Tissue-specific insulin signaling in the regulation of metabolism and aging.

In mammals, insulin signaling regulates glucose homeostasis and plays an essential role in metabolism, organ growth, development, fertility, and lifespan. The defects in this signaling pathway contribute to various metabolic diseases such as type 2 diabetes, polycystic ovarian disease, hypertension, hyperlipidemia, and atherosclerosis. However, reducing the insulin signaling pathway has been found to increase longevity and delay the aging-associated diseases in various animals, ranging from nematodes to mice. These seemly paradoxical findings raise an interesting question as to how modulation of the insulin signaling pathway could be an effective approach to improve metabolism and aging. In this review, we summarize current understanding on tissue-specific functions of insulin signaling in the regulation of metabolism and lifespan. We also discuss the potential benefits and limitations in modulating tissue-specific insulin signaling pathway to improve metabolism and healthspan.