Excodra Barcelonra
CBM Severo Ochoa

CBM Severo Ochoa

En el CBMSO centramos nuestra investigación en el estudio de las bases moleculares de patologías humanas con el objetivo final de proporcionar los conocimientos necesarios para el diseño de terapias, procedimientos y métodos de diagnóstico que ayuden a mejorar la calidad y la esperanza de vida de la población. Nuestra investigación en biomedicina molecular se basa en dos realidades: La necesidad de reducir el impacto social de las enfermedades más invalidantes. La necesidad de comprender los mecanismos moleculares de enfermedades para poderlos traducir en aplicaciones biomédicas. http://www.cbm.uam.es

Entrevista con el Dr. Carlos Dotti

Fuente: Excodra | Publicado: 17-07-2017
El cerebro (y cualquier órgano) envejece debido a la confluencia de numerosos factores, como son la inestabilidad genómica, la falta de producción de células nuevas por el envejecimiento de células madres, alteraciones en la función de las mitocondrias, del proteasoma, y varios más.
Derechos: Dr. Carlos Dotti
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Carlos, para comenzar, a grandes rasgos, ¿cómo envejece nuestro cerebro, qué factores son los más determinantes en el proceso del envejecimiento del sistema nervioso?

El cerebro (y cualquier órgano) envejece debido a la confluencia de numerosos factores, como son la inestabilidad genómica, la falta de producción de células nuevas por el envejecimiento de células madres, alteraciones en la función de las mitocondrias, del proteasoma, y varios más. Varios de estos defectos son debidos a cambios en la expresión de genes que determinan que proteínas esenciales para diversas funciones celulares estén en mayor o menor concentración, o simplemente que sean diferentes. Los defectos en la expresión de genes pueden deberse a procesos autónomos (reloj interno de envejecimiento) o no autónomos (asociados a factores ambientales, internos o externos).



Entre los genes que cambian como parte del reloj interno del envejecimiento, uno que es fácil de entender, corresponde a los cambios en la expresión de genes de hormonas sexuales y reproductivas. Estas hormonas tienen un rol esencial en el metabolismo celular en diferentes poblaciones neuronales y se han involucrado en los déficits cognitivos que acompañan esta etapa de la vida.


Otros genes que se afectan como parte del reloj interno son aquellos que controlan la actividad del reloj circadiano. El reloj circadiano es el responsable de que nuestras actividades metabólicas, la producción hormonal, el ritmo cardíaco vayan oscilando durante las 24 horas del día. El reloj circadiano es también el responsable del patrón sueño-vigilia por lo que, sumado al rol de este sistema en la producción hormonal y en metabolismo, es fácil imaginar que cambios en la expresión de genes de este sistema van a contribuir a los trastornos cognitivos y motores que ocurren con la edad.
Los mecanismos no autónomos que llevan a cambios en expresión génica están relacionados con el efecto del estrés metabólico sobre el ADN neuronal. El estrés metabólico (el estrés que proviene del mismo hecho de respirar, metabolizar nutrientes o contrarrestar estímulos nocivos) genera radicales que producen daño en ácidos nucleicos y también en los mecanismos de reparación de fallas en el ADN, resultando en la sobre-expresión o disminución de genes, los que a su vez llevan a defectos en la función celular. Además de los defectos a nivel de ADN, el estrés metabólico produce daño en los componentes, proteínas y lípidos, de las diferentes organelas, llevando a alteraciones en las vías de metabolismo, inflamación y regeneración. Así, el envejecimiento cerebral es la consecuencia de entre otros varios, los inevitables cambios en la expresión de genes, por razones autónomas y no autónomas, y la inevitable acumulación de daño intracelular proveniente del metabolismo normal.

A nivel cerebral, el indagar en las relaciones moleculares y celulares con las actividades cognitivas es apasionante, ¿cuáles son vuestros enfoques básicos para establecer la relación, por ejemplo, entre una inactivación de un gen y el déficit cognitivo de alguna tarea, en general?

Nosotros partimos de dos parámetros básicos de certeza: i) existen déficits cognitivos y motores en la edad avanzada, y ii) estos déficits tienen manifestaciones a nivel bioquímico, histológico y/o eléctrico. Por lo tanto, ante la identificación de un cambio en la expresión de un gen en particular, o en, por ejemplo, los niveles de fosforilación de una proteína determinada, nos lleva a practicar dos tipos de aproximaciones experimentales. Primero, y esencial, debemos determinar si el cambio en expresión/fosforilación lleva a la aparición del déficit. Y segundo, si se confirmó lo anterior, determinamos el mecanismo por el que ocurre. De esto no me puedo extender porque es altamente dependiente de la pregunta, del resultado.

Cerebro y ácidos grasos como fuente de energía, colesterol y envejecimiento, estos cuatro conceptos tienen curiosas relaciones entre ellos, coméntanos sobre esto por favor, pues siguen algunas de vuestras vías de investigación.

En realidad no están muy relacionadas nuestras líneas de investigación con el uso de ácidos grasos como fuente de energía. Lo que nosotros estudiamos es como un cambio en un gen con la edad, que regula la oxidación del colesterol y por ende su cantidad en la membrana, afecta vías de señalización importantes para la función sináptica. Por otro lado, el hecho de que con la edad (al menos en insectos) los ácidos grasos sean utilizados en el cerebro para generar energía puede estar indicando que este es un proceso que las neuronas viejas utilizan para suplir los defectos en el metabolismo de los glúcidos que ocurre con el envejecimiento. Por otro lado, por estudios en insectos, el uso de ácidos grasos como fuente de energía en el cerebro viejo puede ser beneficioso a corto plazo pero deletéreo a largo plazo, ya que estaría generando más daño celular a partir de radicales del metabolismo de los triglicéridos. Pero esto es solo una suposición.

Siempre me han llamado la atención las cascadas de señales, las vías metabólicas, esas secuencias de acontecimientos moleculares que van desencadenando acciones determinadas, como un engranaje de posibilidades moleculares que son dadas, desde la expresión proteica de un gen a la acción de una molécula a metro y medio de distancia de donde se desencadenó su vía. ¿Qué vía o qué vías consideras que son las más relevantes, para el correcto funcionamiento del cerebro, para su mejor preservación en el tiempo?

Creo que por una cuestión evolutiva, la vía que cualquier especie que ya ha cumplido con su ciclo reproductivo va a intentar favorecer es la de sobrevida. De hecho, el cerebro viejo tiene muy poca muerte neuronal, a pesar de no funcionar muy bien. Esto significa que todo el daño que pudieron haber causado los cambios en expresión génica y en la organización y función de las diversas organelas afectó funcionalidad pero no sobrevida. Es incluso hasta posible que parte de la pérdida de función sea un mecanismo para potenciar sobrevida, a partir del ahorro de energía que de otro modo se gasta con la plasticidad sináptica o con la síntesis de sustancias con complicadas y energéticamente caras vías de síntesis. La capacidad de sobrevivir es lo que define la fortaleza de una especie.

Recuperando las respuestas anteriores, las vías relacionadas con los ácidos grasos y los daños acumulados con el tiempo por el entramado cerebral, ¿dónde se cruzan y cómo se pueden acometer estas rutas metabólicas para menguar la senescencia? Y, ¿con qué otras rutas podría incrementarse los efectos positivos para retrasar la vejez del sistema nervioso?

Los mecanismos involucrados en la pérdida de función con la edad son de tan variado origen y la necesidad evolutiva de eliminar al sujeto viejo (no reproductivo) o enfermo es tan fuerte que los sistemas biológicos están muy bien aceitados para que envejezcamos y muramos. Pero eso no quita que intentemos retrasar o mejorar la vejez.



Esto se está logrando porque vamos conociendo el efecto de la vejez sobre diferentes vías de señalización, y vamos interviniendo sobre estas vías. Pero son demasiadas vías en paralelo las que se afectan con el paso del tiempo, y no podemos intervenir sobre todas ellas.


Es más, es posible que interferir con alguna de ellas sea contraproducente. La vía del colesterol neuronal, cómo se pierde con la vejez y lo que le hace a la función neuronal, es una diana importante para intervención, porque al regular la función de la membrana neuronal va a determinar la función de numerosas vías de señalización. Pero por otro lado, la misma vía que determina pérdida de función es promotora de potenciación de sobrevida, por lo que, a corto plazo la reducción de la pérdida de colesterol puede llevar a mejorar la función cerebral y, a largo plazo, empeorar la sobrevida. Hay por lo tanto que buscar vías que estén involucradas en la pérdida de función sin para ello favorecer la sobrevida.


¿Es la plasticidad neuronal la clave de la memoria? ¿Cómo funciona concretamente, cuáles son los principales mecanismos moleculares implicados en la plasticidad y cómo se puede prevenir su deterioro en la vejez, para preservar la memoria, además de lo comentado?

Sí, la plasticidad sináptica es la clave de la memoria, y también del aprendizaje, del movimiento, del sueño y de todas las actividades desarrolladas por nuestro cerebro. Porque la plasticidad neuronal no es otra cosa que una propiedad intrínseca de las neuronas, su capacidad para reaccionar ante cualquier tipo de estímulo, sea este proveniente del ambiente externo o interno.



Cada estímulo que le llega a una neurona ésta luego lo procesa y, dependiendo de su intensidad, del estado previo de la neurona que lo recibe, del momento en que esto ocurre y de otras variables va a desencadenar una respuesta que puede ser inmediata o mediata, luego de ser almacenada y que va a dejar una marca más o menos duradera que podrá ser rescatada o sumada a nuevos estímulos.


El principal mecanismo molecular de la plasticidad neuronal es el cambio de potencial de membrana que ocurre cuando llega un estímulo, debido a la apertura de canales iónicos. Los cambios iónicos determinan a su vez cambios a nivel de la propia membrana y de proteínas inmediatamente subyacentes que a su vez producen cambios en el citoesqueleto que regula el tamaño y la dinámica de las sinapsis y también en la expresión de genes, que son, junto con las modificaciones estructurales de la sinapsis, los que contribuyen a que los cambios que ocurrieron durante el contacto puedan ser utilizados luego, en forma de un aprendizaje o recuerdos. Para prevenir la pérdida de plasticidad neuronal con la edad se han probado, y se siguen probando, numerosas estrategias, que van desde el mental training, estimulación visual, exposición a un ambiente rico en estímulos sensoriales, ejercicio, dieta y suplementos dietéticos, estimulación magnética transcraneal, y, por supuesto, medicamentos (especialmente aquellos que modulan los sistemas dopaminérgicos y colinérgicos). La indicación de cuál de éstas aplicar dependerá en primer lugar del grado de déficit cognitivo del sujeto y también del estado general del individuo, sus antecedentes.

Por otro lado, ¿qué ventajas aporta nuestra mosca del vinagre, Drosophila melanogaster, para el estudio de los efectos del paso del tiempo en el sistema nervioso, en nuestra biología? ¿Muchas complicaciones en la traslación de resultados, cuáles son las ventajas que mejor consideras?

El uso de Drosophila nos ha permitido identificar algunas de las vías bioquímicas esenciales involucradas en el proceso de envejecimiento normal del mamífero. También, gracias a la Drosophila hemos sido capaces de saber del alcance de defectos en proteínas involucradas en patologías humanas como es el Alzheimer. Naturalmente, la variabilidad (robustez) de sistemas complejos como el de mamífero hace que aspectos cognitivos complejos, su formación o su pérdida con la edad, no puedan ser fácilmente trasladables de la mosca al mamífero, mucho menos al humano. Por lo tanto, la Drosophila sigue y seguirá siendo un instrumento esencial para el descubrimiento de los mecanismos esenciales de la biología del sistema nervioso (el crecimiento celular, formación de grupos neuronales específicos, cómo se conectan, los mecanismos de muerte neuronal, la regeneración), aunque de menor valor para la comprensión de conductas complejas como son el aprendizaje de procesos complejos, la ansiedad, la sociabilidad. El uso de Drosophila tiene muchas ventajas pero, como cualquier modelo, no es útil para todo. 

¿Cómo se está enfocando ahora mismo, desde la medicina, el paliar los efectos del envejecimiento en las propiedades cognitivas y sus enfermedades asociadas y, cómo imaginas que en el futuro sea su prevención, su disminución en efectos negativos para nuestro bienestar con el transcurso de los años?

Creo esta pregunta está respondida en la pregunta 6. De todos modos, la prevención de la pérdida cognitiva se basará fundamentalmente en fomentar buenos hábitos de vida desde etapas tempranas, no cuando uno ya es mayor. Obviamente, esos hábitos buenos incluyen aspectos que no estarán al alcance de todos, ya que entre los buenos hábitos está el tener una vida con poco estrés, y eso es difícil de que sea posible para la mayoría de los mortales. Otras cosas sin embargo sí son posibles, como son la dieta saludable.



Aunque, otra vez, no es tan fácil tener una dieta saludable si uno debe trabajar 14 horas por día para poder llegar a fin de mes. Lo mismo pasa con el ejercicio. Lamentablemente, la mayor parte de las recomendaciones para tener una vejez saludable sólo la puede seguir una parte, mayor o menor según qué parte del mundo se mire, de la población.


Es en este punto donde la ciencia puede ayudar a “democratizar” el envejecimiento saludable, a través de la identificación de moléculas que estén involucradas en este proceso y sean susceptibles de ser atacadas por compuestos, naturales o sintéticos, que se puedan administrar, idealmente por vía oral. Si bien hay en el mercado numerosos suplementos anti-edad (coenzima Q-10, la combinación Selenio-Vitamina E, el Resveratrol, vitaminas anti-oxidantes (A, C, E), cúrcuma, extracto de arándano, la dehidroepiandrosterona o DHEA) no hay aún estudios clínicos que avalen que su uso vaya a prevenir los trastornos cognitivos con la edad. Hacer dichos estudios por otro lado llevaría muchísimos años (habría que seleccionar grupos de gente en edad adulta y analizarlos cuando mayores) y es más que probable que los resultados no vayan a ser homogéneos, dada la heterogeneidad genética y epigenética de los humanos. No estoy diciendo que no funcionen, simplemente que no hay ensayos clínicos sólidos que apoyen que funcionan en la prevención de los trastornos cognitivos de la edad.


Enlace a su grupo de investigación: http://www.cbm.uam.es/joomla-rl/index.php/en/scientific-departments?id=563
Comentarios:
 
chanyuan
chanyuan2017.07.26

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Carlos Dotti

Carlos Dotti

I have obtained a Medical Doctor degree from the National University of Córdoba in 1980 and PhD degree in Neuroendocrinology from the same university, under the sponsorship of the Argentine National Research Council (CONICET). Next I pursued two postdoctoral specializations, first (1985-1988) in the USA with a NIH Fogarty International Fellowship and second in Germany (1988-1991), with an Alexander von Humboldt fellowship at the European Molecular Biology Laboratory (EMBL). Between 1991 and 2000 I was independent researcher in the Department of Cell Biology at the European Molecular Biology Laboratory in Heidelberg (Germany). During this period I supervised two PhD theses (Frank Bradke and Eugenia Piddini) and 12 postdocs. Between 2000 and 2005 I acted as Scientific Director of the Cavalieri Ottolenghi Institute of Neuroscience at the University of Turin (Italy). During this period I directed 4 PhD theses and supervised numerous postdocs. In 2005 I took on a Full Professor position at the Department of Human Genetics of the Catholic University of Leuven (KUL). During this period I directed 4 PhD theses and supervised numerous postdocs. For family reasons I left his position in Belgium and moved to the CBMSO in Madrid (Spain) in 2009, with a Profesor de Investigación position from the Spanish National Research Council (CSIC). Since then I have built a Carlos G. Dotti laboratory with 3 postdocs, one technician, three PhD students and two Master students and have obtained consecutive funds from the Ministry of Economy and Competitiveness in 2010, 2013 and 2016; I have coordinated a Consolider network on the effect of age on normal and pathological cognitive deficits and I currently coordinate a BBVA grant.

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