Mechanisms of Aging in Phenylketonuria ( PKU )

ABSTRACT Phenylketonuria (PKU) is an autosomal recessive inherited metabolic disorder (IMD) characterized by elevated phenylalanine (Phe) levels, requiring a low‐protein diet and low‐Phe amino acid supplementation from birth to prevent cognitive impairment. Despite early and continuous treatment, emerging evidence indicates that adults with PKU may experience subtle cognitive deficits and features consistent with accelerated aging. This narrative review synthesizes the current evidence on accelerated aging in PKU, describes its clinical manifestations, and explores potential underlying mechanisms. Adults with PKU exhibit greater cardiovascular aging, including arterial stiffness and dyslipidaemia, alongside higher rates of obesity, diabetes, and hypertension compared to adults without PKU. They also tend to demonstrate lower bone mineral density, more extensive white matter changes, and poorer cognitive performance alongside a higher prevalence of mood disorders and reduced quality of life, despite treatment. These physiological differences are thought to be primarily driven by oxidative stress (OS), which appears to be inherent to the pathophysiology of PKU. OS leads to secondary mitochondrial dysfunction and DNA damage, which are also implicated in accelerated aging in PKU, along with epigenetic changes. This review explores in detail the mechanisms implicated in premature aging in PKU and proposes potential aging biomarkers and treatment targets.