Longevity Papers

Arsenic, a widespread environmental toxicant, is increasingly implicated in female reproductive dysfunction. Long-term exposure to low concentrations of arsenic leads to diminished ovarian reserve. However, the mechanisms by which arsenic exposure accelerates ovarian aging remain unclear. Here, we demonstrate that arsenic exposure induces widespread disruption of pre-mRNA splicing programs in granulosa cells, and these aberrantly spliced genes are predominantly responsible for maintaining genomic stability. Arsenic exposure induces proteasomal degradation of the RNA helicase DDX5 through the UBE3A-mediated ubiquitin-proteasome pathway. Loss of DDX5 impairs the alternative splicing of FANCA, a core gene in the Fanconi anemia pathway, resulting in the production of a truncated isoform. This aberration leads to the excessive accumulation of R-loops and γH2AX-marked DNA damage in ovarian granulosa cells. Consequently, arsenic-exposed mice exhibit hallmark features of premature ovarian aging. Our findings establish the DDX5-FANCA axis as a novel paradigm in which environmental toxins dysregulate RNA splicing, driving reproductive aging through R-loops-mediated genomic instability. These insights highlight splice-switching therapies as a promising strategy to counteract pollutant-induced fertility decline.

Aging-related accumulation of DNA damage adversely affects hematopoietic stem cell (HSC). However, the mechanisms underlying this accumulation and strategies for its elimination to rejuvenate aged HSC remain largely obscure. This study uncovers a notable surge in R-Loop presence within aged HSC, notably co-localized with γH2AX and replication protein A (RPA), and correlated with RNA residency in the nucleus. Targeted induction of R-Loop impairs the function of HSC. Mechanistically, RNA exportation is compromised in aged HSC due to a decline in Alyref, the primary constituent of the transcription- export complex (TREX). Specifically, Alyref dysfunction results in RNA retention within the nucleus, mimicking the functional characteristics of aged HSC. The nuclear accumulation of RNA leads to the formation of RNA:DNA hybrids, known as R-Loop structures, consequently inducing replication stress and DNA damage. Introducing a quantitative boost of Alyref in aged HSC notably reinstates RNA transportation, diminishes R-Loop formation and replication stress, and ultimately enhances the performance of aged HSC. Taken together, our research demonstrates the initial revelation that aging-triggered replication stress stems from abnormal RNA transportation-propelled R-Loop configurations, hinting at the potential of quantitatively modulating RNA transportation to mitigate the physiological drawbacks of aging on HSC.

Longevity interventions in mammals are typically discovered on a case-by-case basis, hindering systematic geroprotector development. We developed a platform for the identification of longevity interventions integrating longevity gene expression biomarkers within and across species, in silico chemical screening, analyses of selected compounds in cell culture, short-term dietary interventions coupled with omics profiling, and ultimately lifespan studies in mice. This approach identified compounds (selumetinib, vorinostat, celastrol, AZD-8055, LY-294002) that extended lifespan and/or healthspan in aged C57BL/6JN male mice, with limited effects in females. In addition, selumetinib and vorinostat increased lifespan when administered to young, genetically heterogeneous UM-HET3 mice. Our biomarker-driven platform accelerates geroprotector discovery, offering a scalable approach to target conserved longevity pathways.