The Alzheimer's Disease-Diabetes Angle: Inevitable Fate of Aging or Metabolic Imbalance Limiting Successful Aging

Abstract

Modern societies face the increasing burden of agerelated diseases, in particular Alzheimer's disease (AD) and type 2 diabetes (T2D). While numerous epidemiological studies have described the incidence of both diseases in the Western world and extensively defined common environmental risk factors, only little is known on the pathomechanisms linking both diseases [1][2][3]. Thus, it is not yet clear whether both diseases represent the endpoint of aged, exhausted, and dysfunctional cells having reached their maximal life expectancy or whether AD and T2D are the consequences of living in superabundance including excessive food supply, work demands, psychosocial stress, and an excessive sedentary life style [4][5][6][7][8][9]. Evidence for the latter is provided by the fact that high adiposity increases the risk of AD [10][11][12] and T2D [10,13] and implies that the progressive loss of energy balance is one underlying pathomechanism of both diseases.Interestingly, mammalian hibernators such as ground squirrels and hamsters demonstrate comparable and annual recurrent periods of obesity with concomitant insulin resistance and key features of AD such as tau phosphorylation [14,15]. These pathologies, however, are reversed by a time-dependent metabolic shift be- * Corresponding author: Angelika Bierhaus, PhD, Department of Medicine I, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Tel.: +49 6221 564752; Fax: +49 6221 564754; E-mail: angelika bierhaus@med.uni-heidelberg.de.tween carbohydrate-and fat-based metabolism, a delicate balance of kinases and phosphatases and changes in gene expression [15][16][17]. While massive fat depots serve as the main source of metabolic fuel throughout the winter [18], phosphorylation of tau during obligate hibernation seems to be a reversible consequence of hypothermia [19,20]. These changes gradually decrease over a period of months until the animals emerge from hibernation each spring [18]. Thus, fat storage and tau phosphorylation occur predictably on an annual basis, but subsequent fasting depletes fat during the course of winter and ensures that each spring the obese hibernator emerges lean [18]. Another example for a phylogenetic conserved adaptive response to energetic stress is provided by hummingbirds [21], which consume a high sugar diet and seasonally develop hyperglycemia and obesity, which is normalized during the breeding season [21]. Thus, hibernating mammals and hummingbirds provide an extreme example of the utility of accumulating body resources in nutrient-rich times for later use during times of fasting.These observations, however, indicate that mechanisms have to exist that enable cells to re-program their metabolism and maintain accurate energy balance despite repeated situations of excessive energy surplus. Fasting periods might also change and/or normalize gene expression patterns and activate cellular defense mechanisms that protect cells from being impaired by subsequent nutrition supply [18]. Noteworthy, centenarians seem to be eq...

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