dos Santos, G. A.; Castro, J. P.; Galante, P. A. F.

Aging and cancer share complex molecular mechanisms, yet distinguishing between causative factors and byproducts remains challenging. Here, we investigated the role of transcriptomic entropy in aging and cancer processes by analyzing RNA-sequencing data from thousands of human and mouse samples. We found that entropy changes during aging are highly tissue-specific, with some tissues showing increased entropy while others exhibit decreased or stable entropy levels. Transcriptomic entropy strongly correlates with age-related processes, showing positive associations with proliferation, cellular senescence, and somatic mutation burden, while negatively correlating with stemness. Surprisingly, cellular reprogramming also increases transcriptomic entropy. In cancer, we observed that primary tumors generally display higher entropy than normal tissue, with entropy levels further increasing in metastatic stages. Notably, treatment-resistant tumors showed distinct entropy patterns, with acquired resistance associated with increased entropy, while primary resistance and immediate post-treatment responses showed decreased entropy. Higher entropy levels predicted poor survival outcomes in multiple cancer types, suggesting its potential as a prognostic marker. Furthermore, differential expression analysis revealed that entropy-associated genes are enriched in developmental processes and depleted in metabolic pathways, indicating a possible link to cellular dedifferentiation. Finally, we found increased entropy in various age-related diseases beyond cancer, suggesting that transcriptomic disorder may be a common feature in age-related pathologies. Our findings establish transcriptomic entropy as a fundamental parameter in aging and cancer progression, offering new insights into disease mechanisms and challenging the current view that increased disorder is always detrimental.