Litter expansion alters metabolic homeostasis in a sex specific manner.

Nutritional manipulations early in life have been shown to influence growth rate and elicit long lasting effects which in turn has been found to impact lifespan. Therefore, we studied the long-term effects of pre-weaning dietary restriction implemented by litter expansion (4, 6, 8, 10, and 12 pups per dam: LS4, LS6, LS8, LS10, LS12) on male and female C57BL/6J mice. After weaning, these mice were fed ad libitum a commercial lab chow for the 15-month duration of the study. The male mice from large litter size (LS12) were significantly leaner and had reduced total fat mass compared to the normal size litters (LS 6) starting from weaning through to 15 months of age. Male LS10 & 12 mice also showed significant reduction in their fat depot masses at 15 months of age: gonadal, subcutaneous, and brown fat whereas the females did not mimic these findings. At 9 months of age, only male LS12 mice showed improved glucose tolerance and male LS12 mice also showed improved insulin tolerance starting at 5 months of age. In addition, we found that the male LS8, 10 & 12 mice at 15 months of age showed significantly reduced IGF-1 levels in the serum and various other organs (liver, gastrocnemius and brain cortex). Interestingly, the female LS8, 10, 12 mice showed a different pattern with reduced IGF-1 levels in serum, liver and gastrocnemius but not in the brain cortex. Similarly, the litter expanded mice showed sex specific response to levels of FGF21 and adiponectin with only the male mice showing increased FGF21 and adiponectin levels at 15 months of age. In summary, our data show that, litter expansion results in long-lasting metabolic changes that are age and sex dependent with the male mice showing an early and robust response compared to female mice.

Calorie restriction prevents age-related changes in the intestinal microbiota.

The effect of calorie restriction (CR) on the microbiome, fecal metabolome, and colon transcriptome of adult and old male mice was compared. Life-long CR increased microbial diversity and the Bacteroidetes/Firmicutes ratio and prevented the age-related changes in the microbiota, shifting it to a younger microbial and fecal metabolite profile in both C57BL/6JN and B6D2F1 mice. Old mice fed CR were enriched in the Rikenellaceae, S24-7 and Bacteroides families. The changes in the microbiome that occur with age and CR were initiated in the cecum and further modified in the colon. Short-term CR in adult mice had a minor effect on the microbiome but a major effect on the transcriptome of the colon mucosa. These data suggest that CR has a major impact on the physiological status of the gastrointestinal system, maintaining it in a more youthful state, which in turn could result in a more diverse and youthful microbiome.

Is Rapamycin a Dietary Restriction Mimetic?

Since the initial suggestion that rapamycin, an inhibitor of target of rapamycin (TOR) nutrient signaling, increased lifespan comparable to dietary restriction, investigators have viewed rapamycin as a potential dietary restriction mimetic. Both dietary restriction and rapamycin increase lifespan across a wide range of evolutionarily diverse species (including yeast, Caenorhabditis elegans, Drosophila, and mice) as well as reducing pathology and improving physiological functions that decline with age in mice. The purpose of this article is to review the research comparing the effect of dietary restriction and rapamycin in mice. The current data show that dietary restriction and rapamycin have different effects on many pathways and molecular processes. In addition, these interventions affect the lifespan of many genetically manipulated mouse models differently. In other words, while dietary restriction and rapamycin may have similar effects on some pathways and processes; overall, they affect many pathways/processes quite differently. Therefore, rapamycin is likely not a true dietary restriction mimetic. Rather dietary restriction and rapamycin appear to be increasing lifespan and retarding aging largely through different mechanisms/pathways, suggesting that a combination of dietary restriction and rapamycin will have a greater effect on lifespan than either manipulation alone.

Functional fragments of disorder in outer membrane ß barrel proteins.

The traditional view of "sequence-structure-function" has been amended by the discovery of intrinsically disordered proteins. Almost 50% of PDB structures are now known to have one or more regions of disorder, which are involved in diverse functions. These regions typically possess low aromatic content and sequence complexity as well as high net charge and flexibility. In this study, we examined the composition and contribution of intrinsic disorder in outer membrane ß barrel protein functions. Our systematic analysis to find the dual personality (DP) fragments, which often function by disorder-order transitions, revealed the presence of 61 DP fragments with 234 residues in ß barrel trans membrane protein structures. It was found that though the disorder is more prevalent in the periplasmic regions, most of the residues which undergo disorder-order transitions are found in the extracellular regions. For example, the calcium binding sites in BtuB protein are found to undergo disorder to order transition upon binding calcium. The conformational change in the cell receptor binding site of the OpcA protein, which is important in host cell interactions of N. meningitidis, was also found to be due to the disorder-order transitions occurring in the presence of the ligand. The natively disordered nature of DP fragments makes it more appropriate to call them "functional fragments of disorder." The present study provides insight into the roles played by intrinsically disordered regions in outer membrane protein functions.

Intergenics: A tool for extraction of intergenicregions.

For the past one decade, there has been considerable explosion of interest in searching novel regulatory elements in the intergenic region between the protein coding regions. The microbial genomes are the most exploited in terms of intergenic (noncoding) regions due to its less complexity. We think, the increasing pace of genome sequencing calls for a tool which will be useful for the extraction of intergenic regions. IntergenicS (Intergenic Sequence) is a tool which can extract the intergenic regions of microbial genomes at NCBI. All the unannotated regions between annotated protein coding genes and noncoding RNA genes can be extracted. It also deals with the calculation of GC base composition of the intergenic regions. This will be a useful tool for the analysis of noncoding regions of both bacterial and archael genomes.