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The gut microbiome is emerging as a key regulator of several metabolic, immune and neuroendocrine pathways1,2. Gut microbiome deregulation has been implicated in major conditions such as obesity, type 2 diabetes, cardiovascular disease, non-alcoholic fatty acid liver disease and cancer3,4,5,6, but its precise role in aging remains to be elucidated. Here, we find that two different mouse models of progeria are characterized by intestinal dysbiosis with alterations that include an increase in the abundance of Proteobacteria and Cyanobacteria, and a decrease in the abundance of Verrucomicrobia. Consistent with these findings, we found that human progeria patients also display intestinal dysbiosis and that long-lived humans (that is, centenarians) exhibit a substantial increase in Verrucomicrobia and a reduction in Proteobacteria. Fecal microbiota transplantation from wild-type mice enhanced healthspan and lifespan in both progeroid mouse models, and transplantation with the verrucomicrobia Akkermansia muciniphila was sufficient to exert beneficial effects. Moreover, metabolomic analysis of ileal content points to the restoration of secondary bile acids as a possible mechanism for the beneficial effects of reestablishing a healthy microbiome. Our results demonstrate that correction of the accelerated aging-associated intestinal dysbiosis is beneficial, suggesting the existence of a link between aging and the gut microbiota that provides a rationale for microbiome-based interventions against age-related diseases. Sin financiación 36.130 JCR (2019) Q1, 2/297 Biochemistry & Molecular Biology, 3/195 Cell Biology, 1/138 Medicine, Research & Experimental 15.812 SJR (2019) Q1, 2/271 Biochemistry, Genetics and Molecular Biology (miscellaneous), 5/2754 Medicine (miscellaneous) No data IDR 2019 UEM

Giant tortoises are among the longest-lived vertebrate animals and, as such, provide an excellent model to study traits like longevity and age-related diseases. However, genomic and molecular evolutionary information on giant tortoises is scarce. Here, we describe a global analysis of the genomes of Lonesome George—the iconic last member of Chelonoidis abingdonii—and the Aldabra giant tortoise (Aldabrachelys gigantea). Comparison of these genomes with those of related species, using both unsupervised and supervised analyses, led us to detect lineage-specific variants affecting DNA repair genes, inflammatory mediators and genes related to cancer development. Our study also hints at specific evolutionary strategies linked to increased lifespan, and expands our understanding of the genomic determinants of ageing. These new genome sequences also provide important resources to help the efforts for restoration of giant tortoise populations., We thank Banco Santander for funding a short stay of S.F.-R. and D.C.-I. at Yale University. V.Q. is supported by grants from the Principado de Asturias and Ministerio de Economía y Competitividad, including FEDER funding. L.F.K.K. is supported by an FPI fellowship associated with BFU2014-55090-P (FEDER). T.M.-B. is supported by MINECO BFU2017-86471-P (MINECO/FEDER, UE), an NIH U01 MH106874 grant, the Howard Hughes International Early Career programme, Obra Social ‘La Caixa’ and Secretaria d’Universitats i Recerca, and CERCA Programme del Departament d’Economia i Coneixement de la Generalitat de Catalunya. C.L.-O. is supported by grants from the European Research Council (DeAge; ERC Advanced Grant), Ministerio de Economía y Competitividad, Instituto de Salud Carlos III (RTICC) and Progeria Research Foundation. The Instituto Universitario de Oncología is supported by Fundación Bancaria Caja de Ahorros de Asturias. We also thank staff at the Galapagos National Park and Galapagos Conservancy for logistic and financial support.

Mitohormesis is a term used to define a biological response where the induction of a reduced amount of mitochondrial stress leads to an increment in health and viability within a cell, tissue, or organism. The mitochondrial stress response activated by a potentially damaging stimulus requires a coordinated dialogue with the cellular nucleus, known as mitonuclear communication. This interplay induced by the hormetic response in mitochondria relies in a variety of signals among which the most relevant ones are reactive oxygen species (ROS), mitochondrial metabolites, proteotoxic signals, the mitochondria-cytosol stress response, and the release of mitokines. The activation of the mitohormetic response increases lifespan in different animal models, from worms to mammals. Further, mitohormesis also enhances healthspan, particularly improving metabolism and immune system. Although multiple mediators and stress signals have been proposed to activate this protective mechanism, beneficial outcomes of mitohormesis are most probably due to an increase in mitochondrial ROS. Activation of other protective stress mechanisms as mitochondrial unfolded protein response or the increase in the expression of mitokines are also associated with the positive benefits exerted by mitohormesis. Herein, we review the different mitohormetic signals and pathways described from worms to mammals and their effects on health and survival. The identification and description of pathways and molecules implicated in the beneficial effects of mitohormesis will help understand the complex balance between death and survival in the face of mitochondrial damage and will allow to open a novel area of therapies aimed at improving health in humans.

Hutchinson–Gilford progeria syndrome (HGPS) is a disorder characterized by accelerated aging due to mutations in LMNA gene. The generation of mouse models of progeria has helped to unmask the molecular basis of this syndrome as well as to design therapeutic approaches aimed at improving the health span and life span of children affected. In this chapter, we describe two murine models developed for progeria research, named LmnaG609G/G609G and Zmpste24−/−, assessing the physical and molecular features that characterize them. We also recapitulate other mouse models available for the study of premature aging. Finally, we review the main therapeutic strategies that are being assayed to find a suitable treatment for HGPS.

Mitoproteases display an essential role in the preservation of mitochondrial homeostasis under regular and stress conditions. These enzymes perform tightly regulated proteolytic reactions by which they participate in mitochondrial protein trafficking, processing and activation of proteins, protein quality control, regulation of mitochondrial biogenesis, control of mitochondrial dynamics, mitophagy, and apoptosis. In this chapter, we have revised the physiological functions of the intrinsic mitochondrial proteases, analyzing their roles in the different compartments of this organelle and their connection to human pathology, primarily cancer, neurodegenerative disorders, and multisystemic diseases.