title: In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming.
abstract: Aging is the major risk factor for many human diseases. In vitro studies have demonstrated that cellular reprogramming to pluripotency reverses cellular age, but alteration of the aging process through reprogramming has not been directly demonstrated in vivo. Here, we report that partial reprogramming by short-term cyclic expression of Oct4, Sox2, Klf4, and c-Myc (OSKM) ameliorates cellular and physiological hallmarks of aging and prolongs lifespan in a mouse model of premature aging. Similarly, expression of OSKM in vivo improves recovery from metabolic disease and muscle injury in older wild-type mice. The amelioration of age-associated phenotypes by epigenetic remodeling during cellular reprogramming highlights the role of epigenetic dysregulation as a driver of mammalian aging. Establishing in vivo platforms to modulate age-associated epigenetic marks may provide further insights into the biology of aging.
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Ocampo
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Reddy
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Paloma
authors.initials: P
authors.lastname: Martinez-Redondo
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Aida
authors.initials: A
authors.lastname: Platero-Luengo
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Hatanaka
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Hishida
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Mo
authors.initials: M
authors.lastname: Li
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: David
authors.initials: D
authors.lastname: Lam
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Universidad Católica San Antonio de Murcia (UCAM) Campus de los Jerónimos, 30107 Guadalupe, Murcia, Spain.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kurita
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Ergin
authors.initials: E
authors.lastname: Beyret
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Universidad Católica San Antonio de Murcia (UCAM) Campus de los Jerónimos, 30107 Guadalupe, Murcia, Spain.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Araoka
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Vazquez-Ferrer
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: David
authors.initials: D
authors.lastname: Donoso
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Roman
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Jinna
authors.initials: J
authors.lastname: Xu
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Concepcion
authors.initials: C
authors.lastname: Rodriguez Esteban
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nuñez
authors.affiliation: Universidad Católica San Antonio de Murcia (UCAM) Campus de los Jerónimos, 30107 Guadalupe, Murcia, Spain.
authors.forename: Estrella
authors.initials: E
authors.lastname: Nuñez Delicado
authors.affiliation: Hospital Clinic, University of Barcelona, IDIBAPS, 08036 Barcelona, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Campistol
authors.affiliation: Fundación Dr. Pedro Guillén, Clínica Cemtro, 28035 Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Guillen
authors.affiliation: Fundación Dr. Pedro Guillén, Clínica Cemtro, 28035 Madrid, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Guillen
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: belmonte@salk.edu.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Izpisua Belmonte
mesh_terms: D000375:Aging / Q000235:genetics*; D019588:Aging, Premature / Q000235:genetics / Q000378:metabolism; D000818:Animals; D065150:Cellular Reprogramming; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced / Q000378:metabolism; D044127:Epigenesis, Genetic; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D034904:Lamin Type A / Q000235:genetics; D008659:Metabolic Diseases / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D023421:Models, Animal; D010179:Pancreas / Q000378:metabolism; D055948:Sarcopenia / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D034904:Lamin Type A; C576142:Lmna protein, mouse; D014157:Transcription Factors
keywords: aging; cellular reprogramming; epigenetics; lifespan