Dietary restriction (DR) extends lifespan in multiple species. To examine the mechanisms of lifespan extension upon DR, we assayed genome-wide translational changes in Drosophila. A number of nuclear encoded mitochondrial genes, including those in Complex I and IV of the electron transport chain, showed increased ribosomal loading and enhanced overall activity upon DR. We found that various mitochondrial genes possessed shorter and less structured 5′UTRs, which were important for their enhanced mRNA translation. The translational repressor 4E-BP, the eukaryotic translation initiation factor 4E binding protein, was upregulated upon DR and mediated DR dependent changes in mitochondrial activity and lifespan extension. Inhibition of individual mitochondrial subunits from Complex I and IV diminished the lifespan extension obtained upon DR, reflecting the importance of enhanced mitochondrial function during DR. Our results implicate translational regulation of mitochondrial gene expression by 4E-BP which plays an important role in lifespan extension upon DR.

TOR (target of rapamycin) is an evolutionarily conserved nutrient sensing protein kinase that regulates growth and metabolism in all eukaryotic cells. Studies in flies, worms, yeast and mice support the notion that the TOR signaling network plays a pivotal role in modulating aging. TOR is emerging as the most robust mediator of the protective effects of various forms of dietary restriction (DR), which has been shown to extend lifespan and slow the onset of certain age-related diseases across species. Here we discuss how modulating the TOR signaling network slows aging by affecting a number of downstream processes including mRNA translation, autophagy, endoplasmic reticulum (ER) stress signaling, stress responses and metabolism. Identifying the mechanisms by which the TOR signaling network works as a pacemaker of aging is a major challenge in the field and may help identify potential drug targets for age–related diseases thereby facilitating healthful lifespan extension in humans.

Summary Changes in fat content have been associated with dietary restriction (DR), but whether they play a causal role in mediating various responses to DR remains unknown. We demonstrate that upon DR, Drosophila melanogaster shift their metabolism towards increasing both fatty acid synthesis and breakdown, which is required for various responses to DR. Inhibition of fatty acid synthesis or oxidation genes specifically in the muscle tissue inhibited lifespan extension upon DR. Furthermore, DR enhances spontaneous activity of flies which was found to be dependent on the enhanced fatty acid metabolism. This increase in activity was found to be at least partially required for the lifespan extension upon DR. Over-expression of adipokinetic hormone (dAKH), the functional ortholog of glucagon, enhances fat metabolism, spontaneous activity and lifespan. Together, these results suggest that enhanced fat metabolism in the muscle and physical activity play a key role in the protective effects of DR.

. Maternal high-fat diet consumption results in fetal malprogramming predisposing to the onset of metabolic syndrome-like phenotype in adulthood. Am J Physiol Endocrinol Metab 291: E792-E799, 2006. First published May 23, 2006; doi:10.1152/ajpendo.00078.2006.-Chronic consumption of a high-fat (HF) diet by female rats in their postweaning period resulted in significant increases in body weight and plasma levels of insulin, glucose, and triglycerides during pregnancy compared with female rats consuming a standard rodent laboratory chow (LC). On gestational day 21, plasma insulin levels and the insulin secretory response of islets to various secretogogues were significantly increased in HF fetuses. The HF male progeny weaned onto LC (HF/LC) demonstrated increases in body weight from postnatal day 60 onward. In adulthood, HF/LC male rats were significantly heavier than controls, had increased plasma levels of insulin, glucose, free fatty acids, and triglycerides, and demonstrated glucose intolerance. HF/LC male islets secreted increased amounts of insulin in response to low glucose concentrations, but their response to a high glucose concentration was similar to that of LC/LC islets. In another set of experiments, when the male progeny of HF female rats were weaned onto a high-sucrose diet (HF/HSu), their metabolic profile was further worsened. These results indicate that chronic consumption of a HF diet by female rats malprograms the male progeny for glucose intolerance and development of increased body weight in adulthood. The long-term high-fat feeding to female rats employed in this study bears resemblance to the dietary habits in Western societies. The results of this study implicate dietary practices of women in the etiology of the present epidemic of human obesity and related disorders.fat-enriched diet; intrauterine environment; fetal hyperinsulinemia; adult-onset obesity; glucose intolerance OVER THE PAST TWO TO THREE DECADES, the prevalence of obesity has increased steadily and has now reached epidemic proportions in developed countries. In the US alone, more than two-thirds of the adult population have been classified as overweight, with about one-half of them being obese (27). Obesity is a risk factor for the onset of metabolic diseases in adulthood, including type 2 diabetes and cardiovascular diseases (13). More than 80% of people with diabetes are overweight or obese, indicating a close correlation between being overweight and having diabetes (35). It is now recognized that genetics alone cannot explain the unprecedented increase in the number of overweight/obese individuals worldwide. Several environmental factors have been implicated in the etiology of obesity. Hales and Barker (17) coined the term "fetal programming," which was based on data from several epidemiological studies, to demonstrate that metabolic diseases have their origin in early life nutritional experience during gestation and lactation. A nutritional stress/stimulus occurring during the period of fetal development results in adaptiv...

Endogenous circadian clocks orchestrate several metabolic and signaling pathways that are known to modulate lifespan, suggesting clocks as potential targets for manipulation of metabolism and lifespan. We report here that the core circadian clock genes, timeless (tim) and period (per), are required for the metabolic and lifespan responses to DR in Drosophila. Consistent with the involvement of a circadian mechanism, DR enhances the amplitude of cycling of most circadian clock genes, including tim, in peripheral tissues. Mass spectrometry-based lipidomic analysis suggests a role of tim in cycling of specific medium chain triglycerides under DR. Furthermore, overexpression of tim in peripheral tissues improves its oscillatory amplitude and extends lifespan under ad libitum conditions. Importantly, effects of tim on lifespan appear to be mediated through enhanced fat turnover. These findings identify a critical role for specific clock genes in modulating the effects of nutrient manipulation on fat metabolism and aging.