Suchergebnisse

24 páginas, 7 figuras. Borras C, et al. Human exceptional longevity: transcriptome from centenarians is distinct from septuagenarians and reveals a role of Bcl-xL in successful aging. Aging (Albany NY). 2016 Oct 28;8(12):3185-3208. doi:10.18632/aging.101078. ; Centenarians not only enjoy an extraordinary aging, but also show a compression of morbidity. Using functional transcriptomic analysis of peripheral blood mononuclear cells (PMBC) we identified 1721 mRNAs differentially expressed by centenarians when compared with septuagenarians and young people. Sub-network analysis led us to identify Bcl-xL as an important gene up-regulated in centenarians. It is involved in the control of apoptosis, cellular damage protection and also in modulation of immune response, all associated to healthy aging. Indeed, centenarians display lower plasma cytochrome C levels, higher mitochondrial membrane potential and also less cellular damage accumulation than septuagenarians. Leukocyte chemotaxis and NK cell activity are significantly impaired in septuagenarians compared with young people whereas centenarians maintain them. To further ascertain the functional role of Bcl-xL in cellular aging, we found that lymphocytes from septuagenarians transduced with Bcl-xL display a reduction in senescent-related markers. Finally, to demonstrate the role of Bcl-xL in longevity at the organism level, C. elegans bearing a gain of function mutation in the Bcl-xL ortholog ced-9, showed a significant increase in mean and maximal life span. These results show that mRNA expression in centenarians is unique and reveals that Bcl-xL plays an important role in exceptional aging. ; This work was supported by grants SAF2013-44663-R, from the Spanish Ministry of Education and Science (MEC); ISCIII2012-RED-43-029 from the "Red Tematica de investigacion cooperative en envejecimiento y fragilidad" (RETICEF); PROMETEOII/2014/056 from "Conselleria d'Educació, Cultura I Esport de la Generalitat Valenciana"; and EU Funded CM1001 and FRAILOMIC-HEALTH.2012.2.1.1-2 (To J.V) APM-03/15 from Conselleria de Sanitat, AICO/2016/067 and from Conselleria d'Educació, Cultura i Esport de la Generalitat Valenciana, Intramural Grant from INCLIVA (to C.B.),VAL i+d Fellowship from Generalitat Valenciana (to C.L.-F.) and Marie Curie Career Integration Grant (to N.F). This study has been co-financed by FEDER funds from the European Union. ; Peer reviewed

S.N.-P. and P.J.F.-M. have been funded by the Spanish Association Against Cancer(aecc). Work in the laboratory of M.S. is funded by the CNIO and by grants from the Spanish Ministry of Economy co-funded by the European Regional Development Fund(SAF project), the European Research Council (ERC Advanced Grant), the Regional Government of Madrid co-funded by the European Social Fund (ReCaRe project), the European Union (RISK-IR project), the Botin Foundation and Banco Santander(Santander Universities Global Division), the Ramon Areces Foundation, and the AXA Foundation. Work in the laboratory of J.V. was supported by grants SAF2013-44663-R,from the Spanish Ministry of Education and Science (MEC); ISCIII2012-RED-43-029from RETICEF; PROMETEO2014/056 from "Conselleria d'Educacio , Cultura i Esport de la Generalitat Valenciana"; RS2012-609 Intramural Grant from INCLIVA and EUFunded CM1001 andFRAILOMIC-HEALTH.2012.2.1.1-2. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ; Reactive oxygen species (ROS) are constantly generated by cells and ROS-derived damage contributes to ageing. Protection against oxidative damage largely relies on the reductive power of NAPDH, whose levels are mostly determined by the enzyme glucose-6-phosphate dehydrogenase (G6PD). Here, we report a transgenic mouse model with moderate overexpression of human G6PD under its endogenous promoter. Importantly, G6PD-Tg mice have higher levels of NADPH, lower levels of ROS-derived damage, and better protection from ageing-associated functional decline, including extended median lifespan in females. The G6PD transgene has no effect on tumour development, even after combining with various tumour-prone genetic alterations. We conclude that a modest increase in G6PD activity is beneficial for healthspan through increased NADPH levels and protection from the deleterious effects of ROS. ; Sí