Knockout of Ku86 accelerates cellular senescence induced by high NaCl.

NaCl induces DNA breaks, thus leading to cellular senescence. Here we showed that Ku86 deficiency accelerated the high NaCl-induced cellular senescence. We find that 1) high NaCl induces rapid cellular senescence in Ku86 deficient(xrs5) cells, 2) Ku86 deficiency shortens lifespan of C. elegans in high NaCl, and 3) cellular senescence is greatly accelerated in renal inner medullas of Ku86 (-/-) mice. Further, although water balance is known to be compromised in old mice, this occurs at much earlier age in Ku86(-/-) mice. When subjected to mild water restriction, 3 month old Ku86(-/-), but not Ku86(+/+),mice rapidly become dehydrated as evidenced by decrease in body weight, increased production of antidiuretic hormone,increased urine osmolality and decreased urine volume. The deficiency in water balance does not occur in Ku86(+/+)mice until they are much older (14 months). We conclude that Ku86 deficiency accelerates high NaCl(-) induced cellular senescence,particularly in the renal medulla where NaCl normally is high.