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.

Epigenetic age is accelerated in schizophrenia with age- and sex-specific effects and associated with polygenic disease risk

“…Our findings also demonstrate that analyzing these clocks simultaneously can reveal new insights that may otherwise be missed. A systematic review of aging biomarkers found that less than a quarter of studies explored an interaction effect or statistically compared the regression slope between groups in SCZ 11 . Our findings support their recommendations to specifically examine age-specific effects in aging studies but also more general in epigenetic studies of SCZ, such as epigenome-wide association studies.…”

“…Despite elevated rates of suicide and other unnatural causes of death, most morbidity in SCZ is attributed to age-related diseases (e.g., cardiovascular and respiratory diseases, and diabetes mellitus 8,9,5 ). The increased prevalence of age-related disabilities and morbidities suggests that biological aging may be accelerated in SCZ 10,11 . DNA methylation (DNAm) age predictors, or "epigenetic clocks", are biomarkers of ageing that generate a highly accurate estimate of chronological age, known as DNAm age [12][13][14] .…”

“…While different aging biomarkers have been studied, there is no clear demonstration of altered aging in SCZ 11 . More specifically, DNAm age predictors have found limited to no evidence for altered epigenetic aging in either brain or blood [27][28][29][30][31] .…”

Do Immune Dysregulations and Oxidative Damage Drive Mood and Psychotic Disorders?

“…Reversely, the free-radical theory of aging assumes that aging (partially) occurs as a result of damage to cells and connective tissue caused by free radicals [23]. In this line, several aging-related physiological abnormalities can be seen in younger patients with schizophrenia and mood disorders, including a higher prevalence of metabolic and cardiovascular disease, a reduction in life expectancy of 10-20 years, a reduced telomere length, and brain volume reductions [23,31]. These findings form the basis of the so-called "aging hypothesis" for schizophrenia and mood disorders [23,27,32], also suggesting these disorders to be "whole-body disorders" rather than disorders restricted to the brain [33].…”

Struggling With Aging and Illness: Life Experiences of Elderly Schizophrenia Patients in the Community of Taiwan

“…In many countries, patients above the age of 55 are regarded as elderly. As these patients age 20% faster than the average person, they often have to face the health impacts of aging earlier (Nguyen, Eyler, & Jeste, 2017;Jeste & Maglione, 2013). Furthermore, since the symptoms of schizophrenia usually appear during the teenage or early adulthood period, this means that most patients above the age of 55 have been schizophrenic for 20 to 30 years.…”