Summary: Researchers have identified a series of genes that could modulate the effect of mood and the response to stress on lifespan.
Source: Indiana University.
The visible impacts of depression and stress that can be seen in a person’s face, and contribute to shorter lives, can also be found in alterations in genetic activity, according to newly published research.
In a series of studies involving both C. elegans worms and human cohorts, researchers from the Indiana University School of Medicine and the Scripps Research Institute have identified a series of genes that may modulate the effects of good or bad mood and response to stress on lifespan. In particular, the research pointed to a gene known as ANK3 as playing a key role in affecting longevity. The research was published May 24, 2016 in the journal Molecular Psychiatry.
“We were looking for genes that might be at the interface between mood, stress and longevity”, said Alexander B. Niculescu III, M.D., Ph.D., professor of psychiatry and medical neuroscience at the IU School of Medicine. “We have found a series of genes involved in mood disorders and stress disorders which also seem to be involved in longevity.
“Our subsequent analyses of these genes found that they change in expression with age, and that people subject to significant stress and/or mood disorders, such as people who completed suicide, had a shift in expression levels of these genes that would be associated with premature aging and reduced longevity” said Dr. Niculescu, who is also attending psychiatrist and research and development investigator at the Indianapolis Veterans Affairs Medical Center.
The research began with studies in C. elegans, a worm widely used in life sciences research. An earlier study by one of the study co-authors, Michael Petrascheck, Ph.D., of the Scripps Research Institute, found that exposing C. elegans to the antidepressant mianserin, which is used to treat mood and stress disorders, extended the animal’s lifespan.
In the Molecular Psychiatry study, the researchers methodically conducted a series of analyses to discover, prioritize,
In C. elegans, 241 genes were identified whose activities were altered after administration of mianserin and for which there were 347 similar genes in humans.
The 347 human genes were cross-referenced with a genome analysis of data from 3,577 older adults to identify those genes that might be associated with depressive symptoms in humans, resulting in 134 genes that overlapped.
The 134 genes were prioritized for involvement in mood disorders and stress disorders, using the Niculescu lab’s Convergent Functional Genomics approach and comprehensive databases of human and animal model genetic and gene expression studies in psychiatric disorders. The top scoring gene from the list was ANK3, which in recent years has become well known as playing a role in psychiatric disorders.
Returning to the C. elegans model, the researchers tested the effects of mianserin and of oxidative stress on worms with mutated — and therefore inactive — versions of the ANK3 gene, compared to non-mutated wild-type worms. ANK3 expression increases with age in worms. Mianserin maintains lower, youthful levels of ANK3 expression, but does require some ANK3 to be present for its effects on longevity. Thus, there seems to be a “Goldilocks” effect.
Next, using more than 700 blood samples from patients diagnosed with psychiatric disorders, as well as studying samples from the Marion County (Indianapolis, Ind.) Coroner’s office of people who had committed suicide, the investigators found significantly higher levels of expression of ANK3 in older (middle aged) patients than in younger patients, and a shift towards higher ANK3 levels in those who had committed suicide. Higher levels of ANK3 have also been reported independently by others in individuals with Hutchinson-Gilford progeria syndrome, a form of accelerated aging.
Adding genes that had scored nearly as high as ANK3 in the Convergent Functional Genomics analysis to create a panel of biomarkers showed similar but somewhat stronger results, particularly among those who had committed suicide.
Mitochondrial dysfunction was the top biological pathway where the top candidate genes for mood and stress-modulated longevity mapped. Over the last decade, accumulating evidence has suggested a causative link between mitochondrial dysfunction and aging.
A few of the genes identified in this study are changed in opposite direction in longevity compared to previous reports in Alzheimer’s disease, raising the possibility that the treatment of mood and stress disorders earlier in life might have an impact on later life Alzheimer’s disease.
A large number of top genes identified in this study were changed in opposite direction in longevity compared to patterns of expression in suicide revealed by previous studies from the Niculescu group, suggesting the possibility of an evolutionary organismal “life switch”, actively controlled by mood and stress.
Bioinformatics drug repurposing analyses revealed a series of compounds that may act on these genes and promote longevity, such as the relatively innocuous omega-3 fatty acid DHA (docosahexaenoic acid), piracetam, quercetin, vitamin D and resveratrol, along with a series of existing drugs, such as estrogen-like compounds, antidiabetics and rapamycin.
The authors said that “these studies uncover ANK3 and other genes in our dataset as biological links between mood, stress and lifespan, that may be biomarkers for biological age as well as targets for personalized preventive or therapeutic interventions.”
About this neuroscience research article
Additional investigators contributing to the research were Sunitha Rangaraju, Daniel R. Salomon and Michael Petrascheck of the Scripps Research Institute; Daniel F. Levey, Kwangsik Nho, Nitika Jain, Katie Andrews, Helen Le-Niculescu and Andrew J. Saykin of the Indiana University School of Medicine.
Funding: The research was supported by two National Institutes of Health Directors’ New Innovator Awards (1DP2OD007363 and 1DP2OD008398), as well as NIH U19 A1063603, NIH R00 LM011384 and IADC P30 AG010133.
Source: Eric Schoch – Indiana University Image Source: This NeuroscienceNews.com image is in the public domain. Original Research:Abstract for “Mood, stress and longevity: convergence on ANK3” by S Rangaraju, D F Levey, K Nho, N Jain, K D Andrews, H Le-Niculescu, D R Salomon, A J Saykin, M Petrascheck & A B Niculescu in Molecular Psychiatry. Published online May 24 2016 doi:10.1038/mp.2016.65
Cite This NeuroscienceNews.com Article
[cbtabs][cbtab title=”MLA”]Indiana University. “Genes Linked to the Effect of Stress and Mood on Longevity Identified.” NeuroscienceNews. NeuroscienceNews, 24 May 2016. <https://neurosciencenews.com/mood-longevity-genetics-4285/>.[/cbtab][cbtab title=”APA”]Indiana University. (2016, May 24). Genes Linked to the Effect of Stress and Mood on Longevity Identified. NeuroscienceNews. Retrieved May 24, 2016 from https://neurosciencenews.com/mood-longevity-genetics-4285/[/cbtab][cbtab title=”Chicago”]Indiana University. “Genes Linked to the Effect of Stress and Mood on Longevity Identified.” https://neurosciencenews.com/mood-longevity-genetics-4285/ (accessed May 24, 2016).[/cbtab][/cbtabs]
Antidepressants have been shown to improve longevity in C. elegans. It is plausible that orthologs of genes involved in mood regulation and stress response are involved in such an effect. We sought to understand the underlying biology. First, we analyzed the transcriptome from worms treated with the antidepressant mianserin, previously identified in a large-scale unbiased drug screen as promoting increased lifespan in worms. We identified the most robust treatment-related changes in gene expression, and identified the corresponding human orthologs. Our analysis uncovered a series of genes and biological pathways that may be at the interface between antidepressant effects and longevity, notably pathways involved in drug metabolism/degradation (nicotine and melatonin). Second, we examined which of these genes overlap with genes which may be involved in depressive symptoms in an aging non-psychiatric human population (n=3577), discovered using a genome-wide association study (GWAS) approach in a design with extremes of distribution of phenotype. Third, we used a convergent functional genomics (CFG) approach to prioritize these genes for relevance to mood disorders and stress. The top gene identified was ANK3. To validate our findings, we conducted genetic and gene-expression studies, in C. elegans and in humans. We studied C. elegans inactivating mutants for ANK3/unc-44, and show that they survive longer than wild-type, particularly in older worms, independently of mianserin treatment. We also show that some ANK3/unc-44 expression is necessary for the effects of mianserin on prolonging lifespan and survival in the face of oxidative stress, particularly in younger worms. Wild-type ANK3/unc-44 increases in expression with age in C. elegans, and is maintained at lower youthful levels by mianserin treatment. These lower levels may be optimal in terms of longevity, offering a favorable balance between sufficient oxidative stress resistance in younger worms and survival effects in older worms. Thus, ANK3/unc-44 may represent an example of antagonistic pleiotropy, in which low-expression level in young animals are beneficial, but the age-associated increase becomes detrimental. Inactivating mutations in ANK3/unc-44 reverse this effect and cause detrimental effects in young animals (sensitivity to oxidative stress) and beneficial effect in old animals (increased survival). In humans, we studied if the most significant single nucleotide polymorphism (SNP) for depressive symptoms in ANK3 from our GWAS has a relationship to lifespan, and show a trend towards longer lifespan in individuals with the risk allele for depressive symptoms in men (odds ratio (OR) 1.41, P=0.031) but not in women (OR 1.08, P=0.33). We also examined whether ANK3, by itself or in a panel with other top CFG-prioritized genes, acts as a blood gene-expression biomarker for biological age, in two independent cohorts, one of live psychiatric patients (n=737), and one of suicide completers from the coroner’s office (n=45). We show significantly lower levels of ANK3 expression in chronologically younger individuals than in middle age individuals, with a diminution of that effect in suicide completers, who presumably have been exposed to more severe and acute negative mood and stress. Of note, ANK3 was previously reported to be overexpressed in fibroblasts from patients with Hutchinson–Gilford progeria syndrome, a form of accelerated aging. Taken together, these studies uncover ANK3 and other genes in our dataset as biological links between mood, stress and longevity/aging, that may be biomarkers as well as targets for preventive or therapeutic interventions. Drug repurposing bioinformatics analyses identified the relatively innocuous omega-3 fatty acid DHA (docosahexaenoic acid), piracetam, quercetin, vitamin D and resveratrol as potential longevity promoting compounds, along with a series of existing drugs, such as estrogen-like compounds, antidiabetics and sirolimus/rapamycin. Intriguingly, some of our top candidate genes for mood and stress-modulated longevity were changed in expression in opposite direction in previous studies in the Alzheimer disease. Additionally, a whole series of others were changed in expression in opposite direction in our previous studies on suicide, suggesting the possibility of a “life switch” actively controlled by mood and stress.
“Mood, stress and longevity: convergence on ANK3” by S Rangaraju, D F Levey, K Nho, N Jain, K D Andrews, H Le-Niculescu, D R Salomon, A J Saykin, M Petrascheck & A B Niculescu in Molecular Psychiatry. Published online May 24 2016 doi:10.1038/mp.2016.65