动物造模 z-bio 2022-08-10 901

　　POLG knockout mice - a mouse model of mitochondrial disease and premature aging that can easily be mistaken for older than chronological age - had hair loss, osteoporosis, hearing loss, Infertility, heart problems and weight loss. Although the mice were born with the disease, they had a "secret weapon" in their teenage years that delayed the signs of aging for a period of time.

　　A new study from the Salk Institute for Biological Studies shows that a longevity hormone helps these mice, whose mitochondria are born with thousands of mutations, maintain metabolic balance at a young age. This work provides new insights into potential new treatments for mitochondrial and metabolic diseases in humans. The findings were published in the June 29 issue of PNAS.

　　Ronald Evans, senior author of the paper and director of the Salk Institute's Gene Expression Laboratory, said: "These findings help us understand the links between diet, health and aging, and make it possible to dissect these links in a molecular way, ultimately leading to bring new treatments."

　　When Evans and his collaborators studied these mice, they found that the endocrine hormone fgf21, which promotes longevity, was highly active, even though the mice displayed hallmarks of accelerated aging.

　　"FGF21 has traditionally been thought of as an anti-aging gene that can be turned on by exercise or diet and is thought to extend lifespan," explains Christopher Wall, first author of the paper and a graduate student in Evans' lab. "However, although these mice had high levels of This hormone, they end up aging prematurely."

　　To explain this paradox, the team found that FGF21 actually helped pressurize mitochondria and reorganize the metabolic state of these mice. In the paper, Evans and collaborators describe how FGF21 switches tissues with important metabolic functions from burning sugar to burning fat -- a fuel that is more easily handled 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 fat to burn. FGF21 needs some extra fat from the diet to continue Work." The team also found that mice fed a high-fat diet amplified the effects of FGF21, making them fully resistant to diet-induced obesity and many related diseases.

　　"We now believe that turning on FGF21 is an adaptation that helps animals maintain their metabolic health," Evans said. "If mice didn't have this hormone's 'fountain of youth', they might age faster."

　　The new results have the potential to impact human health in a number of ways, Evans said. Elevated levels of FGF21 have previously been observed in patients with mitochondrial disease, so increasing dietary fat intake may help relieve symptoms in patients by helping the hormone reduce stress on mitochondria. At the same time, these findings suggest that mild stress on mitochondria using drugs can activate beneficial FGF21-dependent metabolic shifts in patients with obesity and other metabolic diseases.

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