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The influence of life-style and psychosocial factors on ageing
The identification of factors that promote healthier ageing may help in the design of suitable interventions to mitigate the burdens that the increase in life expectancy is having in our society. To address this important issue we are investigating relationships between biomarkers of ageing and a variety of lifestyle and psycho-social variables in different human cohorts.
In a project carried out in collaboration with Professors Andrew Steptoe (University College London) and Elizabeth Blackburn (University of California, San Francisco), in which we analysed a subsample of the Whitehall II cohort, recruited during 2006-2008 as part of the “Heart Scan Study”, we found an association between low educational attainment and short leukocyte telomere length, a marker of cellular ageing. Similarly, when examining personality traits we found that high-hostile men had shorter leukocyte telomere length and higher telomerase activity than their low-hostile counterparts. These findings highlight the importance that psychosocial factors may have on the ageing process and provide a biological insight into the development of public health policies. Our current work in this area focuses on the investigation of mediating mechanisms, such as oxidative stress and inflammation responses to stress.
Zalli A., Carvalho L., Lin J., Hamer M., Erusalimsky J.D., Blackburn E.H. and Steptoe A. (2014) Shorter telomeres with high telomerase activity are associated with raised allostatic load and impoverished psychosocial resources
Proc. Natl. Acad. Sci. USA 111, 4519-4524.
Jackowska M., Hamer M., Carvalho L., Erusalimsky J.D., Butcher L. and Steptoe A. (2012) Short sleep duration is associated with shorter telomere length in healthy men: Findings from the Whitehall II cohort study. PLoS ONE 7, e47292.
Steptoe A., Hamer M., Butcher L., Lin J., Brydon L., Kivimaki M., Marmot M., Blackburn E. and Erusalimsky J.D. (2011) Educational attainment but not current socioeconomic status is associated with leukocyte telomere length. Brain Behav. Immun. 25, 1292-1298.
Brydon L., Lin J., Butcher L., Hamer M., Erusalimsky J.D., Blackburn E.H. and Steptoe A. (2011) Hostility and cellular aging in men from the Whitehall II cohort Biol. Psychiatry.71, 767-773.
Cooper R., Fehily A.M., Pickering J.E, Erusalimsky J.D. and Elwood P.C. (2010) Honey, health and longevity. Curr. Aging. Sci. 3, 239-241.
Biomarkers of Frailty
The increase in life expectancy of Western societies is having major socio-economic and public health impacts. One crucial aspect emanating from this scenario is the increase in the number of frail people. Frailty places elderly adults at increased risk of disability, falls, hospitalization and premature death. Hence preventing frailty is an important goal to help older adults to maintain their health and independence, and to reduce the burden on the health care and welfare systems.
Currently, assessment of frailty relies primarily on measuring functional parameters such as cognitive function, weight loss, walking speed and grip strength. However, it is now increasingly recognised that the clinical utility of such parameters in terms of risk prediction, diagnosis and prognosis is limited. Hence there is an urgent need to ameliorate this situation. To this end we are participating in a major European project, The
FRAILOMIC initiative, which will measure the levels of candidate blood and urine cellular and omic-based molecules in old people selected from eight cohorts (Toledo Study of Healthy Ageing, ENRICA, Three-City-Bordeaux, InChianti, SardiNIA, LIFE Study, SAGE and COURAGE), encompassing up to 75,000 participants.
Within the programme, we are responsible for measuring the blood levels of candidate molecules that may be related to the deterioration of cognitive performance and blood vessel dysfunction observed with ageing. The information obtained from this survey will serve as a platform to devise new clinical biomarkers to detect and tackle frailty.
More information on the FRAILOMIC initiative can be found in
Erusalimsky J.D., Grillari J., Grune T., Jansen-Duerr P. Lippi G., Sinclair A.J., Tegner J., Vina J., Durrance-Bagale A., Minambres R., Viegas M., Rodriguez-Manas L. (2015) In search of 'omics'-based biomarkers to predict the risk of frailty and its consequences in older individuals: The FRAILOMIC initiative
Gerontology 62, 182-190
Mechanisms of endothelial cell senescence and cytoprotection
Vascular diseases have long been considered to be age-related in terms of their onset and progression. The reasons for these associations are unclear, but it is plausible that ageing and vascular pathologies may share common mechanisms. One such mechanism may involve vascular cell senescence and the modulation of this process by certain stress response proteins. Our group is currently working on the role played by two types of such proteins, the sirtuins and the mammalian Tribbles homologue TRIB3.
Sirtuins are a group of seven closely related NAD-dependent protein deacetylases/ADP-ribosyltransferases involved in the regulation of energy metabolism, stress responses, cell survival and lifespan. Activation of SIRT1, the most studied member of the group, is thought to slow down ageing and to reduce the incidence and severity of age-associated diseases. The precise role of the other sirtuins (SIRT2-7) still requires elucidation. In our group we are currently investigating the role played by SIR2 and SIRT6 in the protection of endothelial cells from senescence. Findings from this work could help develop new approaches to fight cardiovascular disease.
TRIB3 is a member of an emerging group of pseudo-kinases which are increasingly implicated in the modulation of responses to external signals and in the regulation of gene activity. In some tissues TRIB3 reacts to harmful stimuli. We are investigating whether this phenomenon constitutes a defensive mechanism by which vascular cells adapt to adverse conditions.
Villalobos L.A., Uryga A., Romacho T., Leivas A., Sánchez-Ferrer C.F., Erusalimsky J.D. and Peiró C. (2014) Visfatin/Nampt induces telomere damage and senescence in human endothelial cells Int. J. Cardiol. 175, 573-575.
Cardus A., Uryga A., Walters G. and Erusalimsky J.D. (2013) SIRT6 protects human endothelial cells from DNA damage, telomere dysfunction and senescence. Cardiovasc. Res. 97, 571-579.
Erusalimsky J.D. (2009) Vascular endothelial senescence: From mechanisms to pathophysiology. J. Appl. Physiol. 106, 326-332
Regulation of megakaryocyte differentiation and platelet production
We have been studying megakaryocytopoiesis (the process of megakaryocyte development from haematopoietic stem cells) for several years. Megakaryocytes are giant cells found in the bone marrow that give rise to blood platelets. Platelets play important roles in health and disease.
In normal physiology platelets prevent bleeding by helping to plug holes and tears in damaged blood vessels. In disease states platelets may give rise to blood clots, which can lead to heart attacks and strokes. In our laboratory we use a technique to grow in a test tube megakaryocytes and platelets from blood stem cells. Using this system in combination with genetic manipulation techniques we can study how the process of megakaryocyte development and platelet production are controlled at the molecular level.
Part of the work in this area is dedicated to unravelling the mechanism of action of anagrelide, a medicine used in the treatment of patients with Essential Thrombocythemia (ET). ET is a rare disorder of the blood in which the number of circulating platelets is abnormally increased due to the overproduction of megakaryocytes in the bone marrow. The rise in platelets in these patients increases their risk of developing thrombotic complications, such as heart attacks and strokes. Anagrelide lowers the platelet count. Although this effect of the drug has been discovered more than 20 years ago, the precise mechanism of action has so far remained elusive. In our laboratory we have found that anagrelide interferes specifically with megakaryocyte growth without affecting the development of other blood cell types and that this mechanism involves the control of megakaryocyte-specific gene transcription.
Ahluwalia M., Butcher L., Donovan H., Killick-Cole C., Jones P. M. and Erusalimsky J. D. (2015) The gene expression signature of anagrelide provides and insight into its mechanism of action and uncovers new regulators of megakaryopoiesis
J. Thromb. Haemost 13, 1103-1112
Ahluwalia M., Donovan H., Singh N., Butcher L. and Erusalimsky J.D. (2010) Anagrelide represses GATA-1 and FOG-1 expression without interfering with thrombopoietin receptor signal transduction. J. Thromb. Haemost. 8, 2252-2261.
Hong Y., Wang G., Gutierrez del Arroyo A., Hernandez J., Skene C. and Erusalimsky J.D. (2006) Comparison between anagrelide and hydroxycarbamide in their activities against haematopoietic progenitor cell growth and differentiation: Selectivity of anagrelide for the megakaryocytic lineage. Leukemia 20, 1117-1122.
Wang G., Franklin R., Hong Y. and Erusalimsky J.D. (2005) Comparison of the biological activities of anagrelide and its major metabolites in haematopoietic cell cultures. Brit. J. Pharmacol. 146, 324-332.