From sadness to senescence: cellular effects of psychiatric syndromes

Abstract

Rationale/statement of the problem : Major depressive disorder (MDD) and other serious mental illnesses are associated with high rates of comorbid medical illnesses. Many of these comorbid conditions are more typically seen in the aged, raising the possibility that these psychiatric illnesses are associated with accelerated aging. An emerging biomarker of cell aging and of increased risk of medical illness is leukocyte telomere length, and several studies have now characterized leukocyte telomere length in MDD and other psychiatric illnesses. Fewer psychiatric studies have characterized the activity of telomerase, an enzyme that can elongate and preserve telomeric DNA, or have investigated the biochemical mediators of accelerated telomere shortening. Methods : Seven studies examining telomere length in MDD, three studies in schizophrenia, two studies in bipolar illness, two studies in PTSD, and one study in generalized anxiety disorder were reviewed, as were one study of telomerase activity in MDD and one study in schizophrenia. Additional studies in chronically stressed individuals and in individuals with histories of childhood adversity were also reviewed. Results : Shortened leukocyte telomeres have been demonstrated in MDD, bipolar illness, schizophrenia, anxiety disorders, and post-traumatic stress disorder, although in some studies, only subgroups of patients (e.g., those with longer lifetime exposure to the illness, those with poor responses to treatment, or those with preexisting histories of childhood adversity) showed shortened telomeres. Leukocyte telomere shortening is correlated with peripheral indices of increased oxidative stress and increased immune activation. Two studies (one in caregivers with high depression ratings and one in unmedicated patients with MDD) reported elevated peripheral blood mononuclear cell (PBMC) telomerase activity, perhaps representing a compensatory attempt by the body to preserve endangered telomeres. Preliminary data in MDD suggest that relatively low telomerase activity before treatment, and greater treatment-associated increases in telomerase activity, are associated with better antidepressant responses. This, plus the preliminary observation that PBMC telomerase activity is directly correlated with hippocampal volume (by MRI) in MDD, support emerging preclinical data that telomerase has intrinsic neurotrophic and antidepressant effects. Conclusion : Telomere shortening in MDD and certain other psychiatric conditions may, at least partially, reflect chronic exposure to inflammation and oxidation. As such, it may be a bellwether of increased medical risk, or it may play a more direct causal role in accelerated aging. The interplay of telomere integrity and telomerase activity may be an important determinant of psychiatric and medical outcome. Overall, the data are consistent with the view that MDD and certain other psychiatric illnesses have systemic manifestations beyond the brain and call into question the dichotomy of “mental” vs. “physical” illnesses.

Keywords

• teleomere length
• MDD
• inflammation
• oxidation
• aging