Research Paper Volume 4, Issue 5 pp 350—358

Figure 3. Low TOR/S6K activity: insulin resistance plus longevity (type 0 diabetes). (A) Severe CR and starvation. Insulin resistance and symptoms of diabetes are observed during starvation [28] and prolong severe CR [55]. Furthermore, CR may reduce rather than enhance insulin effects in the insulin-sensitive dwarf mice [100].

(B) IRS1 knockout. Insulin receptor substrate 1 null mice live longer despite insulin resistance [101].

(C) Klotho mice. Overexpression of Klotho in mice extends life span. Klotho protein represses intracellular signals of insulin and insulin-like growth factor 1 (IGF1), [102]. Also, Klotho interferes with insulin/IGF-like signaling to improve longevity in Caenorhabditis elegans [103].

(D) Chronic treatment with high doses of rapamycin causes insulin resistance and glucose intolerance. This condition can be associated with normal/increased and decreased levels of insulin. Noteworthy, rapamycin induces Klotho [64].