Dóra Révész The interplay between biological stress and cellular aging: an epidemiological perspective

                       
Date of PhD graduation:  27 May 2016
Institute: GGZ inGeest / VUmc, department of Psychiatry, EMGO+ Institute
Promotor  prof. dr. Brenda W.J.H. Penninx
Co-promotor: dr. Yuri Milaneschi

Background

Recently, several cellular markers have been identified that provide more insight into the biological process of aging, in addition to the measurement of chronological aging. We studied telomere length (TL) in leukocytes as a cellular aging marker. Telomeres are situated at the ends of chromosomes and protect DNA from getting damaged. With every cell division, DNA loses some of these repeated base pair sequences and telomeres shorten, until the point at which the cell cannot divide anymore and dies. That is why TL is seen as a 'biological clock' of the cell. TL at birth is mainly genetically determined and varies widely between persons. Subsequently, accelerated telomere shortening (so, cellular aging) takes place, especially in the first 20 years. Literature describes several factors associated with TL such as lifestyle, harmful free radicals in cells, as well as stress-related factors. Moreover, short telomeres have been repeatedly associated with aging-related diseases, such as cardiovascular diseases, cancer, dementia and diabetes mellitus. More and more it is suggested that TL serves as a 'red flag' for early detection or an explanation of complications caused by aging or stress.


Our research

In this thesis we looked at the associations between TL and stress within the Netherlands Study of Depression and Anxiety (NESDA: www.nesda.nl). We distinguished psychological stress (e.g. psychiatric disorders) from biological stress (physiological stress systems and components of metabolic syndrome). We found that short TL is related to biological stress: with increased levels of inflammation, higher heart rate, higher levels of the stress hormone cortisol, but also higher waist circumference, higher triglycerides and glucose in the blood, and lower levels of the 'good' cholesterol. In addition, patients with depressive or anxiety disorders seem to show advanced cellular aging compared to persons who never had these disorders. For a large part, this seems to be explained by dysregulations in physiological stress systems, components of metabolic syndrome, and lifestyle. We also found TL at baseline to be a strong predictor for telomere shortening over time, which could indicate a strong internal regulation of telomeres. Other factors within our study had relatively little impact on the extent of shortening during follow-up. Finally, analyses of parallel changes over time showed that increases in belly fat, and to a lesser extent blood triglycerides and glucose, are associated with cellular aging.


Conclusions

1. TL is associated with a wide range of biological stress markers (i.e. inflammation, autonomic nervous system, the stress hormone cortisol, and components of metabolic syndrome), psychological stress (e.g. depression, anxiety disorders), and lifestyle factors such as smoking. 2. Biological and psychological stress are associated with the current condition of telomeres, but do not necessarily predict accelerated cellular aging over time. 3. The fact that we found relatively few predictors of cellular aging, could indicate that it may be hard to intervene in the cellular process of ‘wear and tear’ of the body. However, this should be studied in future experimental research. Therefore, we set up a clinical trial in patients with depressive and anxiety disorders: the MOod Treatment with Antidepressants or Running (MOTAR) study (www.motar.nl). Data collection for this study is currently on-going. This study will later show whether treatment with antidepressants or running therapy can affect TL (one of the outcomes measured in MOTAR).


Statement

The association between depressive and anxiety disorders and short telomeres can partially be explained by smoking, high levels of inflammation and a bad lipid balance in the blood.

This was a fascinating finding, because it not only explains certain biological mechanisms in psychiatry, but it also provides insights for multidisciplinary treatment in these patients. I find telomeres intriguing, because they showed to be related to biological as well as psychological factors, and therefore they serve as a bridge between soma and psyche.


My best experiences

Life of PhD students isn't always a bed of roses (you can think of meetings when ‘the boss’ decides that ALL analyses have to be rerun differently, or rebuttal letters to annoying reviewers), but there are definitely some highlights. I thoroughly enjoyed beautiful collaborations: with my promotor Brenda and co-promotor Yuri, within the MOTAR-group (incl. ‘mini-MOTAR’ Catherine), running therapists, and with my partner-in-crime Josine Verhoeven. Josine and I started AND finished around the same time, with several amazing conferences (Miami, The Hague ), and with idyllic working months in San Francisco: I’ve had the time of my life.

Dóra Révész