Cellular senescence in migraine – a hypothesis-driven narrative review

Migraine may signal early signs of aging-related processes, such as reduced autophagy, increased reactive oxygen and nitrogen species (RONS), and low-grade inflammation in people prone to migraine, without necessarily indicating systemic aging. While migraine is not an age-related condition, brain aging might be accelerated by cellular senescence in neurons and glia, contributing to cognitive decline in migraine patients. Although neurons are postmitotic cells, they can undergo postmitotic cellular senescence, which may contribute to the chronicity of migraine. Oxidative stress is a key factor inducing senescence and also plays a role in migraine development, as the brains of migraine sufferers show an over-reliance on mitochondria that produce an excess of RONS. These RONS can lower the threshold for cortical spreading depression and directly activate trigeminovascular nociceptors through RONS-sensitive ion channels, resulting in calcitonin gene-related peptide-dependent migraine pain. Excessive RONS can also damage DNA, and abnormal repair of single-strand DNA breaks caused by migraine-related brain activity may connect migraine with senescence. Defects in autophagy could activate cellular senescence and stabilize senescence-associated secretory phenotype. Impaired autophagy in microglia might trigger secretory autophagy and the release of brain-derived nuclear factor, which could induce autophagy in neurons to eliminate cellular debris caused by oxidative stress. This sequence of events is possible but has not yet been demonstrated in material from migraine patients and animal models. Cellular senescence may influence migraine through various mechanisms, including oxidative stress, cortical spreading depression, abnormal DNA damage responses, and impaired autophagy. Currently, there is no direct evidence linking cellular senescence to migraine, but it is unclear whether such research has been conducted to date, and we have argued that these studies are warranted.