title: RasGrf1 deficiency delays aging in mice.
abstract: RasGRF1 is a Ras-guanine nucleotide exchange factor implicated in a variety of physiological processes including learning and memory and glucose homeostasis. To determine the role of RASGRF1 in aging, lifespan and metabolic parameters were analyzed in aged RasGrf1(-/-) mice. We observed that mice deficient for RasGrf1(-/-) display an increase in average and most importantly, in maximal lifespan (20% higher than controls). This was not due to the role of Ras in cancer because tumor-free survival was also enhanced in these animals. Aged RasGrf1(-/-) displayed better motor coordination than control mice. Protection against oxidative stress was similarly preserved in old RasGrf1(-/-). IGF-I levels were lower in RasGrf1(-/-) than in controls. Furthermore, SIRT1 expression was increased in RasGrf1(-/-) animals. Consistent with this, the blood metabolomic profiles of RasGrf1-deficient mice resembled those observed in calorie-restricted animals. In addition, cardiac glucose consumption as determined PET was not altered by aging in the mutant model, indicating that RasGrf1-deficient mice display delayed aging. Our observations link Ras signaling to lifespan and suggest that RasGrf1 is an evolutionary conserved gene which could be targeted for the development of therapies to delay age-related processes.
authors.affiliation: Department of Physiology, School of Medicine, University of Valencia, Spain.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Borrás
authors.forename: Daniel
authors.initials: D
authors.lastname: Monleón
authors.forename: Raul
authors.initials: R
authors.lastname: López-Grueso
authors.forename: Juan
authors.initials: J
authors.lastname: Gambini
authors.forename: Leonardo
authors.initials: L
authors.lastname: Orlando
authors.forename: Federico V
authors.initials: FV
authors.lastname: Pallardó
authors.forename: Eugenio
authors.initials: E
authors.lastname: Santos
authors.forename: José
authors.initials: J
authors.lastname: Viña
authors.forename: Jaime
authors.initials: J
authors.lastname: Font de Mora
mesh_terms: D000375:Aging / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001483:Base Sequence; D031204:Caloric Restriction; D005947:Glucose / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008112:Liver Glycogen / Q000378:metabolism; D008136:Longevity / Q000235:genetics / Q000502:physiology*; D008297:Male; D055442:Metabolome; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D011597:Psychomotor Performance; D012336:RNA, Ribosomal, 16S / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism; D020666:ras-GRF1 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
chemical_list: D008112:Liver Glycogen; D012336:RNA, Ribosomal, 16S; C513037:Rasgrf1 protein, mouse; D020666:ras-GRF1; D007334:Insulin-Like Growth Factor I; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D005947:Glucose