Seabridge Bioenergetics

Maybe the high sugar vegans are not so crazy after all – and the carnivore crowd might have something to think about.

Might the so called benefits of calorie restriction even be confounded with all the benefits of methionine restriction?

Methionine, an essential amino acid is the main source of methyl group donations in mammals. Methionine is abundant in muscle meat and the normal westerner gets many times more methionine than what is considered essential.
On the methionine amino acid, the sulphur atom at the side chain, has a CH3 methyl group bound to it, that is easily donated. This methyl group can easily attach to DNA or enzymes, and thereby alter the functions – of the enzymes or the DNA. While it has it’s essential functions, it seems that too much of this methyl donor, might become a problem to the cell.

We shall now look at a study where all of the benefits on life span extension, insulin sensitivity, fat mass reduction and mitochondrial efficiency are listed.

Mitochondrial ROS production:

Too much methionine in the mitochondria might react with metabolic enzymes in the energy production pathways, and shift glycolysis more towards lactate production, because of impaired electron flow through complex 1 and 3 in the electron transport chain:

“Several studies have shown that methionine can stimulate mitochondrial ROS (MtROS) production and that MetR inhibits this production. Sanz et al. demonstrated that 80% MetR fed to rats (250 g BW) for 6–7 weeks without CR decreases MtROS production of complexes I and III in the liver and complex I in the heart [70]. Similarly, Caro et al. showed that both 80% and 40% MetR without CR fed for 6–7 weeks to rats (250–300 g BW) decreased the MtROS generation in the liver”

…

“These radicals or methanethiol (CH3SH) itself may react with complex I or III in mitochondria, resulting in the overproduction of mtROS. Therefore, MetR may decrease the rates of mtROS production through a reduction in the thiolization of complex I in mitochondria.”

Methionine restriction also upregulates several ROS scavenger pathways through upregulation of hydrogen sulphate:

“In addition, Calvert et al. reported that H₂S shows antioxidative effects through the upregulation of antioxidative molecules, including heme oxygenase-1 and thioredoxin-1, in cardiomyocytes in a NF-E2-related factor 2 (Nrf2)-dependent manner.“

…

“Dietary restriction of SAAs, including methionine, contributes to stress resistance and lifespan extension through H₂S production by enhancing the transsulfuration pathway.”

Autophagy and MTOR

Autophagy, the “cleaning” of damaged mitochondria and other organelles and cellular components, is a very important proces that has been known to extend life span in animal studies.

Keeping autophagy to a level where damaged mithocondria are recycled, might help keep well functioning mitochondria thriving. The more selective form of autophagy that recycles damaged mitochondria, mitophagy, also happens to stimulate mitochondrial biogenesis, the production of new and healthy mitochondria:

“Mitochondria are major sources of ROS, and mitochondria are attacked by ROS. Damaged mitochondria produce additional ROS, which leads to mitochondrial dysfunction and cellular aging. Autophagy is a lysosomal degradation pathway and plays an important role in the removal of damaged organelles, including mitochondria, to maintain cellular homeostasis [34]. However, impairment of autophagy is involved in the accumulation of damaged mitochondria in the cell, which results in enhanced overproduction of ROS in the mitochondria. Among the autophagy, damaged mitochondria are eliminated by the selective autophagy, mitophagy, leading to the induction of mitochondrial biogenesis and suppression of oxidative stress. Indeed, Plummer et al. reported that MetR-mediated chronological lifespan extension of a yeast requires the autophagic recycling of mitochondria; that is, mitophagy”

The way methionine restriction probably activates autophagy, is by downregulating the MTOR pathway. This is very important in understanding how methionine restriction might increase lifespan and decrease cancer incidence:

“Autophagy is regulated by nutrient-sensing molecules, including mTORC1, a serine/threonine kinase subunit of mTOR that functions as a central regulator of cell growth and metabolism in response to changes in nutrient status [36]. mTORC1 is activated by growth factors, such as insulin, and amino acids, including methionine [36,37]. Activated mTORC1 phosphorylates the components of Ulk1 (Ser757), thereby inhibiting its activity and suppressing autophagy [36]. Recent reports show that methionine can activate mTORC1 via multiple pathways involved in the suppression of autophagy.”

Insulin and fat loss:
It seems insulin sensitivity is better in methionine restricted animals. The lens of the eye is less cloudy, t-cells show less age related changes. IGF-1, glucose and insulin is lower, and T4 is lower, suggesting maybe a better conversion from t4 to t3:
“MetR mice develop lens turbidity significantly slower and show age-related changes in T-cell subsets and lower serum insulin, glucose, insulin like growth factor-1 (IGF-1) and thyroxine (T4) levels“

Methionine restriction doesn’t stop being amazing in terms of metabolic health – It increases both energy intake and energy expenditure, limiting fat gain in the tissues:
“Metabolically, MetR reduces adiposity in rodents, whereas, interestingly, both energy intake and energy expenditure (EE) are increased. The increase in EE is induced by a process that compensates for increased energy intake, effectively limiting fat deposition. Furthermore, MetR increases metabolic flexibility and overall insulin sensitivity, and it improves lipid metabolism by decreasing systemic inflammation“

https://www.mdpi.com/2227-9059/9/2/130

Closing thoughts:
Where I have always been very positive on meat, and still am to an extend, I might have to reconsider my beliefs, and if the western consumption of muscle meat is too much. Maybe the overconsumption of muscle meat, might be a causative factor in the development of modern phenomenons such as cancer, obesity and diabetes.
Maybe a focus towards more dairy and organ meat, and less on muscle meat would be helpful to the western health state.

Another day, I will have to look more into the role of methylation of metabolic enzymes and DNA and it’s role in cancer – and how methionine restriction might alleviate proliferation of cancer tumors.