The DREAM complex links somatic mutation, lifespan, and disease

The DREAM complex has emerged as a central repressor of DNA repair, raising questions about whether such repression has long-term effects on human health. Here we establish that DREAM activity significantly impacts lifetime somatic mutation burden, and that these effects are linked to altered lifespan and age-related disease pathology. First, joint profiling of DREAM activity and somatic mutations across a single-cell atlas of 21 mouse tissues shows that cellular niches with lower DREAM activity have decreased mutation rates. Second, DREAM activity predicts the varied lifespans observed across 92 mammals, with low activity marking longer-lived species. Third, reduced DREAM activity in Alzheimer patients predicts later disease onset and decreased risk for severe neuropathology. Finally, we show that DREAM knockout protects against mutation accumulation in vivo, reducing single-base substitutions by 4.2 percent and insertion/deletions by 19.6 percent in mouse brains. These findings position DREAM as a key regulator of aging.