Systemic Biomarkers of Accelerated Aging in Schizophrenia: A Critical Review and Future Directions

Abstract

Background: Schizophrenia is associated with increased physical morbidity and early mortality, suggesting that the aging process may be accelerated in schizophrenia. However, the biological underpinnings of these alterations in aging in schizophrenia are unclear.

Method: We conducted a detailed search of peer-reviewed empirical studies to evaluate evidence for accelerated biological aging in schizophrenia based on systemic, age-related biomarkers. We included studies that investigated differences between persons with schizophrenia and healthy comparison subjects in levels of biomarkers known to be associated with aging and examined the relationship of these biomarkers to age in the 2 groups.

Results: Forty-two articles that met our selection criteria were reviewed. Nearly 75% reported abnormal biomarker levels among individuals with schizophrenia, including indices of inflammation, cytotoxicity, oxidative stress, metabolic health, gene expression, and receptor/synaptic function, with medium to large effect sizes reported in many studies. Twenty-nine percent of the studies observed differential age-related decline in schizophrenia. Markers of receptor/synaptic function and gene expression were most frequently differentially related to age in schizophrenia. Schizophrenia patients with greater disease severity and longer illness duration exhibited higher levels of inflammatory and oxidative stress biomarkers and shorter telomere length.

Conclusions: Most studies show biomarker abnormalities in schizophrenia, and there is some suggestion for accelerated aging. Although definitive interpretation is limited by cross-sectional design of the published reports, findings in the area of gene expression and synaptic function are promising and pave the way for future longitudinal studies needed to fully test this hypothesis.

Fig. 1.

PRISMA flow diagram for selection of published articles for review.

Fig. 2.

Models of altered aging in schizophrenia. The entire shaded area represents the time period during which an individual has the disorder. The darker shaded area represents the period of measurement in a given study (for this example, a study includes individuals between the ages of 35 to 65 years). Solid lines indicate trajectories that are observed within the measurement period and dashed lines represent unobserved trajectories that occur beyond (either before or after) the period of study. The heavier weighted line indicates the trajectory of healthy, nonpsychiatric individuals, while lighter weighted lines represent possible trajectories in schizophrenia. Points A through E signify inflection points during the life course, at which time, changes in biomarker trajectories might occur.