Deciphering the decline of metabolic elasticity in aging and obesity.

Organisms must adapt to fluctuating nutrient availability to maintain energy homeostasis. Here, we term the capacity for such adaptation and restoration "metabolic elasticity" and model it through ad libitum-fasting-refeeding cycles. Metabolic elasticity is achieved by coordinate versatility in gene expression, which we call "gene elasticity." We have developed the gene elasticity score as a systematic method to quantify the elasticity of the transcriptome across metabolically active tissues in mice and non-human primates. Genes involved in lipid and carbohydrate metabolism show high gene elasticity, and their elasticity declines with age, particularly with PPARγ dysregulation in adipose tissue. Synchronizing PPARγ activity with nutrient conditions through feeding-timed agonism optimizes their metabolic benefits and safety. We further broaden the conceptual scope of metabolic and gene elasticity to dietary challenges, revealing declines in diet-induced obesity similar to those in aging. Altogether, our findings provide a dynamic perspective on the dysmetabolic consequences of aging and obesity.