The Cytochrome P450 System, Reactive Oxygen Species and Cellular Ageing: Molecular Mechanisms, Pharmacological Implications and Clinical Management in Frail Older Adults

The cytochrome P450 (CYP450) system mediates the biotransformation of 70–80% of all clinically used drugs and is an obligate source of reactive oxygen species (ROS) through catalytic uncoupling. With ageing, CYP450 activity declines heterogeneously—most notably CYP3A4, by an estimated 30–50% in adults over 70 years—in the context of reduced hepatic mass, sinusoidal blood flow, and progressive pseudocapillarisation. The frail older adult compounds this age-related decline with inflammaging-driven CYP450 suppression and nutritional depletion of antioxidant cofactors, constituting a 'triple pharmacological penalisation syndrome'. Microsomal ROS may contribute—through well-characterised molecular mechanisms—to hallmarks of cellular ageing including genomic instability, telomere shortening, proteostasis failure, mitochondrial dysfunction, and cellular senescence. Whilst direct causal demonstration in humans remains methodologically challenging, this mechanism represents a potentially modifiable dimension of pharmacological vulnerability in frail older patients. This review integrates mechanistic, pharmacokinetic, and clinical evidence with explicit evidence grading, an expanded high-risk drug table with clinical alerts and safer alternatives, and a three-level clinical algorithm applicable across healthcare settings. Key messages include the need to limit paracetamol to ≤2 g/day in frail malnourished patients, to avoid long-acting benzodiazepines in favour of glucuronidation-pathway alternatives, and to substitute CYP3A4-dependent statins when potent inhibitors are co-prescribed. Pharmacogenomic testing, as demonstrated in the PREPARE trial, holds promise for ADR reduction but requires cost-effectiveness evidence in geriatric populations before universal implementation