DNA-PK and Age-Related Decline in Mitochondrial Function

Researchers here have identified one of the proximate causes of mitochondrial decline with aging. The research is pitched as a path to helping control obesity, as that is where the funding is, sadly, but is much more interesting in the context of aging and reduced mitochondrial function. Beyond the sort of damage to mitochondrial DNA described in the SENS view of aging, later life is accompanied by a more general loss of mitochondrial activity, and that is the context for this research. It is important in most tissues, but especially so in those that require a larger amount of energy to function, such as the brain. Loss of mitochondrial capacity is implicated in all of the common neurodegenerative conditions, for example.

A team of scientists has identified an enzyme that could help in the continuous battle against mid-life obesity and fitness loss. They used mice to test the potentially key role this enzyme plays in obesity and exercise capacity. They administered an inhibitor that blocked the enzyme in one group being fed high-fat foods, but withheld it in another. The result was a 40 percent decrease in weight gain in the group that received the inhibitor. Researchers have known for years that losing weight and maintaining the capacity to exercise tend to get harder beginning between ages 30 to 40 – the start of midlife. Scientists have developed new therapies for obesity, including fat-fighting pills. However, many of those therapies have failed because of a lack of understanding about the biological changes that cause middle-aged people to gain weight, particularly around their abdomen.

Researchers searched for biochemical changes that occurred in middle-aged animals (human equivalent of 45 years). They found that an enzyme called DNA-dependent protein kinase, or DNA-PK, increases in activity with age. Further work showed that DNA-PK promotes conversion of nutrients to fat and decreases the number of mitochondria, tiny organelles in the cells that turn fat into energy to fuel the body. Mitochondria can be found in abundance among young people, but the numbers drop considerably in older people. Researchers know that decreased mitochondria can promote obesity as well as loss of exercise capacity. The researchers theorized that reducing DNA-PK activity may decrease fat accumulation and increase mitochondria number as well as promote fat burning. The researchers tested their theory by orally administering a drug that inhibits DNA-PK and found that, in addition to preventing weight gain in the mice, the inhibitor drug boosted mitochondrial content in skeletal muscle, increased aerobic fitness in obese and middle aged mice, and reduced the incidence of obesity and type-2 diabetes. The study opens the door to the development of a new type of weight-loss medication that could work by inhibiting DNA-PK activity, however DNA-PK inhibitors have yet to be tested this way in humans.

Link: http://bit.ly/2qy8X6g



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