Aging, metabolism, and Alzheimer disease: review and hypotheses.

Relationships are considered among aging, metabolism, and Alzheimer disease (AD). In particular, after 60 years, human populations show progressive age-related trends for increased blood glucose that are concurrent with the accelerating incidence of AD. The accumulation of glycated products in the AD brain, such as is also found in peripheral tissues during diabetes, suggests interactions of AD with age-related changes in metabolism. A review of 13 recent studies on AD and diabetes shows no consensus, although most studies indicate an apparent exclusion of AD and diabetes. We argue that longitudinal studies are needed to evaluate the possibility that an initial age-related hyperglycemic state is reversed by the cachexia and weight loss common to later stages of AD. A review of literature on chronic food restriction in rodents shows the slowing of some aspects of aging in the nervous system and generally supports interactions of peripheral metabolism with brain aging. Finally, we discuss aspects of intermediary metabolism that could ensue from oxidative damage to enzymes by glycation or oxidative stress which include excess production of ammonia from the inhibition of glutamine synthetase and the production of glyceraldehyde-3-phosphate, a glycating agent that could contribute to damage in addition to the hyperglycemic trends during aging.