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Introduction
I am head of a research group whose overall research focuses on the implementation of regenerative medicine in the aging brain. For this purpose we have constructed adenoviral vectors expressing the Yamanaka rejuvenation genes (OSKM). With these vectors we implement OSKM gene therapy in the hippocampus and hypothalamus of the old rat brain with the goal to reverse their memory and reproductive age-related deficits. Another major research line is life extension by young plasma.
Publications
Publications (216)
Using DNA methylation profiles (n = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex...
Using DNA methylation profiles (n = 15,456) from 348 mammalian species, we constructed phyloepigenetic
trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all
samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life
span, adult weight, age, sex...
Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from
our Mammalian Methylation Consortium, which encompass 59 tissue
types acr...
Young blood plasma is known to confer beneficial effects on various organs in mice and rats. However, it was not known whether plasma from young pigs rejuvenates old rat 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 validat...
ABSTRACT
The discovery of extrasolar planets as well as the growing number or earth-like exoplanets being detected almost routinely, is galvanizing the interest of the public and space agencies alike to plan for exploratory missions to the exoplanets more likely to harbor life. For manned interstellar space flight, ultralow subzero suspended animat...
Impaired performance in spatial learning and memory during aging in rats is associated with morphological and molecular changes in the brain, particularly in the hippocampus. Here, we assessed the cognitive performance of young (3.5 mo.) untreated rats and old (25.3 mo.) treated and control rats. Treatment was carried out by intrahippocampal inject...
There is substantial evidence that age-related ovarian failure in rats is preceded by abnormal responsiveness of the neuroendocrine axis to estrogen positive feedback. In middle-aged (M-A) female rats, we have demonstrated that intrahypothalamic gene therapy for insulin-like growth factor-I (IGF-I) started at 6 months of age extends the regular cyc...
The view of aging, long considered as an irreversible process, has evolved thanks to breakthrough discoveries like animal cloning and cell reprogramming which deeply changed our understanding of postnatal development, giving rise to the view that aging is a reversible epigenetic process. The hypothesis was significantly strengthened by the finding...
There is converging evidence that young blood conveys cells, vesicles and molecules able to revitalize function and restore organ integrity in old individuals. Here, we assessed the effects of young rat plasma on the lifespan, epigenetic age and healthspan of old female rats. Beginning at 25.3 months of age, a group of 9 rats (group T) was intraper...
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 you...
In humans and rats, aging is associated with a progressive deterioration of spatial learning and memory. These functional alterations are correlated with morphological and molecular changes in the brain, particularly in the hippocampus. Here, we assessed age-related changes in DNA methylation (DNAm) landscape in the rat hippocampus and the correlat...
In humans and rats, aging is associated with a progressive deterioration of spatial learning and memory. These functional alterations are correlated with morphological and molecular changes in the hippocampus. Here, we assessed age-related changes in DNA methylation (DNAm) landscape in the rat hippocampus and the correlation of spatial memory with...
Suspended animation (SA) is the temporary (short- or long-term) slowing or stopping of biological processes. Here, we will briefly review the current state of human long-term SA. There are two main fields where long-term SA constitutes an irreplaceable technology, namely manned deep space travel and cryonics, the cryopreservation of humans after cl...
Living indefinitely young is the oldest dream of humanity. The relatively recent achievement of cell reprogramming paved the way for the successful implementation of full rejuvenation of cells from old mammals. This paradigm shift revealed that a small number of master genes could take a senile somatic cell from a state of apparently terminal dysfu...
Hippocampus serves as a pivotal role in cognitive and emotional processes, as well as in the regulation of the hypothalamus-pituitary axis. It is known to undergo mild neurodegenerative changes during normal aging and severe atrophy in Alzheimer's disease. Furthermore, dysregulation in the hippocampal function leads to epilepsy and mood disorders....
Epigenetic predictors of maximum lifespan and other life history traits in mammals
The list of authors shown in the title page of Research Gate is incomplete and in incorrect order. The correct list of authors is as follows.
Li, C.Z.1#; Haghani, A.2#; Robeck, T.R.3; Villar, D.4; Lu, A.T.2; Zhang, J.2; Faulkes, C.G.5; Vu, H.6; Ablaeva, J.7; Adams,...
Maximum lifespan of a species is the oldest that individuals can survive, reflecting the genetic limit of longevity in an ideal environment. Here we report methylation-based models that accurately predict maximum lifespan (r=0.89), gestational time (r=0.96), and age at sexual maturity (r=0.87), using cytosine methylation patterns collected from ove...
In humans and rats, aging is associated with a progressive deterioration of spatial learning and memory. These functional alterations are correlated with morphological and molecular changes in the brain, particularly in the hippocampus. Here, we assessed the age-related changes in the DNA methylation (DNAm) landscape in the rat hippocampus and asse...
Epigenetics has hitherto been studied and understood largely at the level of individual organisms. Here, we report a multi-faceted investigation of DNA methylation across 11,117 samples from 176 different species. We performed an unbiased clustering of individual cytosines into 55 modules and identified 31 modules related to primary traits includin...
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 eme...
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 eme...
ABSTRACT
Aging is often perceived as a degenerative process caused by random accrual of cellular damage over time. In spite of this, age can be accurately estimated by epigenetic clocks based on DNA methylation profiles from almost any tissue of the body. Since such pan-tissue epigenetic clocks have been successfully developed for several different...
Hippocampus serves as a pivotal role in cognitive and emotional processes, as well as in the regulation of the hypothalamus-pituitary axis. It is known to undergo mild neurodegenerative changes during normal aging and severe atrophy in Alzheimer's disease. Furthermore, dysregulation in the hippocampal function leads to epilepsy and mood disorders....
Spatial memory performance declines in both normal aging and Alzheimer's disease. This cognitive deficit is related to hippocampus dysfunction. Gene therapy using neurotrophic factors like Glial cell line-derived neurotrophic factor (GDNF) emerges as a promising approach to ameliorate age-related cognitive deficits. We constructed a two vector regu...
Rejuvenation by cell reprogramming of fibroblasts from healthy centenarian individuals- In culture, fibroblasts from old individuals display a typical transcriptional signature, different from that of young counterparts as well as shortened telomeres, reduced population doubling (PD) potential, dysfunctional mitochondria and higher levels of oxidat...
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...
Several countries have established self-help cryonics groups whose mission is to cryopreserve human bodies or brains after legal death and ship them to cryonics organizations. The objective here is to report the first case of human brain cryopreservation in Argentina as well as complementary experiments in rats. After legal death, the body of a 78...
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 emerged in 2013 as a highly accurate biomarker of age in huma...
A comprehensive study of relevant aspects of the physics behind in vitro magnetic assisted transfection, or magnetofection is presented. Magnetofection experiments were performed as a function of culture-magnet distance for a fixed time of 30 min, as a function of time for a fixed separation of about 1 mm, and under special geometries chosen to elu...
Biological rejuvenation by partial cell reprogramming is an emerging avenue of research. In this context, regulatable pluripotency gene expression systems are the most widely used at present. We have constructed a regulatable bidirectional adenovector expressing the humanized green fluorescent protein (GFP) and oct4, sox2, klf4, and c-myc genes (kn...
BACKGROUND
Conventional cell reprogramming involves converting a somatic cell line into induced pluripotent stem cells (iPSC), which subsequently can be re-differentiated to specific somatic cell types. Alternatively, partial cell reprogramming converts somatic cells into other somatic cell types by transient expression of pluripotency genes thus g...
Aging is associated with impaired performance in behavioral pattern separation (PS) tasks based on similarities in object features and in object location. Hippocampal dentate gyrus (DG) is required for PS. DG is thought to preprocess information, which facilitates pattern completion in the CA3 region.
In order to evaluate the effect of aging on obj...
Conventional cell reprogramming involves converting a somatic cell line into induced pluripotent stem cells (iPSC), which subsequently can be re-differentiated to specific somatic cell types. Alternatively, partial cell reprogramming converts somatic cells into other somatic cell types by transient expression of pluripotency genes thus generating i...
There is a growing interest in the potential of adult stem cells for implementing regenerative medicine in the brain. We assessed the effect of intracerebroventricular (icv) administration of human umbilical cord perivascular cells (HUCPVCs) on spatial memory of senile (27 mo) female rats, using intact senile counterparts as controls. Approximately...
There is a growing interest in the potential of mesenchymal stem cells (MSCs) for implementing regenerative medicine in the brain as they have shown neurogenic and immunomodulatory activities.
We assessed the effect of intracerebroventricular (icv) administration of human bone marrow-derived MSCs (hBM-MSCs) on spatial memory and hippocampal morphol...
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...
Background:
Insulin-like growth factor1 (IGF1) is a powerful neuroprotective molecule. We have previously shown that short-term hypothalamic IGF1 gene therapy restores tuberoinfundibular dopaminergic neuron function in aging female rats.
Objective:
Our aim was to implement long-term IGF-I gene therapy in pituitary prolactinomas in senile female...
Insulin-like growth factor 1 receptor (IGF-1R) signaling regulates the activity and phosphorylation of downstream kinases linked to inflammation, neurodevelopment, aging and synaptic function. In addition to the control of Ca2+ currents, IGF-1R signaling modulates the activity of calcium-calmodulin-dependent kinase 2 alpha (CaMKIIα) and mitogen act...
El envejecimiento se encuentra asociado a un aumento en la incidencia de enfermedades neu-rodegenerativas tanto en el hombre como en los animales de laboratorio. En el hombre, este fenómeno se manifiesta en dos enfermedades principales, la de Alzheimer y la de Parkinson. En la actualidad sólo se dispone de tratamientos paliativos para ambas dolenci...
The aging female rat constitutes an interesting model of spontaneous and progressive age-related dopaminergic dysfunction as it allows assessing new therapeutic strategies for Parkinson's disease. Insulin-like growth factor I (IGF-I) is emerging as a powerful neuroprotective molecule which is strongly induced in the central nervous system after dif...
Thymulin is a thymic peptide possessing anti-inflammatory effects. In order to manipulate thymulin expression in gene therapy studies, we built a bidirectional regulatable two-vector Tet-Off system and the corresponding control system. The experimental two-vector system, ETV, consists of a recombinant adenovector (RAd) harboring an expression casse...
In rats, learning and memory performance decline during normal aging, which makes this rodent species a suitable model to evaluate therapeutic strategies. In aging rats, insulin-like growth factor-I (IGF-I), is known to significantly improve spatial memory accuracy as compared to control counterparts. A constellation of gene expression changes unde...
The achievement of animal cloning and subsequent development of cell reprogramming technology are having a profound impact on our view of the mechanisms of aging in complex organisms. The experimental evidence showing that an adult somatic nucleus implanted into an enucleated oocyte can give rise to a whole new individual strongly suggests that the...
There have been a few descriptive studies in aged rodents about transcriptome changes in the hippocampus, most of them in males. Here, we assessed the age changes in spatial memory performance and hippocampal morphology in female rats and compared those changes with changes in the hippocampal transcriptome. Old rats displayed significant deficits i...
In rats, learning and memory performance decline during normal aging, which is paralleled by a severe reduction of the levels of neurogenesis in the hippocampal dentate gyrus (DG). A promising therapeutic strategy to restore neurogenesis in the hippocampus of old rats and their spatial memory involves the use of insulin-like growth factor-I (IGF-I)...
In rats, learning and memory performance decline during aging, which makes this rodent species a suitable model to evaluate therapeutic strategies of potential value for correcting age-related cognitive deficits. Some of these strategies involve neurotrophic factors like insulin-like growth factor-I (IGF-I), a powerful neuroprotective molecule in t...
The goal of magnetic field-assisted gene transfer is to enhance internalization of exogenous nucleic acids by association with magnetic nanoparticles (MNPs). This technique named magnetofection is particularly useful in difficult-to-transfect cells. It is well known that human, mouse, and rat skeletal muscle cells suffer a maturation-dependent loss...
El envejecimiento se encuentra asociado a un aumento en la incidencia de enfermedades neu-rodegenerativas tanto en el hombre como en los animales de laboratorio. En el hombre, este fenómeno se manifiesta en dos enfermedades principales, la de Alzheimer y la de Parkinson. En la actualidad sólo se dispone de tratamientos paliativos para ambas dolenci...
Background:
There is a growing interest in the potential of mesenchymal stem cells (MSC) for implementing regenerative medicine.
Methods:
We assessed the effect of intravenous administration of human bone marrow-derived MSC on the lifespan of a single Sprague-Dawley female rat. The treatment was started when the rat was 6 months old and the cell...
The quantification of aspartic acid racemization in the proteins of non-metabolically active tissues can be used as a measure of chronological aging in humans and other long-lived organisms. However, very few studies have been conducted in shorter-lived animals such as rodents, which are increasingly used as genetic and metabolic models of aging. A...
The characteristics of neurological, psychiatric, developmental and substance-use disorders in low-and middle-income countries are unique and the burden that they have will be different from country to country. Many of the differences are explained by the wide variation in population demographics and size, poverty, conflict, culture, land area and...
The hippocampus, a medial temporal lobe structure necessary for the formation of spatial memory, is particularly affected by both normal and pathologic aging. In previous studies, we observed a significant age-related increase in dopaminergic neuron loss in the hypothalamus and the substantia nigra of female rats, which becomes more conspicuous at...
In the central nervous system, cholinergic and dopaminergic (DA) neurons are among the cells most susceptible to the deleterious effects of age. Thus, the basal forebrain cholinergic system is known to undergo moderate neurodegenerative changes during normal aging as well as severe atrophy in Alzheimer's disease (AD). Parkinson's disease (PD), a de...
El envejecimiento se encuentra asociado a un aumento en la incidencia de enfermedades neurodegenerativas tanto en el hombre como en los animales de laboratorio. En el hombre, este fenómeno se manifiesta en dos enfermedades principales, la de Alzheimer y la de Parkinson. En la actualidad sólo se dispone de tratamientos paliativos para ambas dolencia...
Aging is associated with a progressive increase in the incidence of neurodegenerative diseases in both laboratory animals and humans. In the central nervous system, cholinergic and dopaminergic (DA) neurons are among the cells most susceptible to the deleterious effects of age. Thus, the basal forebrain cholinergic system is known to undergo modera...
Thymulin has been shown to present anti-inflammatory and anti-fibrotic properties in experimental lung diseases. We hypothesized that a biologically active thymulin analog gene, methionine serum thymus factor, delivered by highly compacted DNA nanoparticles composed of single molecule of plasmid DNA compacted with block copolymers of poly-l-lysine...
