Role Of Genotype In Maintaining Trlomere Length At Prolonged Psychological Stress

Abstract

One of the most widely studied potential markers associated with life expectancy and resistance to stress is terminal regions of chromosomes - telomeres. The telomere theory of aging claims that telomeres are both a marker of cellular aging and its main cause. Short telomeres are a risk factor for age-related diseases. Recently, quite a few studies appeared that revealed accelerated telomere shortening as a response to long-term psychological stress. Working on the destruction of chemical weapon was stressful for people who conducted this task in the Russian Federation. Our research included general medical and psychological examination, as well as measurement of telomere lengths of peripheral blood lymphocytes, and determination of alleles of the serotonin system genes, i.e. serotonin receptor 2A 5-HTR2A (102T>C polymorphism, alleles A1 and A2) by 87 people who took part in the demolition of chemical weapon, and by 65 in control group. Serotonin system is actively involved into the body's response to stress, thus the aforementioned alleles should be regarded as most significant. It was shown that the maximal and the average length of telomeres in the main group were higher than those in the control group, while minimal telomere lengths did not differ significantly. Joint examination of telomere lengths, age and genetic polymorphism, demonstrated that the length of telomeres tended to decrease with age by carriers of genotypes A1A2 and A2A2, and to a much smaller extent than by carriers of A1A1. Thus, carriers of the A2 allele proved to be more resistant to long-term stress.

Keywords: Long-term stressserotonin receptor 2ATelomere length

Introduction

Among the existing theories of aging, the telomere theory takes the leading place (Anisimov, 2003). To date, many studies have been done that describe the relationship between the processes of normal and accelerated aging with telomere length (Bernadotte, Mikhelson, & Spivak, 2016).

Problem Statement

Comparison of data on the effect of stress on the length of telomeres and the role of polymorphism in the genes of the serotonin system in mediating this effect led us to search of a direct link between the genetic background and the telomere response to stress. In Han Chinese, shorter leukocyte telomere length is significantly associated with the 5-HTTLPR S/S allelic variant, which may be implicated into psychological stress-related health problems (Li et al., 2014). But aforementioned psychological factors were not taken into account.

Mitchell et al. (2014) reported occurrence of significant associations between low income, low maternal education, unstable family structure, harsh parenting - and telomere length. These effects were moderated by genetic variants in serotonergic and dopaminergic pathways. Consistent with the differential susceptibility hypothesis, subjects with the highest genetic sensitivity scores had the shortest telomere length, when exposed to disadvantaged social environments and the longest telomere length, when exposed to ‘advantaged environments’. However, the 5HTR2A polymorphism was not included into this study. Father loss is definitely linked to his children's salivary telomere length, the way losing one’s father being highly important. At the same time, there was no reliable correlation between the degree of telomere shortening and the polymorphism of serotonin system genes (Mitchell, McLanahan, Schneper, Garfinkel, Brooks-Gunn, & Notterman, 2017).

Research Questions

Destruction of chemical weapon is a highly stressful and harmful activity. The question of how workers cope with this long-term stress, whether it affects the length of telomeres, and whether the body has got some kind of basic defense against such stress requires an urgent answer. Is it possible to determine a greater or smallerdegree of professional competence forpeople intending to work in such difficult conditions? Works linking difficult working conditions with the polymorphism of the 5-НТR2A gene were conducted in China. Wu, Wang, Zhou, Gu, & Yu (2016) found that the risk of depression by people working at a thermal power plant with high-level daily hassles and / or with more negative emotions, who carried A1A2 genotype or, A2A2 genotype of T102C, was 5 to 8 times higher than that in those with low-level daily hassles and / or with less negative emotions, who carried A1A1 genotype. Oilfield workers with A2A2 and A1A2 genotypes had significantly higher role boundary scores than those with A1A1 genotype, and workers with A2A2 genotype had a significantly higher vocational stress score than those with A1A2 genotype (Jiang, Palizhati, Gao, Guan, & Liu, 2016). Unfortunately, in these studies there was no such marker of general health as telomere length.

Purpose of the Study

Purpose of this study consists in analysis of a marker of general health status (telomere length), in its connection with polymorphism of serotonin 2A receptor gene (5-HTR2A), in workers exposed to severe psychological stress, regarded basing upon the model of taking part in destruction of chemical weapons. A more general perspective consists in ranging professionals intending to work in conditions of long-term stress, basing on data of genetic screening.

Research Methods

Findings

Distribution of 5HTR2A genotypes

To determine the reliability of the differences between the study and the control sample, the standard Pearson χ2 criterion was used. To analyze the effect of HTR2A gene polymorphism on telomere length, a correlation coefficient was calculated. To illustrate the results obtained, linear regression models were constructed.

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Telomeres length

The length of telomeres in the peripheral blood lymphocytes of the main and control groups are highly variable and do not correlate with age (see figure 2 and table 2 ).

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We also compared average telomere lengths in carriers of different genotypes in the main group, and found that the longest telomeres are present in carriers of the A1A2 and A2A2 genotypes, while carriers of the A1A1 genotype tend to have shorter telomeres (Figure 03 ).

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In a joint examination of telomere lengths, age, and polymorphismsA1A2 and A2A2, no reliable link was found. This means that by carriers of these genotypes, telomere length decreases with age significantly less than by A1A1 carriers (Figures 05 and 06 ).

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Respondents with genotype A1A1 have shorter telomeres. This means that they are most vulnerable to long-term stress. Correlation between A2 allele of 5-HTR2A gene and stable telomere length in both groups was also registered. In the course of ageing, long telomeres do not decrease reliably by carriers of this allele. In the main group, a large number of significantly longer telomeres are observed than in the control.

Conclusion

The data obtained by us confirm the fact that the serotonin system takes active part in dealing with long-term stress - in particular, the serotonin 2A receptor (5-HTR2A). In this case, carriers of the allele A2 have got protective mechanisms that help maintain the length of telomeres or even increase it, to avoid accelerated aging, as a result of prolonged stress. Probably, in this situation, the activity of telomerase increases, contributing to the maintenance of telomere length. A similar reaction was earlier observed in the study comparing influence of traditional and of non-traditional music. Music which was not traditional for the Ss, tended to be perceived as stressful, in some cases resulting in a shortening of telomeres. However, in some volunteers this shortening was prevented by an increase in telomerase activity (Spivak, Urazova, Zakharchuk, & Spivak, 2018). Unfortunately, due to the relatively small size of the groups, we could not establish reliable connection with the polymorphism of the genes of the serotonin system. Correlation with an increase in telomerase activity was also observed in carriers of the ApoE allele associated with the predisposition to Alzheimer's disease. This supposition is corroborated by structurally similar data, acquired in studies of relatives of patients suffering from Alzheimer's disease (Damjanovic et al., 2007), and of carriers of the allele of predisposition to this disease (APOE ε4, cf. Wikgren et al., 2012), as well as to depression (Wolkowitz et al., 2012). Also, Jacobs, Kroenke, Lin, Epel, Kenna, Blackburn, & Rasgon (2013) showed that replacement hormone therapy in female carriers of the genotype ApoE4 leads to reliable telomere elongation. This genotype can also affect the level of 5-HT2A serotonin receptor. Low level of telomerase activity is associated with chronic stress in Alzheimer patients, however response to acute stress is similar by them and by members of the control group (Epel, Lin, Dhabhar, Wolkowitz, Puterman, Karan, & Blackburn, 2010). Chhibber & Zhao (2017), using a mice model, showed that ApoE influenced the expression of brain-derived neurotrophic factor (BDNF) and the 5-HTR2A serotonin receptor in an isoform-dependent manner, with the ApoE4 brain exhibiting the lowest level of BDNF, and the highest level of 5-HTR2A. In addition, both presynaptic and postsynaptic proteins were downregulated, indicating a synaptic deficit in ApoE4 brains.

Many studies describe the association of the A2 allele with unfavorable psychological characteristics, such as increased anxiety, alcoholism, suicidal tendencies, possible risk of developing schizophrenia.

It is possible that longer telomeres, and absence of telomere length dependence on age in carriers of the A2 allele, are just a result of a compensatory increase in telomerase activity, due to a higher rate of telomere shortening. This may indicate that, under long-term stress, the A2 allele becomes protective.

Similar results were obtained at our Radiation Cytology Laboratory, Institute of Cytology, Russian Academy of Sciences last year: presence of a link between the genotype A2A2 and longer telomeres was demonstrated in male subjects.

On the other hand, we found that respondents in the main group were homozygous for the A1 allele, and, on average, had shorter telomeres, compared to carriers of the other two genotypes. In the control group, such a relationship was not found. However, in both groups, the telomere length was negatively related to age. This can be explained by the fact that under conditions of prolonged stress, carriers of allele A1, which is characterized by a higher level of expression of the 5-HTR2A gene, had more receptors on the surface of the tonsil neurons, which is associated with longer excitation duration. Consequently, they showed a more pronounced reaction of anxiety and fear to stress.

The results obtained earlier in our laboratory show that the A1A1 genotype was practically absent in the oldest age group (> 80 years), and that it was associated with shorter telomeres in other age groups. The A2A2 genotype, on the contrary, predominated in the older age category and it was associated with longer telomeres (Smirnova et al., 2012).

In the future, we hope to measure the activity of telomerase in all Ss involved into our study, and to detect the methylation level of the 5-HTR2A gene, since it is associated with accelerated aging.

The results obtained by now would allow to take into account genetic resistance to long-term stress when screening candidate for definite types of education and employment, which implies the conditions of long unavoidable stress.

Acknowledgments

The present study was supported by the Russian Foundation for Basic Research, grant 16-06-00172а.

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