remain unclear. This study examines the relationships among independence, relational mobility, residential mobility, and preference for cosmopolitan cities among 296 Chinese senior undergraduates. The results indicate that: (1) independence remains a positive predictor of the preference for cosmopolitan cities above and beyond relational mobility, residential mobility (i.e., history, state, and intention), and other covariates; (2) intention of residential mobility also positively predicts preference for cosmopolitan cities when controlling for related covariates; and (3) relational mobility indirectly predicts perceived preference for cosmopolitan cities through dependence. This research underscores the importance of identifying the factors and mechanisms affecting cosmopolitan settlement.