Many candidate biomarkers of human ageing have been proposed in the scientific literature but in all cases their variability in cross-sectional studies is considerable, and therefore no single measurement has proven to serve a useful marker to determine, on its own, biological age. A plausible reason for this is the intrinsic multi-causal and multi-system nature of the ageing process. The recently completed MARK-AGE study was a large-scale integrated project supported by the European Commission. The major aim of this project was to conduct a population study comprising about 3200 subjects in order to identify a set of biomarkers of ageing which, as a combination of parameters with appropriate weighting, would measure biological age better than any marker in isolation.
We compared the DNA-binding activity of transcription factors and gene expression patterns in BJ human diploid fibroblasts (HDFs) expressing or not telomerase (hTERT) in stress-induced premature senescence (SIPS). Senescent BJ cells were also studied. Hydrogen peroxide (H 2 O 2)-induced SIPS modulated gene expression in both BJ and hTERT-BJ1 cells. Increased p21 WAF-1 mRNA level was amongst the common gene expression changes in BJ and hTERT-BJ1 cells induced by SIPS. Telomerase expression markedly changed gene expression in non-stressful conditions. Expression patterns of senescent BJ cells partially overlapped those of BJ and hTERT-BJ1 cells in SIPS. The basal levels of DNA-binding activity of NF-kB and phosphorylated ATF-2 were different in BJ and hTERT-BJ1 cells. Both cell lines displayed a higher DNA-binding activity of p53 and HIF-1 72 h after H 2 O 2 exposure. Our results indicate that similar mechanisms involving p21 WAF-1 and probably p53 are at work in BJ and hTERT-BJ1 HDFs under H 2 O 2-induced SIPS, suggesting that generalized DNA damage rather than telomere length/telomerase plays a crucial role in H 2 O 2-induced SIPS. We propose that H 2 O 2-induced SIPS involves a rearrangement of proliferative and apoptotic pathways. The marked changes in gene expression induced by telomerase suggest that apart from immortalization of HDFs, telomerase also alters the normal cellular functions but does not protect against SIPS.
The ccd operon of the F plasmid contributes to the high stability of the episome by postsegregational killing of plasmid-free bacteria. It contains two genes, ccdA and ccdB, which are negatively autoregulated at the level of transcription, probably by a complex comprising the two gene products. Using the bacterial gyrA462 CcdB resistance mutation and a Pccd-lacZ transcriptional fusion, we have obtained evidence that the CcdB protein by itself has no regulatory activity or operator DNA-binding affinity and needs CcdA in order to effect transcriptional control. The ccd killing mechanism is based on the poison-antidote principle. The CcdB protein is cytotoxic, poisoning DNA-gyrase complexes, while CcdA antagonizes this activity. In order to define functional domains of the CcdA antidote involved in the anti-killer effect, autoregulation or both, we introduced several missense or amber mutations into the CcdA protein by directed mutagenesis. We report on missense CcdA proteins that have lost their autoregulatory properties but are still able to antagonize the lethal activity of CcdB. We show that the five carboxy-terminal amino acid residues of the antidote protein are not required for the antidote effect or for autoregulation. Several missense CcdA polypeptides were generated by suppression of nonsense codons. Two substitutions lead to CcdB-promoted killing: glutamine 33-->cysteine and glutamine 33-->phenylalanine.
Self-rated health (SRH) is one of the most frequently used indicators in health and social research. Its robust association with mortality in very different populations implies that it is a comprehensive measure of health status and may even reflect the condition of the human organism beyond clinical diagnoses. Yet the biological basis of SRH is poorly understood. We used data from three independent European population samples (N approx. 15,000) to investigate the associations of SRH with 150 biomolecules in blood or urine (biomarkers). Altogether 57 biomarkers representing different organ systems were associated with SRH. In almost half of the cases the association was independent of disease and physical functioning. Biomarkers weakened but did not remove the association between SRH and mortality. We propose three potential pathways through which biomarkers may be incorporated into an individual’s subjective health assessment, including (1) their role in clinical diseases; (2) their association with health-related lifestyles; and (3) their potential to stimulate physical sensations through interoceptive mechanisms. Our findings indicate that SRH has a solid biological basis and it is a valid but non-specific indicator of the biological condition of the human organism.
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