Peroxisomes orchestrate metabolic flexibility and longevity via an interorganelle cascade

However, the drivers of organelle collapse and their temporal order remain unclear. Here, we identify peroxisomal function as a critical regulator of metabolic flexibility during youth and low-energy states.

Using Caenorhabditis elegans, we show that fasting robustly induces peroxisomal function in youth, while this response is blunted during aging. Loss of peroxisomal import via PRX-5 declines over age, causing pathological lipid droplet expansion, dysfunctional mitochondrial bioenergetics, and metabolic inflexibility. While targeted PRX-5 degradation recapitulates metabolic aging, its overexpression preserves lipid dynamics and mitochondrial integrity.