Those who can eat as much as they please without gaining avoirdupois may feel smug about a paper in today’s Science, which reports that mice that lack insulin receptors only in their fat tissue outlive their normal brethren by about 18 percent. The paper, by Matthias Blueher, Ronald Kahn, and colleagues at the Joslin Diabetes Center in Boston, Massachusetts, is not directly related to Alzheimer’s, or even neurodegeneration and aging. But it touches sufficiently many threads across these fields to provoke thought by those interested in neurodegeneration and aging. For one, both fat intake and age-related type II diabetes have been linked to AD risk.
The Kahns have made their name in obesity and diabetes research. Here they asked whether caloric restriction, which has long been known to prolong life in different organisms, did so by reducing the metabolic rate associated with digesting food or did so as a consequence of leanness. Speaking for the former, mitochondrial respiration generates reactive oxygen species (ROS), which are widely thought to accelerate aging and are also implicated in Alzheimer’s disease through a variety of pathways including DNA damage, sensitivity to Aβ toxicity, and apoptosis. Speaking for the latter, age-related dysregulation of these complex pathways have also been implicated with longevity and with Alzheimer’s. For example, some researcher are finding that fat intake and age-related obesity increase the risk of developing AD, especially in ApoE4 carriers (see ARF related news story), but see also (see ARF related news story); see Peila et al.).
Insulin and insulin-related signal transduction pathways occur not only in fat but also in liver and muscle. To tease out the role of insulin in fat, Blueher et al. created knockout mice that lack only the fat-specific insulin receptor. These mice developed normally, but had 50 to 70 percent less fat than their normal littermates. Last July, Blueher had reported that these lean mice eat normally-even a tad more relative to body weight than the controls-yet remain free of the age-related obesity and ensuing glucose intolerance and insulin resistance that besets normal lab mice (Blueher et al, 2002) Now, it turns out that the thin mice also hung on to life in the mouse house more tenaciously. At 30 months, only half of the wildtype mice, but 80 percent of the knockouts, were still chowing down, and a quarter of them lived at 36 months when the wildtype mice had all died.
How so? The authors note that fruit flies and roundworms live longer if their mitochondrial respiration is repressed (e.g., Rogina et al., 2000, but see Steve Helfand’s comment below.) At the same time, both flies and worms also have been used to show that reducing insulin signaling increases lifespan (e.g., Kenyon et al., 1993). Of course, the insulin signaling connection is not nearly so simple, as overall insulin resistance is clearly pathologic (causing dwarfism when severe and diabetes when subtle) and shortens life span in mice and humans. This paper suggests that a key to this puzzle might lie in tissue selectivity in such a way that continued normal insulin signaling in muscle and liver, but reduced insulin signaling in fat are the most beneficial, and this is where caloric restriction may act through leanness.—Gabrielle Strobel
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