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 Blood, 15 August 2007, Vol. 110, No. 4, pp. 1334-1342.
Prepublished online as a Blood First Edition Paper on April 24, 2007; DOI 10.1182/blood-2006-11-057232.

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RED CELLS

Effects of age-dependent membrane transport changes on the homeostasis of senescent human red blood cells

Virgilio L. Lew1, Nuala Daw1, Zipora Etzion2, Teresa Tiffert1, Adaeze Muoma1, Laura Vanagas1, and Robert M. Bookchin2

1 Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom; and 2 Department of Medicine, Albert Einstein College of Medicine, Bronx, NY

Little is known about age-related changes in red blood cell (RBC) membrane transport and homeostasis. We investigated first whether the known large variation in plasma membrane Ca2+ (PMCA) pump activity was correlated with RBC age. Glycated hemoglobin, Hb A1c, was used as a reliable age marker for normal RBCs. We found an inverse correlation between PMCA strength and Hb A1c content, indicating that PMCA activity declines monotonically with RBC age. The previously described subpopulation of high-Na+, low-density RBCs had the highest Hb A1c levels, suggesting it represents a late homeostatic condition of senescent RBCs. Thus, the normal densification process of RBCs with age must undergo late reversal, requiring a membrane permeability increase with net NaCl gain exceeding KCl loss. Activation of a nonselective cation channel, Pcat, was considered the key link in this density reversal. Investigation of Pcat properties showed that its most powerful activator was increased intracellular Ca2+. Pcat was comparably selective to Na+, K+, choline, and N-methyl-D-glucamine, indicating a fairly large, poorly selective cation permeability pathway. Based on these observations, a working hypothesis is proposed to explain the mechanism of progressive RBC densification with age and of the late reversal to a low-density condition with altered ionic gradients.


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