Nutritional Geometry Provides Food for Thought

Dietary Restriction extends lifespan in a diverse range of animals, but this often comes at a cost to reproduction. While a number of molecular pathways integral to these relationships have been characterised, we still do not fully understand whether restriction of specific nutrients or calories is responsible. Two recent studies on insects have offered novel insights into this longstanding issue via the application of Nutritional Geometry. This technique promises to significantly advance our understanding of how nutrition influences reproduction and longevity

drr-2 encodes an eIF4H that acts downstream of TOR in diet-restriction-induced longevity of C. elegans

Dietary restriction (DR) results in a robust increase in lifespan while maintaining the physiology of much younger animals in a wide range of species. Here, we examine the role of drr-2 , a DR-responsive gene recently identified, in determining the longevity of Caenorhabditis elegans . Inhibition of drr-2 has been shown to increase longevity. However, the molecular mechanisms by which drr-2 influences longevity remain unknown. We report here that drr-2 encodes an ortholog of human eukaryotic translation initiation factor 4H (eIF4H), whose function is to mediate the initiation step of mRNA translation. The molecular function of DRR-2 is validated by the association of DRR-2 with polysomes and by the decreased rate of protein synthesis observed in drr-2 knockdown animals. Previous studies have also suggested that DR might trigger a regulated reduction in drr-2 expression to initiate its longevity response. By examining the effect of increasing drr-2 expression on DR animals, we find that drr-2 is essential for a large portion of the longevity response to DR. The nutrient-sensing target of rapamycin (TOR) pathway has been shown to mediate the longevity effects of DR in C. elegans . Results from our genetic analyses suggest that eIF4H/DRR-2 functions downstream of TOR, but in parallel to the S6K/PHA-4 pathway to mediate the lifespan effects of DR. Together, our findings reveal an important role for eIF4H/drr-2 in the TOR-mediated longevity responses to DR.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79256/1/ACEL_580_sm_tableS1-3.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/79256/2/j.1474-9726.2010.00580.x.pd

Occupational exposure to inhaled nanoparticles: Are young workers being left in the dust?

Occupational exposure to inhaled nanoparticles (NPs) represents a significant concern for worker health. Adolescent workers may face unique risks for exposure and resulting health effects when compared with adult workers. This manuscript discusses key differences in risks for occupational exposures to inhaled NPs and resulting health effects between young workers and adult workers via an examination of both physiological and occupational setting factors. Previous studies document how adolescents often face distinct and unique exposure scenarios to occupational hazards when compared to adults. Moreover, they also face different and unpredictable health effects because biological functions such as detoxification pathways and neurological mechanisms are still developing well into late adolescence. Early exposure also increases the chances of developing long-latency disease earlier in life. Taken together, adolescents' rapid growth and development encompasses highly dynamic and complex processes. An aggravating factor is that these processes do not necessarily fall in line with legal classifications of adulthood, nor with occupational exposure limits created for adult workers. The differences in exposures and health consequences from NPs on young workers are insufficiently understood. Research is needed to better understand what adolescent-specific mitigation strategies may be most suitable to address these risk factors

Extension of Yeast Chronological Lifespan by Methylamine

Background: Chronological aging of yeast cells is commonly used as a model for aging of human post-mitotic cells. The yeast Saccharomyces cerevisiae grown on glucose in the presence of ammonium sulphate is mainly used in yeast aging research. We have analyzed chronological aging of the yeast Hansenula polymorpha grown at conditions that require primary peroxisome metabolism for growth. Methodology/Principal Findings: The chronological lifespan of H. polymorpha is strongly enhanced when cells are grown on methanol or ethanol, metabolized by peroxisome enzymes, relative to growth on glucose that does not require peroxisomes. The short lifespan of H. polymorpha on glucose is mainly due to medium acidification, whereas most likely ROS do not play an important role. Growth of cells on methanol/methylamine instead of methanol/ammonium sulphate resulted in further lifespan enhancement. This was unrelated to medium acidification. We show that oxidation of methylamine by peroxisomal amine oxidase at carbon starvation conditions is responsible for lifespan extension. The methylamine oxidation product formaldehyde is further oxidized resulting in NADH generation, which contributes to increased ATP generation and reduction of ROS levels in the stationary phase. Conclusion/Significance: We conclude that primary peroxisome metabolism enhanced chronological lifespan of H. polymorpha. Moreover, the possibility to generate NADH at carbon starvation conditions by an organic nitrogen source supports further extension of the lifespan of the cell. Consequently, the interpretation of CLS analyses in yeast should include possible effects on the energy status of the cell.

Life History Response of Mediterranean Fruit Flies to Dietary Restriction

The purpose of this study was to investigate medfly longevity and reproduction across a broad spectrum of diet restriction using a protocol similar to those applied in most rodent studies. Age-specific reproduction and age of death were monitored for 1,200 adult males and 1,200 females, each individually maintained on one of 12 diets from ad libitum to 30% of ad libitum. Diet was provided in a fixed volume of solution that was fully consumed each day, ensuring control of total nutrient consumption for every fly. Contrary to expectation and precedence, increased longevity was not observed at any level of diet restriction. Among females, reproduction continued across all diet levels despite the cost in terms of increased mortality. Among males, life expectancy exceeded that of females at most diet levels. However, in both sexes, mortality increased more sharply and the pattern of survival changed abruptly once the diet level fell to 50% of ad libitum or below, even though the energetic demands of egg production has no obvious counterpart in males. We believe that a more complete picture of the life table response to dietary restriction will emerge when studies are conducted on a wider range of species and include both sexes, more levels of diet, and the opportunity for mating and reproduction

The effects of palmitylcarnitine on hepatic fatty acid synthesis and on acetyl CoA carboxylase activity

Depressed rates of fatty acid synthesis from acetate-1-C14 by liver preparations from starved rats were increased approximately 13-fold by addition of (+)-palmitylcarnitine but not by (-)-palmitylcarnitine. In contrast, malonyl-2-C14 CoA incorporation into fatty acids was not decreased by starvation, and it was increased only 30% by (+)-palmitylcarnitine. Partially purified acetyl CoA carboxylase activity was enhanced by either (+)- or (-)-palmitylcarnitine in both the presence and absence of citrate or malonate. Palmityl CoA inhibition could be partially overcome by (+)- or (-)-palmitylcarnitine addition to the isolated enzyme system. A possible role of palmitylcarnitine in the regulation of fatty acid synthesis was discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/33466/1/0000870.pd

Generation and bioenergetic analysis of cybrids containing mitochondrial DNA from mouse skeletal muscle during aging

Mitochondrial respiratory chain defects have been associated with various diseases and normal aging, particularly in tissues with high energy demands including skeletal muscle. Muscle-specific mitochondrial DNA (mtDNA) mutations have also been reported to accumulate with aging. Our understanding of the molecular processes mediating altered mitochondrial gene expression to dysfunction associated with mtDNA mutations in muscle would be greatly enhanced by our ability to transfer muscle mtDNA to established cell lines. Here, we report the successful generation of mouse cybrids carrying skeletal muscle mtDNA. Using this novel approach, we performed bioenergetic analysis of cells bearing mtDNA derived from young and old mouse skeletal muscles. A significant decrease in oxidative phosphorylation coupling and regulation capacity has been observed with cybrids carrying mtDNA from skeletal muscle of old mice. Our results also revealed decrease growth capacity and cell viability associated with the mtDNA derived from muscle of old mice. These findings indicate that a decline in mitochondrial function associated with compromised mtDNA quality during aging leads to a decrease in both the capacity and regulation of oxidative phosphorylation

Protein Reporter Bioassay Systems for the Phenotypic Screening of Candidate Drugs: A Mouse Platform for Anti-Aging Drug Screening

Recent drug discovery efforts have utilized high throughput screening (HTS) of large chemical libraries to identify compounds that modify the activity of discrete molecular targets. The molecular target approach to drug screening is widely used in the pharmaceutical and biotechnology industries, because of the amount of knowledge now available regarding protein structure that has been obtained by computer simulation. The molecular target approach requires that the structure of target molecules, and an understanding of their physiological functions, is known. This approach to drug discovery may, however, limit the identification of novel drugs. As an alternative, the phenotypic- or pathway-screening approach to drug discovery is gaining popularity, particularly in the academic sector. This approach not only provides the opportunity to identify promising drug candidates, but also enables novel information regarding biological pathways to be unveiled. Reporter assays are a powerful tool for the phenotypic screening of compound libraries. Of the various reporter genes that can be used in such assays, those encoding secreted proteins enable the screening of hit molecules in both living cells and animals. Cell- and animal-based screens enable simultaneous evaluation of drug metabolism or toxicity with biological activity. Therefore, drug candidates identified in these screens may have increased biological efficacy and a lower risk of side effects in humans. In this article, we review the reporter bioassay systems available for phenotypic drug discovery

Water- and nutrient-dependent effects of dietary restriction on Drosophila lifespan

Dietary restriction (DR) is a widely conserved intervention leading to lifespan extension. Despite considerable effort, the mechanisms underlying DR remain poorly understood. In particular, it remains unclear whether DR prolongs life through conserved mechanisms in different species. Here, we show that, in the most common experimental conditions, lifespan extension by DR is abolished by providing Drosophila with ad libitum water, without altering food intake, indicating that DR, as conventionally studied in flies, is fundamentally different from the phenomenon studied in mammals. We characterize an alternative dietary paradigm that elicits robust lifespan extension irrespective of water availability, and thus likely represents a more relevant model for mammalian DR. Our results support the view that protein:carbohydrate ratio is the main dietary determinant of fly lifespan. These findings have broad implications for the study of lifespan and nutrition