Nature子刊:情绪和压力何以影响寿命?
生物通 · 2016/05/27
根据新发表的一项研究表明,抑郁和紧张的影响可能从一个人的脸上看出来,并可能影响寿命,而且还有可能存在于遗传活动的变化中。这项研究发表在5月24日的Nature子刊《Molecular Psychiatry》。


根据新发表的一项研究表明,抑郁和紧张的影响可能从一个人的脸上看出来,并可能影响寿命,而且还有可能存在于遗传活动的变化中。这项研究发表在5月24日的Nature子刊《Molecular Psychiatry》。

在涉及秀丽隐杆线虫和人类群体的一系列研究中,来自印第安纳大学医学院和斯克里普斯研究所的研究人员,确定了一系列的基因,可能调节好/坏情绪和应激反应对寿命的影响。特别是,该研究指出了一个被称为ANK3的基因,在对长寿的影响中发挥着关键的作用。

IU医学院精神病学和医学神经科学教授Alexander B. Niculescu III说:“我们正在寻找,哪些基因可能将情绪、压力和长寿联系在一起。我们已经找到了一系列的基因,参与情绪障碍和压力障碍,这些障碍似乎也与长寿有关。”

Niculescu博士说:“我们后续对这些基因的分析发现,随着年龄的增长它们的表达有所变化,在那些遭受重大压力和/或情绪障碍(如自杀)的人中,与过早衰老和寿命缩短相关的这些基因,其表达水平发生了转变。”

该研究开始于对秀丽隐杆线虫的研究,这种蠕虫广泛应用于生命科学的研究。其中一名作者Michael Petrascheck早前的研究发现,暴露于抗抑郁剂米安色林(用于治疗情绪和压力障碍)的秀丽隐杆线虫,动物的寿命有所延长。相关阅读:科学家相继报道新的“长寿”药;线虫揭开长生不老药的秘密。

在《Molecular Psychiatry》的研究中,研究人员有条不紊地进行了一系列的分析,结果如下:

在秀丽隐杆线虫中,确定了231个基因,在施用米安色林后这些的活性有所变化,人类有347个相似的基因。

将347个人类基因与来自3577名老年人的基因组分析进行相互参照,来识别这些可能与人类抑郁症状有关的基因,从而发现有134个基因重叠。

使用Niculescu实验室的Convergent Functional Genomics方法和综合人类和动物模型在精神疾病方面的遗传和基因表达研究综合数据库,研究人员发现,这134个基因优先参与情绪障碍和压力障碍。列表中最高得分的基因是ANK3,众所周知,近年来它已在精神障碍中扮演一个角色。

回到秀丽隐杆线虫模型,研究人员测试了米安色林和氧化应激对携带ANK3基因突变(因此不活跃)的线虫的影响,并与非突变的野生型线虫进行了对比。在线虫中,随着年龄的增加ANK3表达升高。米安色林保持越低, ANK3表达水平越年轻,但确实需要一些ANK3存在,才能对寿命产生影响。因此,似乎有一种“金发”效应。

接下来,通过使用超过700名精神疾病患者的血液样本,以及研究自杀者的样本。研究人员发现,ANK3在老年人(中年人)患者体内的表达水平明显高于年轻患者,在那些自杀的人当中ANK3的表达水平较高。也有其他研究人员在Hutchinson-Gilford早衰症综合征(加速老化的一种形式)患者中报道过更高水平的ANK3。

在Convergent Functional Genomics中添加得分几乎跟ANK3一样高的基因,以创建一组生物标志物,显示出了相似但有所增强的结果,尤其是在那些自杀者当中。

线粒体功能障碍是最顶级的生物通路,其中情绪和压力调节的长寿相关的候选基因已被定位。在过去的十年里,越来越多的证据表明,线粒体功能障碍和衰老之间有着一种因果联系。

在本研究中确定的几个基因,在长寿中的表达模式,与之前阿尔茨海默氏病中报道的相反,从而提出了一种可能性:在更早期治疗情绪和压力障碍,可能对晚年的阿尔茨海默氏症有影响。

在本研究中确定的大量顶级基因,在长寿中的表达模式,与在Niculescu小组之前发现的自杀者中的方向相反,从而表明可能有一种进化生物的“开关”,受到情绪和压力的主动控制。

生物信息学药物分析分析显示,一系列的化合物可能作用于这些基因并促进长寿,比如相对无害的ω- 3脂肪酸DHA(二十二碳六烯酸)、吡拉西坦、槲皮素、维生素D和白藜芦醇,以及一系列现有的药物,如雌激素样的化合物、抗糖尿病药和雷帕霉素。

作者说:“这些研究,揭示了ANK3和其他基因是情绪、压力和寿命之间的一种联系,可能是生物年龄的生物标记物,以及个性化预防或治疗干预的靶标。”

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  • Mood, stress and longevity: convergence on ANK3

    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.

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