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Prolonged fasting (PF) lasting 48–120 hr reduces progrowth signaling and activates pathways that enhance cellular resistance to toxins in mice and humans. Only after more than 24 hours of fasting, the stored glycogen in the body is depleted and the body fully switches to a fat- and ketone bodies catabolism.
Previous studies in mice have shown that PF can reduce the circulating insulin-like growth factor-1 (IGF-1), which protects cells against chemotoxicity. There are also some studies, which show that PF can cure several side effects of chemotherapy. Part of this study focuses on myelosuppression, which is reduction in production of blood cells. This side effect often cause dose limiting in chemotherapy treatment.
Hematopoietic stem and progenitor cells (HSPCs) include long-term (LT-HSC) and short-term hematopoietic stem cells (ST-HSC) and the multipotent progenitors (MPP). These cells reside in the adult bone marrow (BM) and responsible for hematopoietic regeneration.
Chemotherapy drugs cause DNA damage and cell death of cancer cells. However, this process is not limited to cancer cells. Along with them, chemotherapy drugs also affect somatic cells, which include LT-HSC, ST-HSC, and MPP cells. This treatment, eventually causes impairment of hematopoiesis.
In the experiments, they have used multiple cycles of cyclophosphamide (CP), which is a chemotherapy drug, on fasted or fed mice. 48 hr PF decreased the DNA damage caused by CP and had an effect of protection in leukocytes and BM cells. Then they have checked whether CP causes apoptosis in PF treated cells and shown that PF actually protects HSPCs against CP-induced apoptosis, especially for two subtypes of HSPCs.
They have also shown that PF doesn’t protect HSPCs against chemotherapy at first, however it improves hematopoietic recovery in later cycles. After 4th cycle of CP treatment (39th day), the beneficial effect of PF was observed by the scientists. After 5th cycle of CP treatment (56th day), lymphocyte levels returned to the normal levels. At the end of 6th cycle of CP treatment (70th day), lymphoid cell levels and ratio of lymphoid and myeloid cells (L/M) returned to normal levels.
In humans, they have tried PF for cancer patients from a phase I clinical trial. For 72 hr of PF, the lymphocyte counts were returned back to normal. Now, they need to make the same experiments with patients from phase II clinical trial.
Furthermore, they have taken CP-treated and PF + CP-treated mice BM cells and transplanted them to mice with impaired immune system. As a result, they have observed that PF + CP-treated mice BM cells had higher regeneration capacity.
Then, they wanted to find if PF can induce HSC self-renewal without chemotherapy. They have seen 6-fold increase in newly generated HSPCs compared to the control group. They have checked cell numbers of each subtype and found that LT-HSC and ST-HSC levels are increased and the number of total BM cells was not increased by PF.
Furthermore, number of common myeloid progenitor number was slightly decreased as a result of PF. Then, they have observed that PF induced a major increase of S/G2/M phase of LT-HSCs and ST-HSCs. Another interesting result was that PF reduced apoptosis significantly.
8 cycles of PF can also reverse age-dependent myeloid bias in HSC subtypes and reverse effect of aging on WBC number.
In a previous study, they have shown that PF reduces circulating IGF-1 levels, which protect mice against chemotherapy toxicity. In the low amounts of IGF-1, the cells are protected against apoptosis, too. They also have increased self-renewal of HSC, similar to PF. PKA catalytic subunit alpha expression level was reduced in all tissues of starved mice and humans. They have also confirmed a link between IGF-1 and PKA/CREB and PF can reduce PKA signaling via low IGF-1 levels.
Prolong fasting reduces circulating IGF-1 in blood, thus, downregulates PKA levels, which in turn promotes hematopoietic stem cell self-renewal. PF can also be used along with chemotherapy. It showed promising results in humans and recovered white blood cell levels to their normal levels after 6 cycle of PF and CP (chemotherapy drug) treatment.
Cheng, Chia-Wei, et al. “Prolonged Fasting Reduces IGF-1/PKA to Promote Hematopoietic-Stem-Cell-Based Regeneration and Reverse Immunosuppression.” Cell Stem Cell 18.2 (2016): 291-292.