Last update and review: August 27, 2021.
A short summary.
In this article, we share several notes on a 2014 study by Cheng and coworkers (Valter Longo group), as well as on a commentary by Hine and Mitchell, 2014 (1), on the use of prolonged fasting in mice and humans to prevent chemotherapy-induced damage.
We also mention a heart-breaking story of an activist doctor Sarah Hallberg who was diagnosed with cancer.
A heart-breaking story of Sarah Hallberg.
Sarah Hallberg, an activist doctor who, together with Stephen Phinney and Jeff Volek, has been treating diabetic patients with a “ketogenic diet” at the “Virta Health” start-up, was diagnosed with an aggressive form of lung cancer in 2017. Sarah shared her heart-breaking story during a podcast with Peter Attia.
According to her account, Sarah Hallberg was treated with a “traditional” short-term chemotherapy. The treatment, chemotherapy (“chemo”) and other treatments, were successful, apparently. There was an improvement.
Later, as a part of her treatment strategy, Sarah Hallberg also went on chronic prolonged low-dose chemotherapy. At one point, it turned out that Sarah was not eliminating properly the particular chemotherapeutic agent used in that chronic prolonged low-dose chemotherapy. Sarah apparently missed the signs of abnormal toxicity in her blood markers and ended up in an emergency department.
After an initial success with different chemotherapies and other treatments, Sarah’s cancer came back in 2020.
Sarah’s courage and strength in fighting cancer are infinite. In 2021, during the podcast, Sarah looks great on video. However, that prolonged chemotherapy could have seriously damage Sarah’s immune system. Cycles of chemotherapy combined with fasting, a regiment that is apparently protective for the immune system, could have been a better strategy.
In this article, share some our notes on an work published by the group of Valter Longo in 2014 (2). Longo obtained some encouraging results in both mice and humans in combining chemotherapy and fasting. There are currently ongoing clinical trials using similar regiments in cancer patients and there are papers that have been published recently. We recommend to those who have to deal with cancer to explore the subject of cyclical fasts as a part of their treatment regiment. Preserving immune system when treating cancer appears as an absolute priority. If there is a way to achieve this, it shouldn’t be neglected.
Also, consulting with a collaborative working group that includes credible medical doctors and researchers could be a better approach when dealing with cancer. For example, it is not clear if Sarah Hallberg was informed about the possibility of using cyclic fasts with cycles of chemotherapy, and if so, why did she eventually went on a prolonged low dose chemotherapy which appear incompatible with cycles of fasting.
Photo: Sarah Hallberg, an activist doctor who, together with Stephen Phinney and Jeff Volek, has been treating diabetic patients with a “ketogenic diet” at the “Virta Health” start-up, was diagnosed with an aggressive form of lung cancer in 2017.
Sarah Hallberg describes her cancer treatment regiment to Peter Attia. An extract from the automatically generated transcript.
Sarah Hallberg, at around minute 118:
“i started chemo
um regular chemo i went through the
regular cycles of chemo
and then when i was done with that i
immediately went to
anti-estrogen therapy okay because i had
a very specific mutation besides the
egfr1 and there was a medication to
treat it
it just so happened to be a breast
cancer medication but
it was the same mutation for either
cancer
so immediately upon
stopping um the
chemo i went on the anti-estrogen
therapy
so i was put into early menopause with
the number of
you know regular medications lupron full
of strand
and then i was started on a medication
called pablocyclib
okay which again is primarily a breast
cancer medication
but was targeting one of my very
specific secondary mutations
i was on that for the summer and all
this time i’m still on the
tagrasso or asamartanib that never
stopped
as soon as the eight weeks of that was
over with
i went back on chemo but very different
low dose chemo
single agent very low dose which agent
so the first one was cis platinum
okay and you know everyone says oh
cisplatin you know you’re
you know you’re gonna do terrible on
this i mean this is harsh
it and it is but you know i did fine
i did fine i was able to still you know
i mean i’m not saying i wasn’t tired
you know i’ve basically been nauseous
for the last four almost four years
every single day you know it’s just you
learn to manage that
you know so i learned to manage it i
learned to manage
you know being tired um and the things
that came along i still traveled
for work i still did i was still able to
do everything”
Fasting Protects Hematopoietic Stem Cells from Chemotherapy and Aging. A study by Cheng et al. (Valter Longo group), 2014 (2) and a commentary by Hine, Mitchell, 2014 (1).
Hine, Mitchell, 2014 (1):
“Aging and chemotherapeutics damage hematopoietic stem cells (HSCs), leading to dysregulation of asymmetric division and subsequent immunosuppression and blood-related diseases.
Damage caused by chemotherapy. The key points:
In cancer/chemotherapy survivors, DNA damage to normal cells can promote pro-oncogenic mutations, leading to an increased risk of secondary cancers.
Chemotherapy can also irreversibly alter hematopoietic stem cell (HSC) leading to eventual immunosuppression, anemia, and bone marrow failure.
Hine, Mitchell, 2014 (1):
“Chemotherapeutic strategies for treating blood-based and solid cancers using genotoxic alkylating agents such as cyclophosphamide (CP) have a number of highly undesirable side effects, including depletion of circulating white blood cells (WBC) and loss of bone marrow (BM) cellularity (Mauch et al., 1995). Over 20% of cancer-related deaths are hastened, or even caused, by toxic effects of chemotherapy rather than the cancer itself (Mort et al., 2008). These acute toxicities reduce overall efficacy by limiting the dosage and schedule frequency of chemotherapeutic interventions. In cancer/chemotherapy survivors, DNA damage to normal cells can promote pro-oncogenic mutations, leading to an increased risk of secondary cancers. It can also irreversibly alter hematopoietic stem cell (HSC) and progenitor cell function in the BM, resulting in dysregulation of asymmetric division and a decrease in the lymphoid to myeloid (L/M) ratio, leading to eventual immunosuppression, anemia, and BM failure (Bartucci et al., 2011; Ding et al., 2014).”
Normal aging takes a heavy toll on stem cell homeostasis, including reduced HSC self-renewal capacity and function as well as a decreased lymphoid/myeloid ratio.
Hine, Mitchell, 2014 (1):
“Even in the absence of exogenous genotoxic chemotherapeutics, normal aging takes a heavy toll on stem cell homeostasis, including reduced HSC self-renewal capacity and function as well as a decreased lymphoid/myeloid ratio. Endogenous DNA damage and changes in circulating factors have both been implicated in this process (Pang et al., 2011).”
A noteworthy reference: Pang WW, Price EA, Sahoo D, Beerman I, Maloney WJ, Rossi DJ, Schrier SL, Weissman IL. Proc. Natl. Acad. Sci. USA. 2011; 108:20012–20017. [PubMed: 22123971]
Hine, Mitchell, 2014 (1):
“Currently there are no therapies available to mitigate off-target chemotherapeutics effects on immunosuppression or BM depletion, nor any interventions to prevent HSC dysfunction with aging.”
Protection from the toxic effects of chemotherapy in mice and humans.
Chen (the group of Valter Longo), 2014 (2), showed that cycles of water-only fasting for 2 days immediately prior to CP treatment, which is administered once every 2 weeks over a total of 6 cycles (~12 weeks total), protected against CP-induced mortality in mice. Fasting cycles also facilitated a rebound from CP-mediated peripheral WBC loss and preservation of a healthy L/M ratio by the sixth cycle relative to continually fed animals.
Similar protection against peripheral WBC loss and preservation of the L/M ratio was seen in human patients fasted for a single 72 hr (48 hours before and 25 hours after) period concomitant with platinum-based chemotherapy as part of a Phase I clinical trial for safety and feasibility.
Fasting reduced damage to bone marrow.
Hine, Mitchell, 2014 (1):
“In order to explain these protective effects, the authors looked to the BM, where they found evidence of reduced DNA damage, reduced apoptosis and increased numbers of HSCs, including omnipotent LT-HSCs, after the sixth fasting/CP cycle. As a result, competitive BM transplantation with total BM from periodic fasted versus continually fed mice favored the fasted group.”
Strikingly, even a single bout of fasting significantly increased HSC numbers.
Hine, Mitchell, 2014 (1):
“To further explain fasting-induced preservation of HSC function upon CP treatment, the authors tested the hypothesis that fasting can stimulate HSC renewal independent of chemotoxicity altogether. Strikingly, even a single bout of fasting significantly increased HSC numbers.”
Reduced IGF-1 signaling would be the mechanism.
Hine, Mitchell, 2014 (1):
“By what mechanism does nutrient/ energy restriction promote HSC renewal and promote BM health? Previous work by the Longo group demonstrated the importance of reduced IGF-1 in resistance to chemotoxicity. Here, they confirmed the importance of reduced IGF-1 signaling specifically in BM using mice deficient in growth hormone receptor (GHR) signaling upstream of IGF-1 production. These mice had reduced IGF-1 in circulation as well as in the BM and displayed properties similar to WT mice subject to fasting cycles upon CP treatment, including reduced BM DNA damage and preservation of circulating WBC numbers and L/M ratios, and increased numbers of cycling HSCs and preservation of L/M ratios as a function of age in the absence of CP treatment.”
The authors identified protein kinase A (PKA) as a relevant downstream target of IGF-1R signaling involved in fasting-mediated HSC self-renewal. Inhibition of IGF-1R or PKA in ex vivo BM cultures increased HSC proliferation independent of nutrient availability, and promoted efficient BM reconstitution in vivo.
Hine, Mitchell, 2014 (1):
“While PKA and its target, CREB, can negatively regulate FoxO1, a critical regulator of stress resistance and stem cell pluripotency, future experiments will be required to test genetic requirements of these factors in fasting-based HSC renewal.”
“Figure 1”: A model summarizing the mechanism by which fasting promotes HSC self-renewal and BM homeostasis via inhibition of IGF-1 signaling and PKA/ CREB activity.
“Prolonged Fasting Boosts Bone Marrow HSC Self-Renewal and Increases Resistance to Chemotherapeutic Toxicity and Aging-Related Loss of Homeostasis through Decreased IGF-1/PKA Signaling This results in maintenance of lymphoid cell (LC) and myeloid cell (MC) numbers and ratios and improved immune function.”
Fasting by the healthy donor is a potential way to improve the efficacy of bone marrow transplants.
The work of Chen et al. (Valter Longo group), 2014 (2), suggests a potential way to improve the efficacy of BM transplants.
Hine, Mitchell, 2014 (1):
“At face value, these data suggest that fasting the healthy donor may increase the number, and possibly the functionality, of HSCs in the graft, facilitating regrowth of a balanced and healthy BM in both donor and recipient.”
Conclusions.
We recommend to those who have to deal with cancer to explore the subject of cyclical fasts as a part of their treatment regiment. Preserving immune system when treating cancer appears as an absolute priority. If there is a way to achieve this, it shouldn’t be neglected.
Also, consulting with a collaborative working group that includes credible medical doctors and researchers could be a better approach when dealing with cancer. For example, it is not clear if Sarah Hallberg was informed about the possibility of using cyclic fasts with cycles of chemotherapy, and if so, why did she eventually went on a prolonged low dose chemotherapy which appear incompatible with cycles of fasting.
Selected references:
1. Hine, Mitchell. Cell Stem Cell. 2014 June 5; 14(6): 704–705. doi:10.1016/j.stem.2014.05.016.
2. Chia-Wei Cheng, Valter D. Longo et al. Cell Stem Cell. 2014 June 5; 14(6): 810–823. doi:10.1016/j.stem.2014.04.014.
