High NaCl promotes cellular senescence.

High extracellular NaCl was previously shown to increase the number of DNA breaks in mammalian cells in tissue culture, renal medullary cells in vivo, C. elegans and marine invertebrates. It was also shown to increase reactive oxygen species in renal cells, resulting in oxidation of proteins and DNA. Cellular senescence is a common response to such damage. Therefore, in the present studies we looked for signs of senescence in cells exposed to high NaCl. We find that (1) the rate of proliferation of HeLa cells exposed to high NaCl decreases gradually to the point of arrest, and the cells display signs of senescence, including hypertrophy and increased auto fluorescence. (2) High NaCl accelerates the appearance of senescence in primary mouse embryonic fibroblasts, as measured by senescence-associated beta-galactosidase activity (SA-beta-gal). (3) High NaCl retards growth and markedly decreases the life span of C. elegans, accompanied by features of accelerated aging, such as decreased locomotion and increased number of SA-beta-gal positive cells. (4) Mouse renal medullary cells, which are normally continuously exposed to high NaCl, express increased p16(INK4) (another indicator of senescence) much earlier than do cells in the renal cortex, which has the same level of NaCl as peripheral blood. We conclude that high NaCl accelerates cellular senescence and aging, most likely secondary to the DNA breaks and oxidative damage that it causes.