DNA-PK Promotes the Mitochondrial, Metabolic, and Physical Decline that Occurs During Aging

Abstract

SUMMARY Hallmarks of aging that negatively impact health include weight gain and reduced physical fitness, which can increase insulin resistance and risk for many diseases including type 2 diabetes. The underlying mechanism(s) for these phenomena is poorly understood. Here we report that aging increases DNA breaks and activates DNA-dependent protein kinase (DNA-PK) in skeletal muscle, which suppresses mitochondrial function, energy metabolism and physical fitness. DNA-PK phosphorylates threonines 5 and 7 of HSP90α, decreasing its chaperone function for clients such as AMP-activated protein kinase (AMPK), which is critical for mitochondrial biogenesis and energy metabolism. Decreasing DNA-PK activity increases AMPK activity and prevents weight gain, decline of mitochondrial function and physical fitness in middle aged mice and protects against type 2 diabetes. Therefore, DNA-PK is one of the drivers of the metabolic and fitness decline during aging, which make staying lean and physically fit difficult and increase susceptibility to metabolic diseases.

The role of DNA‐PK in aging and energy metabolism

“…This raises the question as to whether DNA‐PK is really sensing chromosomal breaks for the aging‐related pathways. Although both chromosomal breaks and DNA‐PK activity increase with aging , we cannot conclude that the increase in DNA‐PK activity is mediated solely by chromosomal breaks as DNA‐PK is also activated by ROS independently of chromosomal breaks . This may be relevant because ROS also increases with aging and mitochondria, which are regulated by DNA‐PK (via AMPK), are the main source of ROS production .…”

“…Could a small‐molecule inhibitor of DNA‐PK be an effective fitness enhancer? Indeed, feeding obese and middle‐aged WT mice NU7441 increased the exercise capacity of mice by approximately 60% and 40%, respectively . The metabolic effects of NU7441 were mediated by AMPK as NU7441 did not increase mitochondrial biogenesis in skeletal muscle of or exercise capacity in AMPKα2 KO mice, indicating that the fitness‐enhancing effect of NU7441 requires AMPK.…”

“…As AMPK plays a critical role in mitochondrial biogenesis, increasing DNA‐PK activity at older age may promote mitochondrial loss in skeletal muscle. Indeed, there is a strong inverse correlation between mitochondrial content and DNA‐PK activity in skeletal muscle of middle‐aged rhesus monkeys , and mitochondrial loss does not occur in older SCID mice. In skeletal muscle, activation of AMPK promotes a switch from glycolytic fibers to oxidative fibers .…”

“…Regardless of the nature of the primary defect, inhibiting DNA‐PK may improve insulin sensitivity and protect against type 2 diabetes by activating AMPK and thereby increasing mitochondrial function. Indeed, in mice fed with a high‐fat diet, the inclusion of NU7441 in the food significantly decreased weight gain . Moreover, NU7441 increased both insulin sensitivity and glucose tolerance primarily by increasing glucose uptake in skeletal muscle and adipose tissue.…”

“…The connection between DNA-PK and the functions of HSP90a clients such as LKB1 and AMPK was made when it was discovered that DNA-PK phosphorylates Thr5,7 (T5,7) in HSP90a both in vitro [17] and in vivo [107][108][109]. Thr5,7 phosphorylation decreases HSP90a-client interaction and presumably the folding of these clients [107]. Consistent with the increase in genetic breaks [107,110,111] and DNA-PK activity [107] at older age, T5,7 phosphorylation increased with age in skeletal muscle of both rhesus monkeys and mice (Fig.…”