Schizophrenia and accelerated ageing: systematic review and future research directions

Background: Schizophrenia has been proposed as 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. Aims: To evaluate whether schizophrenia shows evidence of an accelerated or advanced ageing phenotype across biological systems and to assess the consistency of its underlying molecular mechanisms. Method: A systematic review (PROSPERO CRD42024574059) was conducted following PRISMA guidelines. PubMed and Google Scholar were searched for studies published after 2009 cited the original accelerated ageing hypothesis publication or ageing in the context of schizophrenia/psychosis. Evidence was synthesised narratively by domain, with emphasis on meta-analyses, minimally treated, and longitudinal cohorts. Results: A total of 923 manuscripts were identified and a final 170 were included in the systematic review. Schizophrenia shows a reproducible ageing phenotype, evident in increased mortality, higher dementia risk, brain-predicted age elevation, and cognitive decline. BrainAGE studies reveal mean age gaps of 3–4 years, often present at first episode. At the mechanistic level, meta-analyses report consistent telomere shortening (SMD ≈ –0.4 to –0.5) and modest acceleration in selected epigenetic clocks. Dysregulation of oxidative stress, inflammation, mitochondrial function, and IGF-1 signalling are frequent and partly precede antipsychotic exposure. Conclusions: Schizophrenia is associated with a multisystem ageing phenotype underpinned by convergent biological mechanisms, most consistently involving telomere attrition and oxidative/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.