Palmitoylethanolamide and Luteolin in Brain Aging and Cognitive Decline: Biological Rationale and Current Evidence
Abstract
Cognitive decline is closely associated with biological aging and with interconnected processes, including chronic low-grade inflammation, oxidative stress, mitochondrial dysfunction, and cellular senescence. Nutraceutical strategies capable of modulating several of these pathways may represent a complementary approach to supporting cognitive health. This narrative review examines the biological rationale and available evidence regarding palmitoylethanolamide (PEA), luteolin, and their co-ultramicronized formulation (PEA-Lut) in cognitive impairment and dementia. Evidence from mechanistic studies, animal models, observational studies, and clinical trials was considered. PEA is an endogenous N-acylethanolamine with anti-inflammatory and neuroprotective properties, whereas luteolin exerts complementary antioxidant and anti-inflammatory effects. Co-ultramicronization may improve their physicochemical properties and biological activity. Preclinical studies suggest that PEA-Lut may attenuate glial activation, pro-inflammatory signaling, oxidative and nitrosative stress, and amyloid-β-induced cellular injury while supporting neurotrophic signaling and neuronal survival. Preliminary clinical findings have suggested possible benefits in stroke rehabilitation, frontotemporal dementia, and other neuroinflammatory conditions. However, human evidence specifically addressing mild cognitive impairment and Alzheimer's disease remains limited, heterogeneous, and largely derived from…
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