News Release 13-Apr-2020

Stanford Medicine

A nightly jaunt on the exercise wheel enhances muscle-repair capabilities in old mice, according to a new study by researchers at Stanford School of Medicine.

Only older mice saw this benefit, which the researchers found is due to the rejuvenation of the animals’ muscle stem cells.

“The effect in old animals is very significant,” said Thomas Rando, MD, PhD, professor of neurology and neurological sciences and director of Stanford’s Glenn Center for the Biology of Aging. “We found that regular exercise restores youthfulness to tissue repair. Their muscle stem cells start to look and behave like those of much younger animals.”

The researchers also identified a molecular pathway involved in turning back the clock on the cells. Drugs that manipulate the pathway might be an effective substitute for exercise, they suggest.

Rando is the senior author of the study, which will be published April 13 in Nature Metabolism. Medical student Jamie Brett, PhD, postdoctoral scholar Marina Arjona, PhD, and visiting scholar Mika Ikeda, PhD, are the lead authors.

Unlike embryonic or induced pluripotent stem cells, which can give rise to any tissue in the body, tissue-specific stem cells are restricted in their potential. Muscle stem cells wait in the wings along the muscle fibers in a resting state known as quiescence until called upon to repair damage.

“Studies conducted by us and others have shown that tissue regeneration decreases with age, and that this is due to declining function in adult stem cells,” Rando said. “Many researchers are looking for a way to restore youthfulness.”

Benefits of lifestyle adjustments

While no researchers have discovered a reliable fountain of youth, it’s well known that certain lifestyle adjustments can be beneficial.

“Exercise is known to reduce the risk of a wide variety of age-related problems, including cardiovascular disease, cancer and perhaps even Alzheimer’s disease,” Rando said. “There’s a lot of interest in understanding how exercise confers these health benefits.”

In particular, the researchers wanted to know whether and how voluntary exercise affects the function of muscle stem cells in mice. They gave mice that were about 20 months old, the equivalent of being 60-70 years old in humans, and mice that were 3 to 4 months old, the equivalent of 20- to 30-year-old humans, access to an exercise wheel and allowed them to run at will. Young mice averaged about 10 kilometers each night, and the older mice covered about 5 kilometers. Two other groups of young and old mice were given wheels that didn’t rotate to serve as controls.

“The animals were exercising at the intensity levels at which they were comfortable,” Rando said, “much like what people do for their own health. This is a less stressful situation than resistance training or intense endurance exercise, which may themselves affect muscle stem cell function.” Subsequent analysis showed that the muscle stem cells of the exercising animals remained quiescent, and that the animals did not develop significant numbers of new muscle fibers in response to the exercise.

After three weeks of nightly aerobics for the active groups, the researchers compared the ability of the animals to repair muscle damage. They found that, as expected, the aged, sedentary mice were significantly less able to repair muscle damage than younger sedentary mice. However, the older animals that had exercised regularly were significantly better at repairing muscle damage than were their counterparts that did not exercise. This exercise benefit was not observed in the younger animals.

Similar results were obtained when muscle stem cells from older mice that had exercised were transplanted into younger mice. The stem cells from the exercising animals contributed more to the repair process than did those from their sedentary peers.

Benefit of young blood

The researchers also showed that injecting blood from an old mouse that had exercised into an old mouse that hadn’t conferred a similar benefit in stem cell function, suggesting that exercise simulates the production of some factors that then circulate in the blood and enhance the function of older stem cells.

“That’s really fascinating,” Rando said, noting that the result mirrors those from earlier studies jointly conducted by him and Tony Wyss-Coray, PhD, a professor of neurology and neurological sciences at the School of Medicine, indicating that blood from a young mouse appears to somehow enhance the tissue-specific stem cells in an older animal.

Further studies indicated that the exercise-induced rejuvenation observed by the researchers could be mimicked by increasing the expression of a signaling molecule called cyclin D1, which is involved in rousing resting muscle stem cells in response to damage. The discovery suggests that it may one day be possible to artificially activate this pathway to keep aging muscle stem cells functioning at their youthful best.

“If we could develop a drug that mimics this effect, we may be able to experience the benefit without having to do months of exercise,” Rando said.

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Other Stanford co-authors of the study are Wyss-Coray; instructor Antoine de Morree, PhD; postdoctoral scholars Daniel Benjamin, PhD, and Cristina Rodriguez-Mateo, PhD; visiting scientists Ingrid Egner, PhD, and Luiz Perandini, PhD; lab manager Heather Ishak; research assistant Armon Goshayeshi; graduate student Pieter Both; and former graduate student Michael Betley.

The research was supported by the Stanford’s Medical Science Training Program, the California Institute for Regenerative Medicine, the National Institutes of Health (grants TR01AG047820, P01AG036695, R37AG023806 and R01AR062185), the Glenn Foundation for Medical Research and the Department of Veterans Affairs.

The Stanford University School of Medicine consistently ranks among the nation’s top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://med.stanford.edu/school.html. The medical school is part of Stanford Medicine, which includes Stanford Health Care and Stanford Children’s Health. For information about all three, please visit http://med.stanford.edu.

斯坦福醫學院研究人員的一項新研究顯示，每天晚上在運動輪上進行一次短跑刺激可以增強老年小鼠的肌肉修復能力。
研究人員發現，只有年紀較大的小鼠才能看到這種益處，這是由於動物的肌肉乾細胞恢復了活力。

“對老年動物的影響非常顯著，”神經病學和神經科學教授，斯坦福大學格倫衰老生物學中心主任托馬斯·蘭多博士說。 “我們發現，定期鍛煉可使組織修復恢復青春。他們的肌肉乾細胞開始看起來和表現起來就像年輕的動物一樣。”

研究人員還發現了一條與細胞時鐘逆轉有關的分子途徑。他們認為，操縱這種途徑的藥物可能是運動的有效替代品。
Rando是這項研究的資深作者，該研究將於4月13日發表在《自然新陳代謝》上。醫學生Jamie Brett博士，博士後學者Marina Arjona博士和訪問學者Mika Ikeda博士是主要作者。

與胚胎或誘導性多能幹細胞不同，它可以在體內產生任何組織，而組織特異性幹細胞的潛力受到限制。肌肉乾細胞在靜止的狀態下沿著肌肉纖維在機翼中等待，這種狀態稱為靜止，直到被要求修復損傷為止。

Rando說：“我們和其他人進行的研究表明，組織再生隨著年齡的增長而減少，這是由於成人幹細胞功能下降所致。” “許多研究人員正在尋找一種恢復青春的方法。”

調整生活方式的好處儘管沒有研究人員發現可靠的年輕人源，但眾所周知，某些生活方式的調整可能是有益的。

Rando說：“眾所周知，鍛煉可以降低各種與年齡有關的問題的風險，包括心血管疾病，癌症甚至是阿爾茨海默氏病。” “對運動如何賦予這些健康益處非常感興趣。”

研究人員尤其想知道自願鍛煉是否以及如何影響小鼠肌肉乾細胞的功能。他們給了大約20個月大的老鼠（相當於人類60-70歲）和3到4個月大的老鼠（相當於20至30歲人類）使用了運動輪。並允許他們隨意奔跑。年幼的老鼠平均每晚約10公里，年長的老鼠約5公里。給另外兩組成年和未成年小鼠提供了不會旋轉的輪子作為對照組。

蘭多說：“動物們在舒適的強度水平上運動，就像人們為自身健康所做的事情一樣。”與阻力訓練或激烈的耐力鍛煉相比，這種壓力減輕的程度可能會影響肌肉乾細胞的功能。”隨後的分析表明，運動動物的肌肉乾細胞保持靜止狀態，並且動物在運動後並未發育出大量新的肌肉纖維。

在活動組每晚進行三周有氧運動後，研究人員比較了動物修復肌肉損傷的能力。他們發現，與預期的相比，老年久坐的小鼠修復肌肉損傷的能力明顯低於年輕久坐的小鼠。但是，定期鍛煉的年長動物在修復肌肉損傷方面比不鍛煉的動物好得多。在年幼的動物中未觀察到這種運動益處。
將運動後的老年小鼠的肌肉乾細胞移植到年輕的小鼠中，可以獲得類似的結果。與久坐的同齡人相比，來自運動動物的干細胞對修復過程的貢獻更大。

年輕血液的好處

研究人員還表明，從鍛煉了一隻老老鼠的血液中註入沒有對乾細胞功能產生類似益處的老老鼠，這表明鍛煉模擬了某些因子的產生，然後這些因子在血液中循環並增強了功能較老的干細胞. Rando說：“這真令人著迷。”該結果反映了他和他與醫學院醫學院神經病學和神經科學教授Tony Wyss-Coray博士聯合進行的早期研究的結果，表明年輕老鼠的血液似乎以某種方式增強了老年動物的組織特異性幹細胞。

進一步的研究表明，研究人員觀察到的運動誘導的年輕化可以通過增加一種稱為細胞週期蛋白D1的信號分子的表達來模仿，該信號分子參與喚醒靜息的肌肉乾細胞以應對損傷。這一發現表明，有一天可能會人工激活這一途徑，以使衰老的肌肉乾細胞保持年輕狀態。

蘭多說：“如果我們能夠開發出一種模仿這種作用的藥物，那麼我們可能無需經歷數月的運動就能體驗到這種益處。”
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