Why Does More Cancer Imply Less Neurodegeneration and Vice Versa?
Human epidemiological data robustly indicates a trade-off between risk of cancer and risk of neurodegenerative conditions. Why is this the case? While all too little is understood of the precise details, at the high level it is thought that this is a reflection of the degree to which tissue maintenance activities decline with age. The less work undertaken by stem cells, the less cell replication in general, the lower the risk of a potentially cancerous combination of mutations occurring. But without that ongoing maintenance, the loss of tissue function accelerates, and neurodegenerative conditions are one of the more prominent outcomes. In essence one is forced to choose between cancer or regeneration. Not all species face that choice, of course. Some, like naked mole rats, can have their cake and eat it too; their cancer suppression mechanisms are so exceptionally effective that individuals can maintain youthful levels of regeneration and function well into late life without any downsides.
Neurodegeneration and cancer are fundamentally distinct disorders: one signifies gradual neuronal loss while the latter signifies uncontrolled cell growth and survival. However, emerging evidence explores an inverse association between these conditions, suggesting that they do not arise from independent biological processes. Understanding the context-dependent behaviour of major pathways (for example, p53, PI3K/AKT/mTOR, Wnt, and immune-stress signaling) remains pivotal in elucidating the relationship between these two diseases. Pathways promoting early-life fitness, tissue repair, and tumor suppression in dividing cells can become detrimental later in life for post-mitotic neurons.
Cross-species genomics studies reveal how evolution has repeatedly adapted these shared networks to balance cancer resistance with survival. Research on species exhibiting exceptional longevity and disease resistance, including naked mole rats and bowhead whales, shows that cancer resistance and longevity are not fixed traits but rather are controlled by precise regulatory mechanisms. In this review, we integrate insights from broad species genomics and multi-omic and single-cell studies to understand how evolutionarily conserved molecular crosstalks diverge at the interface of cancer and neurodegeneration.