REJUVENATION RESEARCH Volume 17, Number 4, 2014 ª Mary Ann Liebert, Inc. DOI: 10.1089/rej.2014.1595

Prolonged Fasting/Refeeding Promotes Hematopoietic Stem Cell Regeneration and Rejuvenation Andrew R. Mendelsohn and James W. Larrick

Abstract

The sensitivity of hematopoietic stem cells (HSCs) to toxic effects of cancer chemotherapy is one of the major roadblocks in cancer therapy. Moreover, the loss of HSC function in the elderly (‘‘immunosenescence’’) is a major source of morbidity and mortality. Until recently, it was believed that HSCs were irreversibly damaged by the aging process. Recent work in mice shows that cycles of prolonged fasting (PF) of greater than 72 hr followed by refeeding can protect HSCs from the toxicity associated with chemotherapy and stimulate the proliferation of and rejuvenate old HSCs. A preliminary phase I trial in humans suggests that PF may confer benefit to people undergoing chemotherapy. These effects are at least partially mediated by lowered insulin-like growth factor-1 levels in the blood and stem cell microenvironment, which leads to lowered protein kinase A (PKA) activity. Reducing PKA levels or activity can replicate at least some of the effects of PF on HSCs. Shorter periods of fasting were not effective. PF represents a potentially profound, low-tech means to enhance cancer treatment and reverse aging of the immune system in the elderly. Because PF is likely to be stressful to the old and fragile, the development of PF mimetics may be warranted.

Introduction

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ancer chemotherapy is often limited by toxicity that can lead to substantial morbidity and mortality. Chemotherapeutic drug dosage needs to be carefully maintained within tolerable limits. Many of the detrimental effects of chemotherapy and radiation result from damage to the immune system. Hematopoietic stem cells (HSCs), which are the population of cells from which all immune cells originate, are particularly sensitive to chemotherapy because they proliferate both to maintain themselves and to populate the immune system by differentiation into progenitors and terminally differentiated cells, which include lymphocytes and myeloid cells. Immunosuppression from chemotherapy is a major medical problem.1,2 Immunosenescence, associated with aging of the immune system, shares many of the characteristics of immunosuppression resulting from chemotherapy. These include fewer numbers of lymphocytes, a bias toward myeloid cells, and reduced regenerative capacity of old HSCs.3 Old HSCs were believed to be irreversibly damaged by insults associated with aging, including DNA damage from increased reactive oxygen species (ROS); however, recent work has suggested that it is possible to rejuvenate HSCs, for example, by altering gene expression of sirtui 3 (SIRT3), reducing ROS, or inhibiting the mechanistic target of rapamycin (mTOR).4–6

These results suggest that other ways may exist to rejuvenate HSCs. Prolonged fasting (PF) (of greater than 72 hr) before and during chemotherapy has been reported to reduce toxicity due to chemotherapy in mice by Longo’s group at the University of Southern California (USC) by a mechanism that involved lowering insulin-like growth factor-1 (IGF-1). However, the mechanisms and critical cell types remained uncharacterized. A recent report by this group extends these results and uncovers PF as a general way to potentially effect rejuvenation of the immune system.7 PF/Refeeding Restores Normal HSC Function and Protects HSCs from Chemotherapy

In a potentially very important paper, Cheng et al.7 report that multiple cycles of PF (greater than 72 hr) followed by refeeding reduce IGF-1 levels and protein kinase A (PKA) activity to protect HSCs from the detrimental effects of chemotherapy in mice.7 These results may translate to humans because PF appeared to protect people from chemotoxicity in a small phase I clinical trial. Moreover, PF eliminated the old age–associated differentiation bias of HSCs toward the myeloid lineage. Drugs used in cancer chemotherapy, such as doxorubicin, etoposide, or cyclophosphamide (CP), induce DNA damage

Panorama Research Institute and Regenerative Sciences Institute, Sunnyvale, California.

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in proliferating cells, preferentially killing them.8 Such drugs are often effective against rapidly proliferating cancer cells, but they also damage normal dividing cells. It had been previously observed by the same research group that PF protected normal cells and mice from cell death.8,9 In this report, these researchers focus on HSCs. One of the consequences of chemotherapy is immunosuppressive toxicity, which results from damage to HSCs and their progeny. After six rounds of fasting (3 days), treatment with CP, followed by feeding (11 days), bone marrow–derived HSCs separated by fluorescence-activated cell sorting (FACS) on the basis of characteristic cell-surface markers showed diminished apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) (which detects double-stranded breaks) and annexin V assays (which detect repositioning of annexin V to the extracellular face of the plasma membrane during apoptosis) than well-fed (ad libitum) controls treated with CP at the same time intervals. Interestingly, short-term fasting of 24 hr had no protective effect. PF effectively blocked HSC cell death associated with chemotherapy.7 Analysis of hematological profiles showed that white blood cell (WBC) counts, especially of lymphocytes, initially dropped after each dose of CP, suggesting that proliferating WBCs were killed by the chemotherapy, regardless of PF. However, by the fourth cycle of chemotherapy, animals receiving PF had higher numbers of lymphocytes than the ad libitum–fed mice. By the sixth cycle of chemotherapy and PF, animals undergoing PF had normal levels of lymphocytes and normal ratios of lymphocytes to myeloid cells, unlike ad libitum–fed mice, which showed no recovery of lymphocytes with an abnormally low ratio of lymphocytes to myeloid cells (L/M). Self-renewing longterm HSCs (LT-HSCs), which are Lin-Sca-1 + -c-Kit + , CD48 - , CD150 + , can be distinguished from short-term HSCs (ST-HSC), which are Lin-Sca-1 + -c-Kit + , CD48 - , CD150 - , by differential expression of cell-surface proteins, in this case CD150. FACS analysis indicated that numbers of LT-HSCs and ST-HSCs were better preserved in the animals receiving PF. To confirm that the HSCs retained function, similar numbers of bone marrow cells from mice receiving CP with and without PF were transplanted into mice immunocompromised by irradiation with competing bone marrow cells from mice that did not receive chemotherapy. Cells from the experimental donors and competitors were marked genetically with different CD45 alleles. Cells from mice treated with PF competed effectively with the cells from mice that had not received chemotherapy, whereas cells that were fed ad libitum did not compete well. The PF-derived HSCs had higher regeneration capacity than the ad libitum–fed mice, and hematological profile analysis showed that PF HSCs reconstituted the immune system with a normal L/M cell ratio.7 Cheng et al. investigated whether PF affected HSC function more generally than just protection from chemotoxicity. PF resulted in a six-fold increase in the number of HSCs that completed DNA replication by measuring incorporation of the nucleotide analog bromodeoxyuridine (BrdU) into DNA. These correlated with increased numbers of LT-HSCs, ST-HSCs, and multipotent progenitors (MPPs) observed by FACS. Interestingly, PF did not result in increased numbers of total bone marrow cells, nor of the total

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number of progenitor cells, for example, common myeloid or common lymphoid progenitors. FACS-based cell cycle analysis was consistent with the idea that PF stimulated LTHSCs, ST-HSCs, and MPPs to enter the cell cycle. Apoptotic cell death rates, which are low for HSCs, were reduced even further by PF. The conclusion is that PF stimulates cell cycle entry and subsequent proliferation of HSCs to effect self-renewal.7 Old animals have reduced immune function (‘‘immunosenescence’’) that is thought to result from irreversible damage to DNA. However, recent work has shown that it is possible to rejuvenate old HSCs by ectopic expression of SIRT3 or treatment with the antioxidant N-acetylcysteine (NAC).4,5 HSCs from old mice have limited regenerative ability and become myeloid biased, resulting in fewer lymphoid cells, more myeloid cells, and overall fewer white blood cells. Relatively old mice (18 months) were subjected to numerous cycles of PF and refeeding. After eight cycles of PF, myeloid bias was eliminated, and the L/M ratio was similar to that of young animals fed ad libitum. Moreover, total WBCs were restored to levels of young animals. Repeated PF appears to rejuvenate old HSCs.7 Unfortunately, Cheng et al. did not measure the regenerative capacity of the rejuvenated HSCs, which would have been helpful to assess the extent of the rejuvenation. Previous work by this group showed that PF reduces IGF-1 levels and that low IGF-1 levels protect mice from chemotoxicity.9 To model conditions of reduced IGF-1, Cheng et al. used growth hormone knockout mice (GHRKO), which express low levels of IGF-1 in the serum and bone marrow. CP-induced apoptosis was reduced in GHRKO mice similar to levels seen by PF treatment in wild-type mice. HSC number was preserved in GHRKO mice after chemotherapy. Similar to PF mice, old GHRKO mice had higher numbers of HSCs than wild-type mice and no myeloid bias, suggesting that IGF-1 signaling plays a key role in PF-mediated chemoprotecton and rejuvenation.7 Stronger proof of the role of IGF-1 in PF could have been established using either antibodies or conditional genetic inactivation to block IGF-1 in adult mice using similar kinetic to the PF experiments. However, Cheng et al. did perform the reverse experiment of adding exogenous IGF-1 during PF treatment. In animals not undergoing chemotherapy, IGF-1 blunted both the PF-induced increase of HSCs and the enhanced regenerative capacity of PF-treated HSCs in young animals.7 IGF-1 clearly plays an important role in PF chemoprotection and rejuvenation. To assess whether the stem cell microenvironment was involved, bone marrow stromal niche cells (Lin - CD45 - ) from PF or ad libitum–fed mice were isolated and cocultured with LT-HSCs from PF or ad libitum–fed mice. PFtreated niche cells promoted the survival and proliferation of LT-HSCs from both PF-treated and ad libitum–fed mice, suggesting that PF changes to the stem cell microenvironment are sufficient to alter HSC function.7 Analysis of their previously published microarray data10,11 led Cheng et al. to identify PKA catalytic subunit a (PKACa) as reduced in all tested tissue of PF mice. PKA phosphorylates the transcription factor cAMP response element-binding protein (CREB) at Ser-133 to form active p-CREB. Western blots showed that PF reduces p-CREB levels, whereas IGF receptor (IGF-1R) expression was

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unaffected, suggesting that PKA activity was reduced by PF.7 PKA is known to have a conserved proaging activity12,13: Inhibition of PKA protects yeast and mammalian cells from peroxide-induced oxidative stress.14 PKA positively regulates CREB and G9a, which promote hematopoietic lineage commitment and differentiation,15,16 and negatively regulates transcription factor Foxo1, which promotes HSC self-renewal and stress resistance17,18 (Fig. 1). G9a H3 Lys-9 methyltransferase is an epigenome modifier. PF reduced IGF-1/pAKT and PKA/pCREB signaling, resulting in increased Foxo1 and reduced G9a expression. Because inhibition of mTOR is also known to increase HSC maintenance and self-renewal,6 and caloric restriction re-

FIG. 1. Prolonged fasting involves suppression of insulinlike growth factor-1 (IGF-1) signaling and stimulation of FOXO1. Prolonged fasting reduces IGF-1 levels, which in turn lower activity of adneylate cyclase, protein kinase A (PKA), and its downstream effectors cAMP response element-binding protein (CREB) and G9a (G9A). Reduced PKA activity relieves repression of transcription factor FOXO1, which helps stimulate self-renewal of long-term hematopoietic stem cells (LT-HSCs) and short-term hematopoietic stem cells (ST-HSCs) and restoration of youthful white blood cells (WBCs). (Color image available on www.liebertpub.com/rej).

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sults in reduced mTOR activity, the effects of mTOR inhibition by rapamycin were explored. Contrary to previous studies, rapamycin did not induce HSC proliferation,19,20 possibly due to the shorter time period of the experiment. However, in cultured HSCs, rapamycin potentiated the ability of RNA knockdown of PKA to stimulate proliferation of ST-HSC and MPPs. Interestingly, rapamycin and RNA knockdown (using small interfering RNA [siRNA]) of PKA did not result in the increase of LT-HSC, which are induced by either PF or by anti-PKA siRNA. Knockdown of the IGF-1 receptor IGF-1R also increased ST-HSCs and MPPs, but not LT-HSCs. PF should reduce mTOR activity, which was not measured, thus these results suggest that the effect of PF is actually more complex than the model proposed by Cheng et al. PF is clearly causing an effect that is at least partially dependent on reduced IGF-1 and PKA activity, but other as yet uncharacterized changes are likely significant. On the other hand, treating HSCs with siRNA targeting IGF-1R or PKA resulted in increased bone marrow regenerative capacity in the competition bone marrow reconstitution assay similar to that seen with PF. The increased regenerative capacity of HSCs by PF can be at least partially reproduced by more focused alterations relating to IGF-1 signaling. The question of whether these results translate to humans is paramount. Preliminary results on the chemoprotective ability of PF in a phase I clinical trial indicate that 72 hr of PF, but not short-term fasting of 24 hr, correlate with maintenance of normal lymphocyte counts and lineage balance. While encouraging, the effects of PF on preventing chemotoxicity need to be performed on larger numbers of people. A phase II clinical trial is in progress. Exploration of whether PF can alter immunosenescence associated with aging in humans would be of great interest as well. The results of Cheng et al. are potentially of great significance both as a means to prevent toxicity seen with chemotherapy and to the rejuvenation of immune system function in old people. However, much work remains to be performed. These results are surprising, even in light of the conserved roles for PKA and IGF-1/pAKT in stress protection and earlier studies linking dietary restriction to maintenance of a young phenotype in murine HSCs.21 Not only does nutrient deprivation actually stimulate proliferation, but given that CP damages DNA and kills proliferating cells, the stimulation of HSC proliferation might have been expected to kill the stimulated HSCs. If the reported proliferative effect is confirmed by others, then the benefit of PF probably extends beyond mere stimulation of proliferation to induction of protective mechanisms. Moreover, given that CP kills proliferating cells, the timing of the PF relative to the CP treatment (72 hr after initiating PF and then switching to ad libitum feeding) is probably critical to the success of PF. Perhaps only 24 hr of fasting does not protect against CP because cells are replicating DNA at too high levels at that time point. Medical Implications

The medical implications of rejuvenation of immune function in the elderly and chemoprotection by PF are potentially profound. However, these results are in need of replication by other groups. Applicability to humans needs

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to be more firmly established. Fortunately, at least one phase II trial is ongoing to evalue PF in chemoprotection. It is important to recognize that PF is different from caloric restriction and alternate-day fasting. Because both have been reported to lower IGF-1 levels,22 they may be beneficial to maintaining HSC function. Dietary restriction had previously been reported to maintain HSCs in mice.21 However, neither has been reported to rejuvenate the immune system or HSCs, and Cheng et al. suggest that a 24-hr fasting period (such as that used in alternate-day fasting) is insufficient for rejuvenation or chemoprotection. The role and kinetics of refeeding need to be established. It is interesting that both the stem cell niche cells and the HSCs appear capable of at least some rejuvenating effects. The mechanisms underlying the rejuvenative/chemoprotective effects of PF need to be elucidated further. For example, is expression of growth differentiation factor-11 (GDF11), a factor known to promote rejuvenation in the heart, skeletal muscle, and the brain,23–25 increased? Of great interest to human aging are questions relating to the extent of rejuvenation of immunosenescent HSCs. Do HSCs from old animals subjected to eight or more cycles of PF have increased regenerative capacity? This experiment should be relatively easy to perform, and the results telling. Will this rejuvenation effect carry over to humans? What effect does rejuvenation have on telomere length? Is telomerase activated? If not, functional rejuvenation could lead to telomere-based replicative senescence as they shorten with each round of proliferation. How many other stem cell populations respond similarly to increase proliferation and maintain stem cell populations? Most mammalian tissues, excluding the brain, are known to shrink in response to fasting, then repopulate after feeding. Are stem cell numbers actually increasing as overall numbers of differentiated cells decrease? Are any tissues negatively impacted by PF? The safety of PF needs to be investigated. PF should probably be avoided by diabetics and the very old, even though they might be among those who could benefit most. One potential problem is that fasting may reinforce cachexia. Moreover, there is a fundamental question that needs to be answered. Will PF select for survival of cancer stem cells that are capable of quiescence and contribute to increased number of dormant cancer cells? It appears that conventional tumor cells can be negatively impacted by fasting,11 but dormant cancer stem cells have been associated in some cases with poor prognoses.26,27 If so, PF might accelerate the progression of some cancers, especially those that appear to generate cancer stem cells capable of quiescence. Chemotherapy can be mutagenic. Increased numbers of cancer stem cells can be problematic because they are almost completely resistant to currently available therapeutics. The effects of prolonged fasting cannot be estimated because cancer dormancy and the role of quiescence in cancer stem cell physiology are poorly understood. Protection from the harmful side effects of radiotherapy should be investigated as well. Conclusion

PF represents a potentially powerful means to protect against the ravages of chemotherapy, perhaps even allowing

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higher doses of drugs. PF appears to be a way to rejuvenate the immune systems of the elderly. Immune dysfunction in old age often leads to significant morbidity and mortality. If the ability of PF to rejuvenate immunosenesced HSCs is confirmed in humans, great utility could result. Furthermore, elucidation of the mechanisms that underlie HSC chemoprotection and rejuvenation could lead to the development of drugs that would be more suitable for the treatment of fragile, elderly individuals than 72 hr of fasting. Major questions remain concerning how general the effects of PF are and whether there are any detrimental effects. The development of rejuvenative therapies is in their infancy, but these results suggest that a large number of interventions may be developed in the near future. Author Disclosure Statement

No competing financial interests exist. References

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Address correspondence to: Andrew R. Mendelsohn James W. Larrick Panorama Research Institute and Regenerative Sciences Institute 1230 Bordeaux Drive Sunnyvale, CA 94089 E-mail: [email protected] [email protected]

refeeding promotes hematopoietic stem cell regeneration and rejuvenation.

The sensitivity of hematopoietic stem cells (HSCs) to toxic effects of cancer chemotherapy is one of the major roadblocks in cancer therapy. Moreover,...
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