Extreme Human Longevity Research Articles

Methylation by Set9 modulates FoxO3 stability and transcriptional activity

The FoxO family of transcription factors plays an important role in longevity and tumor suppression by regulating the expression of a wide range of target genes. FoxO3 has recently been found to be associated with extreme longevity in humans and to regulate the homeostasis of adult stem cell pools in mammals, which may contribute to longevity. The activity of FoxO3 is controlled by a variety of post-translational modifications that have been proposed to form a 'code' affecting FoxO3 subcellular localization, DNA binding ability, protein-protein interactions and protein stability. Lysine methylation is a crucial post-translational modification on histones that regulates chromatin accessibility and is a key part of the 'histone code'. However, whether lysine methylation plays a role in modulating FoxO3 activity has never been examined. Here we show that the methyltransferase Set9 directly methylates FoxO3 in vitro and in cells. Using a combination of tandem mass spectrometry and methyl-specific antibodies, we find that Set9 methylates FoxO3 at a single residue, lysine 271, a site previously known to be deacetylated by Sirt1. Methylation of FoxO3 by Set9 decreases FoxO3 protein stability, while moderately increasing FoxO3 transcriptional activity. The modulation of FoxO3 stability and activity by methylation may be critical for fine-tuning cellular responses to stress stimuli, which may in turn affect FoxO3's ability to promote tumor suppression and longevity.

Variations of the angiotensin II type 1 receptor gene are associated with extreme human longevity

Longevity phenotype in humans results from the influence of environmental and genetic factors. Few gene polymorphisms have been identified so far with a modest effect on lifespan leaving room for the search of other players in the longevity game. It has been recently demonstrated that targeted disruption of the mouse homolog of the human angiotensin II type 1 receptor (AT1R) gene (AGTR1) translates into marked prolongation of animal lifespan (Benigni et al., J Clin Invest 119(3):524-530, 2009). Based on the above study in mice, here we sought to search for AGTR1 variations associated to reduced AT1 receptor protein levels and to prolonged lifespan in humans. AGTR1 was sequenced in 173 Italian centenarians and 376 younger controls. A novel non-synonymous mutation was detected in a centenarian. Two polymorphisms in AGTR1 promoter, rs422858 and rs275653, in complete linkage disequilibrium, were significantly associated with the ability to attain extreme old age. We then replicated the study of rs275653 in a large independent cohort of Japanese origin (598 centenarians and semi-supercentenarians, 422 younger controls) and indeed confirmed its association with exceptional old age. In combined analyses, rs275653 was associated to extreme longevity either at recessive model (P = 0.007, odds ratio (OR) 3.57) or at genotype level (P = 0.015). Significance was maintained after correcting for confounding factors. Fluorescence activated cell sorting analysis revealed that subjects homozygous for the minor allele of rs275653 had less AT1R-positive peripheral blood polymorphonuclear cells. Moreover, rs275653 was associated to lower blood pressure in centenarians. These findings highlight the role of AGTR1 as a possible candidate among longevity-enabling genes.

Blood group does not appear to affect longevity a pilot study in centenarians from Western Sicily

Centenarians are the best example of extreme human longevity, and they represent a selected population in which the appearance of major age-related diseases, such as cancer, and cardiovascular diseases among others, has been consistently delayed or escaped. The study of the long-lived individual genetic profile has the purpose to possibly identify the genes and the allelic variations influencing extended life expectancy, hence considering them as biomarkers of age-related diseases onset and development. The present study shows no significant differences between allelic variations of ABO blood groups among a group of centenarians from Western Sicily.

The pro-longevity gene FoxO3 is a direct target of the p53 tumor suppressor

FoxO transcription factors play a conserved role in longevity and act as tissue-specific tumor suppressors in mammals. Several nodes of interaction have been identified between FoxO transcription factors and p53, a major tumor suppressor in humans and mice. However, the extent and importance of the functional interaction between FoxO and p53 have not been fully explored. Here, we show that p53 transactivates the expression of FoxO3, one of the four mammalian FoxO genes, in response to DNA damaging agents in both mouse embryonic fibroblasts and in thymocytes. We show that p53 transactivates FoxO3 in cells by binding to a site in the second intron of the FoxO3 gene, a genomic region recently found to be associated with extreme longevity in humans. While FoxO3 is not necessary for p53-dependent cell cycle arrest, FoxO3 appears to modulate p53-dependent apoptosis. We also find that FoxO3 loss does not interact with p53 loss for tumor development in vivo, although the tumor spectrum of p53 deficient mice may be affected by FoxO3 loss. Our findings indicate that FoxO3 is a p53 target gene, and suggest that FoxO3 and p53 are part of a regulatory transcriptional network that may play an important role during aging and cancer.

Genetic Vulnerabilities Associated with Cancer and Aging

Genetic Vulnerabilities Associated with Cancer and Aging

HIGH LEVELS OF SOLUBLE RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS MAY BE A MARKER OF EXTREME LONGEVITY IN HUMANS

Journal of the American Geriatrics SocietyVolume 54, Issue 7 p. 1149-1150 HIGH LEVELS OF SOLUBLE RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS MAY BE A MARKER OF EXTREME LONGEVITY IN HUMANS Diego Geroldi MD, Diego Geroldi MD Interdepartmental Center for Research in Molecular Medicine, University of Pavia, Pavia, ItalySearch for more papers by this authorColomba Falcone MD, Colomba Falcone MD Interdepartmental Center for Research in Molecular Medicine, University of Pavia, Pavia, ItalySearch for more papers by this authorPiercarlo Minoretti MD, Piercarlo Minoretti MD Interdepartmental Center for Research in Molecular Medicine, University of Pavia, Pavia, ItalySearch for more papers by this authorEnzo Emanuele MD, Enzo Emanuele MD Interdepartmental Center for Research in Molecular Medicine, University of Pavia, Pavia, ItalySearch for more papers by this authorMariarosa Arra SciD, Mariarosa Arra SciD Interdepartmental Center for Research in Molecular Medicine, University of Pavia, Pavia, ItalySearch for more papers by this authorAngela D'Angelo PhD, Angela D'Angelo PhD Department of Internal Medicine and, Medical Therapeutics, IRCCS San Matteo Hospital, Pavia, ItalySearch for more papers by this author Diego Geroldi MD, Diego Geroldi MD Interdepartmental Center for Research in Molecular Medicine, University of Pavia, Pavia, ItalySearch for more papers by this authorColomba Falcone MD, Colomba Falcone MD Interdepartmental Center for Research in Molecular Medicine, University of Pavia, Pavia, ItalySearch for more papers by this authorPiercarlo Minoretti MD, Piercarlo Minoretti MD Interdepartmental Center for Research in Molecular Medicine, University of Pavia, Pavia, ItalySearch for more papers by this authorEnzo Emanuele MD, Enzo Emanuele MD Interdepartmental Center for Research in Molecular Medicine, University of Pavia, Pavia, ItalySearch for more papers by this authorMariarosa Arra SciD, Mariarosa Arra SciD Interdepartmental Center for Research in Molecular Medicine, University of Pavia, Pavia, ItalySearch for more papers by this authorAngela D'Angelo PhD, Angela D'Angelo PhD Department of Internal Medicine and, Medical Therapeutics, IRCCS San Matteo Hospital, Pavia, ItalySearch for more papers by this author First published: 06 July 2006 https://doi.org/10.1111/j.1532-5415.2006.00776.xCitations: 47Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume54, Issue7July 2006Pages 1149-1150 RelatedInformation

Common gene variants, mortality and extreme longevity in humans.

Genetic factors influence variation in human life span. The fast technological advancements in genome research and the methodology for statistical analysis of complex traits provided new tools to unravel these genetic influences. Most of the genetic epidemiology and quantitative genetics is focused on the dissection of the genetic component of specific diseases rather than of human life span. Nevertheless, common variants of 22 genes have been tested for their contribution to mortality in the general population and extreme longevity in one or more studies. These studies provide indications as to the nature of biological pathways that might play a role in human ageing. Perhaps even more important at this time is the fact that they give valuable insights in the strengths and weaknesses of current strategies to identify gene variants affecting human life span and point at more powerful approaches.