title: Activation of cardiac progenitor cells reverses the failing heart senescent phenotype and prolongs lifespan.
abstract: Heart failure is the leading cause of death in the elderly, but whether this is the result of a primary aging myopathy dictated by depletion of the cardiac progenitor cell (CPC) pool is unknown. Similarly, whether current lifespan reflects the ineluctable genetic clock or heart failure interferes with the genetically determined fate of the organ and organism is an important question. We have identified that chronological age leads to telomeric shortening in CPCs, which by necessity generate a differentiated progeny that rapidly acquires the senescent phenotype conditioning organ aging. CPC aging is mediated by attenuation of the insulin-like growth factor-1/insulin-like growth factor-1 receptor and hepatocyte growth factor/c-Met systems, which do not counteract any longer the CPC renin-angiotensin system, resulting in cellular senescence, growth arrest, and apoptosis. However, pulse-chase 5-bromodeoxyuridine-labeling assay revealed that the senescent heart contains functionally competent CPCs that have the properties of stem cells. This subset of telomerase-competent CPCs have long telomeres and, following activation, migrate to the regions of damage, where they generate a population of young cardiomyocytes, reversing partly the aging myopathy. The senescent heart phenotype and heart failure are corrected to some extent, leading to prolongation of maximum lifespan.
authors.affiliation: Department of Anesthesia, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Arantxa
authors.initials: A
authors.lastname: Gonzalez
authors.forename: Marcello
authors.initials: M
authors.lastname: Rota
authors.forename: Daria
authors.initials: D
authors.lastname: Nurzynska
authors.forename: Yu
authors.initials: Y
authors.lastname: Misao
authors.forename: Jochen
authors.initials: J
authors.lastname: Tillmanns
authors.forename: Caroline
authors.initials: C
authors.lastname: Ojaimi
authors.forename: M Elena
authors.initials: ME
authors.lastname: Padin-Iruegas
authors.forename: Patrick
authors.initials: P
authors.lastname: Müller
authors.forename: Grazia
authors.initials: G
authors.lastname: Esposito
authors.forename: Claudia
authors.initials: C
authors.lastname: Bearzi
authors.forename: Serena
authors.initials: S
authors.lastname: Vitale
authors.forename: Buddhadeb
authors.initials: B
authors.lastname: Dawn
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Sanganalmath
authors.forename: Mathue
authors.initials: M
authors.lastname: Baker
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Hintze
authors.forename: Roberto
authors.initials: R
authors.lastname: Bolli
authors.forename: Konrad
authors.initials: K
authors.lastname: Urbanek
authors.forename: Toru
authors.initials: T
authors.lastname: Hosoda
authors.forename: Piero
authors.initials: P
authors.lastname: Anversa
authors.forename: Jan
authors.initials: J
authors.lastname: Kajstura
authors.forename: Annarosa
authors.initials: A
authors.lastname: Leri
mesh_terms: D053687:Adult Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000375:Aging / Q000187:drug effects* / Q000473:pathology; D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis; D017209:Apoptosis / Q000187:drug effects; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D006321:Heart / Q000187:drug effects / Q000254:growth & development; D006333:Heart Failure / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D017228:Hepatocyte Growth Factor / Q000627:therapeutic use*; D007334:Insulin-Like Growth Factor I / Q000627:therapeutic use*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D051381:Rats; D011916:Rats, Inbred F344; D017978:Receptors, Growth Factor / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects; D015996:Survival Rate; D016615:Telomere / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; D019941:Cyclin-Dependent Kinase Inhibitor p16; D017978:Receptors, Growth Factor; D017228:Hepatocyte Growth Factor; D007334:Insulin-Like Growth Factor I