RESUMEN

As human life expectancy is prolonged, age-related diseases are thriving. Aging is a complex multifactorial process of molecular and cellular decline that affects tissue function over time, rendering organisms frail and susceptible to disease and death. Over the last decades, a growing body of scientific literature across different biological models, ranging from yeast, worms, flies, and mice to primates, humans and other long-lived animals, has contributed greatly towards identifying conserved biological mechanisms that ward off structural and functional deterioration within living systems. Collectively, these data offer powerful insights into healthy aging and longevity. For example, molecular integrity of the genome, telomere length, epigenetic landscape stability, and protein homeostasis are all features linked to "youthful" states. These molecular hallmarks underlie cellular functions associated with aging like mitochondrial fitness, nutrient sensing, efficient intercellular communication, stem cell renewal, and regenerative capacity in tissues. At present, calorie restriction remains the most robust strategy for extending health and lifespan in most biological models tested. Thus, pathways that mediate the beneficial effects of calorie restriction by integrating metabolic signals to aging processes have received major attention, such as insulin/insulin growth factor-1, sirtuins, mammalian target of rapamycin, and 5' adenosine monophosphate-activated protein kinase. Consequently, small-molecule targets of these pathways have emerged in the impetuous search for calorie restriction mimetics, of which resveratrol, metformin, and rapamycin are the most extensively studied. A comprehensive understanding of the molecular and cellular mechanisms that underlie age-related deterioration and repair, and how these pathways interconnect, remains a major challenge for uncovering interventions to slow human aging while extending molecular and physiological youthfulness, vitality, and health. This review summarizes key molecular mechanisms underlying the biology of healthy aging and longevity.

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RESUMEN

Among diverse environmental factors that modify aging, diet has a profound effect. Calorie restriction (CR), which entails reduced calorie consumption without malnutrition, is the only natural regimen shown to extend maximum and mean lifespan, as well as healthspan in a wide range of organisms. Although the knowledge about the biological mechanisms underlying CR is still incipient, various approaches in biogerontology research suggest that CR can ameliorate hallmarks of aging at the cellular level including telomere erosion, epigenetic alterations, stem cells depletion, cellular senescence, mitochondrial dysfunction, genomic instability, proteostasis imbalance, impaired nutrient sensing and abnormal intercellular communication. Currently, the NAD + /sirtuin pathway is one of the few mechanisms described to mediate CR effects and sirtuin-activating compounds (STACs) mimic many effects of CR. Herein, we discuss the effects of CR on healthspan with emphasis on neuroprotection, how CR counteracts cellular aging, how sirtuin pathways intertwine with CR, and the relevance of STACs in mimicking CR effects.

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RESUMEN

La forma de estudiar la genética ha progresado notablemente en las últimas décadas. Sus orígenes se remontan al estudio de los caracteres hereditarios, seguido por el descubrimiento de los genes y los cromosomas hasta conocer la estructura del ADN. Este último evento impulsó el desarrollo de la tecnología del ADN recombinante y de la secuenciación masiva y automatizada, los cuales permitieron determinar posterior-mente la anatomía de los genomas. Todos estos descubrimientos han promovido la evolución de la biomedicina hacia las eras genómica y posgenómica en las que el uso de la genética reversa impera sobre la genética básica o directa. Además, surge la genética molecular, la genómica funcional y las diversas tecnologías -ómicas- que en conjunto pretenden comprender de manera integral la función de todos los componentes del genoma y sus productos. La biogerontología, disciplina que estudia los mecanismos biológicos del envejecimiento, es uno de los campos que se han desarrollado notoriamente en los últimos 15 años y refleja los avances científicos de la era posgenómica. Actualmente se han identificado varios gerontogenes y vías moleculares que modifican longevidad y regulan procesos y enfermedades relacionadas con envejecimiento. Dentro de estos genes se encuentran las sirtuinas, una familia de genes conservada evolutivamente que codifica para proteínas con actividad de desacetilasa dependiente de NAD+ y que tienen un papel importante en envejecimiento. En este trabajo revisamos diferentes aproximaciones de genética reversa que se han empleado para identificar algunas de las funciones de estos genes en mamíferos.

The way to study genetics has notably progressed in the last decades. Their origins date back to the study of hereditary features, followed by the discovery of genes and chromosomes up to the knowledge of DNA structure. This last event led to the development of recombinant DNA technology and the massive and automated sequencing, which allowed later to determine the anatomy of genomes. All of these discoveries have pushed the evolution of biomedicine towards the genomic and postgenomic eras, in which the use of reverse genetics prevails over the basic or direct one. Furthermore, it emerges the molecular genetics, the functional genomics and the diverse -omics- technologies that together pretend to understand, in an integrative way, the function of all of the genome components and its products. Biogerontology, discipline that studies the biological mechanisms of aging, is one of the fields that has developed notoriously in the last 15 years and reflects the scientific advances of the postgenomic era. Currently, there have been identified several gerontogenes and molecular pathways that modify and regulate age-related processes and diseases. Among these genes are the sirtuins, an evolutionarily preserved family of genes, which codify for proteins with NAD+ dependent deacetylase activity and that play an important role on aging. In this work, we review different reverse genetics approaches that have been used in order to identify some of the functions of these genes in mammals.