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  • br Acknowledgments Grant support was provided by the

    2020-01-11


    Acknowledgments Grant support was provided by the Leading Academic Discipline Projects of Shanghai Municipal Education Commission (J5028) (J50201) to Dr. Mi, the China National Science Foundation Project (81072076) to Dr. Mi, the China National Science Foundation Project (31000349) to Dr. Shen, and by the Science and Technology Commission of Shanghai Municipality to Dr. Fei (09zr1417700).
    Main Text DNA-dependent protein kinase (DNA-PK) plays key roles in DNA double-strand break (DSB) repair and V(D)J recombination. DNA-PK is a trimeric complex, composed of DNA-PK catalytic subunit (DNA-PKcs) and DNA binding subunits, Ku70 and Ku80. Ku70 and Ku80 bind to DNA breaks and activate DNA-PKcs kinase activity to initiate DNA repair by nonhomologous end joining (NHEJ) pathway. Knocking out any of the three components in mice causes premature aging and immunodeficiency. Emerging evidence links DNA-PK to functions beyond DSB repair, specifically metabolic regulation. DNA-PK was shown to transcriptionally upregulate genes involved in lipogenesis in response to feeding and insulin signaling (Wong et al., 2009). In the case of glucose deprivation, DNA-PK was shown to promote the activation of AMP-activated protein kinase (AMPK), a crucial MCC950 sodium sensor, to restore energy balance (Amatya et al., 2012). In this issue of Cell Metabolism, Park et al. (2017) demonstrate that during aging in skeletal muscle, increased DSBs lead to constitutive activation of DNA-PK, which in turn downregulates AMPK and promotes functional decline. The mechanism for this unexpected age-promoting effect of DNA-PK involves HSP90α, whose function is to facilitate AMPK folding. DNA-PK phosphorylates HSP90α and decreases its ability to bind AMPK. Decreased AMPK activity in aged skeletal muscle leads to decline of mitochondrial function and reduced fitness. Remarkably, Park et al. (2017) showed that age-associated metabolic decline can be rescued by inhibiting DNA-PK. SCID mice that carry mutation in DNA-PK as well as a tissue-specific knockout of DNA-PKcs increased running speed and endurance of aged animals. Chemical inhibitor of DNA-PK, NU7441, achieved a similar effect. Importantly, the rescue effect was dependent on AMPK, as no beneficial effect of inhibiting DNA-PK was observed in AMPK knockout animals. Dysregulated AMPK is associated with multiple age-related diseases, including type 2 diabetes, cardiovascular diseases, and cancer. Park et al. (2017) found that administration of the DNA-PK inhibitor protected the animals from obesity and type 2 diabetes by activating multiple AMPK targets. These findings are of great importance to the aging field because they uncover a novel mechanism by which accumulation of DNA damage leads to functional decline during aging. The role of DNA damage in aging has been a subject of debate (Campisi and Vijg, 2009). Clearly, artificially increased levels of DNA damage accelerate the aging process; however, whether the basal levels of damage drive age-related functional decline had been unclear. One consequence of DNA damage is accumulation of mutations, which may also impact the functionality of normal tissues (Vijg, 2014) and ultimately lead to cancer. Furthermore, DNA damage may trigger cellular senescence, which contributes to age-related functional decline (Baar et al., 2017). Now, Park et al. (2017) added a new mechanism whereby DNA damage leads to a signaling and metabolic imbalance via inhibition of AMPK. The latter mechanism works in skeletal muscle, but not in the lung. It would be important to test other tissues to understand how universal these effects are. For instance, liver plays a key role in metabolic regulation, and understanding whether DNA damage results in AMPK inhibition in the liver is of great importance. The most remarkable observation made by Park et al. (2017) is that a small molecule inhibitor of DNA-PK improved fitness of the aged mice. Does this mean we should all start taking DNA-PK inhibitors? Perhaps not. Silencing the DNA damage signal to improve cellular metabolism is akin to treating a symptom without addressing the underlying disease. If you have appendicitis, taking a painkiller may let you come to work in the morning, but you still must go to the hospital to receive life-saving treatment. In the case of DNA-PK, the underlying cause is DNA damage and DNA-PK enzyme becomes activated to promote repair of this damage. If the damage is not repaired it may lead to cancer and further functional decline. In this regard, human lifespan is dramatically longer than mouse lifespan while cancer causing mutational events need time to accumulate. A temporary relief from DNA-PK may serve the mouse well since an aged mouse only has a few months left to live. In contrast, aged humans may have a decade or two of life ahead of them, and gaining some improvement in muscle performance while increasing the risk of cancer may not be the best solution.