Prolonged Fasting Reduces IGF-1/PKA to Promote Hematopoietic-stem-cell-based Regeneration and Reverse Immunosuppression

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2014 Jun 7

PMID 24905167

Citations 233

Authors

Chia-Wei Cheng

Gregor B Adams

Laura Perin

Min Wei

Xiaoying Zhou

Ben S Lam

Stefano Da Sacco

Mario Mirisola

David I Quinn

Tanya B Dorff

John J Kopchick

Valter D Longo

Affiliations

Soon will be listed here.

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.

Citing Articles

Hangry hairs: intermittent fasting linked to hair loss.

Galvan C, Lowry W Cell Res. 2025; .

PMID: 40000774 DOI: 10.1038/s41422-025-01082-y.

Chemosensory and cardiometabolic improvements after a fasting-mimicking diet: A randomized cross-over clinical trial.

Micarelli A, Mrakic-Sposta S, Vezzoli A, Malacrida S, Caputo S, Micarelli B Cell Rep Med. 2025; 6(2):101971.

PMID: 39970875 PMC: 11866515. DOI: 10.1016/j.xcrm.2025.101971.

Intermittent Fasting Reduces Intestinal Inflammation in Dextran Sulfate Sodium-Induced Colitis of Mice.

Song S, Zhang X, Zheng H, Liao Y, Tang P, Liu Y Food Sci Nutr. 2025; 13(2):e70014.

PMID: 39898122 PMC: 11787962. DOI: 10.1002/fsn3.70014.

Prolonged Water-Only Fasting Followed by a Whole-Plant-Food Diet Is a Potential Long-Term Management Strategy for Hypertension and Obesity.

Zeiler E, Gabriel S, Ncube M, Thompson N, Newmire D, Scharf E Nutrients. 2024; 16(22).

PMID: 39599745 PMC: 11597177. DOI: 10.3390/nu16223959.

Metabolic reprogramming and therapeutic resistance in primary and metastatic breast cancer.

Liu S, Zhang X, Wang W, Li X, Sun X, Zhao Y Mol Cancer. 2024; 23(1):261.

PMID: 39574178 PMC: 11580516. DOI: 10.1186/s12943-024-02165-x.

References

Chen C, Liu Y, Liu Y, Zheng P . mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal. 2009; 2(98):ra75. PMC: 4020596. DOI: 10.1126/scisignal.2000559. View

Longo V, Finch C . Evolutionary medicine: from dwarf model systems to healthy centenarians?. Science. 2003; 299(5611):1342-6. DOI: 10.1126/science.1077991. View

Ertl R, Chen J, Astle C, Duffy T, Harrison D . Effects of dietary restriction on hematopoietic stem-cell aging are genetically regulated. Blood. 2007; 111(3):1709-16. PMC: 2214738. DOI: 10.1182/blood-2007-01-069807. View

Chen X, Skutt-Kakaria K, Davison J, Ou Y, Choi E, Malik P . G9a/GLP-dependent histone H3K9me2 patterning during human hematopoietic stem cell lineage commitment. Genes Dev. 2012; 26(22):2499-511. PMC: 3505820. DOI: 10.1101/gad.200329.112. View

Bondolfi L, Ermini F, Long J, Ingram D, Jucker M . Impact of age and caloric restriction on neurogenesis in the dentate gyrus of C57BL/6 mice. Neurobiol Aging. 2004; 25(3):333-40. DOI: 10.1016/S0197-4580(03)00083-6. View

Kenyon C . A conserved regulatory system for aging. Cell. 2001; 105(2):165-8. DOI: 10.1016/s0092-8674(01)00306-3. View

Fabrizio P, Pozza F, Pletcher S, Gendron C, Longo V . Regulation of longevity and stress resistance by Sch9 in yeast. Science. 2001; 292(5515):288-90. DOI: 10.1126/science.1059497. View

Lee C, Safdie F, Raffaghello L, Wei M, Madia F, Parrella E . Reduced levels of IGF-I mediate differential protection of normal and cancer cells in response to fasting and improve chemotherapeutic index. Cancer Res. 2010; 70(4):1564-72. PMC: 2836202. DOI: 10.1158/0008-5472.CAN-09-3228. View

Gonzalez G, Montminy M . Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell. 1989; 59(4):675-80. DOI: 10.1016/0092-8674(89)90013-5. View

10.

Challen G, Boles N, Chambers S, Goodell M . Distinct hematopoietic stem cell subtypes are differentially regulated by TGF-beta1. Cell Stem Cell. 2010; 6(3):265-78. PMC: 2837284. DOI: 10.1016/j.stem.2010.02.002. View

11.

Kaeberlein M, Powers 3rd R, Steffen K, Westman E, Hu D, Dang N . Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science. 2005; 310(5751):1193-6. DOI: 10.1126/science.1115535. View

12.

Pang W, Price E, Sahoo D, Beerman I, Maloney W, Rossi D . Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proc Natl Acad Sci U S A. 2011; 108(50):20012-7. PMC: 3250139. DOI: 10.1073/pnas.1116110108. View

13.

Bedford P, Berger M, Eisenbrand G, Schmahl D . The level of DNA interstrand crosslinking in bone marrow parallels the extent of myelosuppression in mice treated with four chloroethylnitrosoureas. J Cancer Res Clin Oncol. 1984; 108(1):141-7. DOI: 10.1007/BF00390986. View

14.

Salmon A, Murakami S, Bartke A, Kopchick J, Yasumura K, Miller R . Fibroblast cell lines from young adult mice of long-lived mutant strains are resistant to multiple forms of stress. Am J Physiol Endocrinol Metab. 2005; 289(1):E23-9. DOI: 10.1152/ajpendo.00575.2004. View

15.

Kim S, Volsky D . PAGE: parametric analysis of gene set enrichment. BMC Bioinformatics. 2005; 6:144. PMC: 1183189. DOI: 10.1186/1471-2105-6-144. View

16.

Sanghera K, Mathalone N, Baigi R, Panov E, Wang D, Zhao X . The PI3K/Akt/mTOR pathway mediates retinal progenitor cell survival under hypoxic and superoxide stress. Mol Cell Neurosci. 2011; 47(2):145-53. DOI: 10.1016/j.mcn.2011.03.010. View

17.

Rafalski V, Brunet A . Energy metabolism in adult neural stem cell fate. Prog Neurobiol. 2010; 93(2):182-203. DOI: 10.1016/j.pneurobio.2010.10.007. View

18.

Rando T, Chang H . Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. Cell. 2012; 148(1-2):46-57. PMC: 3336960. DOI: 10.1016/j.cell.2012.01.003. View

19.

Beerman I, Bhattacharya D, Zandi S, Sigvardsson M, Weissman I, Bryder D . Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proc Natl Acad Sci U S A. 2010; 107(12):5465-70. PMC: 2851806. DOI: 10.1073/pnas.1000834107. View

20.

Mackall C, Fleisher T, Brown M, Magrath I, Shad A, Horowitz M . Lymphocyte depletion during treatment with intensive chemotherapy for cancer. Blood. 1994; 84(7):2221-8. View