Cold on the outside – Warm on the inside

Introduction

We are now in the year 2020.  A lot of research has been performed regarding different diets yet still so much controversy exists around whether or not we should eat a lot of carbohydrates or fat or protein.  Those are the 3 macronutrients that are played around with in research.  Diets with different compositions compete with each other for being the best at weight loss, health and longevity.

So will I be able to provide a definite answer?  I cannot claim that I do but I will present you the material I have been able to gather to provide a picture that will hopefully bring more clarity (and probably as always a lot of questions too).

I have always been interested in health and in lifespan.  Healthspan means to stay as healthy as possible for as long as possible and minimize the time in which health deteriorates followed by death.  It is my suspicion that if we can live optimally by increasing our healthspan then we may also be pushing our lifespan to what we are naturally capable of.

This has brought me to the point where it is important to know how all of the cells within the human body work together and what makes each cell survive individually.

In order to get a good picture of things, there are a few individual concepts that we need to go through before we can talk about a potential way to affect our health- and lifespan positively.

What are we?

It may come as a surprise to some but “we”, “you” and “I” don’t really exist.  Our body is a cooperation of cells.  Throughout evolution individual cells have started to form bodies in order to increase their chances at survival and reproduction.  In its most rudimentary form these bodies have helped to avoid being destroyed, being eaten or damaged by environmental elements and also helped in waiting for more ideal times to replicate. 

Replicating is the essence of life.

It feels strange to think that everything we do in our lives, the complexity of our society, is driven by the desire to survive and reproduce by the billions of cells that we are made up of.

But it is true, the cells that we are made out of are the actual life forms.

Reproduction

Via the book “Lifespan: Why We Age–And Why We Don’t Have to” of author David Sinclair, PhD. it became clear that cells have 2 distinct states in which they operate.  They are either running in a mode of repair and maintenance or, when the times are right, they turn to proliferation.  When they proliferate, the cells spend much less of their energy on repair and maintenance.  All energy goes to creating the building blocks for new versions of themselves.

The Hayflick limitation

The cells in our body are continuously proliferating.  All of our organs are undergoing cell renewal to some degree although brain cells practically don’t as everything we’ve learned and remember depends on the connections between the cells.  If such a cell would die then that memory connection is lost.

With each cell division, the telomeres that protect the unraveling of the DNA in our cells, gets shorter and shorter.  When it is too short, the cell fails to replicate.  This effectively puts a limit to how many generations can exist.

When that limit is reached the cell will become senescent over time.  It will gradually lose its identity.  Although all cells have the same DNA in their nucleus, they all differentiate into a specific cell type (a heart cell, lung cell, muscle cell etc).  Throughout time, the cell will accumulate DNA damage causing it to behave differently and lose that identity.

“Hayflick Limit” https://en.wikipedia.org/wiki/Hayflick_limit

There are possibilities for cells to overcome this limit because we have an enzyme called telomerase which repairs the telomere ending of our DNA.  In humans we primarily see this in cancer and stem cells.  Both types are undifferentiated to some degree which suggest that it is important to limit growth when the cell is part of a community such as an organ.

Healthspan

So what does this tell us with respect to health span?  It is important to spare ourselves from DNA damage and mutations to stay healthy and when we are grown up, if we can slow down the cell replication over time, then we are adding time to our existence so prolonging our lives.

How can we achieve this?  By reducing cell replication we automatically drive up the potential for cell maintenance and DNA repair.

Cell metabolism

One of the ways that DNA is repaired is by a group of enzymes called sirtuins.  The enzyme SIRT1 performs repair at the nucleic DNA.  The activity of SIRT1 is regulated by the ratio NAD/NADH.  A higher NAD availability is required for SIRT1.

A cell that is stimulated in metabolism has a lower SIRT1 activity.  This metabolism is modulated by our thyroid hormone free T3 (fT3) so a potential suggestion is to reduce this stimulation.  fT3 stimulates cell proliferation as shown in different cell lines, which is opposite of what we want to achieve.

“3-Iodothyronamine and 3,5,3′-triiodo-L-thyronine reduce SIRT1 protein expression in the HepG2 cell line” https://www.degruyter.com/view/journals/hmbci/41/1/article-20190045.xml

“3,5,3′-triiodothyronine (T3) stimulates cell proliferation through the activation of the PI3K/Akt pathway and reactive oxygen species (ROS) production in chick embryo hepatocytes” https://pubmed.ncbi.nlm.nih.gov/22366194/

Caloric intake

One of the ways to reduce fT3 is to reduce caloric intake.  This has been shown successful in many different species to extend lifespan.

“ENDOCRINE ALTERATIONS IN RESPONSE TO CALORIE RESTRICTION IN HUMANS” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3856718/

“Diversion of peripheral thyroxine metabolism from activating to inactivating pathways during complete fasting” https://pubmed.ncbi.nlm.nih.gov/1150863/

Caloric restriction definitely does its job by increasing SIRT1 activity and NAD availability.  This is not the case in all tissue according to this study.  They noted a lower ratio in the liver while the muscle and white adipose tissue both had increased ratios.

“Tissue-specific regulation of SIRT1 by calorie restriction” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2492662/

But is it achievable to subject ourselves to a lifelong caloric restriction?  It comes with a whole host of side effects such as fatigue, feeling cold, feeling hungry and if pushed too far then it is also detrimental for your psychological well being.

“Caloric Restriction in Humans: Impact on Physiological, Psychological, and Behavioral Outcomes” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3014770/

“Long-term calorie restriction, but not endurance exercise, lowers core body temperature in humans” https://pubmed.ncbi.nlm.nih.gov/21483032/

https://en.wikipedia.org/wiki/Minnesota_Starvation_Experiment#Results

In an 11-year study on rhesus monkeys they found that the resting energy expenditure was down for about 13%.  It did come with the desired effect of health and lifespan.

“Energy expenditure of rhesus monkeys subjected to 11 years of dietary restriction” https://pubmed.ncbi.nlm.nih.gov/12519821/

It could be manageable to live in a warm climate so the reduction in body temperature is less of an issue but still the lack of energy, possible mental impact and hunger feeling will remain a challenge.

Growth stimulating hormones

There are 2 other important hormones affected by caloric intake and those are insulin and IGF-1.

“Effects of insulin on cellular growth and proliferation” https://www.sciencedirect.com/science/article/abs/pii/0024320581904823

“Insulin-Like Growth Factor-1 Promotes G1/S Cell Cycle Progression through Bidirectional Regulation of Cyclins and Cyclin-Dependent Kinase Inhibitors via the Phosphatidylinositol 3-Kinase/Akt Pathway in Developing Rat Cerebral Cortex” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256126/

It is not a coincidence that food intake drives up metabolism via these hormones and T3.  When nutrients become available, it is an ideal moment to proliferate, to replace malfunctioning cells with new ones.  The cells that make up our body see this as a signal to grow.

Food

Carbohydrates and protein are responsible for insulin and IGF-1 stimulation for the biggest part.

Our current diet causes chronic inflammation which requires renewal of cells but also tends to build up insulin resistance over time.  The muscle and liver are the highest recipients of insulin-driven glucose uptake.  Over time they become resistant leading to prolonged elevated levels of insulin which affects all cells in the body.

Protein itself stimulates IGF-1.  Dietary protein delivers the cells the necessary building blocks to function.  The amino acids that make up the protein can even stimulate the thyroid to produce more fT3.

“Dietary protein-induced hepatic IGF-1 secretion mediated by PPARγ activation” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5336265/

“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” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988204/

“Effect of excitatory amino acids on serum TSH and thyroid hormone levels in freely moving rats” https://pubmed.ncbi.nlm.nih.gov/11251371/

It looks like we have no choice!  We can’t live without food and when we take in food we stimulate the growth mechanism.  Although it is correct that we can’t live without food, the composition of our food can be changed in such a way that we benefit the most from it in terms of health span.

Can we somehow reduce metabolism while remaining warm, energetic and mentally focused?

Climate

In order to keep warm, we can look at what animals do in colder more northern climates.

When we compare animal life in a warm climate versus a cold climate then we notice a change in survival strategy.  In cold climates, surviving the next day does not depend on food but on heat production and protection from cooling down and freezing to death.

The answer that nature has provided to us is fat.  By developing a subcutaneous layer we have created a bit of insulation.  But insulation is nothing if both sides of the layer are equal in temperature so we have our own heat production (thermogenesis) as a second important component.

That heat production is not a static element.  It can be intensified via cold exposure but also by consuming high amounts of fat.  The traditional Inuit diet consists of high amounts of fat.  One of the side effects of consuming a diet low on fat is that they feel colder due to it.

“We were really getting three-quarters of our calories from fat.” 

“The Inuit Paradox” https://www.discovermagazine.com/health/the-inuit-paradox

“When one eats seal, you are full all day. When you eat packaged foods, two hours later you get cold. If [you] eat Inuit food, you stay warm.”

“The Changing Landscape of Arctic Traditional Food” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2944111/

Given the above info regarding metabolism, having a higher production of heat thanks to consuming fat would give us a way around the colder body temperature that is normally part of a lower metabolism.  That is, if this fat consumption does not increase our cell metabolism.

Into a bit of science

Thermogenesis is currently being researched for longevity.  This is for other reasons though because the researchers suspect benefits from it by reducing diseases.  Although that by itself would also have the potential to help you to extend healthspan, which is certainly what we are after, it may not necessarily indicate an extension of lifespan.

One interesting bit from the article is the following:

thermogenic adipose tissue activation in response to cold exposure induces the release of eosinophil-activating cytokines by type 2 innate lymphoid cells.

Type 2 innate lymphoid cells (ILC2) will be present in the lungs to surveil potential viral infections.  When they pick up the relevant signal, they’ll stimulate mucus production and also increase other effects such as memory b-cell recruitment.

Stimulated by IL-33, these ILC2’s are also required to convert white adipose tissue into beige (due to the increase in mitochondria).

“IL-33-driven ILC2/eosinophil Axis in Fat Is Induced by Sympathetic Tone and Suppressed by Obesity” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5003423/

Already by keeping insulin low, studies in mice show that the WAT becomes more active and, depending on the location, starts to express more UCP1 for heat production.

“Adipose depot-specific upregulation of Ucp1 or mitochondrial oxidative complex proteins are early consequences of genetic insulin reduction in mice” https://journals.physiology.org/doi/abs/10.1152/ajpendo.00128.2020?journalCode=ajpendo

When we further investigate, we see that there is an increase in uptake of T4 into the brown and beige adipose tissue under stimulation of the sympathetic nervous system.  This T4 is locally converted into T3 to drive up the metabolism of the fat cell itself and thereby its heat production.

“A-FABP mediates adaptive thermogenesis by promoting intracellular activation of thyroid hormones in brown adipocytes” https://www.nature.com/articles/ncomms14147

This is very interesting as it gives us a clue on how this higher metabolism is achieved.  Not by stimulating metabolism overall in the body but very much focused in fat cells themselves.

I can only speculate about it but by taking up more T4, there is less conversion towards T3.  This could be counteracted by increased T4 production.  What it could mean is that at least we don’t have a systemic increase in metabolism in order to increase warmth production.

Interestingly all these effects also take place during cold exposure.

What does it all mean?

If longevity depends on reducing growth and health depends on the time spent in maintenance/repair then a very high fat diet could be a possible solution.  

I’ve only covered the metabolic part in this article but the consequences reach further than just metabolism.  By making the switch from primarily glucose to primarily ketones and fat we can modulate what happens inside our cells.

As indicated under the section “Cell Metabolism”, nuclear DNA repair is mediated by SIRT1.  Intrinsically linked, a very high fat diet raises SIRT1.  We can see this already in the brain of mice but there is other research indicating the same.

“Mechanism of Action of Ketogenic Diet Treatment: Impact of Decanoic Acid and Beta—Hydroxybutyrate on Sirtuins and Energy Metabolism in Hippocampal Murine Neurons” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468807/

“Ketogenic Diet Modulates NAD+-Dependent Enzymes and Reduces DNA Damage in Hippocampus” https://www.frontiersin.org/articles/10.3389/fncel.2018.00263/full

I’m saying intrinsically because a reliance on fat and higher dietary fat intake seems to signal to the overall organism that our body is that times are not right for reproduction, that we are living in a tougher climate so that time is better spent on repair and maintenance.

My speculation

Rather than mimicking starvation, to me the overall picture looks like a high fat diet is meant to sustain life through cold climates.  Fat is THE energy source in winter.  

  • The activation of the ILC2’s represent a higher surveillance against viral infections.  Respiratory infections is something we see typically return every winter.
  • Increased heat production is required to survive the cold through the night and through the day.  We don’t need this anymore today but it was necessary in our past.
  • Winter typically is harder to hunt and find food.  The extra fat mass in our body helps to endure sporadic tough days.
  • Sporadic because in our past there were large mammals available who delivered a big volume of fat.  Our food during winter likely was always high in fat availability.

Keep in mind though that a very high diet does mean consuming a lot of fat.  Not just avoiding carbohydrates.  Frequently people are afraid of calories and think they will gain from it.

If you keep carbohydrates out of your diet and keep protein intake to a minimum then you fill up the rest with fat to satiety.  If you don’t eat enough fat, you will feel cold.

Keep in mind the rhesus monkeys, they had a 13% lower metabolism.  Estimations of increased energy metabolism on a high fat diet are indicating +/- 12% extra metabolism on top of a normal diet.  

As a wild guess, we can compensate for the reduction in metabolism by letting thermogenesis cover an extra 29% of calories.

2000kcal – 13% = 1740kcal (on reduced metabolism)

2000kcal + 12% = 2240kcal (on a very high fat diet)

The experiment in mice showed a state that mimics caloric restriction yet showed an 11% increase in metabolism, primarily due to heat production.

“A high-fat, ketogenic diet induces a unique metabolic state in mice” https://journals.physiology.org/doi/full/10.1152/ajpendo.00717.2006

Studies have also been conducted in humans where a similar pattern of higher energy consumption is visible.

“Energy Requirement Is Higher During Weight-Loss Maintenance in Adults Consuming a Low- Compared with High-Carbohydrate Diet” https://pubmed.ncbi.nlm.nih.gov/32470981/

If you want to stay warm during winter.. don’t pass on the butter 😉

—- END —-

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