New Insights Into Cardiac Aging

Abstract

All animals have limited life spans, and work in a variety of organisms has established that caloric restriction results in increased longevity. For example, inbred female mice fed an ad libitum diet had an average life span of 27 months, whereas calorie-restricted mice fed a diet with 65% fewer calories had an average life span of 45 months.1 The mechanisms by which caloric restriction retards aging and promotes longevity are likely manifold, but reduced insulin action in various tissues is a well-accepted mechanism of this phenomenon. Indeed, in the nematode Caenorhabditis elegans , a loss-of-function mutation in the insulin receptor-like gene daf-2 significantly promoted longevity.2 In mice, generalized overexpression of the insulin/insulin-like growth factor signaling inhibitor Klotho resulted in animals that had significantly increased longevity and reduced insulin sensitivity.3 In addition, tissue-specific targeted disruption of the insulin receptor gene in the adipose tissue of mice led to significantly increased life span.4 Article see p 1695 Insulin receptor stimulation leads to the activation of the intracellular lipid kinase phosphoinositide 3-kinase (PI3K). A loss-of-function mutation in the age-1 gene that encodes a PI3K also promotes increased longevity in C elegans .5 Activated PI3K that is localized at the internal surface of the plasma membrane generates phopshatidylinositol-3′, 4′, 5′-phosphate (PIP3). PIP3 activates various kinases and ion channels, including phosphatidylinositol-dependent kinase 1, which, in turn, activates Akt family members among other kinases.6,7 A loss-of-function mutation in the C elegans pdk1 gene resulted in significantly increased life span in worms.8 Furthermore, overexpression of pdk-1 relieved the requirement for AGE-1 PI3K signaling. Therefore, caloric restriction, reduced insulin receptor, reduced PI3K, and reduced PDK1 activity all promote longevity in animals, but the role of these manipulations in cardiac aging is unclear. In mammals, pancreatic insulin release in response to caloric …