Saturday, 6 June 2015

Life extension research - relevance to ME/CFS?

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.

Cellular mechanisms
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.

Modern diets
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.

1.         Fontana, L. & Partridge, L. Promoting health and longevity through diet: from model organisms to humans. Cell 161, 106–18 (2015).
2.         Longo, V. D. et al. Interventions to Slow Aging in Humans: Are We Ready? Aging Cell n/a–n/a (2015). doi:10.1111/acel.12338
3.         Solon-Biet, S. M. et al. The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice. Cell Metab. 19, 418–30 (2014).
4.         Ramalingam, A. et al. Dietary methionine restriction improves colon tight junction barrier function and alters claudin expression pattern. Am. J. Physiol. Cell Physiol. 299, C1028–35 (2010).
5.         Sanchez-Roman, I. & Barja, G. Regulation of longevity and oxidative stress by nutritional interventions: role of methionine restriction. Exp. Gerontol. 48, 1030–42 (2013).
6.         Mitchell, J. R., Hine, C. M., Ph, D. & Mair, W. B. Endogenous Hydrogen Sulfide Production Is Essential for Dietary Restriction Benefits. Cell 160, 132–144 (2015).
7.         Pall, M. L. & Levine, S. Nrf2, a master regulator of detoxification and also antioxidant, anti-inflammatory and other cytoprotective mechanisms, is raised by health promoting factors. Sheng Li Xue Bao 67, 1–18 (2015).
8.         Cipollina, C., Salvatore, S. R., Muldoon, M. F., Freeman, B. A. & Schopfer, F. J. Generation and dietary modulation of anti-inflammatory electrophilic omega-3 fatty acid derivatives. PLoS One 9, e94836 (2014).
9.         Besten, G. den et al. Short-Chain Fatty Acids protect against High-Fat Diet-Induced Obesity via a PPARĪ³-dependent switch from lipogenesis to fat oxidation. Diabetes (2015). doi:10.2337/db14-1213
10.       Del Chierico, F., Vernocchi, P., Dallapiccola, B. & Putignani, L. Mediterranean diet and health: Food effects on gut microbiota and disease control. Int. J. Mol. Sci. 15, 11678–11699 (2014).
11.       Willcox, D. C., Scapagnini, G. & Willcox, B. J. Healthy aging diets other than the Mediterranean: A focus on the Okinawan diet. Mech. Ageing Dev. 136-137, 148–62 (2014).
12.       M, G.-B. & MC, Y. The Health Advantage of a Vegan Diet: Exploring the Gut Microbiota Connection. Nutrients 6, 4822–4838 (2014).
13.       Simpson, H. L. & Campbell, B. J. Review article: dietary fibre-microbiota interactions. Aliment. Pharmacol. Ther. 42, 158–179 (2015).
14.       Levine, M. E. et al. Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population. Cell Metab. 19, 407–17 (2014).
15.       McCarty, M. F., Barroso-Aranda, J. & Contreras, F. The low-methionine content of vegan diets may make methionine restriction feasible as a life extension strategy. Med. Hypotheses 72, 125–128 (2009).
16.       Brown, A. E., Jones, D. E., Walker, M. & Newton, J. L. Abnormalities of AMPK Activation and Glucose Uptake in Cultured Skeletal Muscle Cells from Individuals with Chronic Fatigue Syndrome. PLoS One 10, e0122982 (2015).
17.       Cordero, M. D. et al. Can coenzyme q10 improve clinical and molecular parameters in fibromyalgia? Antioxid. Redox Signal. 19, 1356–61 (2013).
18.       Regland, B. et al. Increased concentrations of homocysteine in the cerebrospinal fluid in patients with fibromyalgia and chronic fatigue syndrome. Scand. J. Rheumatol. 26, 301–7 (1997).
19.       Van Konynenburg, R. A. & Nathan, N. Treatment Study of Methylation Cycle Support in Patients with Chronic Fatigue Syndrome and Fibromyalgia. (2009).
20.       Myhill, S., Booth, N. E. & McLaren-Howard, J. Targeting mitochondrial dysfunction in the treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) - a clinical audit. Int. J. Clin. Exp. Med. 6, 1–15 (2013).
21.       The, G. K. H., Bleijenberg, G. & van der Meer, J. W. M. The effect of acclydine in chronic fatigue syndrome: a randomized controlled trial. PLoS Clin. Trials 2, e19 (2007).
22.       E, A.-G. et al. Metformin and caloric restriction induce an AMPK-dependent restoration of mitochondrial dysfunction in fibroblasts from Fibromyalgia patients. Biochim. Biophys. Acta (2015). at
23.       Goldberg, E. L. et al. Lifespan-extending caloric restriction or mTOR inhibition impair adaptive immunity of old mice by distinct mechanisms. Aging Cell 14, 130–8 (2015).

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