How Ageing Tissues Feed Cancer: GDF15, Lactate, and Epigenetic Reprogramming in Colorectal Tumours

This video summarizes the Nature Aging (2025) paper “GDF15-driven metabolic–epigenetic crosstalk between ageing epithelial cells and colorectal cancer” (PMID: 41339530). As tissues age, their microenvironment changes in ways that can actively promote cancer growth. This study shows that ageing colonic epithelial cells secrete the stress hormone GDF15, which reprograms nearby colorectal cancer cells toward high glycolytic flux and lactate production. The excess lactate feeds back onto epithelial cells, inducing histone H4K8 lactylation and further boosting GDF15 expression, forming a self-reinforcing metabolic-epigenetic loop. Mechanistically, GDF15 signals through a JNK1-STAT3 pathway to upregulate ENO1 and glycolysis, accelerating tumour growth in multiple mouse models. Neutralizing GDF15 or disrupting lactate metabolism breaks this loop, reducing tumour burden. Rather than being a passive backdrop, the ageing tissue microenvironment emerges here as an active driver of cancer metabolism and progression. The findings suggest that targeting age-associated signalling factors like GDF15 could decouple ageing from cancer risk and open new therapeutic strategies.