SUMMARY A small molecule that safely mimics the ability of dietary restriction (DR) to delay age-related diseases in laboratory animals is greatly sought after. We and others have shown that resveratrol mimics effects of DR in lower organisms. In mice, we find that resveratrol induces gene expression patterns in multiple tissues that parallel those induced by DR and every-other-day feeding. Moreover, resveratrol-fed elderly mice show a marked reduction in signs of aging including reduced albuminuria, decreased inflammation and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density. However, mice fed a standard diet did not live longer when treated with resveratrol beginning at 12 months of age. Our findings indicate that resveratrol treatment has a range of beneficial effects in mice but does not increase the longevity of ad libitum-fed animals when started mid-life.

The retinoblastoma (Rb) gene was the first tumour suppressor identified. Inactivation of Rb in mice results in unscheduled cell proliferation, apoptosis and widespread developmental defects, leading to embryonic death by day 14.5 (refs 2-4). However, the actual cause of the embryonic lethality has not been fully investigated. Here we show that loss of Rb leads to excessive proliferation of trophoblast cells and a severe disruption of the normal labyrinth architecture in the placenta. This is accompanied by a decrease in vascularization and a reduction in placental transport function. We used two complementary techniques-tetraploid aggregation and conditional knockout strategies-to demonstrate that Rb-deficient embryos supplied with a wild-type placenta can be carried to term, but die soon after birth. Most of the neurological and erythroid abnormalities thought to be responsible for the embryonic lethality of Rb-null animals were virtually absent in rescued Rb-null pups. These findings identify and define a key function of Rb in extra-embryonic cell lineages that is required for embryonic development and viability, and provide a mechanism for the cell autonomous versus non-cell autonomous roles of Rb in development.

Maternal overweight and obesity in pregnancy often result in fetal overgrowth, which increases the risk for the baby to develop metabolic syndrome later in life. However, the mechanisms underlying fetal overgrowth are not established. We developed a mouse model and hypothesized that a maternal high-fat (HF) diet causes up-regulation of placental nutrient transport, resulting in fetal overgrowth. C57BL/6J female mice were fed a control (11% energy from fat) or HF (32% energy from fat) diet for 8 wk before mating and throughout gestation and were studied at embryonic day 18.5. The HF diet increased maternal adiposity, as assessed by fat pad weight, and circulating maternal leptin, decreased serum adiponectin concentrations, and caused a marked increase in fetal growth (+43%). The HF diet also increased transplacental transport of glucose (5-fold) and neutral amino acids (10-fold) in vivo. In microvillous plasma membranes (MVMs) isolated from placentas of HF-fed animals, protein expression of glucose transporter 1 (GLUT1) was increased 5-fold, and protein expression of sodium-coupled neutral amino acid transporter (SNAT) 2 was elevated 9-fold. In contrast, MVM protein expression of GLUT 3 or SNAT4 was unaltered. These data suggest that up-regulation of specific placental nutrient transporter isoforms constitute a mechanism linking maternal high-fat diet and obesity to fetal overgrowth.