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Senescence is thought to play an important role in the progressive age-related decline in tissue integrity and concomitant diseases, but not much is known about the complex interplay between upstream regulators and downstream effectors. We profiled whole genome gene expression of non-stressed and rotenone-stressed human fibroblast strains from young and oldest old subjects, and measured senescence associated β-gal activity. Microarray results identified gene sets involved in carbohydrate metabolism, Wnt/β-catenin signaling, the cell cycle, glutamate signaling, RNA-processing and mitochondrial function as being differentially regulated with chronological age. The most significantly differentially regulated mRNA corresponded to the p16 gene. p16 was then investigated using qPCR, Western blotting and immunocytochemistry. In conclusion, we have identified cellular pathways that are differentially expressed between fibroblast strains from young and old subjects., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

One of the most conserved methods to significantly increase lifespan in animals is through dietary restriction (DR). The mechanisms by which DR increases survival are controversial but are thought to include improvements in mitochondrial function concomitant with reductions in reactive oxygen species production and alterations in the insulin signalling pathway, resulting in global metabolic adaptation. In order to identify novel genes that may be important for lifespan extension of Brown Norway rats, we compared gene expression profiles from skeletal muscle of 28-month-old animals fed ad libitum or DR diets using whole-genome arrays. Following DR, 426 transcripts were significantly down-regulated whilst only 52 were up-regulated. Included in the up-regulated transcripts were three functionally related previously unidentified DR-regulated genes: Nr4a1, Nr4a2, and Nr4a3. Up-regulation of all three Nr4a receptors was also observed in liver - but not brain - of DR-fed animals. Furthermore, RT-PCR revealed up-regulation of several NR4A transcriptional targets (Ucp-3, Ampk-gamma3, Pgc-1alpha and Pgc-1beta) in skeletal muscle of DR animals. Due to the proposed roles of the NR4A nuclear receptors in sensing and responding to changes in the nutritional environment and in regulating glucose and lipid metabolism and insulin sensitivity, we hypothesise that these proteins may contribute to DR-induced metabolic adaptation.