Science and Health
Cellular Responses to Ketosis: Can Cancer Cells Listen and Behave?
Promising research on the effects of ketogenic diets and fasting on cancer prevention and treatment
During my health sciences research over the last 50 years, I explored the intricacies of cancer cells, recognizing their unparalleled complexity. I gained extensive insights into their behaviors, yet I couldn’t place my trust in their deceptive tendencies.
While our scientific endeavors, fueled by substantial funding from governmental organizations, academic institutes, and research entities, have propelled significant advancements, the journey toward understanding cancer prevention and treatment remains extensive and inconclusive.
Despite remarkable strides in tackling various chronic diseases like diabetes, heart disease, stroke, and infectious diseases, the consensus among field experts reflects that our progress in combating cancer falls short of these achievements. Nevertheless, significant strides have been made.
The thing is there is something special about cancer cells. They possess an extraordinary and formidable nature. They diverge from the expected norms of cellular behavior, exhibiting a wild, elusive, and ruthless character that sets them apart.
Challenges of Cancer Cells
Cancer cells’ multifaceted nature, adaptability, heterogeneity, and interactions with the tumor micro-environment pose significant hurdles for researchers.
“Cancer can result from abnormal proliferation of any of the different kinds of cells in the body, so there are more than a hundred distinct types of cancer, which can vary substantially in their behavior and response to treatment. The most important issue in cancer pathology is the distinction between benign and malignant tumors.” Source
This 2023 paper in Cell states, “The tumor microenvironment includes diverse immune cell types, cancer-associated fibroblasts, endothelial cells, pericytes, and various additional tissue-resident cell types. These host cells were once considered bystanders of tumorigenesis but are now known to play critical roles in cancer pathogenesis.”
Developing effective treatments requires a deep understanding of these complexities and the ability to overcome the challenges they present, which is why cancer research remains a highly intricate and ongoing endeavor.
Cancer’s complexity arises from diverse genetic mutations within tumors, causing variations in treatment responses even among cells in the same tumor. These cells continually evolve, acquiring new mutations and resisting treatments, making their behavior unpredictable.
Their adaptability includes resisting therapies and altering their metabolism to survive in different environments, challenging targeted treatments without harming healthy cells.
Cancer cells also evade immune surveillance and interact intricately with the tumor microenvironment, influencing their growth and response to treatments.
Due to ethical constraints, researchers face hurdles in replicating this complexity in models and obtaining human samples.
Clinically, late detection and the personalized nature of each patient’s cancer add further challenges in devising effective treatments.
Yet, I perceive an opportunity within lifestyle interventions, specifically through dietary adjustments and exercise, both backed by promising empirical evidence.
In this post, I will explore two specific approaches — ketogenic eating and fasting — which, when coupled with vigorous exercise, yield amplified results toward a common goal: ketosis.
Finding the Silver Lining Through Ketosis
Ketosis is a metabolic state in which the body primarily relies on ketone bodies, produced by the liver from fatty acids, as a significant energy source instead of glucose. However, the body always produces glucose, even during ketosis, as some cells, tissues, and organs cannot survive without glucose, and they cannot use ketones.
While many cells effectively utilize ketone bodies for energy, some, like red blood cells lacking mitochondria and specific brain cells reliant on glucose, have limited ability to use ketones directly.
Interestingly, despite producing ketone bodies, liver cells possess a restricted capacity to metabolize them fully. In addition, specific bone marrow cells might also have limited ketone usage due to specific metabolic needs. So, the body produces sugar via the gluconeogenesis process. In contrast to food intake, this glucose production is controlled and occurs as needed.
This metabolic shift (ketosis) from sugar to fat utilization typically occurs when carbohydrate intake is significantly restricted and protein intake moderately lowered, causing the body to break down fats for energy, generating ketones as a byproduct.
In ketosis, the bloodstream carries these ketone bodies, especially β-hydroxybutyrate, which serve as an alternative fuel source for cells, including the brain and heart, without sufficient glucose intake or glycogen storage in the liver. This state is associated with low glucose and low calories via high-fat ketogenic diets and fasting.
The relationship among ketogenic diets, fasting, and their impact on cancer treatment and prevention remains a subject under constant exploration in research.
While initial studies hint at potential benefits, substantiating these connections requires more comprehensive evidence and rigorous clinical trials for validation.
Option 1 — Metabolic Shift through Ketogenic Diets
Cancer cells exhibit increased glucose uptake (Warburg effect), relying on glycolysis for energy even in the presence of oxygen. Ketogenic diets aim to exploit this vulnerability by reducing available glucose.
In addition, ketogenic diets can influence inflammation and metabolic factors linked to cancer development and progression. There is significant evidence of the anti-inflammatory aspect of ketosis as documented by Dr Mehmet Yildiz in an article titled Ketosis Can Lower Chronic Inflammation and Improve Metabolic and Mental Health in 6 Ways.
Ketogenic diets involve high healthy fat, moderate bioavailable protein, and low non-refined carbohydrate intake, producing less sugar for the body, initiating gluconeogenesis, and leading to a metabolic state called ketosis.
Cancer cells, particularly some types, heavily rely on glucose for energy. By depriving the body of glucose, recent theories and compelling hypotheses point out that ketogenic diets might starve cancer cells, hindering their growth. I see this as the silver lining.
This 2021 review highlights “the crucial mechanisms that explain the ketogenic diet’s potential antitumor effects, which probably produce an unfavorable metabolic environment for cancer cells and can be used as a promising adjuvant in cancer therapy. Studies discussed in this review provide a solid background for researchers and physicians to design new combination therapies based on keto diets and conventional therapies.”
Some health scientists and medical practitioners also see a connection between insulin resistance and cancer development, so making the body insulin-sensitive might lower risks.
This 2003 paper states, "Recent evidence supports the role of insulin and IGF-1 as important growth factors, acting through the tyrosine kinase growth factor cascade in enhancing tumor cell proliferation. In addition, the metabolic syndrome associated with a chronic inflammatory state and accompanying cytokine abnormalities may also contribute to tumor progression.”
Two decades ago, the paper reviewed growing links between insulin and the etiology as well as prognosis in colon, prostate, pancreatic, and, particularly, breast cancer. Of particular concern is the evidence that elevated IGF-1 may interfere with cancer therapy, adversely affecting prognosis.
Then, in 2012, researchers summarized recent progress on insulin resistance and cancer, focusing on various implicated mechanisms described recently and discussing how these mechanisms may contribute to cancer initiation and progression.
In 2020, researchers in Cell indicated that clinical studies have not clarified the degree to which hyperinsulinemia can influence cancer occurrence and prognosis. Therefore, to better understand this issue, an improved scientific approach is required, with more careful consideration of the mechanisms related to hyperinsulinemia and carcinogenesis.
Within this context, I support their perspective because ketogenic diets can lower insulin levels and make the body more insulin-sensitive, potentially impacting the signaling pathways related to cancer cell proliferation.
Some animal studies and lab experiments suggest that ketogenic diets might slow tumor growth, particularly in brain cancers. However, extrapolating these findings to human treatment requires caution.
For example, this systemic review on Frontier concluded that “the pre-clinical evidence pointed toward an overall anti-tumor effect of the ketogenic diet in animal studies currently available with limited tumor types.”
Limited clinical trials have shown mixed results. Some have shown positive effects on tumor progression or quality of life, while others have not shown significant benefits.
The laboratory team led by Dr. Nelofer Syed at the Brain Tumour Research Centre at Imperial College, London, is part of a global network of researchers investigating a medical diet. Dr. Syed’s work sheds light on how a keto diet affects the metabolism of brain tumor cells and how it changes the way that brain tumors use nutrients to provide the energy that they need to grow.
A few clinical trials are ongoing to investigate the effects of ketogenic diets on different cancer types, such as brain tumors, breast cancer, and others. We still have a long way to go. However, I remain optimistic as the preliminary findings and hypotheses are compelling.
Dr. Jocelyn Tan-Shalaby, who investigates emerging evidence, summarized some clinical trials in this review paper in 2017. However, some of these trials were ended with poor results. But there are others underway, which I will cover in another story informing about their progress.
As an oncologist, the conclusion of her paper informs that data from case reports and trials suggest ketogenic diet use is safe and tolerable for patients with cancer. She recommends a larger trial using a randomized therapeutic approach. The current emphasis on drug-based trials is a formidable obstacle.
As Dr Tan-Shalaby highlighted, another major obstacle is patient initiative and adherence. For now, investigators must work with anecdotal data. Examination of gene expression patterns in mitochondria and mutations in ketolytic and glycolytic enzymes may prove useful in selecting potentially responsive patients. Combining this dietary approach with standard chemotherapeutic and radiotherapeutic options may help improve tumor response. Further research is desperately needed.
Keep in mind that ketogenic diets are not standalone cancer treatments by oncologists. They are being investigated as possible complements to conventional therapies such as chemotherapy, radiation, and immunotherapy.
Additionally, the effects of ketogenic diets can differ widely among individuals, with varying impacts based on the type and stage of cancer.
Option 2 — Fasting to Influence Cancer Cells
Fasting triggers cellular processes like autophagy and mitophagy, where cells recycle damaged components. This might affect the ability of cancer cells to survive and proliferate.
As covered in this Nature paper titled Fasting and Cancer (Molecular Mechanisms and Clinical Applications), cancer cells are also related to growth factors, such as mTOR. For example, fasting may reduce insulin-like growth factor 1 (IGF-1) and other growth factors that promote cancer cell growth.
Furthermore, as pointed out in the journal Science, fasting can induce stress responses in cells, which may selectively affect cancer cells more than normal cells. Besides, fasting might sensitize cancer cells to chemotherapy and radiation therapy.
Some animal studies have shown that fasting can slow tumor growth and enhance the effectiveness of specific cancer treatments. Limited evidence from human studies indicates potential benefits in reducing side effects of treatment and improving treatment efficacy.
Diets that mimic fasting without complete calorie deprivation are being researched for their potential benefits in cancer treatment. Dr Walter Longo published multiple studies on this, and they look promising. You may check out his noteworthy studies on “Nutrition and Fast-Mimicking Diet for Cancer Prevention.”
Some clinical trials investigate the effects of fasting or fasting-mimicking diets in combination with standard cancer therapies.
For example, as documented in this 2022 paper, of the 101 patients enrolled in the NCT03340935 trial, the researcher identified five patients with advanced, poor prognosis solid neoplasms who achieved complete and long-lasting tumor responses when treated with a combination of cyclic FMD and standard systemic treatments in the context of the NCT03340935 trial.
Intermittent fasting schedules are under intense investigation for their potential impact on cancer prevention and treatment by scientists, clinicians, and oncologists.
Experts like Dr. Thomas Seyfried, Dr. Jason Fung, Dr. Siddhartha Mukherjee, and many more have contributed significantly to this field through their books and research papers, shedding light on the subject. As they wrote prolifically and created many educative videos, adding their work to this story is impossible. Most of their work is publicly available.
Conclusions and Key Considerations
While compelling evidence and intriguing hypotheses suggest favorable connections between ketogenic diets, fasting, and cancer, much of this understanding is derived from preclinical studies or restricted human trials.
To confidently advocate for these approaches, comprehensive and stringent clinical research is imperative to grasp their efficacy, safety, and suitability across diverse cancer types and stages.
It is noteworthy that fasting and ketogenic diets have gained popularity, yet their applicability is not universal and could potentially clash with underlying health conditions, medications, and therapies.
Therefore, seeking guidance from healthcare professionals before implementing substantial dietary changes, particularly concerning cancer treatment or prevention strategies, is crucial.
In my health journey, I have embraced a ketogenic diet, intermittent fasting, and occasional extended fasts cautiously, especially after reaching my 70s, witnessing notable improvements in my biomarkers.
Nevertheless, I recognize that these approaches are only suitable for some. For example, some of my family members cannot fast and cannot consume high-fat foods even if they want to. But they try alternative methods like intense workouts and caloric reduction to get mild ketosis.
So, embracing these differences and finding alternative ways, we honor the uniqueness of our bodies and respect their signals, acknowledging and adapting to our individual needs with open minds and support from qualified healthcare professionals.
Thank you for reading my story. I wish you a healthy life.
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