Reprogramación celular para implementar rejuvenecimiento, manipular el reloj epigenético

El envejecimiento es un proceso natural que conlleva al deterioro de la homeostasis metabólica. En los últimos años han surgido varias estrategias interventivas para atenuar los efectos fisiológicos del mismo. En este contexto, la reprogramación celular mediada por el uso de factores de pluripotencia ha demostrado ser capaz de revertir el fenotipo celular envejecido. Más aún, los protocolos de rejuvenecimiento por reprogramación parcial han logrado revertir la edad biológica, medible por biomarcadores de gran precisión conocidos como relojes epigenéticos. Los alcances de la reprogramación parcial para revertir el deterioro cognitivo asociado al envejecimiento en humanos y roedores aún están siendo estudiados. Nuestro laboratorio cuenta con vasta experiencia en estudios de terapia génica mediante vectores adenovirales. Así, en este trabajo de tesis se propuso desarrollar y evaluar un sistema adenovectorial adecuado que permita implementar tanto rejuvenecimiento por reprogramación parcial de fibroblastos de ratas viejas y de voluntarios humanos sanos de edad avanzada como rejuvenecimiento in vivo en rata. Para tal fin, se desarrolló un adenovirus dependiente de auxiliar que posee los genes de pluripotencia Oct4, Sox2, Klf4 y cMyc, bajo el control de un promotor bidireccional que también controla la expresión de la GFP. Este vector fue caracterizado para su posterior uso en estudios de reprogramación parcial, demostrando su idoneidad para la realización de experimentos de rejuvenecimiento ex vivo e in vivo. Posteriormente, se evaluó su efecto rejuvenecedor en fibroblastos humanos y de rata. La sobreexpresión de los genes de pluripotencia en fibroblastos de rata hembra Sprague Dawley durante cinco días revirtió cambios epigenéticos asociados a la edad como la disminución de H3K9me3 y el aumento de beta-galactosidasa. Los fibroblastos humanos expuestos a los genes durante siete días aumentaron los niveles de organización de la heterocromatina y disminuyeron su inestabilidad genómica. Sin embargo, ni en los fibroblastos humanos ni en los murinos se lograron revertir todas las marcas de envejecimiento asociadas a factores epigenéticos. En cuanto a los estudios in vivo, los efectos en la cognición de los animales debido a cambios epigenéticos asociados al envejecimiento eran desconocidos. En este trabajo se demostró que los cambios asociados a la edad en la metilación de ciertas CpGs se correlacionan con el deterioro en la memoria de los animales, no así su edad epigenética. Finalmente, se evaluaron los efectos de la terapia génica con el adenovirus OSKM en el giro dentado de la rata hembra envejecida sobre el detrimento observado en la memoria espacial y aprendizaje de los animales. Observamos que los animales expuestos a los genes OSKM no sufrieron una mayor letalidad. Además, aumentaron su desempeño cognitivo, mostrando un aprendizaje acelerado. Sin embargo, el tratamiento no alcanzó a revertir su deterioro en la memoria. Este trabajo de tesis es el primer estudio de rejuvenecimiento in vivo en hipocampo de rata envejecida y sus implicancias cognitivas. De igual manera, los hallazgos en envejecimiento epigenético asociados a la pérdida de la memoria espacial de la rata resultan de gran relevancia para este campo.Facultad de Ciencias Exacta

Rejuvenation by cell reprogramming: A new horizon in gerontology

The discovery of animal cloning and subsequent development of cell reprogramming technology were quantum leaps as they led to the achievement of rejuvenation by cell reprogramming and the emerging view that aging is a reversible epigenetic process. Here, we will first summarize the experimental achievements over the last 7 years in cell and animal rejuvenation. Then, a comparison will be made between the principles of the cumulative DNA damage theory of aging and the basic facts underlying the epigenetic model of aging, including Horvath's epigenetic clock. The third part will apply both models to two natural processes, namely, the setting of the aging clock in the mammalian zygote and the changes in the aging clock along successive generations in mammals. The first study demonstrating that skin fibroblasts from healthy centenarians can be rejuvenated by cell reprogramming was published in 2011 and will be discussed in some detail. Other cell rejuvenation studies in old humans and rodents published afterwards will be very briefly mentioned. The only in vivo study reporting that a number of organs of old progeric mice can be rejuvenated by cyclic partial reprogramming will also be described in some detail. The cumulative DNA damage theory of aging postulates that as an animal ages, toxic reactive oxygen species generated as byproducts of the mitochondria during respiration induce a random and progressive damage in genes thus leading cells to a progressive functional decline. The epigenetic model of aging postulates that there are epigenetic marks of aging that increase with age, leading to a progressive derepression of DNA which in turn causes deregulated expression of genes that disrupt cell function. The cumulative DNA damage model of aging fails to explain the resetting of the aging clock at the time of conception as well as the continued vitality of species as millenia go by. In contrast, the epigenetic model of aging straightforwardly explains both biologic phenomena. A plausible initial application of rejuvenation in vivo would be preventing adult individuals from aging thus eliminating a major risk factor for end of life pathologies. Further, it may allow the gradual achievement of whole body rejuvenation.Fil: Goya, Rodolfo Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Lehmann, Marianne. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Chiavellini, Priscila. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Canatelli Mallat, Martina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Hereñú, Claudia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; ArgentinaFil: Brown, Oscar Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentin

Construcción de un adenovirus recombinante regulable portador de los genes de pluripotencia y de gen GFP para implementar en rejuvenecimiento celular mediante reprogramación celular parcial

La reprogramación celular convencional involucra convertir un linaje celular somático a células madre pluripotentes inducidas (iPSC), las cuales pueden ser posteriormente rediferenciadas a tipos celulares específicos. De manera alternativa, la reprogramación celular parcial convierte células somáticas en otros tipos celulares por expresión transitoria de genes de pluripotencia, procedimiento que genera intermediarios celulares pluripotentes que retienen la identidad celular original, pero que están rejuvenecidos y responden a cócteles apropiados de factores de diferenciación específicos. En este contexto, el rejuvenecimiento por reprogramación celular parcial constituye un campo de investigación emergente. Para su implementación, los sistemas de expresión regulables policistrónicos, generalmente integrativos, son ampliamente utilizados. Con el mismo propósito, hemos construido un adenovirus recombinante (no integrativo) regulable de alta capacidad que contiene el gen de la proteína fluorescente verde (GFP) y los genes oct4, sox2, klf4 y c-myc (OSKM, o genes de pluripotencia). Estos genes OSKM se encuentran ensamblados como un tándem bicistrónico (STEMCCA) bajo el control de un promotor bidireccional regulable por sistema Tet-Off que controla también la expresión de la GFP. Separadamente, un segundo cassette expresa constitutivamente la proteína regulatoria tTA. En este trabajo se describe la generación de dicho adenovector dependiente de virus auxiliar y la caracterización del mismo mediante diversas técnicas. Este adenovector constituye una herramienta promisoria para la implementación de reprogramación parcial no integrativa.Eje: Salud humanaInstituto de Investigaciones Bioquímicas de La Plat

A hierarchical model for the control of epigenetic aging in mammals

Regulatory mechanisms range from a single level of control in simple metazoans to multi-level hierarchical control networks in higher animals. Organismal regulation encompasses homeostatic and circadian networks that are interconnected, with no documented exceptions. The epigenetic clock is a highly accurate biomarker of age in humans, defined by a mathematical algorithm based on the methylation of a subset of age-related CpG sites on DNA. Experimental evidence suggests the existence of an underlying regulatory mechanism. By analogy with other integrative systems as the neuroendocrine-immune network and the circadian clocks, a hierarchical organization in the control of the ticking rate of the epigenetic clock is hypothesized here. The hierarchical organization of the neuroendocrine, immune and circadian systems is briefly reviewed. This is followed by a brief review of the epigenetic clock at cell level. Finally, different lines of indirect evidence, consistent with the existence of a central pacemaker controlling the ticking rate of the epigenetic clock at organismal level are discussed. The concluding remarks put the hierarchical model proposed for the control of the clock into an evolutionary perspective. Within this perspective, the present hypothesis is intended as a conceptual outline based on designs consistently favored by evolution in higher animals.Instituto de Investigaciones Bioquímicas de La Plat

Age-related loss of recognition memory and its correlation with hippocampal and perirhinal cortex changes in female Sprague Dawley rats

Ageing is associated with impaired performance in recognition memory, a process that consists of the discrimination of familiar and novel stimuli. Previous studies have shown the impact of ageing on object recognition memories. However, the early stages of memory impairment remain unknown. To fill this gap, we aimed at evaluating the ability of young (Y), middle-aged (MA), and senile (S) female Sprague-Dawley rats to retain 24 h long-term recognition memory. The MA cohort was included to characterise early memory deficits under two behavioural paradigms based on spontaneous location recognition (SLR) and spontaneous object recognition (SOR) tasks. In the SLR task, there was a markedly diminished novel discrimination capacity in the MA and S rats compared with the Y ones. In the SOR task, S rats evidenced a deterioration in novelty discrimination, while MA rats partially preserved the capacity to distinguish the new stimulus as compared with Y rats. Regarding early changes from MA to S rats, immunohistochemistry showed a marked decrease in the number and diameter of adult-born immature neurons in the Dentate Gyrus (DG) with a positive correlation with behavioural performance in the SLR task. Furthermore, we found a slight reduction in CA3 mature neurons and a decrease in the number of total microglia in the perirhinal cortex (Prh) in MA and S rats as compared with Y rats. As regards changes that were only observed in S rats, we found an increase in the number of total and reactive microglia in CA3 and a reduction in the number of total microglia in the DG. We conclude that spatial discrimination capacity could be affected earlier than feature discrimination capacity. We suggest that early depletion of neurogenesis in MA rats is involved in object location recognition deficits, whereas the disruption of microglial homeostasis in the Prh could be associated with object feature discrimination capacity.Instituto de Investigaciones Bioquímicas de La Plat

Aging and rejuvenation - a modular epigenome model

The view of aging has evolved in parallel with the advances in biomedical sciences. Long considered as an irreversible process where interventions were only aimed at slowing down its progression, breakthrough discoveries like animal cloning and cell reprogramming have deeply changed our understanding of postnatal development, giving rise to the emerging view that the epigenome is the driver of aging. The idea was significantly strengthened by the converging discovery that DNA methylation (DNAm) at specific CpG sites could be used as a highly accurate biomarker of age defined by an algorithm known as the Horvath clock. It was at this point where epigenetic rejuvenation came into play as a strategy to reveal to what extent biological age can be set back by making the clock tick backwards. Initial evidence suggests that when the clock is forced to tick backwards in vivo, it is only able to drag the phenotype to a partially rejuvenated condition. In order to explain the results, a bimodular epigenome is proposed, where module A represents the DNAm clock component and module B the remainder of the epigenome. Epigenetic rejuvenation seems to hold the key to arresting or even reversing organismal aging.Instituto de Investigaciones Bioquímicas de La Plat

Reversing age: Dual species measurement of epigenetic age with a single clock

Young blood plasma is known to confer beneficial effects on various organs in mice. However, it was not known whether young plasma rejuvenates cells and tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly-accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n=593 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain-, liver-, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n=850 human tissue samples to the training data. We employed these six clocks to investigate the rejuvenation effects of a plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. Cellular senescence, which is not associated with epigenetic aging, was also considerably reduced in vital organs. Overall, this study demonstrates that a plasma-derived treatment markedly reverses aging according to epigenetic clocks and benchmark biomarkers of aging.Fil: Horvath, Steve. University of California at Los Angeles; Estados UnidosFil: Singh, Kavita. NMIMS University; IndiaFil: Raj, Ken. Public Health England; Reino UnidoFil: Khairnar, Shraddha. NMIMS University; IndiaFil: Sanghav, Akshay. Nugenics Research Pvt Ltd; IndiaFil: Shrivastava, Agnivesh. Nugenics Research Pvt Ltd; IndiaFil: Zoller, Joseph A.. University of California at Los Angeles; Estados UnidosFil: Li, Caesar Z.. University of California at Los Angeles; Estados UnidosFil: Hereñú, Claudia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; ArgentinaFil: Canatelli Mallat, Martina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Lehmann, Marianne. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Solberg Woods, Leah C.. Wake Forest University School of Medicine; Estados UnidosFil: Garcia Martinez, Angel. University of Tennessee; Estados UnidosFil: Wang, Tengfei. University of Tennessee; Estados UnidosFil: Chiavellini, Priscila. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Levine, Andrew J.. University of California at Los Angeles; Estados UnidosFil: Chen, Hao. University of Tennessee; Estados UnidosFil: Goya, Rodolfo Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Katcher, Harold L.. Nugenics Research Pvt Ltd; Indi

A hierarchical model for the control of epigenetic aging in mammals

Regulatory mechanisms range from a single level of control in simple metazoans to multi-level hierarchical control networks in higher animals. Organismal regulation encompasses homeostatic and circadian networks that are interconnected, with no documented exceptions. The epigenetic clock is a highly accurate biomarker of age in humans, defined by a mathematical algorithm based on the methylation of a subset of age-related CpG sites on DNA. Experimental evidence suggests the existence of an underlying regulatory mechanism. By analogy with other integrative systems as the neuroendocrine-immune network and the circadian clocks, a hierarchical organization in the control of the ticking rate of the epigenetic clock is hypothesized here. The hierarchical organization of the neuroendocrine, immune and circadian systems is briefly reviewed. This is followed by a brief review of the epigenetic clock at cell level. Finally, different lines of indirect evidence, consistent with the existence of a central pacemaker controlling the ticking rate of the epigenetic clock at organismal level are discussed. The concluding remarks put the hierarchical model proposed for the control of the clock into an evolutionary perspective. Within this perspective, the present hypothesis is intended as a conceptual outline based on designs consistently favored by evolution in higher animals.Fil: Lehmann, Marianne. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Canatelli Mallat, Martina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Chiavellini, Priscila. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Goya, Rodolfo Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentin

Therapeutic potential of glial cell line-derived neurotrophic factor and cell reprogramming for hippocampal-related neurological disorders

Hippocampus serves as a pivotal role in cognitive and emotional processes, as wellas in the regulation of the hypothalamus-pituitary axis. It is known to undergo mildneurodegenerative changes during normal aging and severe atrophy in Alzheimer?sdisease. Furthermore, dysregulation in the hippocampal function leads to epilepsyand mood disorders. In the first section, we summarized the most salient knowledgeon the role of glial cell-line-derived neurotrophic factor and its receptors focused onaging, cognition and neurodegenerative and hippocampal-related neurological diseasesmentioned above. In the second section, we reviewed the therapeutic approaches,particularly gene therapy, using glial cell-line-derived neurotrophic factor or its gene, asa key molecule in the development of neurological disorders. In the third section, wepointed at the potential of regenerative medicine, as an emerging and less exploredstrategy for the treatment of hippocampal disorders. We briefly reviewed the use of partialreprogramming to restore brain functions, non-neuronal cell reprogramming to generateneural stem cells, and neural progenitor cells as source-specific neuronal types to beimplanted in animal models of specific neurodegenerative disorders.Fil: Chiavellini, Priscila. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Canatelli Mallat, Martina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Lehmann, Marianne. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Goya, Rodolfo Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Morel, Gustavo Ramón. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentin

Rejuvenation by cell reprogramming: a new horizon in gerontology

The discovery of animal cloning and subsequent development of cell reprogramming technology were quantum leaps as they led to the achievement of rejuvenation by cell reprogramming and the emerging view that aging is a reversible epigenetic process. Here, we will first summarize the experimental achievements over the last 7 years in cell and animal rejuvenation. Then, a comparison will be made between the principles of the cumulative DNA damage theory of aging and the basic facts underlying the epigenetic model of aging, including Horvath's epigenetic clock. The third part will apply both models to two natural processes, namely, the setting of the aging clock in the mammalian zygote and the changes in the aging clock along successive generations in mammals. The first study demonstrating that skin fibroblasts from healthy centenarians can be rejuvenated by cell reprogramming was published in 2011 and will be discussed in some detail. Other cell rejuvenation studies in old humans and rodents published afterwards will be very briefly mentioned. The only in vivo study reporting that a number of organs of old progeric mice can be rejuvenated by cyclic partial reprogramming will also be described in some detail. The cumulative DNA damage theory of aging postulates that as an animal ages, toxic reactive oxygen species generated as byproducts of the mitochondria during respiration induce a random and progressive damage in genes thus leading cells to a progressive functional decline. The epigenetic model of aging postulates that there are epigenetic marks of aging that increase with age, leading to a progressive derepression of DNA which in turn causes deregulated expression of genes that disrupt cell function. The cumulative DNA damage model of aging fails to explain the resetting of the aging clock at the time of conception as well as the continued vitality of species as millenia go by. In contrast, the epigenetic model of aging straightforwardly explains both biologic phenomena. A plausible initial application of rejuvenation in vivo would be preventing adult individuals from aging thus eliminating a major risk factor for end of life pathologies. Further, it may allow the gradual achievement of whole body rejuvenation.Facultad de Ciencias MédicasInstituto de Investigaciones Bioquímicas de La Plat