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

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.