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Less Food, Better Haematopoietic Function?

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Review of “Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression” from Cell Stem Cell by Stuart P. Atkinson.

In a recent report in Cell Stem Cell, researchers from the laboratory of Valter D. Longo have studied how prolonged fasting (PF) can affect the haematopoietic system at multiple levels [1]. While caloric intake is understood to affect stem cell self-renewal and differentiation and chronic calorie restriction can promote the function of several stem cell types in mice, this is the first report on the beneficial effect of calorie intake on the function of a major portion of an organ/system.

A previous study demonstrated that PF ameliorated the side effects of chemotherapy in humans [2], and the group initially showed that mice which underwent cycles of 48 hours of PF (PF mice), as compared to mice fed an ad libitum diet (AL mice), demonstrated less DNA damage in leukocytes and bone marrow cells and displayed improved mortality in response to multiple cycles of chemotherapeutic drug treatment. This was accompanied by a reduction in apoptosis in hematopoietic stem and progenitor cells (HSPCs) with the most pronounced effect in short term-HSCs (ST-HSCs) and multipotent progenitors (MPPs). White blood cell (WBC) suppression associated with chemotherapy was also reduced in the PF mice and analysis of patients from a phase I clinical trial also demonstrated the beneficial effect of PF on WBC in humans. In agreement with these findings, PF resulted in an improved preservation of long term HSCs (LT-HSCs) and ST-HSCs, enhanced resistance to myeloid bias, and an enhanced regenerative capacity with a normal lymphoid/myeloid ratio. Independently of chemotherapy, the authors also saw an increase in the self-renewing capacity of HSPCs after PF, leading to an increase in LT-HSCs and ST-HSCs, and a reversal of the age-dependent myeloid bias in HSC subtypes, altogether suggesting that PF mediates lineage-balanced hematopoietic regeneration.

Previous studies by the same group found that PF reduced circulating Insulin-like growth factor 1 (IGF-1) levels while IGF-I deficiency could protect mice against chemotherapy toxicity [3], and in this study, they found that IGF-1 loss mediated a decrease in chemotherapy-induced DNA damage, a preservation of HSC number, and an improvement in haematopoietic recovery, similar to the effects of PF. IGF-1 deficiency also mediated some protective regenerative effects independently of chemotoxicity, again like PF. In their attempts to delineate mechanisms behind hematopoietic recovery/regeneration caused by PF/IGF-1, the group uncovered a link between reduced Protein kinase A (PKA) signalling levels through the reduction in IGF-1 during PF. Interestingly, PKA is already understood to have pro-aging roles in yeast and mammals [4, 5], while disruption of PKA signaling protects against stress [6]. Exogenous IGF-1 injection during PF inhibited the observed reduction of PKA activity, especially in HSCs, reduced the PF-mediated increase in HSC number, and reduced short term and long term haematopoietic reconstitution in peripheral blood and bone marrow. The PF-mediated reduction in IGF-1 and PKA signalling also led to the induction of genes which maintain hematopoietic stress-resistance, self-renewal and lineage homeostasis (Foxo1) and hematopoietic lineage commitment and differentiation (CREB and G9a).

One of the major efforts of stem cell biology is the creation of adult stem cells from pluripotent sources for use in cell replacement therapy. However, uncovering inherent mechanisms to protect or rejuvenate our stem cells when placed under peril (such as chemotherapeutic insult) may circumvent this necessity. The link between fasting, IGF-1, and PKA are also backed up by some clinical findings suggesting that these findings may be translated with speed into the clinical setting. 

References

  1. Cheng CW, Adams GB, Perin L, et al. Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell 2014;14:810-823.
  2. Safdie FM, Dorff T, Quinn D, et al. Fasting and cancer treatment in humans: A case series report. Aging (Albany NY) 2009;1:988-1007.
  3. Lee C, Safdie FM, Raffaghello L, et al. Reduced levels of IGF-I mediate differential protection of normal and cancer cells in response to fasting and improve chemotherapeutic index. Cancer Res 2010;70:1564-1572.
  4. Fabrizio P, Pozza F, Pletcher SD, et al. Regulation of longevity and stress resistance by Sch9 in yeast. Science 2001;292:288-290.
  5. Rinaldi J, Wu J, Yang J, et al. Structure of yeast regulatory subunit: a glimpse into the evolution of PKA signaling. Structure 2010;18:1471-1482.
  6. Yan L, Vatner DE, O'Connor JP, et al. Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell 2007;130:247-258.