Potential Links Between Aging, Mitochondrial Dysfunction, and Drug Transporter Function-Molecular Mechanisms and Pharmacokinetic Implications.

Abstract

Aging is associated with complex physiological changes that influence drug pharmacokinetics, including alterations in mitochondrial function and gastrointestinal (GI) drug transporter activity. Mitochondrial dysfunction-characterized by reduced oxidative phosphorylation, mitochondrial DNA damage, and increased reactive oxygen species-is a hallmark of aging and may affect energy- and redox-dependent cellular processes in the gut. At the same time, aging can modulate the expression and function of key intestinal drug transporters from the ATP-binding cassette (ABC) and solute carrier (SLC) families, which play a central role in oral drug absorption and bioavailability. This review examines the molecular links between age-related mitochondrial dysfunction and regulation of GI drug transporters, with a focus on their pharmacokinetic consequences in older adults. We summarize evidence of mitochondrial decline in the aging intestine and discuss how mitochondrial signals-such as cellular energy status and oxidative stress-regulate transporter expression and activity via pathways including AMPK (AMP-Activated Protein Kinase), Sirtuin-FOXO (Forkhead box O transcription factors), Nrf2 (Nuclear factor erythroid 2-related factor 2), and NF-κB (Nuclear Factor kappa B). We highlight clinical examples of drugs showing age-related changes in bioavailability that may be attributable to transporter dysfunction. Finally, we discuss therapeutic implications for geriatric pharmacotherapy, including dose adjustment, management of transporter-mediated drug-drug interactions, and strategies aimed at preserving mitochondrial health.