Once again on rapamycin-induced insulin resistance and longevity: despite of or owing to

Abstract

Calorie restriction (CR), which deactivates the nutrient-sensing mTOR pathway, slows down aging and prevents age-related diseases such as type II diabetes. Compared with CR, rapamycin more efficiently inhibits mTOR. Noteworthy, severe CR and starvation cause a reversible condition known as "starvation diabetes." As was already discussed, chronic administration of rapamycin can cause a similar condition in some animal models. A recent paper published in Science reported that chronic treatment with rapamycin causes a diabetes-like condition in mice by indirectly inhibiting mTOR complex 2. Here I introduce the notion of benevolent diabetes and discuss whether starvation-like effects of chronic high dose treatment with rapamycin are an obstacle for its use as an anti-aging drug.

Figure 1. The norm and type 2 diabetes (simplified schema)

(A) The norm. Insulin and nutrients such as glucose stimulate mTOR, which blocks insulin signaling (feedback loop). (B-C) High mTOR/S6K activity: insulin resistance plus decreased lifespan. (B) Overactivated by nutrients, cytokins, insulin and other hormones, mTOR blocks insulin signaling causing insulin resistance. Nutrients overstimulate beta-cells and insulin is increased. (C) In type II diabetes, beta-cells eventually fail and levels of insulin may be decreased.

Figure 2. Low mTOR/S6K activity: insulin sensitivity plus longevity

(A) Calorie restriction. Deactivation of the nutrient-sensing mTOR pathway results in insulin sensitivity. (B) Knockout of S6K1 in mice abolishes feedback block of insulin signaling, resulting in insulin sensitivity [94]. (C) Decreased levels of growth hormone (GH). In mice, absence of GH or GH receptor leads to a remarkable extension of longevity [95]. GH receptor deficiency is associated with a reduction in pro-aging signaling, cancer, and diabetes in humans [96]. Growth hormone signaling accelerates aging in mammals [97]. Remarkably, growth stimulation promotes cellular aging, when cells cannot proliferate [98, 99]. Thus, the growth promoting pathways such as mTOR are involved in both organismal and cellular aging. (D) Acute treatment with rapamycin. Deactivation of the nutrient-sensing mTOR pathway abolishes a feedback block of insulin signaling, resulting in insulin sensitivity [50].

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].