Schizophrenia and accelerated ageing: systematic review and future research directions.

Abstract

Schizophrenia has been proposed to be a disorder of accelerated ageing, characterised by a mismatch between biological and chronological age. Evidence accumulated over the past 15 years has examined this model using molecular, neuroimaging, cognitive and epidemiological markers. To evaluate whether schizophrenia shows evidence of an accelerated or advanced ageing phenotype across biological systems and to assess the consistency of the underlying molecular mechanisms. A systematic review (PROSPERO CRD42024574059) was conducted following PRISMA guidelines. PubMed and Google Scholar were searched for studies published after 2009 that cited the original accelerated ageing hypothesis publication or investigated ageing in the context of schizophrenia and/or psychosis. Evidence was synthesised narratively by domain, with emphases on meta-analyses and minimally treated, longitudinal cohorts. A total of 923 manuscripts were identified, and a final 170 were included in the systematic review. Schizophrenia showed a reproducible ageing phenotype, as evidenced by in increased mortality, higher dementia risk, brain-predicted age elevation and cognitive decline. BrainAGE studies revealed mean age gaps of 3-4 years, often present at first episode. At the mechanistic level, meta-analyses reported consistent telomere shortening (standardised mean difference approximately -0.4 to -0.5) and modest acceleration of selected epigenetic clocks. Dysregulation of oxidative stress, inflammation, mitochondrial function and insulin-like growth factor-1 signalling were frequent and partly preceded antipsychotic exposure. Schizophrenia is associated with a multisystem ageing phenotype underpinned by convergent biological mechanisms, most consistently involving telomere attrition and oxidative and/or inflammatory stress. The overall pattern supports a model of advanced rather than uniformly accelerated ageing, reflecting early biological deviation with parallel rather than steeper decline.