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Principal Investigator: THOMAS A. RANDO
Organization: UNIVERSITY OF CALIFORNIA LOS ANGELES
Fiscal Year: 2024
Award: $442,931
Funding agency: National Institute on Aging
PROJECT SUMMARY
Current ideas that systemic factors regulate the aging of cells and tissues, in terms of both promoting and
reversing the aging process, have emerged from studies of heterochronic parabiosis (HP) and heterochronic
blood exchange (HBE) protocols. Our lab performed the first HP studies in order to assess cellular aging and
rejuvenation as it relates to tissue homeostasis and repair and in terms of molecular determinants of cellular age.
Initially, we focused changes in muscle stem cells (MuSCs), but we and others later explored these phenotypic
changes in many different cell populations. Since then, we have explored the molecular mechanisms by which
systemic factors might influence the aging process. Based on numerous lines of evidence, we have hypothesized
that the alteration in cellular aging features is due to a form of epigenetic reprogramming that is akin to that which
occurs during induced pluripotent stem cell generation but without the loss of cellular differentiation.
A general feature of cellular aging is the loss of heterochromatin and subsequent dysregulation of
transcriptional stability. Heterochromatin is prominently associated with specific histone modifications, most
notably by di- and tri-methylation of lysine 9 on histone 3 (H3K9me2 and H3K9me3, respectively). In Preliminary
Studies, we have shown the H3K9me3 and heterochromatin can be regulated in MuSCs, with loss of both leading
to features seen in aging cells. Based on these data and related published findings, the primary hypothesis of
this proposal is that a primary mediator of HP and HBE transposition of aging phenotypes to young and old cells
is the regulation of the cellular epigenome, and with a specific focus on H3K9 methylation and heterochromatin
formation.
To test this hypothesis, this proposal is divided into three Specific Aims. Aim 1: To assess the transcriptional
and epigenetic signature of MuSCs in response to HP. We will establish HP and control pairs, and we will assess
the MuSC molecular signatures compared to control mice in assays of the transcriptome and the epigenome.
Aim 2: To examine the epigenetic mechanisms underlying the transposition of aging phenotypes in MuSCs.
Using genetic and pharmacologic tools, we will modulate H3K9 methylation in young and old MuSCs exposed
to young or old serum in vitro. We will test for the effect of changes in H3K9 methylation on the phenotypic
changes of MuSCs previously described in response to heterochronic serum exposure. Aim 3: To test in vivo
for the essential roles of H3K9 methyltransferase and demethylase activities in mediating the effects of HP on
MuSCs. We will use genetic and pharmacologic tools to modulate H3K9 methylation in MuSCs in vivo. We will
assess epigenetic and heterochromatin status, as well as the functional changes in MuSCs in response to HP.
Together, these studies will elucidate molecular mechanisms of epigenetic programming of age in response to
HP and HBE.
Terms: <65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><> 65 years><ATAC sequencing><ATAC-seq><ATACseq><Address><Affect><Age><Aged 65 and Over><Aging><Assay><Assay for Transposase-Accessible Chromatin using sequencing><Autoregulation><Bioassay><Biological Assay><Blood><Blood Plasma><Blood Reticuloendothelial System><Blood Serum><Body Tissues><Cell Aging><Cell Body><Cell Communication><Cell Differentiation><Cell Differentiation process><Cell Interaction><Cell Reprogramming><Cell Senescence><Cell-to-Cell Interaction><Cells><Cellular Aging><Cellular Regulation><Cellular Senescence><ChIP Sequencing><ChIP-seq><ChIPseq><Characteristics><Complement><Complement Proteins><DNA Methylation><Data><EC 2.1.1><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Exhibits><Exposure to><Gene Transcription><Generations><Genetic><Genetic Transcription><Genetic study><Goals><Heterochromatin><Histones><Homeostasis><In Vitro><In vivo analysis><Intervention><Intervention Strategies><Knock-out><Knockout><L-Lysine><Laboratory Animals><Liver><Lysine><Mediating><Mediator><Methylation><Methyltransferase><Mice><Mice Mammals><Molecular><Molecular Fingerprinting><Molecular Mechanisms of Action><Molecular Profiling><Murine><Mus><Muscle><Muscle Cells><Muscle Tissue><Myocytes><Nucleosomes><Parabiosis><Pathway interactions><Pharmacological Study><Pharmacology Study><Phenotype><Physiological Homeostasis><Plasma><Plasma Serum><Population><Process><Protocol><Protocols documentation><Publishing><RNA Expression><Rejuvenation><Replicative Senescence><Reporting><Reticuloendothelial System, Serum, Plasma><Role><Serum><System><Testing><Tissues><Transcription><above age 65><accelerated aging><accelerated biological age><accelerated biological aging><after age 65><age 65 and greater><age 65 and older><age 65 or older><age > 65><age acceleration><age associated effects><age effect><age of 65 years onward><age related effects><aged><aged 65 and greater><aged 65+><aged mice><aged mouse><aged muscle><aged ≥65><ages><aging effect><aging of muscle><aging process><aging reversal><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><biological age><cell age><cell growth regulation><cellular age><cellular differentiation><cellular reprogramming><chromatin immunoprecipitation-sequencing><compare to control><comparison control><complementation><demethylation><elderly mice><epigenetically><epigenome><experiment><experimental research><experimental study><experiments><global gene expression><global transcription profile><hepatic body system><hepatic organ system><histone H3 methyltransferase><histone demethylase><histone methylase><histone methyltransferase><histone modification><human old age (65+)><iPS><iPSC><iPSCs><impact of age><in vitro Model><in vivo><in vivo evaluation><in vivo testing><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><influence of age><inhibitor><interest><interventional strategy><life span><lifespan><methylase><methylation pattern><molecular profile><molecular signature><muscle aging><muscle progenitor cell><muscle stem cell><muscular><old age><old mice><over 65 years><pathway><pharmacologic><progenitor aging><progenitor cell aging><repair><repaired><response><restoration><reverse aging><reverse aging effects><reversible aging><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><stem cell aging><tool><transcriptome><transmethylase><≥65 years>