RESUMEN
Aging is a complex process resulting from, among other, dynamic non-linear interactions between genetics and environment. Centenarians are the best example of successful aging in humans, as they escaped from, or largely postponed, major age-related diseases. Ionic fluxes changes play a key role in several patho-physiological cellular processes, but their relation to human aging is largely unexplored. In the present study we have compared patch-clamp potassium (K(+)) current recordings from dermal fibroblasts (DF) obtained from young, elderly and centenarian donors. We found that in DF from elderly donors, but not from centenarians, K(+) current amplitude is significantly smaller with respect to DF from young donors. Moreover, cell membrane capacitance of DF from elderly donors is smaller with respect to young donors and centenarians. We also observed that the voltage-gated Shaker Kv1.1 channel is expressed in higher percentage of elderly's and centenarian's DF than young's, whereas the large-conductance calcium-activated K(+) (BK(Ca)) channel ß1 subunit is expressed in lower percentage of centenarian's DF than in elderly's and young's. The maintenance of "young" K(+) currents and the peculiar age-related remodeling of K(+) channel subtypes in centenarian's DF is likely associated with successful aging and might provide a predictive marker of longevity.
Asunto(s)
Envejecimiento/metabolismo , Canales de Potasio de Gran Conductancia Activados por el Calcio/metabolismo , Canales de Potasio de la Superfamilia Shaker/metabolismo , Piel/metabolismo , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Membrana Celular/metabolismo , Células Cultivadas , Fibroblastos/metabolismo , Humanos , Canal de Potasio Kv.1.1/metabolismo , Piel/citología , Adulto JovenRESUMEN
BACKGROUND: Significance analysis at single gene level may suffer from the limited number of samples and experimental noise that can severely limit the power of the chosen statistical test. This problem is typically approached by applying post hoc corrections to control the false discovery rate, without taking into account prior biological knowledge. Pathway or gene ontology analysis can provide an alternative way to relax the significance threshold applied to single genes and may lead to a better biological interpretation. RESULTS: Here we propose a new analysis method based on the study of networks of pathways. These networks are reconstructed considering both the significance of single pathways (network nodes) and the intersection between them (links). We apply this method for the reconstruction of networks of pathways to two gene expression datasets: the first one obtained from a c-Myc rat fibroblast cell line expressing a conditional Myc-estrogen receptor oncoprotein; the second one obtained from the comparison of Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia derived from bone marrow samples. CONCLUSION: Our method extends statistical models that have been recently adopted for the significance analysis of functional groups of genes to infer links between these groups. We show that groups of genes at the interface between different pathways can be considered as relevant even if the pathways they belong to are not significant by themselves.
Asunto(s)
Algoritmos , Perfilación de la Expresión Génica/métodos , Modelos Biológicos , Mapeo de Interacción de Proteínas/métodos , Proteoma/metabolismo , Transducción de Señal/fisiología , Programas Informáticos , Simulación por Computador , Interpretación Estadística de Datos , Modelos EstadísticosRESUMEN
In this paper we analyzed how connectivity (defined as number of connections between network elements) can affect the memory capacity of a network-based model of the Immune System (IS) and of a model of the Nervous System (NS) synaptic plasticity (BCM model). The key point is the concept of competition between the characteristic variables that represent the response of such systems to environmental stimuli: the clonal concentrations for the IS, and the neuron responses for the BCM model. The memory states of both systems are characterized by a high selectivity to specific input patterns, reflecting a similar behaviour of their development rules. This selectivity property of memory states can be controlled by changing the degree of the internal connectivity in each system. We can explain the changes occurring in IS memory states during lifespan as due to a reshaping of its internal connectivity. This assumption is in agreement with experimental observations, reporting an increase of IS memory cells during lifespan. The change of connectivity in the BCM model leads to the introduction of quasilocal variables governing the plasticity of groups of synaptic junctions. This could be interpreted as the result of a refinement of neuron internal mechanisms during development, or it could be seen as a different learning rule deriving from the original BCM theory. We argue that connectivity seems to play an important role in a large class of biological systems controlled by competition mechanisms. Moreover, changes in connectivity may lead to changes in memory properties during development and aging.