Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression

Cell Stem Cell. 2014 Jun 5;14(6):810-23. doi: 10.1016/j.stem.2014.04.014.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Fasting / physiology*
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / enzymology
  • Hematopoietic Stem Cells / metabolism*
  • Immunosuppression*
  • Insulin-Like Growth Factor I / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Regeneration*

Substances

  • insulin-like growth factor-1, mouse
  • Insulin-Like Growth Factor I
  • Cyclic AMP-Dependent Protein Kinases