There are quite a number of papers studying ketosis in rodents to measure outcomes. I just thought it would be a neat exercise to make an inventory of these studies and look at their properties such as feeding ad libitum, type of fat in the diet, level of ketosis reached etc.. to see if we can find a pattern in the outcomes and understand what it takes to get them into ketosis.
|Study||%protein||%carb||%fat||free/restricted||Starting age of diet||BHB mmol||Outcome||type||fat type|
|1||10||1||89||11.2kcal per day after weight gain||12m||0.7||increased median lifespan||C57BL/6 mice||7% soybean oil, 56% lard|
|2||10||0||90||ad lib||12m||1.5||reduced midlife mortality, preservation of memory||C57BL/6 mice||31% crisco, 10.7% cocoa butter, 6% corn oil|
|3||5||0||95||ad lib||8w||0.8||reduced amino acid catabolism, no adverse survival||C57BL/6J mice||lard, butter, corn oil|
|4||4.7||1.8||93.5||ad lib||p21?||1.77||mTOR inhibition||Sprague Dawley rats||lard, butter, corn oil|
|5||4.7||1.8||93.5||ad lib||13w||1.5||enhanced neurovascular function||C57BL/6 mice||lard, butter, corn oil|
|6.a||5.5||1.7||92.8||isocal||12w||2.58||measure ketosis||Wistar rats||beef tallow|
|6.b||11.8||1.9||86.3||isocal||12w||1.18||measure ketosis||Wistar rats||beef tallow|
|6.c||19.1||2.2||78.7||isocal||12w||0.62||measure ketosis||Wistar rats||beef tallow|
One study(7) I wanted to include but couldn’t fit it in the table above due to not being a longer term test, was the only one I could find that used a very different fat, hydrogenated coconut oil. Because of the oil used, we see ketone levels that are not observed in any of the above publications. Both the wild type and knock-out mice had levels above 5mmol on the high fat diet.
I have expressed my concern elsewhere for mouse models on a ketogenic diet not being representative for humans but study 7 shows the best approaching results that we see in humans. Higher levels of ketones are reached with sufficient protein (16% carbohydrates, 19% protein, and 65% fat) and normal similar weight gain for the wild type on the high fat diet as to the wild type on the control diet.
All other approaches are invalid as they feed too little protein, driving overfeeding and weight gain. Especially when different compositions are compared(6) we see that murines, and probably humans too, require sufficient protein. They’ll eat until they have obtained their required volume of protein or, when under restricted feeding, they’ll end up loosing lean mass(6) which is a sign of protein being broken down and converted to glucose.
Apart from the macro composition, the restriction or free feeding makes a difference. Interestingly, comparing 1 and 2 with virtually identical composition, we see that ad lib feeding on fat gives higher ketones. I have often mentioned this to people, if you measure low ketones, increase your fat intake. Otherwise your body does not have sufficient access to fat to generate ketones.
The type of fat certainly makes a difference as we’ve seen in study 7. For being quite identical in macro composition, 6.a does remarkably better in generating ketones versus 4 but to be honest, although both are rats, the breed is different so there is another influencing factor. It could be that Wistar rats have a higher lipolythic capacity. The research doesn’t cover that but they strains certainly have differences in lipolysis. 6.a was isocaloric thus restricted which we saw as a negative influence for ketones when comparing 1 to 2. We also know that Wistar rats are more susceptible to metabolic syndrome compared to Sprague-Dawley rats. How these factors influences their ability to produce ketones on a ketogenic diet is still a guess to me.
So for anyone looking into the results of a ketogenic diet on murines, do check out the fat they were given, the breed, mice or rats, protein amount, feeding regimen etc.. It influences the outcome and certainly cannot be extrapolated directly to humans.
(1) “A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice”, Megan N. Roberts, Marita A. Wallace, Alexey A. Tomilov, Zeyu Zhou, George R. Marcotte, Dianna Tran, Gabriella Perez, Elena Gutierrez-Casado, Shinichiro Koike, Trina A. Knotts, Denise M. Imai, Stephen M. Griffey, Kyoungmi Kim, Kevork Hagopian, Marissa Z. McMackin, Fawaz G. Haj, Keith Baar, Gino A. Cortopassi, Jon J. Ramsey and Jose Alberto Lopez-Dominguez, 2017, https://www.cell.com/cell-metabolism/pdf/S1550-4131(17)30490-4.pdf
(2) “Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice”, John C. Newman, Anthony J. Covarrubias, Minghao Zhao, Yu Huang, Saptarsi Haldar, Eric Verdin, 2017, https://www.cell.com/cell-metabolism/pdf/S1550-4131(17)30489-8.pdf
(3) “Adaptive changes in amino acid metabolism permit normal longevity in mice consuming a low-carbohydrate ketogenic diet”, Nicholas Dourisa, Tamar Melman, Jordan M. Pecherer, Pavlos Pissios, Jeffrey S. Flier, Lewis C. Cantley, Jason W. Locasale, Eleftheria Maratos-Flier, 2015, https://www.sciencedirect.com/science/article/pii/S092544391500201X
(4) “The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway.”, McDaniel SS, Rensing NR, Thio LL, Yamada KA, Wong M, 2011, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3076631/
(5) “Ketogenic diet enhances neurovascular function with altered gut microbiome in young healthy mice”, David Ma, Amy C. Wang, Ishita Parikh, Stefan J. Green, Jared D. Hoffman, George Chlipala, M. Paul Murphy, Brent S. Sokola, Björn Bauer, Anika M. S. Hartz, and Ai-Ling Lin, 2018, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5923270/
(6) “Induction of ketosis in rats fed low-carbohydrate, high-fat diets depends on the relative abundance of dietary fat and protein.” – Bielohuby M, Menhofer D, Kirchner H, Stoehr BJ, Müller TD, Stock P, Hempel M, Stemmer K, Pfluger PT, Kienzle E, Christ B, Tschöp MH, Bidlingmaier M – 2011 – https://www.ncbi.nlm.nih.gov/pubmed/20943751
(7) “A high-fat diet reverses metabolic disorders and premature aging by modulating insulin and IGF1 signaling in SIRT6 knockout mice.” – Li Z, Xu K, Guo Y, Ping L, Gao Y, Qiu Y, Ni J, Liu Q, Wang Z – 2020 – https://www.ncbi.nlm.nih.gov/pubmed/31967391