Synergy between Functional Food and Exercise

It is becoming clearer how both macronutrients and micronutrients have important functional effects and amongst them cell signaling involving expression of genes that increase mitochondrial function and stress resistance.

Of the known strategies to slow ageing and age related diseases the most effective has been calorie restriction (CR) but circulating hormone and nutrient levels are virtually identical whether a result of a ketogenic diet or starvation. The ketogenic state is produced both by carbohydrate restriction as well as calorie restriction and ketogenic diets have been used for 80 years in the successful treatment of epilepsy and more recently have been found to ameliorate adult neurodegenerative diseases such as Parkinson’s and Alzheimer’s.

The ketogenic state is controlled by the opposing influences of the pancreatic hormones, insulin and glucagon, which are in turn largely controlled by glucose levels. High glucose increases insulin levels which suppress lipid mobilization and mitochondrial lipid metabolism leading to increased likelihood of fat storage which over time leads to obesity. Low glucose levels, stimulation of the sympathetic nervous system and increased activity levels all increase glucagon secretion which stimulates lipid mobilization from adipose tissue, increases free fatty acid levels and promotes mitochondrial lipid metabolism.

These opposing substrate and hormone levels are powerful cell signals that can induce or inhibit gene expression that control protein synthesis of respiratory enzymes, stress resistance mechanisms, mitochondrial biogenesis and systems responsible for repairing cell damage. It appears that high levels of glucose and insulin exert a deconditioning effect on mitochondria and oxidative stress resistance. For instance 3 weeks on a ketogenic diet was associated with a striking 46% increase in mitochondria and up-regulation of 39 of the 42 genes encoding mitochondrial proteins in nerve cells of mice. Several fatty acids activate PPAR, a nuclear receptor protein associated with anti-inflammatory and cell protection mechanisms. Elevated fatty acid levels were shown to increase muscle mitochondrial biogenesis through activation of PPAR in an experimental rat model. Ketogenic diets that elevate free fatty acid and ketone body levels have been shown to improve mitochondrial function in brain, muscle, heart and liver cells. [17, 18, 19, 20, 21-23]

Cell signaling involving macrophages may also be important in wound healing and prevention of degenerative disease: Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that is activated by fatty acids, and recent discoveries have focused attention on its role in the polarization of macrophage phenotype. It is now known that macrophage phenotype varies greatly in a manner that is influenced by local microenvironment: classically activated M1 macrophages are recruited to sites of infection and tissue damage, where they engulf debris and trigger adaptive immune responses, whereas alternatively activated M2 macrophages limit local inflammatory responses and promote tissue repair. PPARγ is best known for its influence on adipocyte development and as the target for insulin-sensitizing drugs, the thiazolidinediones. However, PPARγ also exerts a widespread influence on macrophage biology; PPARγ activators repress pro-inflammatory genes, stimulate transcriptional cascades that promote cholesterol export from foam cells (lipid-laden macrophages) in atherosclerotic plaque and inhibit macrophage infiltration into adipose tissue. In 2007, two groups made the remarkable observation that PPARγ is required for M2 macrophage polarization. Equally surprisingly, PPARγ-dependent M2 polarization protects against insulin resistance and other aspects of metabolic syndrome.

A simple strategy for athletic training
Foods can be chosen to create a ketogenic state that promote mitochondrial biogenesis during periods of training and high glycemic carbohydrates should be reserved for glycogen repletion probably no more than 24 hours before competitive events.