Fasting and calorific restriction- Increased longevity or just a slower death?
Does fasting really increase longevity, or a tool for those who over eat?
Intermittent fasting and calorific restriction (CR) seem to be the Zeitgeist of today’s nutrition and wellness sphere and has comparisons with the raw green sludge breakfast smoothie, and similar approaches to health. CR has often being touted as health enhancing because of a premise that sounds something like this. You fast or eat less than X calories and that has the capacity to slow down metabolism, ensuring that you produce less oxidative stress. Autophagy ensues, and this opens up your 8th chakra ready for your beyond meat whopper. It’s true that fasting and CR can probably enhance your health when you are prone to over eating, and beyond that nothing else. Yes, you will lose weight (seen as that’s the only variable that many people care about these days), but that result is down to one key fact. You are in a calorie deficit. The ability to recover from that restriction is the question that most need to evaluate.
CR and fasting promotes improvements to health and extending lifespan but the main reasons that it promotes longevity is probably for several reasons that include.
1. The restriction of polyunsaturated fats or PUFA.
2. The restriction of methionine, cysteine and sometimes tryptophan.
3. Perhaps less consumption of pesticides and metals.
The question of do you need to fast, should be rephrased with do you even need to fast? What about addressing what can extend lifespan and still maintain an optimal level of metabolism?
PUFA and mitochondrial uncoupling
Let’s start with PUFA which are commonly known as vegetable, seed, fish, soy and other oils, including olive oil (which is the better of the lot and when used cold has some useful qualities). The other oils share similarities, as they are all unstable especially so when heated. The most unstable oils in general use, and over recommended are the omega 3’s particularly DHA and EPA. I’ve recently seen so called holistic practitioners recommending in excess of 6 grams of DHA to improve anti-inflammatory responses and so-called membrane fluidity. One of the key problems with this approach is that increased DHA levels are known to occur in the obese and diabetic (Madison Sullivan et al., 2018), and this increase is associated with reduced mitochondrial enzymes (metabolic enhancers).
PUFAs like DHA are often touted as protective because they induce a process called mitochondrial uncoupling. This can occur when your’e cold, when you don’t produce enough thyroid hormone and other stressors. It can indeed be protective but DHA for example creates something called proton leak within the cells, decreasing the efficiency of the cell. Oxygen efficiency is lost and production of energy or adenosine triphosphate (ATP) is also wasteful. This sits well with many who promote theoretical mechanisms of longevity such as the rate of living theory (Speakman et al., 2004) (Vaanholt, Daan, Schubert, & Visser, 2009) and the membrane pacemaker theory (Hulbert, 2007; Hulbert, Kelly, & Abbott, 2014). A. J Hulbert is a well-respected professor and researcher who completed a large body of work on the role of thyroid hormones and fatty acids and their role in ‘membrane fluidity’. Interestingly Hulbert proposes that mammals and birds with a high metabolic rate (much like Elie Metchnikoff’s theories that link low gut bacteria with metabolism in birds, mammals and longevity) and increased longevity often have this key feature in common. They generally have low saturation of PUFAs as determined by something called the peroxidation index (PI). Conversely animals with high PUFA and PI have decreased longevity, but the membrane pacemaker theory postulates it as high metabolic rate, inducing uncoupling and characterised by increased reaction oxygen species (ROS) and the production of superoxide and superoxide dismutase (SOD).
“There’s an inverse relationship between the peroxidation index of skeletal muscle phospholipids and maximum lifespan of mammal and bird species of different sizes.” A.J.Hulbert
“There’s an inverse relationship between the peroxidation index of skeletal muscle phospholipids and maximum lifespan of mammal and bird species of different sizes.” A.J.Hulbert
This forms a major component of the rate of living theory or that increased metabolism generates ROS ergo slowing metabolism down, produces less ROS and that’s productive. Although it’s not and this is where many people get confused about efficient thyroid function, enhanced metabolism and potential oxidative stress. I was reminded by a Ray Peat Newsletter earlier on the year how SOD remains elevated throughout the lifespan of those with Down syndrome and that serotonin increases SOD, contributing to decreased longevity. With excess PUFA consumption and tissue saturation, SOD increases as does uncoupling, lipid peroxidation and high levels of malondialdehyde (MDA) are observed with excess lipid peroxidation (Chen & Li, 2016). SOD can be counteracted by glutathione (SOD/G ratio) but this diminishes over time. This enhances the reductive state and perpetuates the gain of electrons, which are a hallmark of damaged physiology and shift efficient energy production away from oxidative metabolism of glucose and metabolic inflexibility.
PUFA, like DHA does initiate mitochondrial uncoupling but it’s inefficient and increases SOD, degrading aerobic metabolism which comes at a cost to lifespan. Hulbert notes that a 24% decrease in PI is associated with doubling of lifespan and that calorific restriction alters the acyl composition of the cell membrane. Why? Because PUFA are removed from the cell membrane to be used as fuel. Again this can be problematic if you persistently use unsaturated fatty acids as fuel. Not to mention that re-feeding fasted subjects and those on a ketogenic diet are well known to depress thyroid hormone responsiveness, thyroid hormone receptors and glucose tolerance (Boelen, Wiersinga, & Fliers, 2008)(Garbow et al., 2011)(Kose, Guzel, Demir, & Arslan, 2017). Yes there are indeed many short-term studies showing positive changes from CR and ketogenic dieting. If one can benefit from these modalities great but if not metabolically flexible, it isn’t always going to be as fruitful as you think. It’s often these interactions that muddy the water between carbohydrate restriction and beneficial results. Hint, it’s never usually the carbohydrate, and if you’ve been prone to over eating, then that calorie deficit is always going to show a temporary positive effect.
If you’re someone that has tried many different interventions for improved health or even body composition and failed to get the results that you need, then the body requires a level playing field of energy and nutrients to create balance. Further stress from skipping meals, long hours without eating and failure to meet metabolic demands are some of the reasons why many develop metabolic inflexibility. The more stressed your physiology, the more prone it is to activating stress pathways and suppressing thyroid hormone, decreasing insulin responses and creating inflammation. More often than not those with this existing inflexibility may not benefit from increased fatty acid oxidation mediated by a lack of available glucose.
Thyroid, PUFA and membrane composition and fluidity
My understanding of the so-called membrane, membrane pump theory and even membrane fluidity is certainly not of an expert but If I’m wrong here, I’m certainly willing to throw my hands up on in the air and say – I told you I wasn’t an expert. I am reasonably sure of the interactions of thyroid hormone, its generality, it’s actions, organisational qualities but much like the theories of low serotonin, low estrogen, high cholesterol treated by statins, and that Glyphosphate is a safe and friendly compound, people with vested interests promote otherwise. I’m not going to go into the complexities of Gilbert Ling’s work (Gilbert N. Ling, 1965 1997, 2014) I’d be lying if I said I truly understand it but my attempt to summarise such a vast body of work.
The membrane pump theory has been a widely accepted unproven theory that appears on paper, to be unable energetically to support and each pump requiring unaccountable levels of ATP. Ling’s work suggests that membrane interactions are largely supported by organised or structured water interfaces and that there is no cellular membrane to speak of. Thyroid hormone, proteins and cholesterol are other integral components of this interface.
It’s always contentious when someone ends up disproving a theory that’s widely accepted without being proven.
Does it make sense that during fasting, these essential PUFA’s are depleted from this so-called membrane and replaced with cholesterol? Can they really be that essential? Thyroid hormones have been shown to modify this “membrane permeability”, cooperatively influencing behaviour of enzymes and can penetrate the phospholipid bilayers (Issé, Yunes Quartino, Fidelio, & Farías, 2013). Triiodothyronine or T3 appears similar to cholesterol’s action, increasing fluidity in ordered gel phases and decreasing in liquid crystalline states of phospholipids. I’m guessing that alterations in structured water through positive/ negative charges, and interactions between organisational qualities of thyroid hormones and cholesterol could be the ideal interface. This may explain why in hypothyroidism the so-called membrane, becomes more disorganised, less gel like and more abundant in PUFA (PUFAs degrade cholesterol).
Restriction of PUFA, methionine and other agents which reduce biology need to be compared with so called decreased rate of living theories to ascertain what really increases longevity. If we keep looking at theories that promote decreased function instead of maintaining and improving order. The end result may be decreased lifespan and a slow death of cellular function.
NEED SOME HELP WITH HORMONES, ENERGY, SLEEP, MOOD OR DIGESTION?
References:
Boelen, A., Wiersinga, W. M., & Fliers, E. (2008). Fasting-Induced Changes in the Hypothalamus–Pituitary–Thyroid Axis. Thyroid, 18, 12–129. https://doi.org/10.1089/thy.2007.0253
Chen, Y., & Li, P. (2016). Fatty acid metabolism and cancer development. Science Bulletin, 61(19), 1473–1479. https://doi.org/10.1007/S11434-016-1129-4
Garbow, J. R., Doherty, J. M., Schugar, R. C., Travers, S., Weber, M. L., Wentz, A. E., … Crawford, P. A. (2011). Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet. American Journal of Physiology - Gastrointestinal and Liver Physiology. https://doi.org/10.1152/ajpgi.00539.2010
Hulbert, A. J. (2007). Membrane fatty acids as pacemakers of animal metabolism. In Lipids. https://doi.org/10.1007/s11745-007-3058-0
Hulbert, A. J., Kelly, M. A., & Abbott, S. K. (2014). Polyunsaturated fats, membrane lipids and animal longevity. Journal of Comparative Physiology B: Biochemical, Systemic, and Environmental Physiology. https://doi.org/10.1007/s00360-013-0786-8
Issé, B. A., Yunes Quartino, P., Fidelio, G. D., & Farías, R. N. (2013). Thyroid hormones-membrane interaction: Reversible association of hormones with organized phospholipids with changes in fluidity and dipole potential. Chemistry and Physics of Lipids. https://doi.org/10.1016/j.chemphyslip.2013.08.007
Kose, E., Guzel, O., Demir, K., & Arslan, N. (2017). Changes of thyroid hormonal status in patients receiving ketogenic diet due to intractable epilepsy. Journal of Pediatric Endocrinology and Metabolism. https://doi.org/10.1515/jpem-2016-0281
Ling, Gilbert N. (1997). Debunking the Alleged Resurrection of the Sodium Pump Hypothesis. Physiological Chemistry and Physics and Medical NMR.
Ling, Gilbert N. (2014). Canwe see living structure in a cell? Physiological Chemistry and Physics and Medical NMR.
Ling, Gilbert Ning. (1965). THE PHYSICAL STATE OF WATER IN LIVING CELL AND MODEL SYSTEMS. Annals of the New York Academy of Sciences. https://doi.org/10.1111/j.1749-6632.1965.tb45406.x
Madison Sullivan, E., Pennington, E. R., Sparagna, G. C., Torres, M. J., Darrell Neufer, P., Harris, M., … Shaikh, S. R. (2018). Docosahexaenoic acid lowers cardiac mitochondrial enzyme activity by replacing linoleic acid in the phospholipidome. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.M117.812834
Speakman, J. R., Talbot, D. A., Selman, C., Snart, S., McLaren, J. S., Redman, P., … Brand, M. D. (2004). Uncoupled and surviving: Individual mice with high metabolism have greater mitochondrial uncoupling and live longer. Aging Cell. https://doi.org/10.1111/j.1474-9728.2004.00097.x
Vaanholt, L. M., Daan, S., Schubert, K. A., & Visser, G. H. (2009). Metabolism and Aging: Effects of Cold Exposure on Metabolic Rate, Body Composition, and Longevity in Mice. Physiological and Biochemical Zoology. https://doi.org/10.1086/589727