Age-dependent alterations in Ca2+ homeostasis: role of TRPV5 and TRPV6

Aging is associated with alterations in Ca2+ homeostasis, which predisposes elder people to hyperparathyroidism and osteoporosis. Intestinal Ca2+ absorption decreases with aging and, in particular, active transport of Ca2+ by the duodenum. In addition, there are age-related changes in renal Ca2+ handling. To examine age-related changes in expression of the renal and intestinal epithelial Ca2+ channels, control (TRPV5+/+) and TRPV5 knockout (TRPV5-/-) mice aged 10, 30, and 52 wk were studied. Aging of TRPV5(+/+) mice resulted in a tendency toward increased renal Ca2+ excretion and significantly decreased intestinal Ca2+ absorption, which was accompanied by reduced expression of TRPV5 and TRPV6, respectively, despite increased serum 1,25(OH)2D3 levels. Similarly, in TRPV5-/- mice the existing renal Ca2+ loss was more pronounced in elder animals, whereas the compensatory intestinal Ca2+ absorption and TRPV6 expression declined with aging. In both mice strains, aging resulted in a resistance to 1,25(OH)2D3 and diminished renal vitamin D receptor mRNA levels, whereas serum Ca2+ levels remained constant. Furthermore, 52-wk-old TRPV5-/- mice showed severe hyperparathyroidism, whereas PTH levels in elder TRPV5+/+ mice remained normal. In 52-wk-old TRPV5-/- mice, serum osteocalcin levels were increased in accordance with the elevated PTH levels, suggesting an increased bone turnover in these mice. In conclusion, downregulation of TRPV5 and TRPV6 is likely involved in the impaired Ca2+ (re)absorption during aging. Moreover, TRPV5-/- mice likely develop age-related hyperparathyroidism and osteoporotic characteristics before TRPV5+/+ mice, demonstrating the importance of the epithelial Ca2+ channels in Ca2+ homeostasis.