Introduction

“But he answered and said, It is written, Man shall not live by bread alone, but by every word that proceedeth out of the mouth of God.” – Matthew 4:4

This past week, I’ve been helping my father recover from a total knee replacement. It hasn’t been easy, honestly. A few weeks prior, during a Christmas lunch, I talked with him about how he’d been feeling and wanted to figure out what I could do for him post-surgery. After a long discussion with him, we concluded that the best thing I could work with him on was helping him to improve his diet (not just by going on some fad diet), but by developing a model for him that works best with his biology and physiology.

One of my interests is reading about human anatomy and physiology, so I figured I could do some research for my dad to help him improve. And so, over the past week, while I wasn’t helping my dad with different chores around the house, getting him ice, etc., I did some light reading on the physiology of the gut and the metabolic processes that enable every human to utilize carbohydrates, fats, and proteins. Of course, fuel alone isn’t sufficient.

Thus, I’d like to keep this paper light this week and only cover some of the essentials from the materials I read. I’ll be covering information related to phenotypic flexibility as a measurement of nutritional health, protein as the main source of nutrition in a daily diet, how we might optimize protein consumption, metabolic flexibility, and the importance of exercise for metabolic sensitivity, intermittent fasting, or metabolic switching.

I do not plan on making this paper too technical, but there’s no avoiding the necessary nuts-n-bolts. I do not claim to be an expert on these matters, only someone with a desire to understand my own body to improve my health and, at the same time, my father’s. Any information in this article shouldn’t be considered to be actual medical advice, but it is all based on evidence from medical and scientific journals.

At the end of the paper, I’ll try to draw some conclusions using the material covered. These conclusions, if the evidence is valid and the reasoning is sound, should improve my health and hopefully will help my dad. Essentially, I’m seeking to generate a model that I can use to improve my health and my dad’s, and if that’s useful for others to try something for themselves, all the better. However, as we’re human, it’s only natural to face obstacles trying to improve our health, so I’ll try to identify what some of those obstacles may be and why.

Diet and Physiological Stress

In 1948, the WHO defined Health as “a condition of complete physical, mental, and social well-being and not merely the absence of disease or infirmity” (WHO, 1995). However, “[t]here is a growing awareness that health includes adaption and flexibility to continuously changing environmental conditions” (Stroeve et al., 2015). Health can be defined for theoretical purposes as “along the lines of flexibility, adaptability, elasticity, robustness, and others” (Huber et al., 2011). This, as Stroeve et al. has defined the term, is known as phenotypic flexibility or metabolic flexibility.

Stroeve et al., covered how flexible the body is by examining 61 papers covering OGTT (oral glucose tolerance tests), OPTT (oral protein tolerance tests), OLTT (oral lipid tolerance tests), and OPGLTT (oral protein, glucose, and lipid tolerance test). OGTT is “based on the principle that patients with diabetes have more difficulty clearing their blood glucose after a glucose bolus (75 grams after overnight fasting) in comparison with healthy subjects.” Based on their review of papers covering OGTT, Stroeve et al. found that “OGTT [was found] to induce a small temporary increase in circulating leukocytes, suggesting an inflammatory response.” Yet, this finding wasn’t conclusive. “The increase in leukocytes was primarily due to the increased numbers of neutrophils… which have been linked to endothelial function.” Also, OGTT decreases several markers of oxidative stress. Stroeve et al., hypothesize that this decrease in oxidative stress “might be due to the decrease in [triglyceride] levels and blood pressure upon OGTT”. Over time, a persistent diet primarily composed of glucose can lead to diabetes mellitus, which produces tissue damage. Also, Stroeve et al. found that nitrotyrosine levels increased, the levels of which have been correlated with immune disease.

The OLTT produced different conclusions. The lipids were ingested after “an overnight fast” and left to be digested and absorbed in the gut, ultimately entering the bloodstream as chylomicrons. Chylomicron remnants are taken up by the liver, secreted, and transported in the blood. As a result, blood plasma very low-density lipids (VLDL) increase. Some interesting findings from Stroeve et al.’s, analysis follow.

For a start, “Adipokines resistin and adiponectin increased in response to OLTT,” which are associated with inflammation. Secondly, they found that “OLTT increased plasma concentrations… and leukocyte adherence marker expression… accompanied by a decrease in flow-mediated dilation [FMD]” in middle-aged men. In young men, “the postprandial decrease in [flow-mediated dilation] was less pronounced,” suggesting that “in young healthy men, in contrast to middle-aged men, [lipid consumption] does not adversely affect endothelial function”. A decrease in flow-mediated dilation is correlated with heart disease. Interestingly, “[o]xylipins associated with endothelial inflammation and function also responded to OLTT.” This kind of response indicates that “the OLTT actively modulated endothelial inflammation and vascular function and that it is not simply the normal physiological response to fasting.” OLTT has also been known to “[induce] oxidative stress… which is associated with hepatocyte apoptosis,” or destruction of the liver tissue.

100% protein ingestion through OPTT has barely been tested. After consuming a large amount of protein (70-80g of protein), there was an “increase in plasma creatinine… reported, as well as an increase in glomerular filtration rate.” Interestingly, amino acids from the consumed protein formed glucose through gluconeogenesis, meaning that, in the absence of glucose consumption, amino acids from protein are converted into glucose for cellular function.

The combined OPGLTT had the most significant effects. For example, “endothelial function was most modified by the OPGLTT as reflected by vascular inflammatory markers.” I.e., “postprandial levels of myeloperoxidase (MPO), and matrix metallopeptidases (MMP) – 1 and MMP-9, which have been linked to impaired endothelial function, were increased by OPGLTT or a mixed meal challenge.” In other words, mixed meals tend to damage endothelial cells. This is also indicated by “a modest acute inflammatory response” (Stroeve et al., 2015.) To support this finding, “IL-18 gene expression was augmented in response to OPGLTT… [suggesting] the involvement of inflammasome-related processes.” Heart stress also seems to be increased by OPGLTT or mixed meals. “Plasma TBARS increased significantly from fasting to post-meal state which peaked at 4-6h and declined at 8h in healthy subjects” (Stroeve et al., 2015). OPGLTT also seems to have a significant effect on the endocrine system. “[T]he production of gastrointestinal hormones may be modulated by… [t]estosterone, progesterone and the transport-binding protein for sex steroid hormones, sex-hormone binding globulin, showed decreased postprandial concentrations with a recovery after 6h in 36 overweight male subjects” (italics added). The thyroid showed a similar response. Also, “cortisol… showed a linear decrease upon OPGLTT.” And finally, “Peptide YY (PYY), cholecystokinin (CCK), and gastrin significantly increase in response to OPGLTT,” which increase the desire to eat.

In one review of OPGLTT effects, Stroeve et al. found that, for a “high fat” OPGLTT challenge (consisting of 60% fat), adiponectin levels in healthy subjects decreased. In a “high carb” OPGLTT challenge (consisting of 70% carbs), triglyceride levels significantly increased, and there was a reduction in adiponectin. Adiponectin is related to glucose regulation and is known for its anti-inflammatory effects. If adiponectin levels decrease, inflammation is bound to increase. In both high-fat and carb diets, inflammation is likely to occur.

Not all fats are the same either: “[monounsaturated]-rich OLTT induced the largest decrease in [arterial stiffness], followed by [saturated fat] and [polyunsaturated fat]. In other words, vasodilation occurred, decreasing arterial stiffness and blood pressure most from monounsaturated fats. Saturated fats (SFA) were “associated with endothelial function and inflammation.” Monounsaturated (MUFA) “induced larger changes in expression of inflammation genes” and increased “thermogenesis,” which means the body ran hotter after the ingestion of MUFA.

Of note, “high flavonol chocolate (HFC) and normal dark chocolate (NFC)… increased FMD, and decreased AIX [or arterial stiffness], total leukocyte counts [related to inflammation], and plasma soluble adhesion molecules in response to OLTT [or diets consisting of mostly lipids]” (Stroeve et al., 2015).

Based, on this analysis, I think it is safe to say that a diet consisting of mostly protein and various but fewer fats and carbohydrates would cause the least amount of physiological stress on the body. Of course, renal damage is a potential concern, but I think this damage can be mitigated by increasing the number of fruits and vegetables consumed, providing the bicarbonate necessary to alter the lower pH levels of the blood (Passey, 2017). If lipids are consumed with a meal, some kind of chocolate may also help to relieve some of the deleterious effects caused by a “high fat” meal. Of course, this leaves an open question: how much protein is enough protein?

Protein Consumption

Clearly, if protein hasn’t been shown to have as many deleterious effects as consuming large amounts of carbohydrates and lipids, then it should be the main source of nutrition if you want to avoid deleterious effects on your body caused by diet. In their brief synopsis, Pencharz, Elango, and Wolfe (Pencharz et al., 2016), aimed to answer this question. Based on an indicator for amino acid oxidation (IAAO) method, the researchers found that the evidence suggested that most nutritional recommendations “substantially underestimate minimum protein requirements throughout the lifecycle.” Based on two studies by Humayun et al., 2007 and Tian et al., 2011, Pencharz et al., identified that the minimum amount of protein an individual should obtain is ~1g/kg/d, approximately .2g to .4g less than other recommendations. However, this is the minimum amount of protein one should consume daily, and higher estimates were given for pregnant women, e.g., suggesting that ~1.5g/kg/d is required (Stephens et al. 2015) and pre-adolescent children require just about the same (Elango et al., 2011).

On average, the North American adult “intakes… 16% of energy (1.68g/kg/d) and range up to 23% of energy (2.4g/kg/d)” from protein. Based on the Acceptable Macronutrient Distribution Range for adults, the recommended protein consumption should be “1.05 to 3.67g/kg/d.” The USDA “My Pyramid” “recommend[s] protein intake of 17-21% of calorie intake (Fulgoni 2008), or 1.78-2.20g/kg/d for… energy expenditure and body weight.” In other words, most Americans could probably consume more protein to achieve their optimum, macronutrient requirements.

Pencharz et al., also identified that “dietary protein intake greater than the [Recommended Daily Allowance] may increase lean body mass and improve physical function.” Also, “acute stimulation of muscle protein fractional synthetic rate by amino acids translated to a significant amelioration of the decline in functional status in elderly that normally occurred after 10 days of enforced bed rest (Ferrando et al., 2010).” And lastly, “[i]ncreased protein intake [was shown] to have beneficial effects on muscle mass in other studies on older individuals (Chevalier et al., 2003).” All and all, these findings suggest that protein consumption can serve as a vehicle to improve lean body mass and improve physical function for the elderly and young alike.

Pencharz et al., suggest that 2.2g/kg/d of protein would be a “reasonable recommendation for the amount of protein” an adult should eat. They also highlight that, contrary to Stroeve et al., “[t]here are no known adverse effects from [the] level of protein intake” they’re recommending (Philips et al. 2016). However, for individuals with kidney disease or chronic renal failure, while protein likely will still be an essential part of their diet, precaution should likely be taken.

Considering the ileal digestibility of “individual amino acids in the test protein,” the authors recommend proteins such as milk, eggs, and beef but highlight that “vegetable proteins fall below 80%,” the digestible indispensable amino acid score, i.e., a measurement of essential amino acids, “with the exception of soy.” They also highlight that cereal protein is limited in lysine, threonine, and tryptophan, while legumes are sufficient in lysine, threonine, and tryptophan but “limited in Sulphur amino acids.” Thus, for a meal consisting of non-animal proteins, a combination of select cereals and legumes would be necessary. However, at the time Pencharz et al., published their study, the optimum cereals and legumes were still being evaluated.

Another review on essentially the same subject by Wolfe, Cifelli, Kostas, and Kim (Wolfe et al., 2017) highlighted similar effects of protein. They highlight that high-quality protein is an essential part of the diet of adults. By high-quality protein, the authors mean that the protein “provides an abundance of EAAs in a profile that closely resembles the profile of individual EAA requirements, and that the protein should be readily digestible.”  They also identify that the CDC’s and the National Center for Health Statistics' recommendations for daily protein intake are substantially lower than what they should be for a healthy diet.

Wolfe et al., also highlight the beneficial effects of a high-protein diet. They show that “when the diet was supplemented 2 times/d with [an] 11g… mixture of EAAs,” lean body mass, strength, and functional tests all improved (Dillon et al., 2009 and Børsheim et al., 2008). They also show that a “decrease in functional capacity that normally occurs in healthy elderly individuals confined to bed rest could be minimized by supplementation of a diet with EEAs” (Ferrando et al., 2010). They also found that “the loss of [lean body mass (LBM)] and muscle strength that occurred with 28 d of bed rest in healthy young subjects was ameliorated by supplementation with a mixture of EAAs and a small amount of carbohydrate” (Paddon-Jones et al., 2004). They highlighted that “muscle mass [was shown] to be improved in other studies [involving] elderly subjects” (Chevalier et al., 2003) and in “patients with heart failure or cachexia” or the loss of muscle with or without the loss of fat (Rozentryt et al., 2010). They show, as well, that “[l]oss of LBM was lowest in the quintile consuming the most protein (18.6% of caloric intake), whereas the quintile consuming the lowest amount of protein (10.9% of caloric intake) lost 40% more LBM than did the highest quintile” (Houston et al., 2008).

Inflammation was also shown to be “inversely related to the level of protein intake” in elderly individuals (Bartali et al., 2012). They show that “[d]iets containing between 18% and 25% calories as protein have been shown to result in greater maintenance of LBM than diets containing 10-12% of calories” (Paddon-Jones et al., 2008). Children also benefit from a high-protein diet. “In a study of normal-weight children aged 5-18 y who had overweight parents, a diet containing ~20% protein improved cardiovascular disease risk markers such as blood pressure and blood lipids compared with a diet containing ~16% of calories as protein” (Journal of Nutrition, 2013). And lastly, high-protein diets benefit bone health, (Kerstetter et al., 1999). Clearly, protein has a beneficial effect on the human body, almost as if our body has been optimized to consume protein rather than carbohydrates. In fact, “[e]pidemological data indicate that the relations between the amount of carbohydrate intake and adverse responses in humans are similar to those in the rat” (Chiu et al., 2011). These effects could be related to increased glucose and triglyceride concentrations after a high carbohydrate meal, which could have adverse effects on cardiovascular health. The recommended daily allowance for carbohydrates is based on the notion that the brain needs glucose to function properly. However, given that carbohydrate-free diets have no clear adverse effects, and the central nervous system is capable of adapting using ketone bodies, a diet constituted of mostly proteins is eminently recommendable. Clearly, a diet consisting of mostly protein, fruits, and vegetables (to curtail any theoretical damage to the kidney and to ensure bone health) is the optimal one. But how exactly should one go about eating this kind of diet?

Intermittent Fasting and Intermittent Metabolic Switching

Before I address the concept of intermittent fasting and intermittent metabolic switching, I think it would be prudent to explore the concept of metabolic flexibility a little further. Part of the problem most unhealthy and obese individuals face is the fact that there’s an overabundance of calorically-rich foods around them (too much of a good thing is a bad thing), and they live sedentary lives. This desensitizes their metabolic system and blunts their ability to switch between glucose and lipid consumption. (Smith et al., 2018). Essentially, unhealthy and obese individuals have an unflexible metabolism. A flexible metabolism is defined as “an adaptive response of an organism’s metabolism to maintain energy homeostasis by matching fuel availability and demand to periodic fasting, varying meal composition, physical activity, and environmental fluctuations” (Carstens et al., 2013 and van Ommen et al., 2009).

Metabolic flexibility can be achieved through fasting. “During fasting, the decrease in circulating dietary carbohydrates and lipids and decline in insulin glucagon ratio increases a switch toward [fatty acid oxidation (FAO)” (Carmeliet and Jain, 2011). With an overnight fast, “ketone bodies are in the micromolar range (~ 30 muM for women and ~60 muM for men), which is not detected by most assays” (Marinou et al., 2011). In other words, a simple overnight fast already initiates metabolic flexibility in healthy humans. While fasting, ketone bodies (KB) serve as an excellent source of fuel (Manninen 2004). “[M]itochondrial 3-hydroxy-3-methylglutaryl-CoA synthase is the most important enzyme involved in ketogenesis,” specifically because it is inhibited by insulin. Insulin prevents “lipolysis by inhibiting hormone-sensitive lipase in adipose tissue… [preventing] the liberation of fatty acids for hepatic ketogenesis.” In other words, the more glucose that is consumed, the more insulin that is produced to manage the glucose, and the less likely it will be for the liver to activate the metabolic processes necessary for lipolysis (Smith et al., 2018).

Caloric Restrictions (CR) or intermittent fasting is one such way to increase metabolic flexibility. During CR, catabolic processes are increased while anabolic processes are inhibited (Cantó, 2010), and mitochondrial function is improved. During caloric excess, metabolic gridlock occurs, and thus the breakdown of glucose stalls. Mitochondrial biogenesis also decreases, and cells operate less effectively (Houtkooper, 2012). Beta-oxidation can also be reduced, causing an accumulation of long-chain fatty acids, leading to impaired insulin signaling. Suffice it to say, “metabolic flexibility is impaired during long-term caloric excess… [which] is correlated to metabolic syndrome, obesity, [type 2 diabetes mellitus (T2DM)], and cardiovascular disease” (Smith et al., 2018). In other words, everyone could probably benefit from caloric restrictions and intermittent fasting, especially in an environment with so many excess calories.

During intermittent fasting, insulin and leptin sensitivity may be improved. An increase in leptin sensitivity increases ketone body levels and can reduce adipose tissue and inflammation (Mattson, Longo, and Harvie, 2017). CR or intermittent fasting also “results in healthier aging through improved metabolic health, reduced obesity, and the risk of T2DM, cancer, and cardiovascular disease” (Mattison et al., 2017). For the sake of honesty, it must be recognized that there’s simply a lack of clinical evidence highlighting the benefits of intermittent fasting for humans (Harvie and Howell, 2017 and Hutchison and Heilbronn, 2016). However, given the physiological basis that theoretically supports the efficacy of CR and intermittent fasting (IF), it is highly unlikely that neither will have a beneficial effect – especially in a novel, overindulgent, and sedentary human environment. Therefore, both are still applicable remedies for excess adiposity and inflammation.

Given that IF and CR can increase metabolic flexibility, it is also likely that inflammation can be reduced through such measures. Caloric excess can cause obesity and insulin resistance, which can cause inflammation which reduces metabolic flexibility. If metabolic flexibility is increased, insulin resistance and adiposity are likely lower, and the body is probably consuming fewer calories. This can be achieved through IF or CR, although not necessarily. Specifically, as “a result of excess fatty acid intake, organs that reach the maximum of their storage capacity and ectopic tissues that accumulate fatty acids upon overspill can become infiltrated by immune cells resulting in inflammatory processes (Smith et al., 2018 and Calçada et al., 2014). Ultimately, this causes lipid toxicity which creates “a vicious cycle of immune-metabolic degradation” (Ertunc and Hotamisligil, 2016). The endoplasmic reticulum of cells is where this problem originates, specifically because the ER is where the “lipid biogenesis and esterification process as well as inflammatory pathways converge” (Smith et al., 2018). If lipid synthesis is disrupted, the ER membrane composition can change, which triggers apoptosis or cell death and, thus, inflammation (Ertun and Hotamisligil, 2016). This process can be regarded as a feed-forward physiological process. Given that CR and IF reduce fatty acid intake and caloric intake in general, organs are less likely to reach their maximum storage capacity, and the calories stored as fat in those organs are more likely to be used, especially because CR and IF trigger catabolic processes. If catabolic processes are taking place, energy stored as fat will be used up, and thus spill over will be halted, reducing inflammation.

Intermittent Fasting can also benefit the brain significantly. In their paper addressing intermittent fasting and metabolic switching’s effect on brain health, Mattson et al., identify that “sedentary, overindulgent lifestyles can increase the risk of several neurodegenerative and psychiatric disorders, suggesting that intermittent fasting or metabolic switching may have a positive effect on psychological and brain health.

For example, mice on a time-restricted feeding schedule, “beginning at [the age of weaning,] exhibit no age-related learning and memory impairment and improve locomotor performance in middle and old age compared with control mice fed ad libitum” (Ingram et al., 1987). In older mice, after 14 months, “spatial navigation, working memory, strength, and coordination at 22-25 months of age were superior to those control mice fed ad libitum.” Mice on time-restricted feeding diets (TRF) “do not experience a decrement in cognition” compared with control mice fed freely (Means et al., 1993). Anxiety also is reduced in TRF mice (Parikh et al., 2016). Mice on a CR diet, which elevated ketones, “exhibited significantly better spatial learning and memory in the Barnes maze, and significantly higher recognition and working memory in the novel object recognition task and Y-maze than mice… fed ad libitum” (Brandhorst et al., 2015).

Mattson et al., note that “from an evolutionary perspective, it is noteworthy that precise navigational decision making… while rapidly traversing the landscape… in a food-deprived and/or fasted state would be critical for survival… [C]ombing exercise with cognitive challenges and or IF results in improvements in neuroplasticity and cognition performance superior to those from the individual challenges alone.”

In fact, this neuroplastic effect attributable to IF, TRF, or IMS is notable. “Rats or mice that run or are fasted intermittently exhibit enhanced [long-term potentiation (LTP)] at hippocampal synapses compared with sedentary animals fed ad libitum” (van Pragg et al., 1999; Farmer et al., 2004; O’Callaghan et al., 2007). TRF improved spatial-navigation performance in rats and increased “dendritic spine density and LTP in CA1 neurons in rats” (Talani et al., 2016) and decreased age-related LTP losses (Eckles-Smith, et al., 2000 and Hori et al., 1992).

IMS may also benefit the heart. ADF (alternate daily feeding) or TRF is shown to enhance the “parasympathetic tone,” resulting in “reductions in resting heart rate and blood pressure, and increased [heart rate variability (HRV)” (Wan, Camandola, and Mattson, 2003 and Mager et al., 2006). ADF has also been shown to increase fibroblast growth factor-2 (FGF2) “levels in the cerebral cortex and striatum of mice” (Arumugam et al., 2010). Interestingly, FGFT is associated with the “formation and extinction of memories of fearful events… suggesting a role for FGF2 in the critical synaptic plasticity required for survival during periods of food scarcity” (Graham and Richardson, 2011). All of these findings suggest that fasting can improve heart and psychological health in humans.

Specifically, IF, ADF, TRF, and IMS may help to prevent Parkinson’s and Alzheimer’s Disease (PD & AD). Individuals living modern lifestyles are at increased risk for AD and PD due to their overindulgent and sedentary lifestyles, and animal studies support this fact (Frisardi et al., 2010 and Lee and Mattson, 2014). Moderate consumption habits and exercise have been known to reduce the risk of AD and PD (Baumgart et al., 2015 and LaHue, Comella, and Tanner, 2016). Interestingly, IMS reduces clinical symptoms in patients with AD and PD (Groot et al., 2016 and Uhbrand et al., 2015). These findings suggest, given the physiological relationship between exercise (or IMS) and IF, ADF, and TRF, that the latter three may have a similar benefit for individuals with AD and PD, at least.

The modern lifestyle also increases the risk of anxiety disorders and depression (Hryhorczuk, Sharma, and Fulton 2013). Once again, IMS and IF can improve mood and “ameliorate anxiety and depression” (Hallgren et al., 2016; Johnson et al., 2007; Archer, Josefsson, and Lindwall, 2014; and Patki et al., 2014). Something that should also be of interest is that, as noted by Mattson et al., 2018, “autism tracks remarkably closely with the increase in childhood… obesity during the same time period… suggesting a causal link between lack of metabolic switching and autistic behaviors.” Supporting this fact, backed by data from autismspeaks.org and data from US Centers for Disease Control, “are data showing that nearly twice as many children diagnosed with ASD are overweight or obese as control children” (Criado et al., 2018). In support of the possible salvific effects of IMS or IF on symptoms of autism is evidence showing that exercise “is effective in reducing behavioral issues in many children with ASD” (Cremer, Crozier, and Lloyd, 2016) and that “a ketogenic diet also improves symptoms in children with ASD” (El-Rashidy et al., 2017). Continued research is still needed to show an absolute role of IF in ameliorating the symptoms of ASD, but it is possible theoretically.

In summation, IF, ADF, and TRF, along with IMS, clearly have a beneficial effect and should be included in any model that aims to improve health. Of course, the what and how of a diet are not the end-all-be-all of nutrition and health; exercise and environment also play a significant role.

Exercise, Cold Exposure, and Sleep

Returning to Smith et al., it is clear that exercise has a beneficial effect on metabolic flexibility. “Oxidative muscle fibers have a high mitochondrial density; hence they prefer oxidative phosphorylation for ATP production [OXPHOS],” which occurs when one is fasting or on a CR diet (see Figure 3 of Smith et al., 2018). On the other hand, “[g]lycolytic muscle fibers have a low mitochondrial density and rely predominantly on the breakdown of stored glycogen by glycolysis for their ATP production.” These muscles will have to rely on stored fat to function properly when one is CR or the remaining glucose in the body’s plasma (see Figure 3 of Smith et al., 2018). Because intense exercise utilizes glucose too quickly to supply the muscles with energy, and during CR, glucose levels are decreased, and the body is relying on FAO, the cells must learn to produce energy and utilize energy more efficiently.  In other words, “regular physical exercise is a classic example of how metabolic flexibility is regulated by transcription factors.” The transcription factors associated with physical exercise are clearly involved in “mitochondrial energy homeostasis and metabolic adaptions” (Perry et al., 2010). One such factor PPAR “regulates the transcription of genes that encode enzymes involved in lipid transport and catabolism.” The resulting increase in mitochondrial biogenesis caused by factors such as PPAR increases metabolic flexibility and insulin sensitivity. In sedentary subjects, PPAR gamma coactivator 1-alpha (PGA1alpha) – a regulator of exercise-induced adaptions in the capacity of oxidative phosphorylation (OXPHOS) in skeletal muscles – “is reduced in sedentary subjects” (Lira, Benton, and Bonen 2010 and Rowe et al., 2013). In other words, exercise helps the body to become more sensitive to insulin and better at breaking glucose down and using it more efficiently.

In their 2017 paper, Rynders et al. build on this topic. They found that “exercise training was… [correlated] with an increase in the daily variance in [respiratory quotient (RQ)] and a decrease in the daily variance of insulin.” They also found that “sedentary metabolically inflexible subjects [were] characterized as having a large daily variance in insulin for a small variance in RQ (i.e., a small shift in the fuel mix being oxidized at a high insulin signal” (Bergouignan et al., 2013a). Explaining the findings, they stated:

“A metabolically flexible state characterized by a large shift in the fuel mix being oxidized in response to small changes in insulin is thus associated with large differences between the 1st and 99th percentiles of the postprandial RQ values and small differences between the two extreme percentiles for postprandial insulin. A metabolically inflexible state is associated with a decrease in the range between the 1st and 99th percentile in RQ concomitant with an increase in the range between the 1st and 99th percentile insulin values, thus resulting in an increase in the slope of the percentiles–percentiles linear relationship.”

In support of this finding, metabolic flexibility improved after “12 weeks of aerobic exercise training… in 24 older adults with pre-diabetes and obesity” (Malin et al., 2013). In younger individuals, after “10 consecutive days of aerobic exercise training… fat oxidation in skeletal muscle during a high fat meal challenge in obese individuals in a manner that was similar to lean subjects” increased (Battaglia et al., 2012). And lastly, “1 month of exercise training performed at currently recommended levels improved metabolic flexibility in lean sedentary subjects as indicated by shifts in the insulin/RQ variance indices” (Bergouignan et al., 2013a,b). In other words, if exercise improves metabolic flexibility, and if metabolic flexibility is low, the individual likely isn’t exercising and can possibly improve metabolic flexibility through exercise.

Rynders et al., citing Schrauwen et al., 1997, state that “On a high fat diet, fat oxidation remained below fat intake, indicating the slow matching of oxidation intake when switching to a high fat diet. However, after a bout of exercise that lowered glycogen levels, fat oxidation matched fat intake… demonstrat[ing] that it is possible to rapidly adjust fat oxidation to fat intake only when glycogen stores are reduced.” This supports the findings highlighted by Smith et al., which showed that metabolic flexibility is induced through exercise, increasing the body's sensitivity to insulin and increasing mitochondrial efficiency.

Rynders also highlights that increasing fat as fuel, in conjunction with increased physical activity and exercise, likely provides “a higher tolerance to a high fat diet, which favors the control of fat balance and hence energy balance, as energy and fat balance are tightly intertwined” (Schrauwen et al., 1997, 1998). In other words, the body becomes better at handling fat when exercise is increased, and the deleterious effects of FFA (Free-floating fatty acids) are decreased or mitigated.

Metabolic inflexibility can be addressed by merely breaking up sedentary time with brief instances of physical activity (Rynders et al., 2018). The authors also highlighted that muscle contraction, more than simply standing, “[was] a key factor in the use of glucose by the body,” which was supported by a study done by Bergouignan et al., 2016. Continuous bouts of activity were shown to be “associated with lower plasma lipid concentrations, mainly triglycerides and in some instances free fatty acids” (Peddie et al., 2013). In other words, interspersed bouts of activity that initiate muscle contractions and long periods of physical activity help to promote metabolic flexibility and the use of both glucose and lipids within the body.

In their paper, Smith et al., 2018 highlight the fact that, on top of exercise, reducing core body temperature could potentially improve metabolic flexibility (Stager et al., 2015 and Wu and Storey, 2016). Specifically, they noticed that “PPAR agonists in white adipocytes caused conversion to a brite/beige molecular phenotype in vitro defined by increased mitochondria oxygen consumption and amplified expression of the thermogenic gene program… uncouples mitochondrial respiration, releasing heat” (Barquissau et al., 2016). In other words, cold adaptation increased metabolic efficiency. “In bright/beige adipocytes, glucose utilization is likely switched from OXPHOS to glyceroneogenesis favoring triglyceride synthesis.”  I.e., the switch from White Adipose Tissue to Brown or Bright/beige adipose tissue increases the body's ability to utilize triglycerides as a source of fuel rather than just glucose. Importantly, “[o]bese subjects showed lower BAT [brown adipose tissue] activity than lean subjects, and low BAT is associated with metabolic dysfunctions such as T2DM and aging” (Mottillo et al., 2016). It is specifically exposure to the cold that increases the genesis of BAT, which also increases insulin sensitivity (Hanssen et al., 2015). This suggests that cold therapy is a potential variable that should be included in a model whose aim is to increase health.

Of course, a good night’s rest is essential for metabolic health as well. The “circadian clock can have major effects on metabolic flexibility and is even able to coordinate temporal and spatial organization of lipids and circadian rhythmicity of mitochondrial function” (Chatham and Young, 2013; Aviram et al., 2016; Goede et al., 2018). However, the circadian clock may also be influenced by external stimuli, including food consumption. For example, mice on a high-fat diet “showed altered expression of core clock genes and the genes under their control, altered circadian rhythms, and consumed larger amounts of food during their active phase” (Eckel-Mahan et al., 2013). Feeding “rhythm strongly contributes to the reciprocal relationship of the circadian clock and metabolism” (Damiola et al., 2000 and Eckel-Mahan, K. and Sassone-Corsi, 2013). Of great importance is the fact that disruption of the circadian rhythm can cause significant negative effects, including insulin resistance. For example, “[nightshift] workers are at a greater risk to develop obesity, T2DM, cardiovascular disease, and metabolic syndrome” (Karlsson and Lindahl, 2001 and Pan, Schernhammer, Sun, and Hu, 2011). In short, this means that maintaining a proper sleep schedule and avoiding all-nighters is essential to one’s health and metabolic flexibility.

Discussion and Conclusions

“The discipline of suffering, of great suffering—know ye not that it is only this discipline that has produced all the elevations of humanity hitherto? – Fredrick Nietzsche

So, what has been learned? A lot, actually. It’s quite clear from the literature that a diet consisting mostly of carbohydrates is to be avoided. Instead, it seems as if it is much healthier to compose a diet primarily of proteins, fats, and fruits and vegetables. Importantly, fat consumption should vary between the kinds of fats, saturated, monosaturated, and polyunsaturated. If you eat fats as a source of energy, it seems as if it’s probably a good idea to engage in physical activity, as well, to offset the consequences of lipids in the body.

To note once more, it’s clear that a high-protein diet, or a diet consisting primarily of protein, is probably the most effective and healthy choice. This seems to especially be the case given the negative effects of a higher carbohydrate diet. It also seems that the notion that the brain needs glucose, and thus you need carbohydrates, to operate is simply an antiquated notion better left to the refuse bin of history. Of course, in theory, a high-protein diet could damage the kidneys, exacerbate kidney damage, or damage the bones. To offset this effect, I think it would be a good idea to consume fruits and vegetables, the recommended daily requirement, which is around a cup and two cups, respectively, to decrease plasma pH.

The best manner in which this diet should be implemented seems to be through intermittent fasting (IF), alternate-day fasting (AF), or time-restricted feeding (TRF). This diet is most like the eating patterns of our ancestors and the environment they were best adapted to. Our physiology and anatomy are not a product of current conditions, but of past conditions. Thus, to operate efficiently, it is best to look backward. In the past, we clearly did not have access to the same quantity of food we have available to us in a modern environment, and thus are liable to overindulging and sedentary behaviors. Both of these types of behaviors have extremely negative consequences that need to be ameliorated through diet and exercise discipline. Thus, it seems evident that IF, and other forms of diet that challenge the body in a manner similar to how our ancestors were challenged, likely have extremely beneficial effects

Of course, no model for good health is complete without including some reference to whether one should exercise, and this model is not bereft of that reference. I personally enjoy weightlifting and light cardio, but for older individuals, it may be best to limit that exercise to light weightlifting, muscle contractions, and stretching, including some yoga poses that engage the whole body. I think doing these kinds of exercises, at least 30-45 minutes a day, will have clear positive effects. Finding a way to exercise throughout the day might also be a good idea, especially during work; stretching, light cardio, etc., doing something very briefly, multiple times – interspersing more sedentary activities – likely will have a very positive effect both on mood and overall health.

 I also think that it might be a good idea to implement some kind of cold therapy. I know there are ice tanks or ice rooms that you can go into, and I think it would be a good idea to seek out these tools. An ice room or an ice tank has very positive effects theoretically, and the potential benefits of cold therapy should be investigated further. And honestly, there’s something fun about pushing yourself to do ice challenges, especially if it has the possible side-effect of increasing your health in the long term.

And lastly, a good night’s rest is key. Sleep affects metabolic processes, and diet and environment affect sleep, which means that diet and environment affect metabolic processes through sleep patterns. Thus, staying aware of how much sleep we are getting, keeping a schedule, and adjusting behavior patterns (e.g., drinking less coffee later in the evening if it’s deleteriously affecting sleep patterns) are all required for a model intended to increase health.

First and foremost, I think the most difficult part of any change in diet is maintaining that change. The best advice I can think of for this problem is the same advice a doctor might give to an addict: get rid of the things that have more control over you than you have control over them. I’ve written a lot about addiction in the past, and I still think it’s a thoroughly intriguing topic, and it’s clear from that research that some substances, like carbohydrates and sugars, can be as addictive as cocaine. If you want to improve your health, and you honestly can’t control yourself around substances like a sugar cake, get rid of them; don’t keep them in the house. If you’re outside of the house, the best advice I can think of to avoid giving in to your addiction is to create a journal and map out where you want to be with respect to your health and to focus on attaining the goal you want, which should serve as a reminder that eating too much sugar or carbohydrates is an obstacle to achieving that goal. Focusing on future goals has been shown to improve the choices individuals make when given a choice between eating, for example, fruit and a donut. Those who focused on the negative effects of eating a donut with respect to their long-term goals were more likely to choose the piece of fruit or the healthier option. And lastly, it’s best to remember, but to absolutely never lean on the fact, that we’re human and sometimes it’s okay to indulge. However, if overindulging means you won’t be able to control yourself in the future, then remind yourself of your long-term goals and do your best to avoid indulging whatsoever.

Secondly, I think the most difficult aspect of this kind of model will be finding different types of protein to eat or cooking them in a way that makes them boring. Boring food dissuades people from eating it, and if you want to be healthy, you don’t want to be dissuaded from eating healthy food; protein is a healthy aspect of every diet and shouldn’t be boring. Thus, it’s essential that you learn how to cook so that you can make your food interesting and worth consuming. There are many different types of protein you can choose from, and you can doctor them up in many different ways. If price is an issue, I am not one of those people who’s going to tell you to avoid eating soy or even bugs, which include locusts and grasshoppers (Leviticus 11:22). The latter option may not seem the most delectable, but if God permits it, and bugs can be a good source of protein, I’d eat them; I would simply try to ensure they are free of pesticides, carcinogens, or other harmful compounds. I have a more open and less agreeable personality, so, if push came to shove, I don’t think I’d have a problem with this kind of protein, and if it preserves my health, and increases my ability to do good in the world, I’d be content eating them. This ultimately stems from the fact that the ratio between animal protein and the agricultural product used to raise that source of animal protein is 1:10 (Enger, 2003 pp. 311-330) – ~90% of energy is lost from one trophic layer to the next; i.e. for every one serving of animal protein, you can consume 10 servings of the agricultural product used to feed that animal. However, the potential benefits from animal protein are simply too high to be disregarded for the sake of some minor economic benefit that may be lost by the health costs created by a high-carb diet. Thus, it is more prudent to invest in a high-protein diet, given the long-term costs associated with the cheaper high-carb alternative. Regardless, the point is that making sure you get enough protein and that you keep it interesting is key to sticking to the diet and remaining healthy.

Lastly, I think creating a schedule that you can stick to would be a great idea; this is especially helpful when trying to stick to an IF or ADF diet. I also think tracking the macronutrients you eat would be useful, as well. Lastly, creating a schedule or having a journal that allows you to track your physical activities could be beneficial, too. All of these would allow you to keep track of where you are, and what you’ve been doing, and for showing you when you’ve maybe veered off course so that you can quickly get back on track. A good diet always considers the fact that people aren’t perfect and that they make mistakes. However, a good plan ensures that there are contingency options for when mistakes are made. A schedule and journal tracking what you should be doing, and where you are vis-a-vis your goals, keep you accountable; thus, a journal or schedule is a necessary part of a good plan whose goal is to preserve or increase one’s health.

I do not think pills or surgeries are an appropriate course to take to improve one’s metabolic health, especially the health of younger individuals. However, it is true, the model I've created and the suggestions I'm making are not very expensive treatments, relatively speaking. The most expensive aspect of this health model is ensuring that you find a way to do some kind of cold therapy, which promotes brown adipose tissue genesis. I also think that if this model were to be implemented at a larger scale, it would have significant defects, especially because different people have so many different eccentricities and nuances. However, it is clear that the evidence I covered is the result of studies on essential biological processes and mechanisms. This means that, even if people differ, the conclusions reached by this literature review apply to humans in general. Yet ultimately, people have to be free to choose this kind of lifestyle for themselves. We can blame childhood obesity on poor food availability, but maybe that’s not the problem. This model requires the person to be conscientious and self-motived. Not everyone is like that, and as such, not everyone is going to be able to even consider implementing this kind of health plan. Many people struggle with diabetes for just this reason; it’s not necessarily that they don’t know how to take care of themselves, it’s that do not stick to the recommendations given to them, or they do not understand them. For these kinds of people, marketing would probably be the most effective solution. Altering how they think about food at an unconscious level through media seems the least intrusive approach and doesn’t require unnecessary legislation or dealing with some corrupt legislature. And once they feel capable of bettering themselves, give them the tools (e.g., software) to do so.

In the end, I am glad I did this kind of research for myself and for my father. I plan on implementing many of these ideas for my father and myself, and I definitely think these should have some beneficial effects for both of us. If someone else benefits from this kind of research, all the better. Hopefully, I can start this new year off right by focusing on and aiming for the good, no matter how many obstacles stand in the way.

For now, what I think I’ve learned from this exercise is that humans have an optimum level of stress and suffering. If we are too overindulgent and sedentary, if we do not stress ourselves out enough or suffer enough, our bodies degrade, producing negative health outcomes. However, if we stress ourselves out too much or experience too much suffering or pain, our bodies are liable to snap, break, and react physiologically in such a manner as to reflect poor health. As the meme goes, good times create weak men, who create hard times, and hard times create strong men, who create good times. In other words, men can put themselves through an optimum level of stress that ensures their health and thus their strength physically and mentally. If those “good times” can require and maintain the appropriate level of stress on the physical body to ensure its proper maintenance, there’s no knowing when those “good times” might end.

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