Conserved and Tissue-Specific Genic and Physiologic Responses to Caloric Restriction and Altered IGFI Signaling in Mitotic and Postmitotic Tissues

Abstract

Caloric restriction (CR), the consumption of fewer calories without malnutrition, and reduced insulin and/or IGFI receptor signaling delay many age-related physiological changes and extend the lifespan of many model organisms. Here, we present and review microarray and biochemical studies indicating that the potent anticancer effects of CR and disrupted insulin/IGFI receptor signaling evolved as a byproduct of the role of many mitotic tissues as reservoirs of metabolic energy. We argue that the longevity effects of CR are derived from repeated cycles of apoptosis and autophagic cell death in mitotically competent tissues and protein turnover and cellular repair in postmitotic tissues. We review studies showing that CR initiated late in life can rapidly induce many of the benefits of lifelong CR, including its anticancer effects. We also discuss evidence from liver and heart indicating that many benefits of lifelong CR are recapitulated in mitotic and postmitotic tissues when CR is initiated late in life.

Oral Glycotoxins Determine the Effects of Calorie Restriction on Oxidant Stress, Age-Related Diseases, and Lifespan

“…[1][2][3]26 As expected, body weight was lower in CR mice and they maintained normal insulin and GIR levels with aging. [1][2][3][4][5][6][7] In contrast, old CR-high mice had elevated fasting insulin levels and GIRs, consistent with insulin resistance, and they tended to have a higher body weight. Age-related IR in these mice was likely attributable to the increased consumption of oxidants, because their energy intake was restricted, matching that of the CR diet.…”

“…[1][2][3] Calorie restriction (CR), via restriction of food intake, is the principal nongenetic or environmental intervention that prevents these processes and extends lifespan without significant side effects. 4,5 Although the mechanism(s) of CR are complex, the prevention of OS and maintenance of antioxidant reserves are common features. 1,2,6,7 The beneficial effects of lowering OS on lifespan have been shown with anti-oxidant mimetics or genetic models of extended lifespan, ie, loss-of-function mutations of the GH/IGF-1 axis, 8,9 of p66 Shc10 and the FOXO transcription factors, 11 as well as overexpression of catalase.…”

Genes regulated by caloric restriction have unique roles within transcriptional networks

“…The simplest hypothesis is that CR diets promote similar cellular modifications in multiple mammalian tissues, such that extended lifespan is due to a small number of cellular processes that are not tissue-specific. In support of this notion, recent studies have documented gene expression responses to CR that occur in the same fashion across a variety of tissue types, several of which appear related to oxidative stress resistance or tumor suppression (Spindler and Dhahbi, 2007;Swindell, 2008). These "common" responses to CR have been uncovered through the mining of multiple genome-wide microarray datasets.…”

“…Since fundamental mechanisms underlying the mammalian CR response are thought to be shared across taxonomic groups (Sinclair, 2005;Spindler and Dhahbi, 2007), network properties of genes regulated by CR in the Drosophila and C. elegans model systems were also investigated. For this purpose, two independent expression profiling datasets were generated for Drosophila (Drosophila Series A and B), as well as for C. elegans (C. elegans Series A and B).…”

“…This evolutionary view suggests that CR, which is thought to involve conserved and essential pathways, will modulate expression of genes located in dense regions of transcriptional networks. This hypothesis has not been addressed by previous analyses, however, in part because an understanding of which genes have expression patterns consistently associated with CR diets in mammals has begun to emerge only recently (Spindler and Dhahbi, 2007;Swindell, 2008).…”