Beyond the cerebrospinal fluid: Preclinical and clinical evidence on central nervous system penetration and functional activity of oral rapamycin (sirolimus).
Abstract
Rapamycin, a potent mTORC1 inhibitor, is a leading candidate for treating age-related neurodegenerative disease. Numerous studies demonstrate beneficial effects in a variety of diseases that affect the brain. Yet a persistent belief among researchers is that rapamycin cannot penetrate brain tissue, citing as evidence its absence of detection in cerebrospinal fluid (CSF). This narrative review synthesizes clinical and preclinical evidence challenging this "CSF misconception." In humans, direct tissue sampling in glioblastoma detects rapamycin in brain at mTORC1-inhibitory concentrations, while functional measures-tumor regression and seizure control in tuberous sclerosis complex, cerebral metabolic preservation on PET in Alzheimer's disease, increased cerebral blood flow in
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Research summary
The paper claims that oral rapamycin effectively penetrates brain tissue and exerts functional mTORC1-inhibitory activity, refuting the common belief that it is excluded from the central nervous system due to its absence in cerebrospinal fluid. This is relevant to longevity research because rapamycin is a leading candidate for extending healthspan and lifespan via mTOR inhibition, and clarifying its bioavailability in the brain is critical for understanding its efficacy in preventing age-related neurodegeneration.
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