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The Effect of Aging on the Chaperone Concentrations in the Hepatic, Endoplasmic Reticulum of Male Rats: The Possible Role of Protein Misfolding Due to the Loss of Chaperones in the Decline in Physiological Function Seen With Age

Departments of ¹ Pharmacology and ² Medicine, and ³ Division of Environmental Health Sciences, University of Minnesota, Minneapolis.
⁴ Research and ⁵ Medicine Services, Veterans Affairs Medical Center, Minneapolis, Minnesota.

Address correspondence to Jordan L. Holtzman, MD, PhD, 4710 Girard Ave. S., Minneapolis, MN 55419. E-mail: holtz003{at}umn.edu

The endoplasmic reticulum (ER) chaperones are highly conserved proteins that catalyze the posttranslational processing of all secretory and membrane proteins. Our studies suggest that chaperone declines are one of the two central defects in Alzheimer's disease. We propose that similar declines in other organ systems underlie the physiological deficits of aging. Rats were maintained in a colony from age 21 days to death. Animals were killed at regular intervals, and hepatic, ER chaperone contents were determined by immunoblotting. ERp55, ERp57, ERp72, BiP, and calnexin constitutive levels declined 30%–50% with age. Calreticulin was unaffected. BiP (also known as GRP78), ERp55, and ERp57 showed marked swings with peaks occurring in midwinter and midsummer. This cyclics declined 73% with age. Considering the role of the ER chaperones in membrane and secretory protein posttranslational processing, these data support the concept that their loss could lead to many of the physiological declines associated with aging.

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