Decades of research has shown that caloric or dietary restriction (while avoiding malnutrition) can ameliorate age-related disease, improve health and extend lifespan in model organisms, rodents, primates and potentially humans 1,2.
From calories to nutrient balance
This research has been through some interesting developments. At first it was simple caloric restriction which was found to extend health and life, then it became clear that other factors were also crucial. Changes in meal timing, or intermittent fasting, can induce benefits independent of calorie intake. Most important however, is the balance of specific macronutrients, especially protein restriction 1,2. Mice fed ad libitum have the best cardiometabolic health, aging and longevity on a low protein, high carb diet 3. Other research has gone even further and implicated specific amino acids. The benefits of dietary restriction can actually be recaptured simply by restricting the sulfur amino acid methionine 1,2,4,5.
Dietary restriction profoundly improves cellular health, by lowering mitochondrial ROS, oxidative stress and DNA damage, while enhancing autophagy/mitophagy and cellular resilience. The beneficial effects of dietary restriction are mediated by inhibition of major anabolic pathways (e.g. insulin/IGF-1/FOXO and mTOR) and activation of those mediating metabolic adaptation and stress resistance (e.g. AMPK, NAD+/SIRT1, PGC/PPAR and Nrf2). Recently upregulation of transsulfuration and H2S biosynthesis was also identified 6.
Interestingly, many healthy foods can also directly simulate stress resistance pathways, including omega-3 fish oils (EPA and DHA), fibre/starch-derived SCFAs and polyphenolic phytochemicals (e.g. resveratrol) 7–9. Therefore increased consumption of certain food components might also promote the same health and longevity pathways as macronutrient restriction.
This research may also help explain some of the epidemiological links between habitual human diets and health. The diet of western industrialised countries is characteristically high in refined carbs/sugar, fat (omega-6 and saturated) and meat, while being low in whole plant foods (phytochemicals/fibre). This kind of diet is increasingly being shown to promote ill health and modern diseases. By contrast, people living in the blue zones (as defined by the best health and longevity stats in the world) eat a semi-vegetarian diet with around 95% of their calories coming from whole plant foods. Such diets are recognised for their ability to promote microbiota and host health 7,10–13. These plant-based diets will also naturally be lower in protein. Habitual protein intake has been directly linked to blood IGF-1 and mortality in humans; a relationship which was only apparent for animal protein 14. Accordingly since many plant protein sources are low in methionine, a vegan-type diet has been considered as a feasible diet for life extension 15.
Relevance to ME/CFS?
This research may have some relevance to ME/CFS, since many of the same cellular processes are being implicated such as oxidative stress and mitochondrial dysfunction. Also several signaling pathways influenced by dietary restriction have been implicated in ME/CFS, as listed below.
- There is impaired activation of the energy sensor AMPK in muscle cells in CFS 16. CoQ10 deficiency has been linked to impaired AMPK activity and mitochondrial dysfunction in fibromyalgia 17 (may also be important pathway in ME/CFS).
- Several studies suggest sulfur and therefore H2S metabolism is impaired in ME/CFS, such as low SAMe, elevated homocysteine and B vitamin deficiencies 18,19.
- Low levels of NAD+ in CFS 20 may lower NAD+-dependent PARP and sirtuin activity.
- Inconsistent changes to blood IGF-1 have been reported in CFS 21.
Normalising changes to some of these pathways might improve cellular and organ function in ME/CFS. In some cases this might actually be achieved by correcting micronutrient/cofactor deficiencies.
However, assuming good weight and nutritional status, could certain types of broader dietary manipulations and macronutrient restriction also be beneficial? Interestingly a recent study showed that incubation of cells from fibromyalgia patients in sera from calorie-restricted mice induces AMPK activity and restores mitochondrial function 22. This at least shows the ability of signaling pathways to regulate mitochondrial function in these disorders. However in practice there are probably lots of caveats. For instance caloric restriction can impair immune function and increase susceptibility to infections 23. On the other hand, tweaking nutrient balance might be more appropriate, perhaps as a way to optimise metabolism and compensate increased cell damage, for improved resilience and longevity.
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