Epigenetics and mitochondrial adaptations involved in cancer

Nerd Alert. In case you needed some motivation to stay active over the holidays... here are some data points on maintaining your good habits over the long haul and a comparison of the AI tool Consensus against ChatGPT.

Acquired gene mutations that lead to cancer are often caused by environmental factors, including poor diet and a sedentary lifestyle. These lifestyle factors, aka epigenetics, contribute to genetic mutations either directly, by causing DNA damage, or indirectly, by inducing changes in cellular processes like metabolism and inflammation that ultimately promote cancer development.

Additionally, mitochondrial adaptations play a significant role in cancer cell metabolism and survival, and these adaptations are influenced by diet and physical activity. Let’s explore some key examples of acquired gene mutations, their causes, and their links to poor diet and sedentary lifestyle, as well as the mitochondrial adaptations involved in cancer.

I used AI to get my head further around acquired gene mutations and potential links to diet and lifestyle. I've been comparing different approaches to using AI in understanding molecular health to find deeper references, and am loving Consensus.

Here's what it had to say about how epigenetic factors such as lifestyle, specifically yoga practice, can modulate again acquired gene mutations:

Yoga for modulating against mutations

Yoga, a practice with ancient roots, has been shown to influence gene expression and epigenetic modifications, offering various health benefits. Research indicates that yoga can modulate gene expression through mechanisms such as DNA methylation and histone modifications, leading to anti-inflammatory effects, enhanced immunity, and improved cellular health.

Key Epigenetic Effects of Yoga on Gene Expression

Anti-inflammatory Effects

Yoga downregulates pro-inflammatory cytokines and transcription factors, reducing inflammation (Giridharan, 2023; Choudhury, 2017).
It specifically downregulates NF-kB, a master regulator of inflammatory pathways, and its target genes (Choudhury, 2017).

Immune System Modulation

Yoga enhances the expression of genes related to the innate antiviral response and boosts natural defense genes (Giridharan, 2023).
It modulates genes affecting Th1 and NK cells, which are crucial for immune response (Khokhar et al., 2022).

Cellular Longevity and Repair

Yoga activates telomerase, which is linked to cellular longevity (Giridharan, 2023).
It promotes DNA repair and maintains cellular integrity by increasing the expression of oxoguanine glycosylase and p53 genes (Giridharan, 2023).

Brain Health and Neuroprotection

Yoga enhances the expression of neuroprotective genes and nitric oxide synthetase, which are beneficial for brain and ocular health (Giridharan, 2023).
It also increases the expression of microRNA-29c, which is associated with brain health (Giridharan, 2023).

Circadian Rhythm Regulation

Yoga influences genes related to circadian rhythm, such as BHLHE40, which helps regulate sleep and other daily physiological cycles (Khokhar et al., 2022).

Mechanisms of Action

DNA Methylation: Yoga influences DNA methylation patterns, which can alter gene expression without changing the DNA sequence (Giridharan, 2023; Jacques et al., 2019; Brown, 2015).
Histone Modifications: Yoga induces histone modifications, leading to chromatin remodeling and global changes in gene expression (Choudhury, 2017; Brown, 2015).
MicroRNAs: Yoga affects the expression of microRNAs, which play a role in regulating gene expression post-transcriptionally (Giridharan, 2023; Denham et al., 2014).

Conclusion

Yoga exerts significant epigenetic effects that modulate gene expression, leading to reduced inflammation, enhanced immunity, improved cellular health, and better brain function. These changes are mediated through mechanisms such as DNA methylation, histone modifications, and microRNA expression. While current research highlights these benefits, further studies are needed to understand the long-term epigenetic impacts of yoga.

These papers were sourced and synthesized using Consensus, an AI-powered search engine for research. Try it at https://consensus.app

References

Giridharan, S., 2023. Beyond the mat: Exploring the potential clinical benefits of yoga on epigenetics and gene expression: A narrative review of the current scientific evidence. International Journal of Yoga, 16, pp. 64 - 71. https://doi.org/10.4103/ijoy.ijoy_141_23

Khokhar, M., Tomo, S., Gadwal, A., & Purohit, P., 2022. Multi-omics integration and interactomics reveals molecular networks and regulators of the beneficial effect of yoga and exercise. International Journal of Yoga, 15, pp. 25 - 39. https://doi.org/10.4103/ijoy.ijoy_146_21

Choudhury, A., 2017. Yoga and your genes. The research reports, 1.

Jacques, M., Hiam, D., Craig, J., Barrès, R., Eynon, N., & Voisin, S., 2019. Epigenetic changes in healthy human skeletal muscle following exercise– a systematic review. Epigenetics, 14, pp. 633 - 648. https://doi.org/10.1080/15592294.2019.1614416

Denham, J., Marques, F., O'Brien, B., & Charchar, F., 2014. Exercise: Putting Action into Our Epigenome. Sports Medicine, 44, pp. 189-209. https://doi.org/10.1007/s40279-013-0114-1

Brown, W., 2015. Exercise-associated DNA methylation change in skeletal muscle and the importance of imprinted genes: a bioinformatics meta-analysis. British Journal of Sports Medicine, 49, pp. 1567 - 1578. https://doi.org/10.1136/bjsports-2014-094073

1. Acquired Gene Mutations and Their Causes (using ChatGPT)

a. KRAS Mutations

• Cause: KRAS is an oncogene that encodes a small GTPase involved in cell growth and survival. Mutations in KRAS are common in various cancers, including pancreatic, colorectal, and lung cancers. These mutations lead to the constitutive activation of KRAS, promoting unchecked cell proliferation.
• Link to Poor Diet and Sedentary Lifestyle:
  • High-fat diet: Diets rich in saturated fats (found in red meat, processed foods, and fried foods) can lead to obesity, which is a significant risk factor for KRAS-driven cancers. High-fat diets can activate inflammatory pathways and induce metabolic changes that create a pro-cancer environment. Increased fat intake can also lead to changes in insulin and growth factor signaling (such as insulin-like growth factor, IGF), which can activate KRAS and other oncogenes.
  • Sedentary lifestyle: Lack of physical activity leads to increased insulin resistance and obesity, which further promotes insulin and IGF signaling, enhancing KRAS activation and cancer progression.

b. TP53 Mutations (p53)

• Cause: TP53 encodes the tumor suppressor protein p53, which is crucial for DNA repair, apoptosis, and cell cycle regulation. Mutations in TP53 are found in over 50% of human cancers, including breast, colon, and lung cancers. Loss of p53 function leads to the accumulation of genetic mutations, evasion of apoptosis, and uncontrolled cell division.
• Link to Poor Diet and Sedentary Lifestyle:
  • Poor diet: A diet low in antioxidants (e.g., from fruits and vegetables) can reduce the cell’s ability to neutralize reactive oxygen species (ROS). Excessive ROS can cause DNA damage, which may induce mutations in TP53 or inactivate the p53 protein. Diets rich in processed meats and red meat have been shown to increase oxidative stress, further promoting mutations.
  • Sedentary lifestyle: Physical inactivity can lead to higher levels of chronic inflammation and increased ROS production, which damages DNA and promotes TP53 mutations. Inflammation activates signaling pathways (such as NF-κB) that suppress apoptosis, indirectly supporting cancer development.

c. BRCA1/BRCA2 Mutations

• Cause: BRCA1 and BRCA2 are tumor suppressor genes that are involved in DNA repair, particularly through homologous recombination. Mutations in these genes lead to defective DNA repair mechanisms, resulting in genomic instability and an increased risk of breast, ovarian, and other cancers.
• Link to Poor Diet and Sedentary Lifestyle:
  • Diet: Diets high in refined sugars and saturated fats can exacerbate insulin resistance and inflammation, which in turn increase the risk of BRCA-related cancers. Obesity (linked to poor diet) is a known risk factor for breast and ovarian cancers, especially in postmenopausal women. Chronic inflammation can impair DNA repair mechanisms and exacerbate the effects of BRCA mutations.
  • Sedentary lifestyle: Lack of exercise is associated with obesity, higher levels of insulin, and increased inflammation, all of which can indirectly influence the expression or function of BRCA1 and BRCA2, exacerbating the risk of cancer.
  • Studies show an emerging view is that the type or form of breast cancer is determined at the time of its onset, suggesting that genetic and environmental factors that play a role in tumour initiation might also influence how the disease will progress.

d. APC Mutations

• Cause: The APC gene is a tumor suppressor gene that regulates cell growth and Wnt signaling. Mutations in APC are strongly associated with familial adenomatous polyposis (FAP), a condition that significantly increases the risk of colorectal cancer. APC mutations lead to abnormal activation of the Wnt pathway, promoting unchecked cell proliferation in the colon.
• Link to Poor Diet and Sedentary Lifestyle:
  • Diet: Diets high in red and processed meats, which contain heterocyclic amines and polycyclic aromatic hydrocarbons (cancer-causing chemicals), can promote the formation of colon polyps and activate the Wnt signaling pathway. A high-fat diet can also increase the production of bile acids, which can promote inflammation and damage the colon lining, potentially leading to APC mutations.
  • Sedentary lifestyle: Physical inactivity has been shown to increase the risk of colorectal cancer. Sedentary behavior can lead to obesity, which creates a systemic pro-inflammatory state and promotes insulin resistance, both of which can increase the likelihood of APC mutations and enhance cancer progression.

2. Mitochondrial Adaptations Involved in Cancer

Cancer cells often undergo mitochondrial adaptations that support their altered metabolism, survival, and resistance to treatment. These adaptations are influenced by lifestyle factors like diet and physical activity.

a. Altered Mitochondrial Metabolism

• Warburg Effect: Cancer cells often rely on aerobic glycolysis (the Warburg effect), where glucose is converted to lactate even in the presence of oxygen. This shift allows cancer cells to rapidly generate ATP and metabolic intermediates needed for cell proliferation, even when mitochondrial oxidative phosphorylation (OXPHOS) is impaired.
  • Diet: A diet high in sugars (especially refined carbohydrates) promotes elevated blood glucose levels, which can fuel the Warburg effect and enhance glycolysis in cancer cells. Chronic overconsumption of sugar (leading to obesity and insulin resistance) promotes insulin and growth factor signaling, further driving glycolytic metabolism in cancer cells.
  • Sedentary lifestyle: Physical inactivity exacerbates insulin resistance, which increases glucose availability for glycolysis and favors cancer cell growth. Regular physical activity, in contrast, helps maintain insulin sensitivity and limits the glucose availability for tumor cells.

b. Mitochondrial Dysfunction and ROS Production

Mitochondria are the primary source of reactive oxygen species (ROS), which can cause oxidative damage to DNA, proteins, and lipids. In cancer cells, mitochondrial dysfunction often leads to increased ROS production, which contributes to mutations and promotes carcinogenesis. This ROS also plays a role in promoting cell survival, angiogenesis (new blood vessel formation), and metastasis.

• Diet: A poor diet low in antioxidants (vitamin C, E, polyphenols from fruits and vegetables) can reduce the ability of cells to neutralize ROS. Increased ROS levels contribute to mitochondrial mutations and genomic instability, both key features of cancer. On the other hand, a diet rich in anti-inflammatory foods (such as fruits, vegetables, and omega-3 fatty acids) can reduce ROS levels and oxidative stress.
• Sedentary lifestyle: Physical inactivity leads to increased ROS production due to poor mitochondrial efficiency and oxidative stress. Regular exercise improves mitochondrial function, reduces ROS production, and lowers the risk of mitochondrial mutations and associated cancers.

c. Mitochondrial Biogenesis

Cancer cells often increase mitochondrial biogenesis to meet their increased energy demands. This process is regulated by the PGC-1α pathway, which controls mitochondrial DNA replication, protein synthesis, and oxidative phosphorylation. Increased mitochondrial mass helps cancer cells maintain ATP production and adapt to changes in metabolic conditions.

• Diet: Diets high in saturated fats and low in polyunsaturated fats can promote mitochondrial dysfunction and increase the likelihood of mitochondrial adaptations in cancer. In contrast, diets rich in healthy fats (such as omega-3 fatty acids from fish and plant-based sources) may improve mitochondrial function and reduce the need for excessive mitochondrial biogenesis.
• Sedentary lifestyle: Lack of exercise can impair mitochondrial biogenesis, contributing to metabolic dysfunction and increasing cancer risk. Regular physical activity, on the other hand, enhances mitochondrial function, reduces inflammation, and may prevent or reverse mitochondrial adaptations in cancer cells.

d. Mitochondrial Dynamics and Cancer

Mitochondrial dynamics, which include fission (division) and fusion (joining), are essential for maintaining mitochondrial function and cellular homeostasis. In cancer, altered mitochondrial dynamics can support rapid cell division, enhanced survival, and resistance to apoptosis.

• Diet: Diets rich in trans fats and low in nutrients like vitamins D and E can impair mitochondrial fusion, leading to fragmented mitochondria that are less efficient at energy production and more prone to ROS-induced damage. This supports the cancer cell's need for continuous growth and survival.
• Sedentary lifestyle: Physical inactivity can lead to mitochondrial fragmentation, which may contribute to metabolic dysfunction and cancer progression. Regular exercise helps maintain balanced mitochondrial dynamics, reducing the risk of tumor formation.

Acquired gene mutations in cancer are driven by both genetic factors and environmental influences such as poor diet and sedentary lifestyle. Dietary factors (such as high-fat, high-sugar, and low-antioxidant diets) and lack of exercise can promote mutations in key oncogenes and tumor suppressor genes.

Using AI to do blog-level health research

In my experience using several tools for health research (Petal, Type, ChatGPT, and Consensus), I would recommend using Consensus because it puts together deeper level synthesis and backs it all up with actual academic publications and provides references in various styles you can take away. 

I think the Type.ai tool is amazing for writing blog posts, but a bit dangerous for trying to get into the health research! This is because you get a choice of AI models, Claude or GPT.

GPT is good for lists and rote knowledge that you then need to go check, but if you want deeper connections with unique insights, you really need Claude. But I found that Claude was hallucinating the references, as in literally making it up and creating false references. 

At some point, I'll write up a full assessment of my experiences with these tools and put it into a post for anyone aiming to use AI to do legitimate research. The model you choose is everything! Consensus is far and away the most robust AI tool for creating robust research insights backed up with real, scholarly references.