A Genetic Program, not Lifestyle, Dictates Middle-Age Weight Gain

Sung-Jun Park, Oksana Gavrilova, Alexandra L. Brown, Jamie E. Soto, Shannon Bremner, Jeonghan Kim, Xihui Xu, Shutong Yang, Jee-Hyun Um, Lauren G. Koch, Steven L. Britton, Richard L. Lieber, Andrew Philp, Keith Baar, Steven G. Kohama, E. Dale Abel, Myung K. Kim, Jay H. Chung Open ArchivePublished: May 2, 2017; corrected online: July 18, 2017DOI:https://doi.org/10.1016/j.cmet.2017.04.008

Poor lifestyle and laziness have for long been considered the root cause of middle-age weight gain. Yet, there are many people who gain weight as they age in spite of having a good diet and active lifestyle. Now, a recent study shows how a genetic program can cause a decline in our metabolism as we age.

Knowing that mitochondrial biogenesis and function decline in skeletal muscles over time, researchers examined molecular changes in young and old mice as well as rhesus macaque monkeys. Results of their work showed an association between DNA double-stranded breaks and activity of the enzyme, DNA-dependent protein kinase (DNA-PK): ageing increases DNA breaks and phosphorylation of DNA-PK which in turn decreases the chaperone activity of HSP90α and hence mitochondrial biogenesis through AMPK. Inhibition of DNA-PK in obese and middle-aged animals in turn was found to be protective against mitochondrial loss and diabetes, and led to improvements in fitness. Identifying this driver of mitochondrial metabolism not only shifts the blame for weight gain to a genetic program, but also provides a direction for future clinical interventions.