(OR10-07-23) A Low Carbohydrate Diet Containing Soy Protein and Fish Oil Significantly Delays Myelomalignancy in miR-146a Knock Out Mice

Objectives: Since our previous studies found a low carbohydrate (CHO) diet containing soy protein and fish oil (15%Amylose/Soy/FO) significantly reduced a number of solid tumors in mice we asked if this low CHO diet could also delay the onset of blood-borne cancers, specifically myeloid malignancies.

Methods: To test this we employed a miR-146a knock-out (KO) mice, which are highly inflamed and spontaneously develop myelomalignancies as they age. We put these mice on either a Western or the 15%Amylose/Soy/FO diet, starting at 5 weeks of age, and continued them on these diets until they reached their humane endpoint. Blood samples and bone marrow were collected at 6 months of age, prior to the onset of myeloid malignancies, to measure circulating inflammatory cytokines and primitive hematopoietic stem cells (HSCs), characterized by the expression of CD45⁺EPCR⁺CD150⁺CD48^– (ESLAM) markers, respectively. In addition, we also measured a number of metabolic markers, including blood glucose, plasma ß-hydroxybutyrate, insulin and protein expression of liver fatty acid synthase (FAS) and carnitine parmitoyltransferase I (CPT1a) at this time point.

Results: The 15%Amylose/Soy/FO diet extended the median lifespan of miR-146a KO mice by 8.5 months, compared to Western diet fed mice. This increase survival corresponded to significantly (P < 0.05) reduced circulating pro-inflammatory cytokines, suggesting the diet acts to delay myelomalignacy, at least partially, by reducing inflammation. Mice on the 15%Amylose/Soy/FO also had significantly lower blood glucose, plasma insulin, and liver FAS, but higher plasma ß-hydroxybutyrate, and liver CPT1a, suggesting that this diet skewed the mice to rely on fatty acid oxidation as an energy source rather than glucose. Lastly, we found the 15%Amylose/Soy/FO diet resulted in significantly higher numbers of primitive hematopoietic stem cells (HSCs) in the bone marrow of 6-month-old mice than in Western diet fed mice.

Conclusions: Taken together, these results suggest a 15%Amylose/Soy/FO diet reduces chronic inflammation and increases fatty acid oxidation and that this, in turn, may prevent HSC proliferation and exhaustion, thereby delaying myeloid malignancy-induced death of miR-146a KO mice.

Funding Sources: This work was funded by Hecht Grant #4340 to GK and by grants from the CIHR and the Terry Fox Research Institute to AK.