动物实验,线粒体疾病小鼠 z-bio 2021-10-22 273

　　POLG knockout mice-mitochondrial disease and premature aging mouse models may easily be mistaken for older than their actual age. At nine months of age, they have hair loss, osteoporosis, hearing loss, and infertility. Infertility, heart problems, and weight loss. Although these mice have the disease at birth, they have a "secret weapon" in their teenage years that can delay signs of aging for a period of time.

　　 A new study from the Salk Institute of Biology in the United States shows that a longevity hormone can help these mice (with thousands of mutations in their mitochondria at birth) maintain a balanced metabolism when they are young. This work provides new insights into potential new therapies for human mitochondrial diseases and metabolic diseases. Related research results were published in "PNAS" on June 29. Ronald Evans, senior author of this article and director of the Salk Institute’s Gene Expression Laboratory, said: “These findings can help us understand the links between diet, health and aging, and make it possible for us to analyze these links in a molecular way. Bring new treatments."

　　 When Evans and his collaborators studied these mice, they found that the longevity-promoting endocrine hormone fgf21 was highly active, even though these mice showed signs of accelerated aging. Christopher Wall, the first author of this article and a graduate student in the Evans laboratory, explained: “FGF21 is traditionally regarded as an anti-aging gene, which can be turned on by exercise or diet, and is believed to extend lifespan. However, although these mice have high levels of This hormone, they end up aging prematurely."

　　 In order to explain this paradox, the team discovered that FGF21 can actually help pressurize the mitochondria and reorganize the metabolic state of these mice. In this paper, Evans and his collaborators describe how FGF21 switches tissues with important metabolic functions from burning sugar to burning fat—a fuel that is more easily processed by dysfunctional mitochondria. Michael Downes, a senior researcher at the Salk Institute, said: "In these mice, this worked for a while, but eventually their bodies ran out of burned fat. FGF21 needs some extra fat from the diet to continue. Work.” The research team also found that mice fed a high-fat diet amplify the effects of FGF21, making them completely resistant to diet-induced obesity and many related diseases.

　　Evans said: "Now we believe that turning on FGF21 is an adaptation to help animals maintain their metabolic health. If mice do not have the hormone's ‘spring of youth’, they may age faster."

　　Evans said that this new result has the potential to affect human health in many ways. Elevated levels of FGF21 have previously been observed in patients with mitochondrial diseases. Therefore, increasing dietary fat intake can help reduce mitochondrial stress by helping hormones and help relieve the symptoms of patients. At the same time, these research results show that the use of drugs to slightly stress the mitochondria can activate beneficial FGF21-dependent metabolic changes in patients with obesity and other metabolic diseases.

　　Downes said: "Now, we want to study the interaction between FGF21 and dietary fat in human patients with mitochondrial diseases, and begin to explore how we can manipulate this dynamic in different ways."