Nanodelivery Strategies for Caloric Restriction Mimetics in Age-Associated Neurodegeneration.

Brain aging is associated mainly with a decline in cognitive function and is a major risk factor for various neurodegenerative disorders (NDDs). Major hallmarks of aging include oxidative stress, chronic neuroinflammation, mitochondrial dysfunction, and impaired proteostasis. Although caloric restriction (CR) has consistently demonstrated neuroprotective effects, its long-term effects in humans remain challenging. Consequently, CRMs such as metformin, spermidine, and curcumin have been widely used because of their ability to recapitulate key molecular effects of CR. Despite their therapeutic effects, the clinical transition of CRMs is significantly limited because of their poor bioavailability, rapid metabolism, low aqueous solubility, and inefficient penetration across the blood-brain barrier (BBB). A nanoparticle-based drug delivery system provides a promising approach to address these limitations. Polymeric, liposomal, and lipid-based nanocarriers can be engineered to increase BBB transport via receptor-mediated transcytosis and to enable targeted and sustained drug release. Encapsulation of CRMs within nanoparticles has improved their pharmacokinetic and pharmacodynamic profiles by increasing their stability and bioavailability and reducing systemic degradation. However, targeted delivery of CRMs has been shown to modulate aging-associated pathways, which are necessary for the maintenance of neuronal integrity and synaptic function. This review highlights the potential of CRM-loaded nanocarriers as emerging therapeutic systems to delay brain aging and age-associated disorders. Furthermore, the current challenges and future perspectives on optimizing brain-targeted delivery to enable successful clinical translation in age-related NDDs are discussed.