Editors' ChoiceAging

Turning back the clock

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Science Translational Medicine  17 May 2017:
Vol. 9, Issue 390, eaan4290
DOI: 10.1126/scitranslmed.aan4290


Increased DNA breaks in aging skeletal muscle activate the DNA-PK pathway, whereas blocking this pathway improves mitochondrial density, physical fitness, body weight, and insulin resistance in mice.

Aging is associated with negative health consequences, including increased adiposity and decreased muscle mass. Although age is a dominant risk factor for numerous common diseases, including coronary artery disease, diabetes, and cancer, the underlying mechanism for the metabolic changes associated with aging is unknown. Park et al. endeavored to understand how metabolism and physical fitness decline with age.

DNA dependent protein kinase (DNA-PK) is an enzyme that is activated by damage to DNA, an occurrence that increases with age. DNA-PK phosphorylates the chaperone protein HSP90α, disrupting the ability of HSP90α to complex with enzymes such as AMP-activated protein kinases (AMPK). AMPK is critical for mitochondrial biogenesis and energy metabolism. The authors demonstrated that DNA double-stranded breaks and phosphorylated (active) DNA-PK were increased dramatically in middle-aged rhesus macaque skeletal muscle cells compared with young muscle cells. They then hypothesized that blocking DNA-PK would result in increased AMPK and protect against the metabolic effects of aging. Severe combined immunodeficiency (SCID) mice, which carry a mutation in DNA-PK, and a highly specific DNA-PK inhibitor were used to test this hypothesis.

Skeletal muscle from middle-aged SCID mice had increased AMPK and preserved mitochondrial density compared with wild-type mice. Treating wild-type mice with the DNA-PK inhibitor NU7441 increased skeletal muscle mitochondrial content by 50%. SCID mice and DNA-PK inhibitor–treated wild-type mice maintained more type 1 muscle fibers in middle age; these fibers are known to increase fat oxidation and resist fatigue, potentially increasing physical fitness. Accordingly, middle-aged SCID mice ran twice the distance of middle-aged wild-type mice in a treadmill running capacity test. SCID mice were resistant to weight gain on high-fat diet and had less body fat than wild-type mice, despite similar food intake. Middle-aged SCID mice did not develop insulin resistance with age, in contrast with wild-type mice. Similarly, wild-type mice treated with the DNA-PK inhibitor had decreased weight gain and decreased insulin resistance.

This study presents a possible mechanism for the deleterious metabolic changes associated with aging. Inhibiting the DNA-PK pathway may ameliorate obesity, insulin resistance, and loss of physical fitness. It is possible that DNA-PK inhibitors may have therapeutic potential in treating the weight gain and decreased exercise capacity common in aging patients.

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