威尔康奈尔大学医学研究人员的一项最新研究表明,一种与人类超常寿命有关的基因可以保护脑干细胞免受压力的有害影响。
对寿命超过100岁的人的研究表明,许多人都携带FOXO3基因。这一发现促使威尔康奈尔医学院病理学和实验医学副教授Jihye Paik博士和她的同事们研究了该基因在衰老过程中如何促进大脑健康。
2018年,Paik博士和她的研究小组发现,大脑中缺乏FOXO3基因的老鼠无法应对大脑中的应激状态,从而导致脑细胞逐渐死亡。他们发表在1月28日的《自然通讯》杂志上的新研究,揭示了FOXO3通过阻止干细胞分裂来保持大脑的再生能力,直到环境支持新细胞的生存为止。
“干细胞产生新的脑细胞,这对我们整个成年期的学习和记忆至关重要。”Paik博士说。“如果干细胞不受控制地分裂,它们就会耗尽。FOXO3基因的作用似乎是阻止干细胞分裂,直到压力过去。”
许多挑战,如炎症、辐射或缺乏足够的营养素,都会给大脑带来压力。但是Paik博士和她的同事专门研究了当脑干细胞暴露于氧化应激时会发生什么,当有害的氧在体内积聚时就会发生氧化应激。“我们了解到FOXO3蛋白直接被氧化应激修饰,”她说。“这种修饰将蛋白质送入干细胞的细胞核,在那里启动应激反应基因。”
原文标题:
1.Inah Hwang, Hiroki Uchida, Ziwei Dai, Fei Li, Teresa Sanchez, Jason W. Locasale, Lewis C. Cantley, Hongwu Zheng, Jihye Paik. Cellular stress signaling activates type-I IFN response through FOXO3-regulated lamin posttranslational modification. Nature Communications, 2021; 12 (1) DOI: 10.1038/s41467-020-20839-0
A gene linked to unusually long lifespans in humans protects brain stem cells from the harmful effects of stress, according to a new study by Weill Cornell Medicine investigators.
Studies of humans who live longer than 100 years have shown that many share an unusual version of a gene called Forkhead box protein O3 (FOXO3). That discovery led Dr. Jihye Paik, associate professor of pathology and laboratory medicine at Weill Cornell Medicine, and her colleagues to investigate how this gene contributes to brain health during aging.
In 2018, Dr. Paik and her team showed that mice who lack the FOXO3 gene in their brain are unable to cope with stressful conditions in the brain, which leads to the progressive death of brain cells. Their new study, published Jan. 28 in Nature Communications, reveals that FOXO3 preserves the brain's ability to regenerate by preventing stem cells from dividing until the environment will support the new cells' survival.
"Stem cells produce new brain cells, which are essential for learning and memory throughout our adult lives," said Dr. Paik, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. "If stem cells divide without control, they get depleted. The FOXO3 gene appears to do its job by stopping the stem cells from dividing until after the stress has passed."
Many challenges like inflammation, radiation or a lack of adequate nutrients can stress the brain. But Dr. Paik and her colleagues looked specifically what happens when brain stem cells are exposed to oxidative stress, which occurs when harmful types of oxygen build up in the body.
"We learned that the FOXO3 protein is directly modified by oxidative stress," she said. This modification sends the protein into the nucleus of the stem cell where it turns on stress response genes.
The resulting stress response leads to the depletion of a nutrient called s-adenosylmethionine (SAM). This nutrient is needed to help a protein called lamin form a protective envelope around the DNA in the nucleus of the stem cell.
"Without SAM, lamin can't form this strong barrier and DNA starts leaking out," she said.
The cell mistakes this DNA for a virus infection, which triggers an immune response called the type-I interferon response. This causes the stem cell to go dormant and stop producing new neurons.
"This response is actually very good for the stem cells because the outside environment is not ideal for newly born neurons," Dr. Paik explained. "If new cells were made in such stressful conditions they would be killed. It's better for stem cells to remain dormant and wait until the stress is gone to produce neurons."
The study may help explain why certain versions of the FOXO3 are linked to extraordinarily long and healthy lives -- they may help people keep a good reserve of brain stem cells. It may also help explain why regular exercise, which boosts FOXO3 helps preserve mental sharpness. But Dr. Paik cautioned it is too early to know whether this new information could be used to create new therapies for brain diseases.
"It could be a double-edged sword," Dr. Paik explained. "Over activating FOXO3 could be very harmful. We don't want to keep this on all the time."
To better understand the processes involved, she and her colleagues will continue to study how FOXO3 is regulated and whether briefly turning it on or off would be beneficial for health.
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