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May 24, 2016

Gene at Nexus of Mood, Stress, and Longevity

  • Studies that zigged and zagged between worms and humans have uncovered several genes linked to mood- and stress-modulated longevity. One gene in particular, ANK3, is associated with mood and stress disorders as well as accelerated aging, depending on whether it is over- or underexpressed. Versions of the gene occur in both worms and humans.

    ANK3, which has become implicated in recent years in psychiatric disorders, came to the attention of researchers interested in a curious effect exerted by antidepressants. In the nematode worm Caenorhabditis elegans, antidepressants appear to improve longevity.

    Determined to explore the biology behind this effect, researchers based at Indiana University (IU) and The Scripps Research Institute 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. The researchers identified 231 genes whose activities were altered after administration of mianserin and for which there were 347 similar genes in humans.

    Next, the researchers cross-referenced the 347 human genes with a genome analysis of data from 3577 older adults to identify those genes that might be associated with depressive symptoms in humans. This portion of the investigation revealed an overlap of 134 genes.

    To narrow the field of potentially relevant genes yet further, the researchers used a functional genomics approach and sifted through comprehensive databases of human and animal model genetic and gene expression studies in psychiatric disorders. Once this exercise was completed, the researchers identified the top-scoring gene—ANK3.

    These investigations, and subsequent validation efforts, were detailed May 24 in the journal Molecular Psychiatry, in an article entitled, “Mood, Stress and Longevity: Convergence on ANK3.” The article’s senior author is Alexander B. Niculescu III, M.D., Ph.D., professor of psychiatry and medical neuroscience at the IU School of Medicine.

    “To validate our findings, we conducted genetic and gene-expression studies, in C. elegans and in humans," wrote the article’s authors. “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.”

    Essentially, 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.

    The researchers went even further, using more than 700 blood samples from patients diagnosed with psychiatric disorders, as well as studying samples from the Marion County (Indianapolis, IN) 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 toward 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.

    “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,” the study’s authors noted. “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.”

    "We were looking for genes that might be at the interface between mood, stress, and longevity," commented Dr. Niculescu. "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."

    “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,” the study’s authors noted. “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.”

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