Discovery of new chromatin-related mechanisms that delay or prevent aging

Aging is the biggest risk factor for human morbidity and mortality, caused by damage accumulation and resulting functional decline of the organism over time.

Fortunately, aging can be interfered with, and thus detailed mechanistic understanding of the underlying pathways could instruct powerful therapies to extend our healthspan and lifespan.

Our research focuses on one of the most powerful aging regulators, the insulin/IGF signaling (IIS) pathway, relaying nutrient scarcity into a transcriptional program that improves stress resistance, slows damage accumulation, and ultimately defers aging.

Much of this program is driven by the transcription factor (TF) DAF-16/FOXO, but it has long been thought that also the chromatin landscape could play an important role in its coordination.

Indeed, by ATAC-seq we identified vast changes in chromatin accessibility under reduced IIS, and through different approaches we identified four chromatin-associated proteins that either confer or utilize these changes to contribute to the aging-preventive transcriptional outcomes.

These include two chromatin-associated proteins that directly bind to DAF-16/FOXO, namely BAF-1 and PQN-51, and two TFs that bind enhancer regions which open up under reduced IIS, LIN-39 and LIN-32.

Each of them are essential for reduced IIS to prevent aging but they function through distinct mechanisms of action, and we think that their full understanding will provide exciting new insights into aging prevention.