Many folks complain of poor results when it comes to optimizing their health through diets. Numerous high-carb diets are badly designed, while many more low-carb/keto diets are even worse. When we follow fat/obese gurus who tell us to pour oils into our coffees and consume plain butter, no wonder we fail in our way to be healthy.
Plus, while we blame dietary guidelines, the government and big pharma for our poor health, an optimal state goes beyond diet and exercise. I cannot seem to over-emphasize this. It’s not like big pharma or the food industry force us to put food into our mouths. Of course, they may have the power to limit our decisions, but the ultimate call about what to put into our mouths belongs to you and me.
Besides, many of my virtual friends seem to have established hatred over specific macronutrients (cognitive biases towards praising fat and trashing carbohydrates). Carbohydrates, per se, are not bad. Fat is not bad either. However, when they come under labels and ingredient lists, of course they may elicit negative effects on one’s health.
Pharma and big industries may have no power on you if you consume foods with no labels, foods that are as close to a natural (unprocessed) form as possible.
In this context, it would pay little what type of dietary dogma we are following. Plus, we seem to focus too much on macronutrients. Eating diets 80% or higher in fat may not be optimal unless a medical condition implies such drastic measures. We’ve seem to have forgotten the power of micronutrients (which come in plants) while we keep pouring oils into our coffees thinking we’re hacking our brains.
We’re eating too much and too frequently, trying to push away the fear of going into a ‘slower’ metabolism. Yet we keep forgetting that a ‘faster’ metabolism can also, simplistically speaking, translate into accelerated aging. For many of us, limiting food intake, calorie restriction, and fasting are not an option. However, this may be a necessary condition for the body to go into autophagy, to clean itself of toxic load, and to rejuvenate itself.
If we stop repeating messages like a broken-line and if we start making use of the brains that evolution and/or our divine entity have gifted us with, we may begin leveraging on the power that nature has reserved for us. That’s why in this post I’m gonna discuss some of the concepts that I found in a couple of papers which include oxidative stress, mitochondrial hormesis and xenohormesis. Don’t stress on the fanciness of the terms. You will soon understand what they are all about.
Higher Oxidative Stress, Mitohormesis, and Xenohormesis
When it comes to oxidative stress and increasing healthy life span, you will find results and inconclusive conclusions all over the board. Some say that using antioxidant rich foods may help, while others say that increasing oxidative stress (through hormesis, especially) would increase a cell’s ability to cleanse and protect itself :
In conflict with Harman’s free radical theory of aging (FRTA), these effects may be due to increased formation of reactive oxygen species (ROS) within the mitochondria causing an adaptive response that culminates in subsequently increased stress resistance assumed to ultimately cause a long-term reduction of oxidative stress…
In summary, the findings discussed in this review indicate that ROS are essential signaling molecules which are required to promote health and longevity…
In light of these findings, one may have to be cautious on the type and the amount of antioxidant supplements they use.
Currently, I’m only taking alpha lipoic acid. When I finish the stack (in a couple of days), I’m going to take a break from it for a couple of weeks. Plus, since summer is around the corner, I’m going to focus on consuming nutritious rich fruits (all sorts of berries) that are also somewhat rich in antioxidants.
While working on my book Periodic Fasting, I found an ever increasing amount of studies (older and very current) suggesting that higher protein intake and its correlation with the activation of mTOR and IGF-1 signaling pathways may increase the proliferation of tumor tissue.
While I focus on increasing the nutrient richness of my diet by consuming large amounts of plant foods and I also maintain my ketosis state, I try to limit meat, especially steaks and lean cuts and fatty cuts (high in protein but nutritiously poor). Here’s a great talk between Tristan Haggard and Dr. Jack Kruse on Paleo/Keto failures.
When I eat meat though, I aim to consume organ meats as they are some of the most nutritiously rich foods.
Finding a good source may be tricky because same as how the liver, kidneys and other animal organs can concentrate nutrients, they may also concentrate toxins. If they are not properly grown and fed, consuming their organs may prove to have detrimental effects on your wellbeing.
While I’m not a frequent dairy and meat eater, I still keep consuming eggs (from chicken raised by my grandparents). Besides, I stopped using protein supplements almost a year ago. Along the same lines :
While the effects of glucose restriction will be discussed below, in Drosophila melanogaster,
restriction of casein extends life span. Moreover, it has been proposed that restriction of both yeast as well as sugar may extend Drosophila lifespan despite unaltered calorie uptake. Very recently, it was shown that increased abundance of essential amino acids, and particularly methionine counteracts the lifespan-extending effects of CR in D. melanogaster. Notably, restriction of methionine in rodents similarly delays ageing and increasing protein content impairs antioxidant defense in rats.
Similarly, applying 2-deoxyglucose (DOG) in C. elegans may extend lifespan by activating AMPk and SIRT1 :
Accordingly, application of DOG to rodents efficiently mimics features of the metabolic state of CR as well as carbohydrate restriction, suggesting that DOG acts as a CR mimetic.
Altogether, these findings suggest that in-creased intracellular glucose availability exerts detrimental effects on longevity, whereas decreased glucose availability promotes oxidative metabolism and extends life span.
Each of these concepts has been briefly described so that you better understand the mechanism of mitochondrial hormesis.
Mitohormesis refers to the potential stressors inside/on the mitochondria that would improve its efficiency. Some of the proposed hormetic agents are ROS (reactive oxygen species), physical exercise, and increased oxidative metabolism .
Unexpectedly, many prospective clinical trials aiming to find any health-promoting effects of antioxidants failed, in the best case showing no health-promoting effects of these compounds… More importantly, a number of studies suggest that antioxidants may promote cancer in humans. Accordingly, other studies show that antioxidant supplements may be disease-promoting and/or may even reduce lifespan in humans.
Consistently and in conflict with Harman’s hypothesis, evidence has emerged in recent years that ROS may actually work as essential, and potentially lifespan-promoting, signaling molecules which transduce signals from the mitochondrial compartment to other compartments of the cell. 
While some of these conclusions may seem far-fetched and may not have been put into perspective (so that a wider and clearer picture can be seen), in certain cases these insights may be appropriate.
This doesn’t mean that all antioxidants will promote cancer all the time. It does not also mean that they may not elicit positive effects on wellbeing and longevity. But, as Dr. William Lagakos likes to put it, context is key.
One thing that I would like to critic is that many of us take everything for granted, sometimes just to keep fueling our personal biases. Whenever we see a study that approves our beliefs we promote it like crazy, while whenever we see a study that disproves them we try to find all the reasons in the world to make it seem as inappropriate.
Example for keto/low-carb fans:
‘Plant foods and micronutrients essential for optimal health’ – Bullshit, these studies are widely flawed because so and so…
‘High-fat ketogenic diet optimal for weight loss’ – Oh yeah, this is my kind of stuff. Let me overload my social media followers with this message (as it keeps fueling my personal biases).
Things are far more complex than they seem. Many studies are poorly conducted. In fact very few studies are well designed. Add to that the involvement of pharmaceutical industries and political interests and you may see that you have to be extremely careful when deriving conclusions from research studies.
Very few folks take the time and discipline to read entire research studies. Many of us only read the last sentence from the abstract. Then, we try to appear as experts when repeating these sentences to our social media followers.
You may hate me for saying this, but we are very superficial. We like to skim through information. No wonder why only a bunch of people may truly live an optimal life and no wonder why so many cannot see results in their weight loss/life optimization strategies, regardless of the dietary template they consume.
Ristow and Zarse (2010) consider that :
The ROS signal appears to induce ROS defense mechanisms, culminating in extended lifespan, which reflects a typical adaptive response, consistent with the mitohormesis hypothesis…
Antioxidants prevent this adaptive response, and extension of lifespan is abolished. It remains to be resolved, in which time-resolved order these processes occur, and specifically whether increased ROS defense counteracts respiration-derived ROS formation.
Yes, this is still a hypothesis and should be taken as such. Here’s an illustration from the researchers.
To put everything together on mitochondrial hormesis (and my frustration) :
Mitohormesis and lifespan extension: For both calorie restriction as well as physical exercise, experimental evidence suggests that induction of mitochondrial metabolism is required for the lifespan-extending and/or health-promoting effects of these interventions. This increase in mitochondrial metabolism generates a ROS signal that is required to induce an adaptive response to culminate in increased lifespan. For impaired insulin-IGF-1 signaling however, this links remains to be experimentally shown.
Xenohormesis and the Stressed Plant
Xenohormesis is a biological principle that explains how environmentally stressed plants produce bioactive compounds that can confer stress resistance and survival benefits to animals that consume them.
The xenohormetic plant compounds can, when ingested, improve longevity and fitness by activating the animal’s cellular stress response and can be applied in drug discovery, drug production, and nutritional enhancement of diet. 
I’m sorry that some of my fellow keto-diet fans may not see this. Many seem to have been stuck in an obsessive consumption of fat by adding oils to coffees and consuming plain butter and who-knows-what, which in my perspective is nonsensical (as it is energy-rich nutritient-poor).
Another aspect that many folks seem to have forgotten is that ketosis is not exclusively tied to fat consumption. Ketosis may also occur when you fast. So there’s no excuse for eating so much fat so often, other than just pleasing brain’s reward mechanism.
Back to hormesis :
A particularly key realization in this area is the idea that low levels of stress can improve an organism’s health, well-being, adaptability, and fitness through stimulation of the cellular stress response, a phenomenon known as hormesis.
And xenohormesis :
Similarly, drought-stressed strawberries have better taste, antioxidant capacity, and phenol content, an observation supported by the rich flavor of strawberries found in the wild in contrast to those that are cultivated under more controlled conditions.
The big, worm-free, extra-red, very clean and supper appealing strawberries at your local store may not be as nutritiously rich as you’d like to think they are.
Indeed, commonly consumed food products like lettuce and fruits can be nutritionally enhanced by cold stress, light stress, water deficit, or nutrient deficit stress. Heavy metals, salicylic acid, and other compounds can function as hormetic elicitors without compromising crop yield. Finally, viral, fungal, and bacterial infection can, in some cases, paradoxically improve the plant’s nutritional content via hormesis.
It’s least likely you’ll find such foods at the superstore. You may try to befriend a local farmer who knows his stuff.
In addition to that, if you consume 80%+ fat, little chances are you’re going to benefit from the positive effects of :
Flavonoids—which include rutin, quercetin, epigallocatechin gallate (EGCG), isoflavones, and anthrocyanidins—and non-flavonoids—including hydroxybenzoic acid and stilbene derivatives such as resveratrol, cinnamic acid, caffeic acid, curcumin, rosmarinic acid, and ferulic acid.
When ingested, phenols activate the mammalian stress response, are anti-inflammatory, have antioxidant and therapeutic effects against cancer, T2D, renal disease, neurodegenerative diseases, and other conditions . Many of these compounds come in carbohydrate-rich-fiber-rich stressed plants, such as in the lists below :
Polyphenols such as resveratrol, curcumin, and carvacrol, on the other hand, are able to stimulate the animal’s stress response with minimal systemic toxicity .
In a calorically restricted context or in a fasted situation, both the low-energy state of the cell and resveratrol intake can activate AMPk and SIRT1 :
A high AMP/ ATP ratio, as occurs with caloric restriction and exercise, activates AMPK (AMP-activated protein kinase), which then, via the NAD+/NADH redox state, stimulates sirtuin 1
(SIRT-1) deacetylation of key transcription factors includ-ing heat shock factor-1. HSF-1 activates most heat shock proteins (Hsps) and is associated with stress survival and longevity extension across diverse species.
Moreover, activating AMPk limits fat and protein synthesis while stimulating oxidation of fatty acids and glycolysis so that ATP availability is restored. In this context, fatty acid oxidation alone may lead to higher oxidative stress, thus increasing mitochondrial hormesis. I’ve explained the activity of AMPk in higher detail in Periodic Fasting.
We suggest that an activated stress response plays a fundamental role in conferring fitness and survival benefits to animals consuming stressed plants (see the picture at the top) . This is why I think that obsessing over fat consuming and focusing on macronutrients while consuming a nutritiously poor template is the next step in failing to live an optimal life.
It may not be wise to stubbornly hold onto pre-programmed beliefs in the face of contrary evidence. From what you’ve read in this blogpost, you should not understand that I’m moving toward vegetarianism or veganism, though if I’d remove the spiritual BS from those strategies and add some fat they may turn into some good protocols.
I’m not obsessing on fat consumption either. I can easily maintain ketosis (not that ketosis is one size fits all) at 60-65% fat while I limit protein intake (especially animal protein) and consume abundant amounts of nutritiously rich stressed plants.
Plus, there are days when I do total fasting (i.e., consume only water for more than 24-30+ hours) and that’s when my ketosis is at its peak. Dr. Joel Fuhrman has some good points on micronutrient rich diets, though he seems to obsessively be pushing a message to ‘drastically limit fat consumption‘. Not sure how he missed on the importance of DHA for brain, cellular, and sub-cellular health.
I am always ready to change my beliefs if someone shows to me that I may be wrong. It would be irrational for me to stick to certain beliefs (diets) in the face of opposite evidence (especially when that evidence comes from my n=1). I’m thankful to the brilliant Ray Cronise for challenging my beliefs, my personal dogmas and my biases.
What’s next? I don’t know and I’m really excited about that! 🙂
1. Ristow, M., & Zarse, K. (2010). How increased oxidative stress promotes longevity and metabolic health: The concept of mitochondrial hormesis (mitohormesis). Experimental gerontology, 45(6), 410-418.
2. Hooper, P. L., Hooper, P. L., Tytell, M., & Vígh, L. (2010). Xenohormesis: health benefits from an eon of plant stress response evolution. Cell Stress and Chaperones, 15(6), 761-770.
3. Ristow, M. (2014). Unraveling the truth about antioxidants: mitohormesis explains ROS-induced health benefits. Nature medicine, 20(7), 709-711.
4. Forman, H. J., & Ursini, F. (2014). Para-hormesis: An innovative mechanism for the health protection brought by antioxidants in wine. Nutrition and Aging, 2(2), 117-124.
Photos: here and here