禁食促進幹細胞的再生能力

研究發現，模仿禁食的藥物治療也可以提供相同的益處

日期：2018年5月3日

資源：麻省理工學院

概要：根據一項新的研究顯示，年齡相關的干細胞功能下降可以通過24小時快速恢復。 生物學家發現禁食能夠顯著提高幹細胞在老齡和年輕小鼠中的再生能力。

Fasting boosts stem cells' regenerative capacity

A drug treatment that mimics fasting can also provide the same benefit, study finds

Date:

May 3, 2018

Source:

Massachusetts Institute of Technology

Summary:Age-related declines in stem cell function can be reversed by a 24-hour fast, according to a new study. Biologists found fasting dramatically improves stem cells' ability to regenerate, in both aged and young mice.

Intestinal stem cells from mice that fasted for 24 hours, at right, produced much more substantial intestinal organoids than stem cells from mice that did not fast, at left.

Credit: Maria Mihaylova and Chia-Wei Cheng

來自右側禁食24小時的小鼠的腸幹細胞比左側未禁食的小鼠的干細胞產生更多的大量腸類器官。

：Maria Mihaylova和Chia-Wei Cheng

隨著人們年齡的增長，他們的腸道幹細胞開始喪失再生能力。 這些幹細胞是所有新腸細胞的來源，因此這種下降可能使得從胃腸道感染或影響腸道的其他疾病中恢復更加困難。

根據麻省理工學院生物學家的一項新研究，這種年齡相關的干細胞功能喪失可以通過24小時的快速恢復。 研究人員發現，禁食能夠顯著提高老齡和年輕小鼠的干細胞再生能力。

在禁食小鼠中，細胞開始分解脂肪酸而不是葡萄糖，這種變化刺激幹細胞變得更加再生。 研究人員發現，他們還可以通過激活相同代謝開關的分子促進再生。 研究人員說，這樣的干預可能有助於老年人從GI感染或接受化療的癌症患者中恢復。

“禁食在腸道中有許多作用，包括促進再生以及在任何類型的疾病如感染或癌症等疾病中的潛在用途，”麻省理工學院生物學助理教授Omer Yilmaz說。科赫綜合癌症研究所，以及該研究的高級作者之一。 “了解禁食如何改善整體健康狀況，包括成體幹細胞在腸道再生，修復和衰老中的作用，這是我實驗室的根本利益。”

麻省理工學院生物學教授，懷特黑德生物醫學研究所成員戴維薩巴蒂尼也是該論文的高級作者，該論文出現在5月3日的“ 細胞幹細胞”雜誌上 。

Sababini說：“這項研究提供了證據表明禁食誘導腸道幹細胞的代謝開關，從利用碳水化合物到燃燒脂肪。” “有趣的是，將這些細胞轉變為脂肪酸氧化可顯著增強其功能，該途徑的藥理學靶向可能為改善年齡相關病變中的組織穩態提供治療機會。”

該論文的主要作者是懷特黑德研究所博士後瑪麗亞Mihaylova和科赫研究所博士後鄭嘉偉。

促進再生

數十年來，科學家們已經知道低熱量攝入與人類和其他生物的壽命延長有關。 耶爾馬茲和他的同事有興趣探索空腹在分子水平上，特別是在腸道中的作用。

腸道幹細胞負責維持腸道內層，通常每五天更新一次。 當發生損傷或感染時，幹細胞是修復任何損傷的關鍵。 隨著年齡的增長，這些腸道幹細胞的再生能力下降，因此腸道恢復需要更長的時間。

“腸道幹細胞是腸道的主要動力，可產生更多的干細胞和腸道內各種分化細胞類型。值得注意的是，在衰老過程中，腸道幹細胞功能下降，這會損害腸道修復自身的能力在損壞後，“耶爾馬茲說。 “在這一系列的調查中，我們重點了解24小時快速增強年輕和老年腸道幹細胞的功能。”

小鼠禁食24小時後，研究人員將腸道幹細胞移出並在培養皿中生長，使他們能夠確定細胞是否會產生被稱為類風濕菌的“小腸”。

研究人員發現，禁食小鼠的干細胞使其再生能力增加了一倍。

Mihaylova說：“禁食對腸腺隱窩形成更多類器官的能力影響非常明顯，這是乾細胞驅動的。 “這是我們在年輕小鼠和老年小鼠中都看到的，我們真的很想了解推動這一過程的分子機制。”

代謝開關

包括對禁食小鼠的干細胞的信使RNA進行測序的進一步研究揭示，禁食誘導細胞從它們通常的代謝轉換，所述代謝將碳水化合物如醣類燃燒為代謝脂肪酸。 這種轉換通過稱為PPAR的轉錄因子的激活而發生，其開啟了參與代謝脂肪酸的許多基因。

研究人員發現，如果他們關閉這條路，禁食不能再促進再生。 他們現在計劃研究這種代謝開關如何激髮乾細胞來提高其再生能力。

他們還發現，通過用模擬PPARs作用的分子治療小鼠，他們可以重現禁食的有益作用。 “這也非常令人驚訝，”鄭說。 “只要激活一種代謝途徑就足以逆轉某些年齡表型。”

研究結果表明，藥物治療可以刺激再生，而不需要患者禁食，這對大多數人來說是困難的。 一個可以從這種治療中受益的組是接受化療的癌症患者，這經常傷害腸細胞。 它也可以使那些經歷腸道感染或其他腸胃疾病的老年人受益，這些疾病會損害腸道內壁。

研究人員計劃探索這些治療的潛在效果，他們也希望研究禁食是否會影響其他類型組織中乾細胞的再生能力。

來源：

材料由麻省理工學院提供。  

As people age, their intestinal stem cells begin to lose their ability to regenerate. These stem cells are the source for all new intestinal cells, so this decline can make it more difficult to recover from gastrointestinal infections or other conditions that affect the intestine.

This age-related loss of stem cell function can be reversed by a 24-hour fast, according to a new study from MIT biologists. The researchers found that fasting dramatically improves stem cells' ability to regenerate, in both aged and young mice.

In fasting mice, cells begin breaking down fatty acids instead of glucose, a change that stimulates the stem cells to become more regenerative. The researchers found that they could also boost regeneration with a molecule that activates the same metabolic switch. Such an intervention could potentially help older people recovering from GI infections or cancer patients undergoing chemotherapy, the researchers say.

"Fasting has many effects in the intestine, which include boosting regeneration as well as potential uses in any type of ailment that impinges on the intestine, such as infections or cancers," says Omer Yilmaz, an MIT assistant professor of biology, a member of the Koch Institute for Integrative Cancer Research, and one of the senior authors of the study. "Understanding how fasting improves overall health, including the role of adult stem cells in intestinal regeneration, in repair, and in aging, is a fundamental interest of my laboratory."

David Sabatini, an MIT professor of biology and member of the Whitehead Institute for Biomedical Research, is also a senior author of the paper, which appears in the May 3 issue of Cell Stem Cell.

"This study provided evidence that fasting induces a metabolic switch in the intestinal stem cells, from utilizing carbohydrates to burning fat," Sabatini says. "Interestingly, switching these cells to fatty acid oxidation enhanced their function significantly. Pharmacological targeting of this pathway may provide a therapeutic opportunity to improve tissue homeostasis in age-associated pathologies."

The paper's lead authors are Whitehead Institute postdoc Maria Mihaylova and Koch Institute postdoc Chia-Wei Cheng.

Boosting regeneration

For many decades, scientists have known that low caloric intake is linked with enhanced longevity in humans and other organisms. Yilmaz and his colleagues were interested in exploring how fasting exerts its effects at the molecular level, specifically in the intestine.

Intestinal stem cells are responsible for maintaining the lining of the intestine, which typically renews itself every five days. When an injury or infection occurs, stem cells are key to repairing any damage. As people age, the regenerative abilities of these intestinal stem cells decline, so it takes longer for the intestine to recover.

"Intestinal stem cells are the workhorses of the intestine that give rise to more stem cells and to all of the various differentiated cell types of the intestine. Notably, during aging, intestinal stem function declines, which impairs the ability of the intestine to repair itself after damage," Yilmaz says. "In this line of investigation, we focused on understanding how a 24-hour fast enhances the function of young and old intestinal stem cells."

After mice fasted for 24 hours, the researchers removed intestinal stem cells and grew them in a culture dish, allowing them to determine whether the cells can give rise to "mini-intestines" known as organoids.

The researchers found that stem cells from the fasting mice doubled their regenerative capacity.

"It was very obvious that fasting had this really immense effect on the ability of intestinal crypts to form more organoids, which is stem-cell-driven," Mihaylova says. "This was something that we saw in both the young mice and the aged mice, and we really wanted to understand the molecular mechanisms driving this."

Metabolic switch

Further studies, including sequencing the messenger RNA of stem cells from the mice that fasted, revealed that fasting induces cells to switch from their usual metabolism, which burns carbohydrates such as sugars, to metabolizing fatty acids. This switch occurs through the activation of transcription factors called PPARs, which turn on many genes that are involved in metabolizing fatty acids.

The researchers found that if they turned off this pathway, fasting could no longer boost regeneration. They now plan to study how this metabolic switch provokes stem cells to enhance their regenerative abilities.

They also found that they could reproduce the beneficial effects of fasting by treating mice with a molecule that mimics the effects of PPARs. "That was also very surprising," Cheng says. "Just activating one metabolic pathway is sufficient to reverse certain age phenotypes."

The findings suggest that drug treatment could stimulate regeneration without requiring patients to fast, which is difficult for most people. One group that could benefit from such treatment is cancer patients who are receiving chemotherapy, which often harms intestinal cells. It could also benefit older people who experience intestinal infections or other gastrointestinal disorders that can damage the lining of the intestine.

The researchers plan to explore the potential effectiveness of such treatments, and they also hope to study whether fasting affects regenerative abilities in stem cells in other types of tissue.

Story Source:

Materials provided by Massachusetts Institute of Technology. Note: Content may be edited for style and length.

Journal Reference:

1. Maria M. Mihaylova, Chia-Wei Cheng, Amanda Q. Cao, Surya Tripathi, Miyeko D. Mana, Khristian E. Bauer-Rowe, Monther Abu-Remaileh, Laura Clavain, Aysegul Erdemir, Caroline A. Lewis, Elizaveta Freinkman, Audrey S. Dickey, Albert R. La Spada, Yanmei Huang, George W. Bell, Vikram Deshpande, Peter Carmeliet, Pekka Katajisto, David M. Sabatini, Ömer H. Yilmaz. Fasting Activates Fatty Acid Oxidation to Enhance Intestinal Stem Cell Function during Homeostasis and Aging. Cell Stem Cell, 2018; 22 (5): 769 DOI: 10.1016/j.stem.2018.04.001