Mood, stress and longevity: convergence on ANK3

Abstract

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...

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“…The top candidate biomarkers also had prior evidence of involvement in other psychiatric and related disorders (Table S3), providing a molecular underpinning for the possible precursor effects of these disorders in AD. In particular, a majority of them have an overlap with stress (84%), aging (49%) and suicide (75%), consistent with them being part of the effects of stress on aging and the "life switch", as described in a previous study by us [14]. The primary medications used to treat stress disorders are serotonin reuptake inhibitors (SSRIs).…”

“…In the current study, we endeavored to use this comprehensive step-wise approach to identify biomarkers for short-term memory that may have relevance to AD. We conducted our longitudinal studies in psychiatric disorder subjects, a population enriched in memory retention abnormalities, and which may be at increased risk of AD and other aging-related disorders, due at least in part to the effects of stress and depression [13,14]. The subjects had blood gene expression data at multiple testing visits, and were phenotyped at each visit, including with HVLT.…”

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“…The aforementioned transcriptomic study on several major psychiatric disorders also identified genes up-regulated specifically in MDD that are enriched for G protein-coupled receptors, cytokine-cytokine interactions, and hormone activity pathways, which indicate the direct involvement of inflammation and HPA axis dysregulation in depression (33). In another study that investigated the overlap between genes with robust changes in expression caused by the antidepressant Mianserin (a noradrenaline uptake inhibitor) and genes involved in depressive symptoms of an aging non-psychiatric population discovered through a genomewide association (GWAS) approach, the top candidate based on relevance to mood disorders and stress response was identified as ANK3 (54). The protein encoded by ANK3, ankyrin-G, has been found as an critical regulator of synapses and strongly associated with schizophrenia, depression, anxiety disorders, and autism (55,56).…”