There is evidence for accelerated physical aging3
in schizophrenia. It has been known since Kraepelin’s that schizophrenia is associated with increased physical comorbidity and 2–12 times higher mortality rate than age-comparable “normal” population. A review of 37 recent articles drawn from 25 countries found the mean standardized mortality rate for all-cause mortality in schizophrenia to be 2.58.4
The average life span of a person with schizophrenia is 20–25 years shorter than that of an unaffected person. Two-thirds of the excess deaths in schizophrenia are from causes other than suicide. The Antipsychotic Trials of Intervention Effectiveness (CATIE) study reported that 43% of young and middle-aged adults with schizophrenia met criteria for the metabolic syndrome (twice the rate in the general population), and schizophrenia patients had a significant increase in the Framingham 10-year risk of coronary heart disease than matched normal subjects. Our studies5
found that 60% of middle-aged and older persons with schizophrenia had the metabolic syndrome, and the 10-year risk of coronary heart disease was increased by 79% (95% CI: 50%–107%) relative to the general population.
Inflammation and oxidative stress are implicated in the biology of aging and aging-associated medical disorders6
as well as in the pathophysiology of schizophrenia. C-reactive protein, a marker of inflammation, is elevated not only in heart disease and the metabolic syndrome but also in schizophrenia.7
A meta-analysis demonstrated immune activation and an inflammatory syndrome in schizophrenia.8
Insulin resistance too has been reported to increase with aging and in schizophrenia patients as well. Prolonged or repeated exposure to oxidative stress may accelerate aspects of biological aging. Recent meta-analyses9
have concluded that schizophrenia is associated with increased oxidative stress markers, including F2-isoprostanes, with greater oxidative stress being associated with longer duration and earlier age of onset of the illness. Telomere length is a robust indicator of biological age.10
Several studies have reported shorter telomeres in peripheral blood mononuclear cells in persons with schizophrenia compared with healthy subjects.
Possible explanations for rapid physical aging in schizophrenia include the effects of smoking, substance use, sedentary lifestyle, poor health care, and antipsychotic medications (especially the atypical ones). However, a number of studies suggest that the increased medical comorbidity and mortality in schizophrenia may not be solely (or even primarily) attributable to these factors. Smoking and other substance use are considered to be inherent aspects of the neurobiology of the schizophrenia. Sedentary lifestyle and worse health care are mainly consequences of the psychopathology. While many of the atypical antipsychotics definitely increase the risk of metabolic disturbances, several reports have indicated that the greater insulin resistance, shorter telomeres, increased oxidative stress markers, and higher mortality observed in people with schizophrenia are not solely attributable to the use of these medications. Thus, at least some of the excessive comorbidity and mortality in schizophrenia may be a part of the biology of schizophrenia itself. Further research is needed to determine the relative proportions of biological aging caused by schizophrenia per se and that due to associated factors such as smoking, lifestyle, and medications, and whether schizophrenia increases vulnerability to adverse effects of these risk factors.
The accelerated physical aging may not be specific to schizophrenia but may be shared with other serious mental illnesses. For example, several studies have shown accelerated rates of biological aging in depression, as shown by shortened telomere length. In one study, telomere shortening was in direct proportion to the lifetime duration of untreated depression.11
Also, telomere length in the depressed populations was inversely correlated with F2-isoprostanes and other peripheral oxidative stress markers and with proinflammatory cytokines. These findings suggest that oxidative stress and/or chronic exposure to inflammatory cytokines may form a pathogenic pathway culminating in accelerated cell aging in depression as well as schizophrenia. Because telomere shortening is seen in several conditions that are characterized by increased inflammation or oxidation, accelerated biological aging may be related to inflammatory and oxidative mediators rather than to singular clinical syndromes.