Senescence in the aging process.

The accumulation of 'senescent' cells has long been proposed to act as an ageing mechanism. These cells display a radically altered transcriptome and degenerative phenotype compared with their growing counterparts. Tremendous progress has been made in recent years both in understanding the molecular mechanisms controlling entry into the senescent state and in the direct demonstration that senescent cells act as causal agents of mammalian ageing. The challenges now are to gain a better understanding of how the senescent cell phenotype varies between different individuals and tissues, discover how senescence predisposes to organismal frailty, and develop mechanisms by which the deleterious effects of senescent cells can be ameliorated

Chemical Biology is.....

Chemical Biology is a relatively new field, and as such is not yet simply or succinctly defined. It includes such a wide range of fundamental problems that this commentary could only include just a few snapshots of potential areas of interest. Overarching themes and selected recent successes and ideas in chemical biology are described to illustrate broadly the scope of the field, but should not be taken as exhaustive. The Chemical Biology Section of Chemistry Central Journal is pleased to receive manuscripts describing research into all and any aspects of the subject

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Therapeutic Opportunities Presented by Modulation of Cellular Senescence

Cellular senescence is a permanent state of growth arrest coupled with profound changes in phenotype that can be triggered by multiple extrinsic or intrinsic stimuli. Senescence is a process-level example of the evolution of ageing mechanisms through antagonistic pleiotropy and plays a primary role in tumour suppression, although evidence is mounting for its involvement in other fundamental physiological processes. Evidence from human premature ageing diseases and from transgenic mice in which it is possible to specifically delete senescent cells is consistent with a model in which the accumulation of senescent cells through the life course is responsible for later life chronic disease and impairment. The removal of senescent cells or their reversion to a phenotypically benign state is thus an important emerging goal of translational medicine. Modern bioinformatic approaches based on text mining have compiled co-mentions of cell senescence and age-related diseases allowing an impartial ranking of the impairments most closely associated with this process. Following this schema, the evidence for the involvement of senescence in several highly ranked pathologies is reviewed, alongside potential methods for the ablation of senescent cells or their reversion to their primary phenotype with polyphenolics or inhibitors of p38 MAP kinase. Lastly, the potential for senescence to act as a barrier to the development of bioartificial organs designed to treat some of these conditions is discussed.</p

Evidence that the mechanism of antibody-catalysed hydrolysis of arylcarbamates can be determined by the structure of the immunogen used to elicit the catalytic antibody

A kinetically homogeneous anti-phosphate catalytic antibody preparation was shown to catalyse the hydrolysis of a series of O-aryl N-methyl carbamates containing various substituents in the 4-position of the O-phenyl group. The specific nature of the antibody catalysis was demonstrated by the adherence of these reactions to the Michaelis–Menten equation, the complete inhibition by a hapten analogue, and the failure of the antibody to catalyse the hydrolysis of the 2-nitrophenyl analogue of the 4-nitrophenylcarbamate substrate. Hammett σ–ρ analysis suggests that both the non-catalysed and antibody-catalysed reactions proceed by mechanisms in which development of the aryloxyanion of the leaving group is well advanced in the transition state of the rate-determining step. This is probably the ElcB (elimination–addition) mechanism for the non-catalysed reaction, but for the antibody-catalysed reaction might be either ElcB or B(Ac)2 (addition–elimination), in which the elimination of the aryloxy group from the tetrahedral intermediate has become rate-determining. This result provides evidence of the dominance of recognition of phenolate ion character in the phosphate hapten in the elicitation process, and is discussed in connection with data from the literature that suggest a B(Ac)2 mechanism, with rate-determining formation of the tetrahedral intermediate for the hydrolysis of carbamate substrates catalysed by an antibody elicited by a phosphonamidate hapten in which phenolate anion character is minimized. The present paper contributes to the growing awareness that small differences in the structure of haptens can produce large differences in catalytic characteristics

Improvement in hydrolytic antibody activity by change in haptenic structure from phosphate to phosphonate with retention of a common leaving-group determinant: evidence for the 'flexibility' hypothesis.

To investigate the hypothesis that decreased hapten flexibility may lead to increased catalytic antibody activity, we used two closely related immunogens differing only in the flexibility of the atomic framework around the structural motif of the haptens, analogous to the reaction centre of the corresponding substrates. Identical leaving-group determinants in the haptens and identical leaving groups in the substrates removed the ambiguity inherent in some data reported in the literature. Anti-phosphate and anti-phosphonate kinetically homogeneous polyclonal catalytic antibody preparations were compared by using carbonate and ester substrates respectively, each containing a 4-nitrophenolate leaving group. Synthetic routes to a new phosphonate hapten and new ester substrate were developed. The kinetic advantage of the more rigid anti-phosphonate/ester system was demonstrated at pH 8.0 by a 13-fold advantage in k(cat)/k(non-cat) and a 100-fold advantage in the proficiency constant, k(cat)/k (non-cat) x K(m). Despite these differences, the pH-dependences of the kinetic and binding characteristics and the results of chemical modification studies suggest closely similar catalytic mechanisms. The possible origin of the kinetic advantage of the more rigid hapten/substrate system is discussed