SummaryCaloric restriction (CR) without malnutrition has been shown to retard several aspects of the aging process and to extend lifespan in different species. There is strong interest in the identification of CR mimetics (CRMs), compounds that mimic the beneficial effects of CR on lifespan and healthspan without restriction of energy intake. Identification of CRMs in mammals is currently inefficient due to the lack of screening tools. We have performed whole‐genome transcriptional profiling of CR in seven mouse strains (C3H/HeJ, CBA/J, DBA/2J, B6C3F1/J, 129S1/SvImJ, C57BL/6J, and BALB/cJ) in white adipose tissue (WAT), gastrocnemius muscle, heart, and brain neocortex. This analysis has identified tissue‐specific panels of genes that change in expression in multiple mouse strains with CR. We validated a subset of genes with qPCR and used these to evaluate the potential CRMs bezafibrate, pioglitazone, metformin, resveratrol, quercetin, 2,4‐dinitrophenol, and L‐carnitine when fed to C57BL/6J 2‐month‐old mice for 3 months. Compounds were also evaluated for their ability to modulate previously characterized biomarkers of CR, including mitochondrial enzymes citrate synthase and SIRT3, plasma inflammatory cytokines TNF‐α and IFN‐γ, glycated hemoglobin (HbA1c) levels and adipocyte size. Pioglitazone, a PPAR‐γ agonist, and L‐carnitine, an amino acid involved in lipid metabolism, displayed the strongest effects on both the novel transcriptional markers of CR and the additional CR biomarkers tested. Our findings provide panels of tissue‐specific transcriptional markers of CR that can be used to identify novel CRMs, and also represent the first comparative molecular analysis of several potential CRMs in multiple tissues in mammals.

Dietary fiber has been reported to prevent preneoplastic colon lesions. The aim of this study was to determine the effect of resistant starches, novel dietary fibers, on the development of colonic preneoplasia and Wnt signaling in azoxymethane (AOM)-treated rats and mice fed resistant starches at 55% of the diet after AOM treatment. Another objective was to determine the effect of resistant starches on the development of preneoplasia in rats treated with antibiotics (Ab), administered between AOM treatment and resistant starch feeding. Diets containing resistant starches, high-amylose (HA7), high-amylose-octenyl succinic anhydride (OS-HA7), or high-amylose-stearic acid (SA-HA7) were compared with control cornstarch (CS). The resistant starch content of the diets did not alter the yield of colonic lesions but animals treated with AOM and fed the diet with the highest resistant starch content, SA-HA7 developed the highest average aberrant crypt foci (ACF) per animal. Mice fed the OS-HA7 diet had decreased expression of some upstream Wnt genes in the colonic crypts. This study suggests that further research is needed to determine if resistant starch impacts colon carcinogenesis in rodents.

Dietary resistant starch (RS) has been suggested to reduce colonic neoplasia. To determine the effects of digestion-resistant cornstarch on colonic carcinogenesis and Wnt signaling in azoxymethane (AOM)-treated F344 rats, diets containing naturally occurring RS from corn lines derived partially from Guat209 (GUAT), AR16035 (AR), or a hybrid (ARxGUAT), containing 34.5 ± 2.0, 0.2 ± 0.1, and 1.9 ± 0.1% RS, respectively, were fed at 55% of the diet. GUAT-fed rats had increased cecal content and tissue weight and decreased cecal pH compared with AR- or ARxGUAT-fed rats. Numbers of aberrant crypt foci (ACF) were not different among diet groups. Increased numbers of crypts/focus were observed in AOM-injected rats fed GUAT compared with rats fed other diets. β-catenin mRNA expression of the crypts was significantly increased in GUAT-fed rats injected with AOM relative to those injected with saline. These findings suggest that selected dietary RSs may at some level further enhance colonocyte proliferation and differentiation in an AOM-treated colon.

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