title: Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression.
abstract: Immune system defects are at the center of aging and a range of diseases. Here, we show that prolonged fasting reduces circulating IGF-1 levels and PKA activity in various cell populations, leading to signal transduction changes in long-term hematopoietic stem cells (LT-HSCs) and niche cells that promote stress resistance, self-renewal, and lineage-balanced regeneration. Multiple cycles of fasting abated the immunosuppression and mortality caused by chemotherapy and reversed age-dependent myeloid-bias in mice, in agreement with preliminary data on the protection of lymphocytes from chemotoxicity in fasting patients. The proregenerative effects of fasting on stem cells were recapitulated by deficiencies in either IGF-1 or PKA and blunted by exogenous IGF-1. These findings link the reduced levels of IGF-1 caused by fasting to PKA signaling and establish their crucial role in regulating hematopoietic stem cell protection, self-renewal, and regeneration.
authors.affiliation: Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089, USA.
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Cheng
authors.affiliation: Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, 1425 San Pablo Street, Los Angeles, CA 90033, USA.
authors.forename: Gregor B
authors.initials: GB
authors.lastname: Adams
authors.affiliation: Saban Research Institute, Division of Urology, Children's Hospital Los Angeles, University of Southern California, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Perin
authors.affiliation: Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.affiliation: Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, 1425 San Pablo Street, Los Angeles, CA 90033, USA.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, 1425 San Pablo Street, Los Angeles, CA 90033, USA.
authors.forename: Ben S
authors.initials: BS
authors.lastname: Lam
authors.affiliation: Saban Research Institute, Division of Urology, Children's Hospital Los Angeles, University of Southern California, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Da Sacco
authors.affiliation: Department of Medical Biotechnology and Forensics, University of Palermo, via Divisi 83, 90133 Palermo, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Mirisola
authors.affiliation: Translational Oncology Program, Kenneth J. Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
authors.forename: David I
authors.initials: DI
authors.lastname: Quinn
authors.affiliation: Translational Oncology Program, Kenneth J. Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
authors.forename: Tanya B
authors.initials: TB
authors.lastname: Dorff
authors.affiliation: Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, 228 Irvine Hall, Athens, OH 45701, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Kopchick
authors.affiliation: Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089, USA; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, 1425 San Pablo Street, Los Angeles, CA 90033, USA; IFOM, FIRC Institute of Molecular Oncology, Via Adamello, 16, 20139 Milano, Italy. Electronic address: vlongo@usc.edu.
authors.forename: Valter D
authors.initials: VD
authors.lastname: Longo
mesh_terms: D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005215:Fasting / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D007165:Immunosuppression Therapy; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D012038:Regeneration
chemical_list: C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D017868:Cyclic AMP-Dependent Protein Kinases