Accelerated biological aging in serious mental disorders
Authors: Owen M. Wolkowitz
Journal: World Psychiatry (2018)

Individuals with serious mental disorders (SMDs) die at an earlier average age, even after controlling for suicide1. They are also at increased risk for developing somatic diseases that are typically associated with advanced age, such as cardiovascular diseases, metabolic syndrome, immune dysregulation and dementia1. The causes of this are likely multi-factorial, including genetic predisposition, biological changes set in motion by early life adversity, and lifestyle factors. Lifestyle factors, while obviously important, do not fully explain the increased mortality and morbidity in these individuals, and consequently, "accelerated biological aging" is increasingly being seen as an intrinsic factor in SMDs, at least in some individuals2, 3. To the extent this hypothesis is true, the scope of pathophysiology in these illnesses would broaden considerably, and they might no longer be framed as only "mental disorders" or even brain diseases, but rather as whole-body, multi-system illnesses (or at least as illnesses with substantial somatic comorbidity), of which the psychiatric presentation is just the most readily observable pathology3. Understanding the mediators of such potential acceleration of aging should expand preventative and therapeutic opportunities to improve physical as well as mental health in affected individuals. The notion of accelerated biological aging in SMDs is supported by reports of acceleration of certain biomarkers of age, such as leukocyte telomere length2 and epigenetic age4. However, data on these biomarkers remain relatively sparse to this point, and several questions arise: a) Do these markers measure aging per se, or just the presence of factors that themselves mediate aging? b) Are these markers causally related to SMDs or just correlated with them? c) Is accelerated aging specific to particular psychiatric diagnoses or to certain physiological perturbations that traverse diagnostic boundaries? d) Do different aging biomarkers reflect the same or different underlying aging processes? Here I briefly review recent data pertinent to these questions. Leukocyte telomere length and epigenetic age both significantly track chronological age, with correlation coefficients of −0.38 to −0.51 (for the former) and 0.96 (for the latter). Both of these markers significantly predict disease and mortality, strengthening the view that they are measurable markers of the aging process and of rates of aging. However, leukocyte telomere length and epigenetic age are independent predictors of chronological age and mortality risk5. Therefore, while they both measure processes that evolve with aging or are associated with aging, the specific processes are different, and their underlying mediators likely differ. Telomere shortening can occur in response to inflammation, oxidative stress, stress hormones and other factors2, 3. As such, it may signal the cumulative presence of a toxic cellular environment, rather than directly informing on the aging process itself. Indeed, leukocyte telomere length is often found to be inversely correlated with circulating inflammatory and oxidative stress factors2, 3. Another major determinant of telomere shortening is a cell's mitotic history, since telomeres fail to fully replicate after each cell division, unless acted upon by the intracellular enzyme telomerase. When cells reach a critically short telomere length, they may undergo replicative senescence, apoptosis, genomic instability or oncogenic transformation2. This can be especially problematic in tissues whose mitotic capacity is necessary for cellular replacement, such as hematopoietic stem cells and – of particular relevance to psychiatry – neuronal stem cells in the dentate gyrus of the hippocampus. Of great concern (and also of great preventative opportunity), early life stress, even in utero, has been associated with shortened leukocyte telomere length in newborns and in adults. Telomeres in SMDs may progressively shorten with illness chronicity and/or severity, but, interestingly, even never-depressed girls at high genetic risk for developing depression already have short telomeres compared to girls at low genetic risk6, suggesting a genetic (or epigenetic) link to telomere shortening even before illness onset, and raising the possibility that short telomeres are a risk factor for developing certain SMDs. Telomerase has non-canonical effects unrelated to telomere lengthening, and may, in fact, have direct anti-aging, neurotrophic and antidepressant effects7. Human studies are just beginning to explore whether telomerase activation provides such benefits in humans or mediates the therapeutic effects of certain psychotropic drugs8. Epigenetic age is a more recent candidate marker of the aging process, owing largely to the discovery of an "epigenetic clock" by Horvath4 that remarkably tracks chronological age in humans and also predicts all-cause mortality. This "clock" is based on progressive age-related changes in methylation of 5'-C-phosphate-G-3' (CpG) sites at specific DNA loci. While largely pre-programmed, methylation of these sites is also influenced by the environment. Considerably less work has been reported on epigenetic age in SMDs compared to leukocyte telomere length, and the findings are not entirely consistent. However, as was the case with telomere shortening, epigenetic age is apparently accelerated following life stress, perhaps even prenatal stress, and this might be related to glucocorticoid effects on methylation9. Although not strictly a biomarker of aging, another set of relevant subcellular biomarkers involves the mitochondria, which are related to the aging process, are affected by stress and glucocorticoids, interact with telomere length and telomerase, and are likely dysregulated in SMDs. Mitochondrial pathology may be assessed by mitochondrial mutations, inefficient energy generation, increased reactive oxygen species generation and altered mitochondrial DNA copy number. Although widely studied in somatic diseases, the characterization of mitochondria in SMDs is in its infancy, some results are conflicting, and the relationship of mitochondria to epigenetic age and leukocyte telomere length is actively being investigated10. In summary, the landscape of psychiatric illness is changing, with a new focus on subcellular components and processes in addition to neurotransmitters. All or nearly all of the biomarkers discussed here lack diagnostic specificity, but may, rather, be specific to particular biochemical disturbances (e.g., glucocorticoids, inflammation, oxidative stress) that contribute to psychiatric illnesses. Such studies are reinforcing the concept that purely phenomenologic diagnoses may obscure biological underpinnings of psychiatric pathology. The biomarkers discussed here are usually studied in peripheral leukocytes or in saliva. While the relationship between these peripheral markers and brain markers is uncertain, they likely have import in their own right, and may contribute to somatic as well as psychiatric presentations. A key area of investigation is to determine whether biological aging in SMDs can be decelerated with appropriate treatment. When psychiatrists and other clinicians view mental illnesses as whole body diseases, the focus will change from specific behaviors to systemic, whole body pathologies, and personalized medicine will increasingly match target-based therapies to specific biological indicators. Owen M. Wolkowitz University of California San Francisco School of Medicine, San Francisco, CA, USA