Abstract
We used an LC-MS/MS metabolomics approach to investigate one-carbon metabolism in the plasma of flaxseed-fed White Leghorn laying hens (aged 3.5 years). In our study, dietary flaxseed (via the activity of a vitamin B6 antagonist known as “1-amino d-proline”) induced at least 15-fold elevated plasma cystathionine. Surprisingly, plasma homocysteine (Hcy) was stable in flaxseed-fed hens despite such highly elevated cystathionine. To explain stable Hcy, our data suggest accelerated Hcy remethylation via BHMT and MS-B12. Also supporting accelerated Hcy remethylation, we observed elevated S-adenosylmethionine (SAM), an elevated SAM:SAH ratio, and elevated methylthioadenosine (MTA), in flaxseed-fed hens. These results suggest that flaxseed increases SAM biosynthesis and possibly increases polyamine biosynthesis. The following endpoint phenotypes were observed in hens consuming flaxseed: decreased physiological aging, increased empirical lifespan, 9-14% reduced body mass, and improved liver function. Overall, we suggest that flaxseed can protect women from ovarian tumor metastasis by decreasing omental adiposity. We also propose that flaxseed protects cancer patients from cancer-associated cachexia by enhancing liver function.
Link to Full Text
Key Points
This laboratory utilizes the White Leghorn laying hen as a pre-clinical animal model for the study of ovarian cancer. Laying hens spontaneously develop “biologically natural” ovarian tumors starting at around two years of age. This is the age when the hen will have ovulated as frequently as a woman who is approaching menopause. As such, ovarian cancer risk is tightly correlated with the frequency of ovulation. This lab also studies the effect of dietary flaxseed as a nutritional intervention to reduce ovarian cancer severity in laying hens. In this paper, the authors describe a one-carbon metabolic phenomenon that allows flaxseed to shift cancer into a disease that animals can “survive with” instead of “die from”. This supports flaxseed’s potential as an anti-cancer food, especially considering ovarian cancer’s reputation as a highly lethal carcinoma. One-carbon metabolism represents the process of donating, modifying, and transferring single-carbon units within the folate cycle, the methionine (Met) cycle, the transsulfuration pathway, and phospholipid metabolism. Homocysteine (Hcy), a non-protein-coding thiol amino acid, is a central molecule that connects the major pathways of one-carbon metabolism.
This research spotlights a novel nutritional synergy between flaxseed and avian metabolism. Specifically, flaxseed perturbs transsulfuration flux in the laying hen without inducing HHcy. Instead of experiencing HHcy, our data suggest that flaxseed-fed hens exhibit accelerated Hcy remethylation via BHMT and MS-B12. This rerouting of one-carbon metabolism leads to increased SAM synthesis, an increased SAM:SAH ratio, and possibly increased polyamine biosynthesis. The associated biological outcomes include decreased physiological aging, increased empirical lifespan, 9–14% reduced body mass, and improved liver function. These phenotypes reflect flaxseed’s life extending properties as well as flaxseed’s cancer preventative properties. Herein, the mechanism through which flaxseed might act via one-carbon metabolism to protect women from ovarian tumor metastasis, and how flaxseed modifies one-carbon metabolism to protect patients from cancer-associated cachexia are discussed.
This study reports a novel phenomenon whereby flaxseed severely perturbs transsulfuration flux and redirects Hcy toward the Met cycle (via the suspected elevated activity of BHMT and MS-B12). The culminating effect is elevated SAM synthesis, an elevated SAM:SAH ratio, and possibly elevated polyamine biosynthesis. The study demonstrates that 1ADP is a driver behind flaxseed’s main effects, at least in birds. This study indicated that flaxseed, via the anti-B6 effect of 1ADP, redirects carbon flux through one-carbon metabolism in a manner that increases lifespan and reduces ovarian cancer severity in laying hen. Evidence that flaxseed increases the consumption of one-carbon donor molecules (i.e., choline, betaine, DMG, and serine) that fuel BHMT and MS-B12 is presented. The data supports the hypothesis that the anti-B6 effects of flaxseed accelerate Hcy remethylation, SAM synthesis, and polyamine biosynthesis in hens. The associated biological outcomes in these animals are increased lifespan, reduced physiological aging, improved liver function, and decreased body mass. Lifespan was enhanced optimally by the DFM diet, while liver function and body leanness were enhanced optimally by the WFX diet.
Flaxseed induces PEMT hyperactivation, with greater activation stemming from flaxseed diets that are highly enriched with PUFAs (i.e., 15% whole flaxseed). By improving liver function, flaxseed can help to protect cancer patients from the body wasting effects of cachexia. A myriad of metabolic processes in the body are dependent upon proper liver function (e.g., VLDL secretion, gluconeogenesis, and bile secretion). As such, flaxseed is an excellent choice to improve liver function in cancer patients. In turn, these individuals will suffer less from cancer-associated cachexia. Flaxseed is also an excellent choice for reducing fat deposition within the omentum. By reducing omental adiposity, flaxseed can reduce the rate of ovarian tumor metastasis. This would provide a specific means by which flaxseed protects women from late-stage ovarian cancer.