From nature to culture - loss of resilience

Our robust immune system
Modern humans live in an environment that is very far from the environment in which we have evolved. We came from nature and have evolved through millions of years based on natural challenges such as hypoxia, hypercapnia, extreme heat, cold, food shortages, absence of water, violence and infections. Such challenges represented true threats to our survival and humans have remained alive only because we successfully developed biological strategies to help us deal with hostile environments.
If we turn our attention to the immune system, then the adversities of our ancestors led to the development of a so-called robust innate immune system. Robustness in this context describes the fact that our innate immune system responds in the same manner regardless of the threat. Robustness was a natural consequence of the vast number of different environmental threats. If we summarise all the pathogens which are capable of killing humans for example, the estimated number is around 2000. It would have been impossible for our innate immune system to develop a specific strategy to deal with each of these pathogens and robustness was the logical consequence. The innate immune response is non-specific, fast, strong, short lived and effective protecting us against invaders and healing our wounds.

Today humans have moved from nature into culture with the invention of insulated houses, easy storage of food, instant access to water, central heating systems and air conditioning to keep us comfortable, and antibiotics to kill pathogens. The challenges of our ancestors belong firmly in the past. It means that the mechanisms we developed over thousands of generations to help us overcome a hostile environment have lost their original purpose and are now functioning in a world that is completely different to that in which they evolved. Our old genome does not understand overhydration, chronic food intake or prolonged sitting time and given we are designed to preserve energy, our metabolic health suffers. Add to this chronic psycho-social stress such as financial pressures, social media anxiety as well as new and chronic immune irritants including processed foods, air pollution, glyphosate, microplastics and other nano particles, chronic activation of our stress axes and immune system is imminent. The problem is that the immune system cannot metabolise or rid of these irritants and finalise the reaction, so it goes on and on.

Cytokine resistance

Chronic immune activation means chronic production of cytokines. Cytokines are immune signalling molecules, which direct the immune response from start to finish. Due to their size, cytokines cannot cross the lipid bilayer of cells to enter the cytoplasm and therefore typically exert their functions by interacting with specific cytokine receptors on the target cell surface. So, when people become chronically inflamed, we can conclude that something disturbed the natural way of resolving a challenge in time. Could it be that the constant activation of the immune system and therefore chronic production of cytokines lead to cytokine resistance, and might that be the mechanism and cause of all causes for chronic low-grade inflammatory illness?
It turns out that cytokines exert their action through the JAK/STAT/SOCS pathway. The downstream events differ but the signalling pathway is the same. It is outside the scope of this blog to go into the details of the JAK/STAT/SOCS pathway, so for now just note that it is a universal pathway used by cytokines to elicit a response. Why is this pathway so important? SOCS stands for ‘suppressor of cytokine signalling’. So, when cytokine stimulation reaches a certain threshold, SOCS is activated and turns down the cytokine signal. This means that if cytokine stimulation is chronic, SOCS activates, and we become cytokine resistant. If we are cytokine resistant, immune function is disrupted.

Not surprisingly perhaps, microbes such as Borrelia, EBV, CVM HPV, Clostridium, E Coli and SARS-COV-2 have long learned about the JAK/STAT/SOCS pathway and can directly activate SOCS. It means they can hide from the immune system and go on to produce chronic infections. There are numerous different cytokines with different functions so the implications of cytokine resistance can be vast and varied, but it always somewhat ends in chronic low-grade inflammation. But why low-grade? If so many factors can activate our immune system, why do we not get a strong response? To answer this let’s turn to leptin resistance.

The role of leptin resistance in low-grade chronic inflammation
Leptin is a hormone (and cytokine) produced by fat cells. The stomach is another often forgotten source of leptin production. Leptin is an energy signalling hormone – it tells the hypothalamus in the brain that there is enough energy in the body. When produced in association with a meal it signals that we can stop eating for a time, so it is also known as the satiety hormone. Overweight people have more fat tissue and therefore tend to produce higher amounts of leptin. However, modern humans in general it seems, produce more leptin than would be expected – also those that are not overweight. When we chronically produce higher levels of leptin, the JAK/STAT/SOCS pathway ultimately leads to leptin resistance. It is interesting to note that prolonged sitting time is a significant risk factor for leptin resistance and since many people spend their day in front of a computer it is not hard to understand why so many, overweight or not, become leptin resistant.
How is this relevant for chronic low-grade inflammation? Well, every time the immune system is activated it requests permission from the fat tissue or rather leptin to ensure that there is enough energy available to mount a strong inflammatory response. This is because an immune response is very energy expensive. Permission can only be granted if there is enough fat tissue (energy) and leptin reaches the hypothalamus, and importantly, the hypothalamus is sensitive to leptin signalling. If leptin is chronically high, the hypothalamus becomes leptin resistant, and the immune system will not get permission to mount a strong immune response. There may be sufficient energy but the signal to tell the immune system is absent. The result is a weak immune response or low-grade inflammation.
In summary, leptin guards energy availability in the body and is a so-called permissive granting hormone. Even exercising demands permission from leptin so if we are leptin resistant, we become lazy and we are back in the vicious circle of prolonged sitting time.

Those of you who are familiar with Dr Shoemaker’s illustration of the biotoxin pathway will know the widespread devastating effects of leptin resistance in the cohort of people suffering with biotoxin illness, especially the negative impact on MSH (melanocyte stimulating hormone) production and the significant disruptions in our physiology this brings.

Bringing back small dosages of ancestral challenges:

Cytokine resistance in general and especially leptin resistance is an important consideration in the chronically ill. Might it be that we need to bring back a little bit of nature into humans to recover cytokine sensitivity, making humans less fragile again? Research indicates that introducing small dosages of ancestral challenges thereby activating and resetting old pathways as per design can help to restore cytokine sensitivity. A little bit of heat, a little bit of cold, a little bit of thirst and in the case of leptin, a little bit of hunger and a little bit of exercise may just help restore human resilience again.

Testing for leptin resistance via Colab Services:
• LM4687 Inflammation Profile (MeGeMIT)
• Q190 CIRS Ultimate (Chronic Inflammatory Response Syndrome)
• DS820 CytoDX
• LM2275 CFS related Biomarkers
• LM6261 Immune Status (MeGeMIT)
• Biomarker – Leptin and insulin
• Leptin and insulin