Analyzing different aging theories in the context of the brain: DNA damage, inflammation, redox imbalance, and neurodevelopment intertwine

The neuronal tissue is notable for its unique regulation of the immune system, response to DNA damage, endurance against reactive oxygen and nitrogen species, and control of inflammatory pathways. Here, I discuss some uniqueness of the brain’s aging process in light of the free radical theory of aging, DNA-damage accumulation, inflammaging, and aging as a consequence of a programmed developmental process. Key points include (i) the resilience of the neuronal tissue to oxidative stress; (ii) the neuron’s efficiency in repairing learning-induced DNA damage, even with fewer repair pathways than other cell types; (iii) TLR9 and NFκB at the intersection of memory and inflammation; (iv) RELA linking the skin-brain axis during development, DNA damage response, and pro-inflammatory control; (v) PARP1 at the crossroad of all discussed aging theories. Data points to a “burden threshold” where the beneficial regulations of distinct pathways shift toward neurotoxic activities.