Prolonged Fasting Reduces IGF-1/PKA to Promote Hematopoietic-Stem-Cell-Based Regeneration and Reverse Immunosuppression

Cheng, Chi‐Feng; Gb, Adams; Perin, Laura; Wei, Min; Zhou, Xia; Lam, BS; Sacco, Stefano Da; Mirisola, Mario G.; Quinn, DI; Dorff, TB; Kopchick, JJ; Longo, VD

doi:10.1016/j.stem.2016.01.018

Cited by 11 publications

(16 citation statements)

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“…These mice have low levels of circulating IGF-1 and receive no additional longevity benefit from multiple types of CR Bonkowski et al, 2006Bonkowski et al, , 2009. In support of a beneficial role for reduced levels of insulin and IGF-1, dampening of insulin-IGF signaling specifically in fly ISCs improves gut homeostasis and extends lifespan, whereas reduced IGF-1 levels are associated with improved HSC self-renewal (Biteau et al, 2010;Cheng et al, 2014). These results in mice and flies are seemingly in opposition to the fact that insulin, IGF-1 and growth hormone increase the number of NSCs and GSCs in aged animals (Blackmore et al, 2009;Hsu and Drummond-Barbosa, 2009;Lichtenwalner et al, 2001).…”

Section: Metazoamentioning

confidence: 99%

When stem cells grow old: phenotypes and mechanisms of stem cell aging

2016

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All multicellular organisms undergo a decline in tissue and organ function as they age. An attractive theory is that a loss in stem cell number and/or activity over time causes this decline. In accordance with this theory, aging phenotypes have been described for stem cells of multiple tissues, including those of the hematopoietic system, intestine, muscle, brain, skin and germline. Here, we discuss recent advances in our understanding of why adult stem cells age and how this aging impacts diseases and lifespan. With this increased understanding, it is feasible to design and test interventions that delay stem cell aging and improve both health and lifespan.

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Section: Metazoamentioning

confidence: 99%

When stem cells grow old: phenotypes and mechanisms of stem cell aging

2016

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“…Disruption or suppression of this growth axis by caloric restriction prolongs longevity [83,84]. Experimental data from knock-out mice indicate a possible contribution of the mTOR pathway to development of lung emphysema; while loss of the mTOR suppressor Rtp801 protected mice from cigarette-smoke induced emphysema, its lung-specific overexpression promoted lung inflammation and apoptosis of alveolar epithelial cells [85].…”

Section: Deregulated Nutrient Sensingmentioning

confidence: 99%

Hallmarks of the ageing lung

2015

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Ageing is the main risk factor for major non-communicable chronic lung diseases, including chronic obstructive pulmonary disease, most forms of lung cancer and idiopathic pulmonary fibrosis. While the prevalence of these diseases continually increases with age, their respective incidence peaks at different times during the lifespan, suggesting specific effects of ageing on the onset and/or pathogenesis of chronic obstructive pulmonary disease, lung cancer and idiopathic pulmonary fibrosis. Recently, the nine hallmarks of ageing have been defined as cell-autonomous and non-autonomous pathways involved in ageing. Here, we review the available evidence for the involvement of each of these hallmarks in the pathogenesis of chronic obstructive pulmonary disease, lung cancer, or idiopathic pulmonary fibrosis. Importantly, we propose an additional hallmark, "dysregulation of the extracellular matrix", which we argue acts as a crucial modifier of cell-autonomous changes and functions, and as a key feature of the above-mentioned lung diseases. @ERSpublications Hallmarks of ageing are selecting factors for the pathogenesis of COPD, lung cancer and IPF

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“…Fasting can promote hematopoietic stem cell-based regeneration and reverse immunosuppression [7][8][9] , and has been reported to promote the anti-cancer effects of chemotherapy 5,10 . However, the responsiveness of hematopoietic malignancies to dietary restriction, including fasting, remains unknown.…”

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confidence: 99%

Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation

Xie

et al. 2016

Nat Med

121

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Dietary restriction, including fasting, delays aging and has pro-longevity effects in a wide range of organisms, and so has been considered for cancer prevention and the treatment of certain solid tumor types [1][2][3][4][5][6] . Fasting can promote hematopoietic stem cell-based regeneration and reverse immunosuppression [7][8][9] , and has been reported to promote the anti-cancer effects of chemotherapy 5,10 . However, the responsiveness of hematopoietic malignancies to dietary restriction, including fasting, remains unknown.AML is the most common form of adult acute leukemia, whereas ALL is the most common form of cancer in children; ALL also occurs in adults [11][12][13] . Although treatment of pediatric ALL is highly effective, a sizeable number of patients are nonresponders who succumb to this disease. The outcome of ALL in adults is substantially worse than for pediatric ALL, with a 5-year survival rate of approximately 40% 12 . Additionally, some types of ALL have a much poorer prognosis than others 12 . New therapeutic targets and approaches need to be identified to treat these leukemias more effectively. Here we investigated whether and how fasting regulates the development of B-ALL, T-ALL and AML. RESULTSFasting selectively inhibits the development of ALL but not AML To extend our previous work on the extrinsic and metabolic regulation of hematopoietic stem cells and cancer development 14-22 , we studied the effects of fasting on leukemia development. Mice from several retrovirus transplantation acute leukemia models, including the N-Myc B-ALL model 23 , the activated Notch1 T-ALL model 24 and the MLL-AF9 AML model 25,26 , were placed on various dietary regimens. Strikingly, a regimen consisting of six cycles of 1 d of fasting, followed by 1 d of feeding, implemented 2 d after transplantation (Fig. 1a) completely inhibited B-ALL development. The fasted mice had 32.85 ± 5.16, 11.31 ± 5.42 and 0.48 ± 0.12% of leukemic GFP + cells in peripheral blood (PB) at 3, 5 and 7 weeks post-transplantation, respectively, as compared to 49.52 ± 5.75, 56.27 ± 9.36 and 67.68 ± 8.39% of GFP + cells of the control mice (Fig. 1b,c). Concordantly, the percentages of leukemic cells in the bone marrow (BM) and spleen (SP) and the numbers of white blood cells (WBCs) in PB were also dramatically lower in the fasted mice at 7 weeks posttransplantation (Fig. 1c,d).Next, we measured the distribution of B lymphoblastic cells and myeloid cells in the GFP + compartment of the B-ALL mice. Control mice with B-ALL had 65-80% of B220 + cells (pan B lineage marker) and 0.5-2% of Mac-1 + cells (myeloid lineage marker) in GFP + fractions of PB, BM and SP (Fig. 1e,f), indicative of fully developed B-ALL. By contrast, there were only 19-28% of B220 + cells and 5-12% of Mac-1 + in GFP + fractions in fasted mice (Fig. 1e,f), consistent with loss of the B-ALL phenotype. There was also a higher percentage of New therapeutic approaches are needed to treat leukemia effectively. Dietary restriction regimens, including fasting, have been considered ...

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Prolonged Fasting Reduces IGF-1/PKA to Promote Hematopoietic-Stem-Cell-Based Regeneration and Reverse Immunosuppression

Cited by 11 publications

References 0 publications

When stem cells grow old: phenotypes and mechanisms of stem cell aging

When stem cells grow old: phenotypes and mechanisms of stem cell aging

Hallmarks of the ageing lung

Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation

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