Search

Dementia and cognitive disorders are major aging-associated pathologies. The prevalence and severity of these conditions are influenced by both genetic and environmental factors. Reflecting this, epigenetic alterations have been associated with each of these processes, especially at the level of DNA methylation, and such changes may help explain the observed interindividual variability in the development of the 2 pathologies. However, the importance of epigenetic alterations in explaining their etiology is unclear because little is known about the timing of when they appear. Here, using Illumina MethylationEPIC arrays, we have longitudinally analyzed the peripheral blood methylomes of cognitively healthy older adults (>70 year), some of whom went on to develop dementia while others stayed healthy. We have characterized 34 individuals at the prediagnosis stage and at a 4-year follow-up in the postdiagnosis stage (total n = 68). Our results show multiple DNA methylation alterations linked to dementia status, particularly at the level of differentially methylated regions. These loci are associated with several dementia-related genes, including PON1, AP2A2, MAGI2, POT1, ITGAX, PACSIN1, SLC2A8, and EIF4E. We also provide validation of the previously reported epigenetic alteration of HOXB6 and PM20D1. Importantly, we show that most of these regions are already altered in the prediagnosis stage of individuals who go on to develop dementia. In conclusion, our observations suggest that dementia-associated epigenetic patterns that have specific biological features are already present before diagnosis, and thus may be important in the design of epigenetic biomarkers for disease detection based on peripheral tissues., This work was supported by: the Spanish Association Against Cancer (grant number PROYE18061FERN to M.F.F.), the Asturias Government (PCTI) cofunding 2018-2022/FEDER (grant number IDI/2018/146 to M.F.F.), the Fundación General CSIC (grant number 0348_CIE_6_E to M.F.F.) and the Health Institute Carlos III (Plan Nacional de I + D + I) cofunding FEDER (grant numbers PI15/00892, PI18/01527 to M.F.F. and A.F.F.). JRT is supported by a Juan de la Cierva fellowship from the Spanish Ministry of Science and Innovation (grant number FJCI-2015-26965). R.F.P. is supported by the Severo Ochoa program (grant number BP17-114). We also acknowledge support from the Institute of Oncology of Asturias (IUOPA, supported by Obra Social Cajastur Liberbank, Spain), the Health Research Institute of Asturias (ISPA-FINBA) and Consorcio Centro de Investigación Biomédica en Red (CIBERER-ISCIII).

Additional file 1: Table S1. All possible comparisons of the values for the anterior cingulate gyrus before and after treatment with placebo or genistein.

Àcid fòlic; Hhomocisteïna; Deteriorament cognitiu lleu Ácido fólico; Homocisteína; Deterioro cognitivo leve Folic acid; Homocysteine; Mild cognitive impairment Hyperhomocysteinemia is an independent predictor of the risk for cognitive decline and may be a result of low levels of vitamins B12, B6, and folate. Previous findings suggest that adequate intake of these vitamins may reduce homocysteine levels. This review aimed to assess the effects of treatment with vitamins B6, B12, and/or folic acid in the homocysteine levels in patients with mild cognitive impairment (MCI). A systematic literature review was conducted in EMBASE, MEDLINE®, PsycINFO, and Cochrane Central Register of Controlled Trials. The research question was formulated using the Population, Intervention, Comparison, and Outcome (PICO) framework: in patients with MCI (P); what is the efficacy of vitamins B6, B12, and/or folic acid intake (I); compared with baseline values, and/or compared with controls (C); in reducing homocysteine levels from baseline (O). A total of eight primary studies with a total of 1,140 participants were included in the review. Four were randomized controlled trials, one was a quasi-controlled trial, and three were observational studies. All studies included folic acid in their intervention, seven vitamin B12, and four vitamin B6. Mean (SD) length of the intervention period was 18.8 (19.3) months, ranging from 1 to 60 months. All studies showed a statistically significant decrease in homocysteine levels in groups treated with vitamins B6, B12, and/or folic acid compared to controls, with a mean decline of homocysteine concentration of 31.9% in the intervention arms whereas it increased by 0.7% in the control arm. This review identified evidence of a reduction of plasma homocysteine levels in MCI patients taking vitamins B6, B12, and/or folic acid supplements, with statistically significant declines being observed after 1 month of supplementation. Findings support that supplementation with these vitamins might be an option to reduce homocysteine levels in people with MCI and elevated plasma homocysteine. Nestlé Health Science, Switzerland

International audience; Aging is the major risk factor for the development of chronic diseases. After decades of research focused on extending lifespan, current efforts seek primarily to promote healthy aging. Recent advances suggest that biological processes linked to aging are more reliable than chronological age to account for an individual's functional status, i.e. frail or robust. It is becoming increasingly apparent that biological aging may be detectable as a progressive loss of resilience much earlier than the appearance of clinical signs of frailty. In this context, the INSPIRE program was built to identify the mechanisms of accelerated aging and the early biological signs predicting frailty and pathological aging. To address this issue, we designed a cohort of outbred SWISS mice (1576 male and female mice) in which we will continuously monitor spontaneous and voluntary physical activity from 6 to 24 months of age under either normal or high fat/high sucrose diet. At different age points (6, 12, 18, 24 months), multiorgan functional phenotyping will be carried out to identify early signs of organ dysfunction and generate a large biological fluids/feces/organs biobank (100,000 samples). A comprehensive correlation between functional and biological phenotypes will be assessed to determine: 1) the early signs of biological aging and their relationship with chronological age; 2) the role of dietary and exercise interventions on accelerating or decelerating the rate of biological aging; and 3) novel targets for the promotion of healthy aging. All the functional and omics data, as well as the biobank generated in the framework of the INSPIRE cohort will be available to the aging scientific community. The present article describes the scientific background and the strategies employed for the design of the INSPIRE Mouse cohort.

International audience; Aging is the major risk factor for the development of chronic diseases. After decades of research focused on extending lifespan, current efforts seek primarily to promote healthy aging. Recent advances suggest that biological processes linked to aging are more reliable than chronological age to account for an individual's functional status, i.e. frail or robust. It is becoming increasingly apparent that biological aging may be detectable as a progressive loss of resilience much earlier than the appearance of clinical signs of frailty. In this context, the INSPIRE program was built to identify the mechanisms of accelerated aging and the early biological signs predicting frailty and pathological aging. To address this issue, we designed a cohort of outbred SWISS mice (1576 male and female mice) in which we will continuously monitor spontaneous and voluntary physical activity from 6 to 24 months of age under either normal or high fat/high sucrose diet. At different age points (6, 12, 18, 24 months), multiorgan functional phenotyping will be carried out to identify early signs of organ dysfunction and generate a large biological fluids/feces/organs biobank (100,000 samples). A comprehensive correlation between functional and biological phenotypes will be assessed to determine: 1) the early signs of biological aging and their relationship with chronological age; 2) the role of dietary and exercise interventions on accelerating or decelerating the rate of biological aging; and 3) novel targets for the promotion of healthy aging. All the functional and omics data, as well as the biobank generated in the framework of the INSPIRE cohort will be available to the aging scientific community. The present article describes the scientific background and the strategies employed for the design of the INSPIRE Mouse cohort.

International audience; Understanding the molecular pathways involved in the loss of skeletal muscle mass and function induced by muscle disuse is a crucial issue in the context of spaceflight as well as in the clinical field, and development of efficient countermeasures is needed. Recent studies have reported the importance of redox balance dysregulation as a major mechanism leading to muscle wasting. Our study aimed to evaluate the effects of an antioxidant/anti-inflammatory cocktail (741 mg of polyphenols, 138 mg of vitamin E, 80 mu g of selenium, and 2.1 g of omega-3) in the prevention of muscle deconditioning induced by long-term inactivity. The study consisted of 60 days of hypoactivity using the head-down bed rest (HDBR) model. Twenty healthy men were recruited; half of them received a daily antioxidant/anti-inflammatory supplementation, whereas the other half received a placebo. Muscle biopsies were collected from the vastus lateralis muscles before and after bedrest and 10 days after remobilization. After 2 months of HDBR, all subjects presented muscle deconditioning characterized by a loss of muscle strength and an atrophy of muscle fibers, which was not prevented by cocktail supplementation. Our results regarding muscle oxidative damage, mitochondrial content, and protein balance actors refuted the potential protection of the cocktail during long-term inactivity and showed a disturbance of essential signaling pathways (protein balance and mitochondriogenesis) during the remobilization period. This study demonstrated the ineffectiveness of our cocktail supplementation and underlines the complexity of redox balance mechanisms. It raises interrogations regarding the appropriate nutritional intervention to fight against muscle deconditioning.

Cada vez más personas afrontan la vejez de un modo positivo a causa de factores genéticos, hábitos y estilos de vida adecuados, y un entorno social y familiar de apoyo. La esperanza de vida y el número de personas nonagenarias y centenarias en España que tienen envejecimiento exitoso crece. 12.880 centenarios viven actualmente en España. En Valencia son 222 las personas centenarias y 1.295 las nonagenarias. Método: Estudio transversal descriptivo. Se presentan datos de perfil de la longevidad extrema describiendo características sociodemográficas, estilos de vida, salud percibida, funcional, cognitiva, social y participación. Muestra: Sobre una muestra inicial de 552 personas valencianas, se entrevistó a N = 68 personas sin deterioro cognitivo (M = 96, DT = 3,93), 44,1 % centenarios (97-105); 69,1 % mujeres; 83,8 % viudos; un 48,5 % vivía en su casa, un 33,8 % en residencias y un 17,6 % en casa de hijos u otros familiares. Su red social era amplia (un 88,2 % con hijos y nietos, y un 77,9 % con familiares longevos). Resultados: La salud percibida era buena para el 74,5 %; el 84,8 % tenía muy buena salud cognitiva, el 54,5 % era independiente en casi todas las abvd, el 87,2 % no tuvo problemas de salud en el último mes y su salud física no le causó dificultades, y el 63,8 % ha tenido muy poco/ningún dolor durante el último mes. Los estilos de vida eran saludables pues el 33,3 % realizaba ejercicio físico regular y la dieta era mediterránea para el 89,4 %. La mitad de ellos (56,1 %) participaba en actividades semanalmente, con alta satisfacción con el ocio en la mayor parte de los casos (76,6 %). Conclusiones: El envejecimiento exitoso en las personas mayores de 90 años se caracteriza por tener buena salud percibida y cognitiva, buena red de apoyo social familiar, antecedentes de familiares longevos, estilos de vida saludables y participación en actividades diversas. People are increasingly facing up to old age in a positive way as a result of genetic factors, appropriate behaviours and lifestyles and a supportive social and family environment. Life expectancy and the number of people reaching their 90s and 100s with a successful old age in Spain are increasing. 12,880 centenarians currently live in Spain. In Valencia, there are 222 people over 100 and 1295 over 90. Method: Descriptive transversal study. Profile data of extreme longevity are presented, describing sociodemographic features, lifestyles, physical, functional and mental health and rates of social engagement. Sample: From an initial sample of 552 Valencian people, 68 were interviewed without cognitive decline (N = 68, M = 96, DT = 3.93): 44.1 % were centenarians (97-105); 69.1 % women; 83.8 % widowers; 48.5 % living at home; 33.8 % in a retirement home and 17.6 % with their children or other family. Their social network was extensive (88.2 % with children or grandchildren) and 77.9 % with long-lived family members. Results: Reported physical health was good for 74.5 %; 84.8 % had very good mental health; 54.5 % were independent in almost all activities of daily living (ADL); 87.2 % had no health problems in the last month and their physical health posed no difficulties; 63.8 % had very little/no pain in the last month. Their lifestyles were healthy with 33.3 % doing regular physical exercise and 89.4 % eating a Mediterranean diet. Half (56.1 %) were participating weekly in some activity, with most of them (76.6 %) reporting a high degree of satisfaction with their leisure activities. Conclusions: Successful ageing in people over 90 years is characterised by good physical and mental health, a good family and social supporting network, history of long-lived family members, healthy lifestyles and participation in diverse activities. Medicina

Cada vez más personas afrontan la vejez de un modo positivo a causa de factores genéticos, hábitos y estilos de vida adecuados, y un entorno social y familiar de apoyo. La esperanza de vida y el número de personas nonagenarias y centenarias en España que tienen envejecimiento exitoso crece. 12.880 centenarios viven actualmente en España. En Valencia son 222 las personas centenarias y 1.295 las nonagenarias. Método: Estudio transversal descriptivo. Se presentan datos de perfil de la longevidad extrema describiendo características sociodemográficas, estilos de vida, salud percibida, funcional, cognitiva, social y participación. Muestra: Sobre una muestra inicial de 552 personas valencianas, se entrevistó a N = 68 personas sin deterioro cognitivo (M = 96, DT = 3,93), 44,1 % centenarios (97-105); 69,1 % mujeres; 83,8 % viudos; un 48,5 % vivía en su casa, un 33,8 % en residencias y un 17,6 % en casa de hijos u otros familiares. Su red social era amplia (un 88,2 % con hijos y nietos, y un 77,9 % con familiares longevos). Resultados: La salud percibida era buena para el 74,5 %; el 84,8 % tenía muy buena salud cognitiva, el 54,5 % era independiente en casi todas las abvd, el 87,2 % no tuvo problemas de salud en el último mes y su salud física no le causó dificultades, y el 63,8 % ha tenido muy poco/ningún dolor durante el último mes. Los estilos de vida eran saludables pues el 33,3 % realizaba ejercicio físico regular y la dieta era mediterránea para el 89,4 %. La mitad de ellos (56,1 %) participaba en actividades semanalmente, con alta satisfacción con el ocio en la mayor parte de los casos (76,6 %). Conclusiones: El envejecimiento exitoso en las personas mayores de 90 años se caracteriza por tener buena salud percibida y cognitiva, buena red de apoyo social familiar, antecedentes de familiares longevos, estilos de vida saludables y participación en actividades diversas. People are increasingly facing up to old age in a positive way as a result of genetic factors, appropriate behaviours and lifestyles and a supportive social and family environment. Life expectancy and the number of people reaching their 90s and 100s with a successful old age in Spain are increasing. 12,880 centenarians currently live in Spain. In Valencia, there are 222 people over 100 and 1295 over 90. Method: Descriptive transversal study. Profile data of extreme longevity are presented, describing sociodemographic features, lifestyles, physical, functional and mental health and rates of social engagement. Sample: From an initial sample of 552 Valencian people, 68 were interviewed without cognitive decline (N = 68, M = 96, DT = 3.93): 44.1 % were centenarians (97-105); 69.1 % women; 83.8 % widowers; 48.5 % living at home; 33.8 % in a retirement home and 17.6 % with their children or other family. Their social network was extensive (88.2 % with children or grandchildren) and 77.9 % with long-lived family members. Results: Reported physical health was good for 74.5 %; 84.8 % had very good mental health; 54.5 % were independent in almost all activities of daily living (ADL); 87.2 % had no health problems in the last month and their physical health posed no difficulties; 63.8 % had very little/no pain in the last month. Their lifestyles were healthy with 33.3 % doing regular physical exercise and 89.4 % eating a Mediterranean diet. Half (56.1 %) were participating weekly in some activity, with most of them (76.6 %) reporting a high degree of satisfaction with their leisure activities. Conclusions: Successful ageing in people over 90 years is characterised by good physical and mental health, a good family and social supporting network, history of long-lived family members, healthy lifestyles and participation in diverse activities. Medicina

Las colonizaciones de la región andina colombiana en el periodo 1820-1910 terminaron por afectar su amplia biodiversidad. Uno de los conflictos ambientales que se encuentran registrados en las fuentes al respecto fue el acontecido entre los seres humanos y el principal depredador terrestre del continente: el jaguar (Panthera onca). Este felino, conocido en las fuentes como “el tigre”, poseyó hasta esa época poblaciones estables en las selvas y bosques de la región, poblaciones que pudieron presentar diferencias de comportamiento y adaptación respecto a los jaguares de nuestros días. El tigre americano fue una referencia cultural cotidiana para los habitantes de la época y sobre este animal se construyeron connotaciones tanto “negativas” como “positivas”. Las actividades asociadas a la colonización humana (deforestación, ampliación de la frontera agrícola, introducción de la ganadería y los cultivos de extensión) pero sobre todo a la ocupación y el crecimiento de la población en la región llevaron a la disminución crítica de los jaguares. Esta desaparición “física” del tigre contribuyó a que las memorias sobre la criatura se desvanecieran, pero en este proceso también fueron fundamentales los discursos de “civilización” y “progreso” que hicieron que la región rompiera con su pasado salvaje. Pese a la difícil situación en la cual quedó el tigre andino a comienzos del siglo XX, todavía, en un ejemplo de resilicencia ecológica, el jaguar subiste en algunos sitios de la región, lo cual ha permitido un proceso de reinterpretación y reapropiación del animal. Abstract The colonization of the Colombian Andean region between 1820 and 1910 affected its great biodiversity. One of the environmental conflicts most recorded in the sources was the conflict between humans and the jaguar (Panthera onca), the main land predator of the continent. This big cat, known in the sources as "tiger", had stable populations in the jungles and forests of the region. These populations could present differences in behavior and adaptation from current populations of jaguars. The tiger was an everyday cultural reference for the inhabitants of the time. Both "negative" and "positive" connotations were built about the animal. The activities associated with human colonization (deforestation, expansion of the agricultural frontier, introduction of livestock, and crop extension), and especially those associated to the occupation and human population growth in the region, led to a critical reduction of the specie. This "physical" disappearance of tigers contributed to the slow removal of the jaguar from the collective memory. In this process were also relevant discourses about "civilization" and "progress" that disconnected the region from its wild past. Despite the difficult situation of the Andean tiger in the early twentieth century, as an example of ecological resilience, the jaguar still survives in parts of the region, fact that promoted a new process of reinterpretation and reappropriation of the animal Maestría

Objectives: We aimed to determine the effect of exercise training on plasma levels of brain-derived neurotrophic factor (BDNF), and serum insulin-like growth factor-1 (IGF-1) as well as cAMP response element-binding (CREB) activation in peripheral blood mononuclear cells (PBMCs) in adolescents. Methods: Nine trained and seven sedentary male adolescents, matched in age (14.0±2.2 years), were recruited for the study. Trained boys performed higher physical activity levels (expressed both as total energy expenditure and as physical activity energy expenditure) and showed significant bradycardia when compared with sedentary ones. RESULTS: We found that BDNF and IGF-1 levels were significantly higher in trained adolescents than in sedentary ones. However, no effect of training was found in the activation of CREB in PBMCs. Conclusions: We demonstrated the increase of neuroplasticity-related proteins due to exercise training in adolescents. Our results emphasize the significance and impact of exercise in this developmental period.

Prix de meilleur communication orale (Young Investigator Award); International audience; Background : Skeletal muscle aging is characterized by impairments in regenerative processes that promote the decline of its mass, strengthand endurance (Le Grand and Rudnicki 2007). More than the intrinsic regenerative potential of satellite cells (SC), intracellular environment appears responsible to the age-related decrease of SC activity (Conboy, Conboy et al. 2005). This study was designed to study the involvement of myostatin and reactive oxygen species (ROS) on myogenic regulator factors (MRFs) expressions during aging processand in response to endurance training in skeletal muscle of young and aged rats. Methods : 22 young (5 months) and aged (22 months) male Wistar rats were exercised for 3 weeks following endurance training. The intensity of the training was set at 75% VO2max. Analyses were realized in gastrocnemius muscles. Gastrocnemius muscle was chosen because it is one of the most recruited muscles during the exercise training protocol and one of the most affected by sarcopenia due to a large proportion of type II fibers (Arora, Husom et al. 2008) Results : We observed that Myf-5, myoD and myogenin mRNA increased with age, without any change in protein content. mRNA of p21, an inhibitor of SC proliferation, was higher in aged skeletal muscle. Aging also increased oxidative damage (protein carbonylation, glutathione status), myostatin protein content and activated p38-mitogen-activated protein kinase. Endurance training reduces myostatin mRNA only in aged skeletal muscle, but did not change MRFs expression and oxidative stress status. Discussion : Myostatin and ROS could be key-elements of intracellular environment that impaired regenerative processes in aged skeletal muscle, by modulating MRFs and p21 expression. Further investigations using antioxydant treatments and myostatin inhibitors in aged animals are required to confirm this hypothesis. In addition, our results suggest that positive effects of endurance training on muscle mass and strength in aged population cannot be explained by changes in basal MRFs and p21 expression.

BACKGROUND: Considerable variability exists in international prevalence and incidence estimates of dementia. The accuracy of estimates of dementia in the oldest-old and the controversial question of whether dementia incidence and prevalence decline at very old age will be crucial for better understanding the dynamics between survival to extreme old age and the occurrence and risk for various types of dementia and comorbidities. International Centenarian Consortium - Dementia (ICC-Dementia) seeks to harmonise centenarian and near-centenarian studies internationally to describe the cognitive and functional profiles of exceptionally old individuals, and ascertain the trajectories of decline and thereby the age-standardised prevalence and incidence of dementia in this population. The primary goal of the ICC-Dementia is to establish a large and thorough heterogeneous sample that has the power to answer epidemiological questions that small, separate studies cannot. A secondary aim is to examine cohort-specific effects and differential survivorship into very old age. We hope to lay the foundation for further investigation into risk and protective factors for dementia and healthy exceptional brain ageing in centenarians across diverse ethnoracial and sociocultural groups. METHODS: Studies focusing on individuals aged ≥95 years (approximately the oldest 1 percentile for men, oldest 5th percentile for women), with a minimum sample of 80 individuals, including assessment of cognition and functional status, are invited to participate. There are currently seventeen member or potential member studies from Asia, Europe, the Americas, and Oceania. Initial attempts at harmonising key variables are in progress. DISCUSSION: General challenges facing large, international consortia like ICC-Dementia include timely and effective communication among member studies, ethical and practical issues relating to human subject studies and data sharing, and the challenges related to data harmonisation. A specific challenge for ICC-Dementia relates to the concept and definition of'abnormal' in this exceptional group of individuals who are rarely free of physical, sensory and/or cognitive impairments.

International audience; Background : Considerable variability exists in international prevalence and incidence estimates of dementia. The accuracy of estimates of dementia in the oldest-old and the controversial question of whether dementia incidence and prevalence decline at very old age will be crucial for better understanding the dynamics between survival to extreme old age and the occurrence and risk for various types of dementia and comorbidities. International Centenarian Consortium - Dementia (ICC-Dementia) seeks to harmonise centenarian and near-centenarian studies internationally to describe the cognitive and functional profiles of exceptionally old individuals, and ascertain the trajectories of decline and thereby the age-standardised prevalence and incidence of dementia in this population. The primary goal of the ICC-Dementia is to establish a large and thorough heterogeneous sample that has the power to answer epidemiological questions that small, separate studies cannot. A secondary Aim : is to examine cohort-specific effects and differential survivorship into very old age. We hope to lay the foundation for further investigation into risk and protective factors for dementia and healthy exceptional brain ageing in centenarians across diverse ethnoracial and sociocultural groups. METHODS: Studies focusing on individuals aged >/=95 years (approximately the oldest 1 percentile for men, oldest 5th percentile for women), with a minimum sample of 80 individuals, including assessment of cognition and functional status, are invited to participate. There are currently seventeen member or potential member studies from Asia, Europe, the Americas, and Oceania. Initial attempts at harmonising key variables are in progress. DISCUSSION: General challenges facing large, international consortia like ICC-Dementia include timely and effective communication among member studies, ethical and practical issues relating to human subject studies and data sharing, and the challenges related to data harmonisation. A specific challenge for ICC-Dementia relates to the concept and definition of'abnormal' in this exceptional group of individuals who are rarely free of physical, sensory and/or cognitive impairments.

Se han investigado las actividades y centros activos de la ADP-ribosa/CDP-alcohol difosfatasa dependiente de Mn2+ (ADPRibasa-Mn) y la trioquinasa/FMN ciclasa (TKFC), obtenidas como proteínas recombinantes. Respecto a ADPRibasa-Mn se estudiaron las enzimas de rata (“Rattus norvegicus”) y de pez cebra (“Danio rerio”). Por vez primera se ha hecho coincidir información estructural y bioquímica en la misma proteína de la familia “ADPRibase-Mn”. Se han encontrado nuevas actividades de ADPRibasa-Mn, como ADP-ribosa cíclica fosfohidrolasa y fosfodiesterasa de nucleótidos 2´,3´-cíclicos. A partir de la estructura de la ADPRibasa-Mn de “D. rerio”, y por modelado molecular, se han definido los centros activos de ambas enzimas y se identificaron una molécula de agua y un residuo de histidina bien posicionados para la reacción hidrolítica. El papel de dicho residuo se confirmó por mutagénesis. Respecto a TKFC, se estudió la enzima humana (hTKFC), un homodímero de subunidades con dos dominios (L y K). Se construyeron modelos de hTKFC unida a sustratos de quinasa, de ciclasa o sin sustratos. Simulaciones de dinámica molecular desvelaron movimientos de los dominios K necesarios para la actividad quinasa. El modelado molecular permitió identificar interacciones relevantes de diversos aminoácidos. Los estudios bioquímicos hechos con hTKFC incluyeron la demostración de que K y L por separado no tienen actividad quinasa, mientras que K tiene actividad FMN ciclasa. Además se prepararon seis mutantes puntuales que, añadidos a un séptimo anteriormente preparado, dieron información relevante sobre el centro activo y el papel de ambos dominios en la catálisis., The activities and the active centers of Mn2+-dependent ADP-ribose/CDP-alcohol diphosphatase (ADPRibase-Mn) and triokinase/FMN cyclase (TKFC), both obtaines as recombinant proteins, were investigated. Concerning ADPRibase-Mn, the enzymes from rat (“Rattus norvegicus”) and zebrafish (“Danio rerio”) were studied. For the first time, structural and biochemical information were put together for the same protein of the ADPRibase-Mn family. Novel ADPRibase-Mn activities were found, namely cyclic ADP-ribose phosphohydrolase and 2´,3´-cyclic nucleotide phosphodiesterase. The active centers of both ADPRibase-Mn enzymes were defined from the structure of the “D. rerio” protein and by molecular modeling. A molecule of water and a histidine residue well positioned for the hydrolytic reaction were identified. The role of such residue was confirmed by mutagenesis. The study of TKFC was centered on the human enzyme (hTKFC), a homodimer of two-domain (K and L) subunits. hTKFC models bound to kinase substrates, cyclase substrate, or without substrates, were constructed. Molecular dynamics simulations revealed movements of the K domains necessary for the kinase activity. Molecular modeling led to the identification of relevant interactions of several aminoacids. Biochemical studies performed with hTKFC included the demonstration that individual K and L domains are devoid of kinase activity, while K alone is active as FMN cyclase. In addition, six point mutants were prepared and, together with another previously prepared one, gave relevant information on the active center and the role of both domains in catalysis.