Stop-Aging.org

Our friend and colleague, Dr. Richard Hanson, his lab at Case Western Reserve and Cleveland Clinic Researchers bred a “Mighty Mouse”, which is very recent and growing proof-in-principle that deleterious aging can be overcome, or even stopped, when the discovery was made during lab research designed to study the metabolic role of the PEPCK-C enzyme in skeletal muscle and adipose tissue, which is normally not over-expressed to these levels endogenously. “The enhanced level of activity noted in the PEPCK-Cmus mice extends well beyond two years of age; considered old-age for mice". This PEPCK-C enzyme research has a long history at the Case Western Reserve University School of Medicine, which was discovered in 1955 at the medical school by Merton F. Utter. The key is the mice utilize mainly fatty acids for energy and produce very little lactic acid. To read more of the story go to pepck mouse. Their article first appeared in the Journal of Biological Chemistry, entitled "Over Expression of the Cytosolic Form of Phosphoenolpyruvate Carboxykinase (GTP) in Skeletal Muscle Repatterns Energy Metabolism in the Mouse." The transgenic mice were produced with a chimeric gene containing one copy of PEPCK-C cDNA linked to the skeletal actin gene promoter, which directs expression of PEPCK-C exclusively to skeletal muscle followed by a sequence containing the 3'-end of the bovine growth hormone gene. They report that “various lines of PEPCK-Cmus mice expressed PEPCK-C at different levels, but one very active line of PEPCK-Cmus mice had levels of PEPCK-C activity of 9 units/gram skeletal muscle, compared to only 0.08 units/gram in the muscles of control animals”. These PEPCK-Cmus mice have the capability of running five to six kilometers at a speed of 20 meters per minute on a treadmill for up to six hours before stopping, which they anthropomorphise is metabolically similar to Lance Armstrong biking up the Pyrenees, but fall short of advocating the application of the research to humans. Animal behavior studies later demonstrated that the PEPCK-Cmus mice are seven times more active in their home cages than controls and were also markedly more aggressive. After strenuous exercise, the difference in the concentrations of lactate in the blood, which was similar in two groups of mice at the onset, differed at the end of the experiment, with the control group having elevated levels of blood lactate, while the levels in the PEPCK-Cmus mice remained little-changed. These finding indicate that the PEPCK-Cmus mice relied heavily on fatty acids as a source of energy during exercise, while the control animals rapidly switched from fatty acid metabolism to using muscle glycogen (carbohydrates) as a fuel and dramatically raised the blood lactate levels. Caloric Restriction mimetics immediately come to our minds yet, where this intervention in metabolism departs from CR is that these genetically engineered mice also eat 60 percent more than controls, yet remain fitter, are leaner, live longer and breed later than wild-type control mice. It was indicated that some female PEPCK-Cmus mice have had offspring at 2.5 years of age, which they say is like an 80-year old giving birth, considering most mice do not reproduce much after one year of age and normally never live past 3 years. These findings may lead to better CR mimetics. What remains unexplained is why this new mouse line also has an increased content of mitochondria and high concentrations of triglycerides in their skeletal muscles (other than utilization of lipids as a primary energy source), which also contributed to the increased metabolic rate and longevity of the animals. The other question is ketosis, which represents a state of starvation, perhaps why the animals eat so much. Ketosis will not cause ketoacidosis in non-diabetics, but the reactive aldehydes and the by-products of beta oxidation and Anaplerotic reactions could be a concern. Its interesting how these animals adapted from birth and the use of conditional expression systems may have given quite different results and explained any adaptation. Of sppecific concern is the increase in Methyl-glyoxal (MGO) from beta oxidation and how these mice have adapted to increases in MGO should be explored, since it would have considerable interest for the study of diabetes and weight loss. One study actually found that hyperglycemia increased pepck gene expression. Further, the application for diabetes is an interesting one since resting beta cell oxidative phosphorylation may be dependent upon oxidation of fatty acids, the rate of fatty acid beta oxidation may limit oxidative phosphorylation When these mice are made diabetic, it would be interesting to see what would happen with glucose metabolism and gluconeogenesis in systems that mimic type 1 diabetes, since type 2 would seem to be a problem. The increase in Mitochondria may be explained by these increase in these reactions as a compensatory response to the increased load of metabolic intermediates. While the technique used to create the animal model reported in this study is not yet appropriate for application to humans and the caveats of viral-gene delivery are well documented, this research opens the door for many experiments and the application of over-expression of metabolic enzymes to treat disease. This genetic approach doesn’t obviate other means to achieve the same goal, but serves as proof-in-principle that such strategies aimed at eliminating or reversing the deleterious processes of aging are possible. While Dr. Hanson does not advocate attempts to tamper with the metabolic processes in human muscle, fearing it may do more harm than good, the mouse model should provide important insights into the development of cancer, the effect of diet and exercise on longevity and will certainly increase our knowledge of the factors that regulate energy metabolism in skeletal muscle and what impact prolonged exercise has on these parameters. I recommend the cross-breeding experiments at this time between Andrez Bartke's Growth hormone receptor knock out mouse (GHR-KO 11C) and Dr. Hanson's mouse and have made the suggestion know to them. The idea is to extend the lifespan of either, or both. Dr. Bartke is the current leader in the M-prize for the longest lived mouse see the abstract to that paper here GHR-KO mouse. M