Stress Shortens Life




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In today’s increasingly high-paced world, stress has become part and parcel of our lives. It is well-known that chronic stress and depression are detrimental to our well-being and we are often able to tell its physical manifestation in a loved one or close friend. Can we take that one step further and claim that stress affects how long we live?

To this end, researchers have demonstrated recently for the first time that higher level of stress and depression is linked to accelerated aging from a genetic perspective.

The findings in the studies described herein came about from extensive investigations of both C. elegans worms and human cohorts. For the first time, scientists were able to identify a number of genes that appeared to be linked to mood and stress disorders as well as lifespan. This suggests that this group of genes could be at the interface between longevity, stress and our mood. In particular, the expression of a gene called ANK3 appeared to be correlated with our lifespan to some extent.

The following downstream analyses of these genes first revealed that their expression changed with age. More intriguingly, for people who had severe mood disorders and/or were subjected to extreme life stressors (including suicide), there was a marked change in the expression patterns of a series of genes that were also associated with reduced lifespans as well as premature ageing.

It is known the rate of aging is dependent on various environmental factors. Here, the foray into identifying “stress/longevity genes” was started in C. elegans, a model organism that is commonly used in biomedical research. It was earlier reported that when C. elegans were exposed to the drug mianserin (an antidepressant used in the treatment of psychiatric disorders), there was a significant increase in the lifespan of the worms.

Using bioinformatics analyses, it was subsequently found that there were alterations in 241 genes after mianserin administration in C. elegans. Furthermore, when compared to humans, 347 similar genes in humans were identified. The 347 human genes were in turn compared with a genome-wide dataset from 3,577 older adults. From this analysis, 134 overlapping genes possibly associated with depression were found. The top gene from these 134 genes was ANK3, a gene discovered in recent years to be linked to mental disorders.

On the basis of these findings, the scientists then went back to the C. elegans worm model. Here, they generated worms with mutated forms of the ANK3 gene that were inactive. This was followed by subjecting the worms to mianserin and oxidative stress. It was found that ANK3 expression was positively correlated with age. At the same time, mianserin was reported to be able to maintain lower (and “younger”) ANK3 expression levels, though some level of ANK3 was still needed for a long lifespan. This suggested that ANK3 levels can neither be too high nor too low for longevity.

In addition to investigating worm models, the scientists also took more than 700 blood samples from patients who had psychiatric disorders as well as samples from people who had committed suicide. In corroboration with the findings from C. elegans, the scientists found that there was also a higher level of ANK3 in older patients and a shift towards increased ANK3 expression in suicide samples. Furthermore, independent studies have also revealed significantly higher ANK3 expression in patients with Hutchinson-Gilford progeria syndrome, a disease which results in an accelerated rate of ageing.

A series of biomarkers were then generated by adding in the other genes that scored almost as high as ANK3, and similar results were obtained, especially in the samples from people who committed suicide. Importantly, mitochondrial dysfunction was found to be significantly linked to the candidate genes for stress and mood-regulated longevity. This is not surprising given increasing evidence over the past few years for a potential link between old age and mitochondrial dysfunction.

Notably, some of the genes identified in the described study were changed in an opposite direction in relation to a long lifespan in contrast to previous findings on Alzheimer’s disease. This implies that the treatment of stress and mood related disorders in early life could affect the onset of Alzheimer’s disease in later life.

Another interesting highlight of this study is that many of the top genes from this study were changed in an opposite direction in longevity when the gene expression patterns were compared with samples from people who committed suicide from earlier work. In this regard, it is possible this could be indicative of the evolution of a “life switch”, which is in turn modulated by mood and stress levels.

Additionally, analyses conducted also revealed a number of compounds which could act on the identified genes and hence potentially increase lifespan. These included compounds such as vitamin D and the omega-3 fatty acid DHA, as well as certain drugs that are currently in use, including rapamycin and estrogen-like compounds.

In summary, the studies described herein identify a potential role of ANK3 and other genes in mood, stress and longevity. More importantly, these genes could act as effective biomarkers for age and in so doing possibly become putative drug targets in the treatment and management of related diseases. This could give rise to numerous applications and the hope is that these pioneer studies will one day translate into improved health for people around the world.

References

Le-Niculescu, H., Kurian, S., Yehyawi, N., Dike, C., Patel, S., Edenberg, H., Tsuang, M., Salomon, D., Nurnberger, J., & Niculescu, A. (2008). Identifying blood biomarkers for mood disorders using convergent functional genomics Molecular Psychiatry, 14 (2), 156-174 DOI: 10.1038/mp.2008.11

Niculescu, A., Levey, D., Phalen, P., Le-Niculescu, H., Dainton, H., Jain, N., Belanger, E., James, A., George, S., Weber, H., Graham, D., Schweitzer, R., Ladd, T., Learman, R., Niculescu, E., Vanipenta, N., Khan, F., Mullen, J., Shankar, G., Cook, S., Humbert, C., Ballew, A., Yard, M., Gelbart, T., Shekhar, A., Schork, N., Kurian, S., Sandusky, G., & Salomon, D. (2015). Understanding and predicting suicidality using a combined genomic and clinical risk assessment approach Molecular Psychiatry, 20 (11), 1266-1285 DOI: 10.1038/mp.2015.112

Rangaraju, S., Solis, G., Thompson, R., Gomez-Amaro, R., Kurian, L., Encalada, S., Niculescu, A., Salomon, D., & Petrascheck, M. (2015). Suppression of transcriptional drift extends lifespan by postponing the onset of mortalityeLife, 4 DOI: 10.7554/eLife.08833

Rangaraju, S., Levey, D., Nho, K., Jain, N., Andrews, K., Le-Niculescu, H., Salomon, D., Saykin, A., Petrascheck, M., & Niculescu, A. (2016). Mood, stress and longevity: convergence on ANK3 Molecular Psychiatry DOI: 10.1038/mp.2016.65

Rueckert, E., Barker, D., Ruderfer, D., Bergen, S., O’Dushlaine, C., Luce, C., Sheridan, S., Theriault, K., Chambert, K., Moran, J., Purcell, S., Madison, J., Haggarty, S., & Sklar, P. (2012). Cis-acting regulation of brain-specific ANK3 gene expression by a genetic variant associated with bipolar disorder Molecular Psychiatry, 18 (8), 922-929 DOI: 10.1038/mp.2012.104

Image via MasimbaTinasheMadondo / Pixabay.

Viatcheslav Wlassoff, PhD

Viatcheslav Wlassoff, PhD, is a scientific and medical consultant with experience in pharmaceutical and genetic research. He has an extensive publication history on various topics related to medical sciences. He worked at several leading academic institutions around the globe (Cambridge University (UK), University of New South Wales (Australia), National Institute of Genetics (Japan). Dr. Wlassoff runs consulting service specialized on preparation of scientific publications, medical and scientific writing and editing.
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