A very compelling read from a New York Times op/ed, making the point that we have made previously on our blog:  today's chronic diseases have their origin in the evolutionary mismatch between our current environment and behaviors and what our bodies evolved to be.

In this article, we learn how evolution set out to protect us from starvation, infections and injuries leaving us vulnerable to atherosclerosis - the disease process underlying heart disease.

​https://www.nytimes.com/2019/08/06/opinion/evolution-heart-disease.html?action=click&module=Opinion&pgtype=Homepage

At Wellness Garage - we take a precision health approach to atherosclerosis prevention, treatment and reversal, by working with our members through a structured change process: Assess, Change Behaviors, Re-assess and Adjust. 
 
Learn more about what it looks like to do a Precision Health Tune Up and take control of your health.

This is the first of a two part series on atherosclerosis and will explain:

• What atherosclerosis actually is (and what it is not)
• Why it’s important, and
• What causes it

We will lay down a basic framework that will help you form a mental model so that next week we can cover what you need to know in order to prevent or reverse atherosclerosis.

What is atherosclerosis?
Atherosclerosis - commonly known as “ hardening of the arteries” refers to a disease process that causes damage to the arteries resulting in narrowing, blockage, occlusion and even rupture.
Atherosclerosis is the underlying cause of most cardiovascular disease (CVD) - including heart disease and stroke.

• Every 7 minutes a Canadian dies from heart disease or stroke
• Heart disease and stroke is the number one cause of death in Canada - accounting for 46% of all deaths; and also represent the single biggest cause of disability adjusted life years lost (DALY’s) - a measure of “lost healthy years”.
• 80% of premature heart disease and stroke can be prevented through healthy lifestyle choices
• Only 1 in 10 Canadians are in ideal heart health
• Over 90% of Canadians have at least one risk factor  

Atherosclerosis is both very common and very preventable.
Our view is that the key to prevention comes from really understanding how atherosclerosis develops.  This involves getting past some common misconceptions that have resulted from an oversimplification of the disease through the two dominant conceptual models used to explain atherosclerosis:

1. Clogged pipes (arteries) are the problem; and
2. Fat Clogs Arteries

The issue with each of these models is that they overlook some key facts and observations:

• Most cardiac events occur where there is minimal or moderate narrowing
• The cholesterol (fat) found in atherosclerotic lesions is not from the diet but produced by the liver.
• Most cardiac events occur in people with normal cholesterol levels

Before we go further here - let's back up and better understand the disease process:

• Low Density Lipoproteins (LDL) particles (the dominant transport vehicle for liver-produced cholesterol) enter the lining of the arteries - the subendothelial space.  
• Here LDL particles attach to proteoglycans molecules expressed in the lining of the artery.
• Once attached, the LDL particles, specifically, the phospholipds within, are prone to oxidation by reactive oxygen species.

At this stage - 3 things have happened:

1. LDL particles get in the lining of the arteries,
2. They get stuck and
3. They get oxidized.  

Oxidized LDL is toxic to the endothelial cells lining the arteries and this is the key step in the development of atherosclerosis.

• Endothelial cells, injured by oxidized LDL, now express molecules on their surface to mark their injury and trigger an immune response
• These molecules, vascular cell adhesion molecules, VCAM’s, attract monocytes, a type of white blood cell
• The now dysfunctional endothelial cells, also send out molecular messenger signals such as IL-6 and TNF-alpha which trigger liver cells to increase production of the inflammatory molecule C-reactive protein.
• The monocytes that attach to the endothelium, enter the subendothelial space, the intima and differentiate in macrophages - a specialized immune cell designed to inges toxic substances
• In this case the macrophages essentially eat up the oxidized LDL particles, and as these cells become full, stuffed with cholesterol, they are aptly named “foam cells”
• Multiple foam cells coalesce together to form a “fatty streak” in the artery wall - this is the hallmark of early atherosclerosis

Fatty streaks are almost ubiquitous and have even been found in utero!  This is the very earliest stage of atherosclerosis and almost all of us have disease at this stage.

• High Density Lipoprotein (HDL) - another lipid transport molecule - can enter the subendothelial space and take cholesterol from the foam cells, and subsequently distribute the cholesterol to other tissues in the body.
• Foam cells that do not get relieved of the cholesterol burden - produce a variety of molecules including angiotensin II, metalloproteinases, collagenases, elastases, and other proteins - all of which can further undermine the integrity and function of the endothelium
• At this point, the damage really begins.  The endothelial damage signals smooth muscle cells to the damaged area where they secrete a matrix to heal the arterial wall.  This matrix forms a fibrous cap that now can intrude into the lumen of the artery.

The atherosclerotic plaque, so formed, can become very large and can impede arterial blood flow to the extent in the heart that the muscle the artery serves can become starved of oxygen.  This narrowing and decreased blood flow, results in the the exertional chest discomfort known as angina.

• The metalloproteinases and collagenases produced by foam cells can also weaken the fibrous cap resulting in rupture of the plaque
• Rupture triggers a coagulation response - initially platelets accumulate, then fibrin forms, and clot can form.
• This process can occur rapidly and result in complete occlusion of the artery - even when the initial lesion did not produce significant narrowing - this occlusion occurring in a coronary artery is known as a myocardial infarction (MI) or more commonly referred to as a heart attack.

To summarize, atherosclerosis is caused by an inflammatory response to oxidized lipoproteins within the artery wall.  There are three main ingredients that trigger a lesion:

1. ApoB containing lipoprotein (mostly LDL) particles accumulating under the endothelial lining of arteries
2. Oxidation of the sub-endothelial LDL-particles, causes inflammation resulting in
3. Dysfunctional endothelial cells that trigger further immune response.

The developing process can be mitigated in its earliest phases by HDL-particles that take away the sub-endothelial cholesterol - even after it is taken up by the foam cells.

Evidence shows that the risk of atherosclerosis increases with increasing concentrations of LDL-particles in linear fashion - note this LDL-particle numbers, not LDL-cholesterol concentration. (while LDL-C and LDL-p are generally concordant, ie. they increase and decrease together, this is not always true - especially when insulin resistance is present).  LDL-cholesterol is what is commonly reported on the standard lipid panel.  A better test to understand your risk is the ApoB100 protein- which gives you the number of LDL-particles as each LDL-particle has one ApoB100

It must be stressed that LDL-P easily enter and exit the sub-endothelial space all the time - it is the oxidation of LDL-P that is key step in initiating atherosclerosis.  Only oxidized LDP-P is taken up by macrophages and foam cells.

What triggers the oxidation of the LDP-P?

Damaged, inflamed or dysfunctional endothelial cells create the conditions for LDL-P oxidation.
Common causes of endothelial dysfunction are:

• tobacco use,
• obesity,
• age,
• hypertension,
• hyperlipidemia,
• physical inactivity, and
• poor dietary habits or anything that results in low-grade chronic inflammation

Another key point is that the process that leads to an atherosclerotic lesion is systemic - so just identifying and treating lesions that cause blockage (ie. plumbing model) does not sufficiently decrease risk as there may be other non-obstructive lesions that can rupture and cause acute occlusion.

So in essence, with atherosclerosis we have a reinforcing cycle of:

• Endothelial dysfunction leading to the
• Oxidation and retention of lipoproteins in the subendothelial space leading to
• Inflammation that results in further
• Endothelial dysfunction

The take-home points to remember are:

• atherosclerosis is the number cause of death in Canada
• 80% of premature deaths from atherosclerosis are preventable
• the disease process is systemic and the conditions that lead to atherosclerosis affect all arteries
• because it is systemic - a systemic approach to prevention, treatment, and reversal of atherosclerosis is required
• atherosclerosis takes a long time to become symptomatic and most heart attacks occur in people who have had no prior symptoms
• atherosclerosis is caused by a combination of endothelial dysfunction that allows for the oxidation of LDL cholesterol in the lining of the artery, resulting in an inflammatory response that triggers further endothelial dysfunction.
• understanding an individual's
  • lipoprotein status
  • inflammation levels
  • endothelial function
• are essential in order to develop a coherent reduction strategy.

Next week - we will apply this framework to explain the Wellness Garage prevention and risk reduction strategy for atherosclerosis.

At Wellness Garage - we can help you understand and take control of your health.  Our comprehensive medical, fitness, nutritional and behavioral assessments give you baseline from which to measure your progress.  Our coaching helps you improve your behaviors, one habit at a time.

For more information - please book a free consultation.

Humans need to eat.  Cells throughout the body are predominantly fueled by glucose delivered through the blood.

In evolutionary times food was not predictable, most often scarce, sometimes abundant. To maintain a consistent energy supply of blood glucose, evolution created a complex signaling system to control the process, delivering glucose when it is needed and efficiently storing it, when calories are abundant, ready to be mobilized in times of scarcity.  Two hormones are central to this signaling process: insulin and glucagon.  When blood sugar drops, pancreatic alpha cells release glucagon which then triggers the release of glucose from the liver.  Correspondingly, when blood sugars rise, pancreatic beta cells release insulin which promotes glucose uptake in the  liver and muscle, storing it as glycogen initially and then when glycogen stores are maximized, insulin prompts the conversion of carbohydrates and proteins to fat, our most efficient way to store calories for the future.  Both insulin and glucagon are small proteins recognized by specific receptors on individual cells.

This process, developed over 600M years of evolution, now is under challenge in humans.  The conditions for which we are optimized: calorie scarcity with intermittent abundance, no longer exist.  Instead we live in a world of continuous excess calories, with processed foods that rapidly spike blood sugars and trigger massive insulin release, and correspondingly massive insulin directed storage of excess calories as fat in adipose tissue.

For many this process has become a one-way street, the flexibility to shift metabolically from glucose to fat as fuel that was once the key to our survival has, for many people, been lost.  They are dependent on maintaining blood sugars through the constant consumption of carbohydrates. - if you find yourself craving sweats, getting tired after eating and feeling generally fatigued - this could be happening to you.

As a result of excess calories, sedentary lifestyles and this loss of metabolic flexibility, global levels of obesity are soaring:  2 Billion people are overweight - 650M are obese.  In Canada close to 50% of the population is overweight!.  With obesity has come a corresponding epidemic of obesity related diseases:

• Metabolic syndrome - 1 in 5 Canadians have metabolic syndrome - many are unaware
• Type II diabetes - by 2020 it is estimated that 10% of Canadians will be diabetic - with almost 1/3 unaware
• Atherosclerotic heart disease - 29% of Canadians die from heart disease
• Non-alcoholic fatty liver disease (NAFLD) - 75% of people who are obese are at risk for NAFLD

The process underlying this epidemic of epidemics is insulin resistance.

The cellular mechanisms by which insulin resistance manifests are complex and beyond the scope of this blog, but at a high level, dysfunctions in three areas appear to alone, or in combination affect the ability of insulin to efficiently activate the insulin receptor and trigger the cascade of reactions that allows insulin to do it's job:

1. ectopic lipid accumulation - lipids build up within the cells and in turn adversely affecting the insulin signaling pathways
2. unfolded protein response and endoplasmic reticulum stress - the endoplasmic reticulum is the organelle where complex proteins - including cell membrane receptors - are folded to gain their functional state.  A build up of mis-shaped proteins triggers the unfolded protein response that in turn leads to intracellular lipid accumulation, inflammation and in pancreatic beta cells affects insulin biosynthesis and can eventually lead to the cellular death of the beta cells - a key step in the progression of Type II Diabetes.
3. inflammatory response - activation of the inflammatory systems - starting with activated macrophages in adipose cells over-run with fat, results in a cascaded release of multiple inflammation signals - molecules called cytokines.  These inflammatory signals themselves disrupt the normal action of insulin and lead to disruption of normal metabolic processes.

The process by which insulin resistance progresses to pre-diabetes and diabetes is understandable and predictable - it is also very preventable.

As insulin resistance sets in, muscle, fat, and liver cells do not respond properly to insulin and thus cannot easily absorb glucose from the bloodstream. As a result, the body needs higher levels of insulin to help glucose enter cells.

The beta cells in the pancreas try to keep up with this increased demand for insulin by producing more. As long as the beta cells are able to produce enough insulin to overcome the insulin resistance, blood glucose levels stay in the normal range.

Over time, the processes that led to insulin resistance in the first place cause pancreatic beta cells to become less efficient and eventually triggers beta cell death.  As this begins to happen, blood sugars fall out of the normal range and people begin to be diagnosed with pre-diabetes or diabetes on the basis of abnormal blood sugars.

The time that it takes to progress from insulin resistance to pre-diabetes is generally in the order of 10-15 years - during this whole time a person will have normal blood sugars and may feel reassured that they do not have diabetes - YET - they are manifesting the underlying process of insulin resistance that will lead to diabetes and it's complications.  

So the big question that you should be asking is - how do I know whether I have insulin resistance?
Direct testing of insulin response is not broadly available, so we are most often left looking for other signs of insulin resistance.
For the most part, we can work with this:

• the TG/HDL ratio from a standard lipid panel correlates with insulin resistance - levels above 3.0 indicate a clear metabolic disruption.
• advanced metabolomic testing from Molecular You will also provide clues that insulin resistance is present (elevations in branched-chain amino acids for example)
• the accumulation of visceral fat (measured by DXA or by tape-measure) is also highly correlated with insulin resistance.
• hsCRP will give us a good measure of underlying inflammation which generally accompanies insulin resistance to some extent.
• and of course we can check blood sugars and HbA1c (the 120 average of blood sugars) but these will be normal until insulin resistance becomes pre-diabetes.

My blood sugars are normal, but I think I have insulin resistance, what do I do
The good news is the process that leads to diabetes is reversible through lifestyle changes:

• Food first - the absolute first step is to correct the patterns of eating that have led to insulin resistance.   Eliminating refined carbohydrates, eating a variety of whole foods, shifting to a mostly plant-based diet are all solid strategies.  More aggressive therapeutic nutrition strategies like a ketogenic diet have been shown to be very successful but definitely warrant medical direction and monitoring (especially if you are diabetic on medications).
• Activity - nothing crazy here - but building up your aerobic base will help restore a degree of metabolic flexibility as your body learns to burn fat while you exercise.  Weight lifting dramatically improves metabolic health by improving mitochondrial function.
• Sleep - undiagnosed sleep issues like sleep apnea can lead to obesity and insulin resistance.  If you snore or your spouse notices that you stop breathing in your sleep, you should get yourself screened for sleep apnea.  It is relatively straightforward and it is free.  Wellness Garage works with Clinical Sleep Solutions.

One of the major reasons we started Wellness Garage was to help people intervene early in preventable disease processes like insulin resistance  rather than wait until blood sugars become abnormal (after 10-15 years!) and prescribe medications.

If you think that you could be affected by insulin resistance - please reach out to us and book a free consultation, we can help you come up with a plan to address your health needs.

Reason #3 - DXA provides hard-to-get-otherwise information
Maintaining lean muscle mass, along with strength and bone density are strongly positive indicators for longevity - or said another way:  loss of muscle mass and bone density are associated with premature death.

Here the challenge for the clinician is greater than with abdominal obesity.  Often there is simply no way to know a patients lean muscle mass and bone density without DXA measurement.

Reason #4 - this is the best part
So we now know that DXA gives us some really good information, but the best part is that all of the important markers for vital longevity it tracks

1. Body Fat
2. Abdominal or Visceral Fat
3. Lean Muscle Mass
4. Bone Density

All of these, are highly modifiable by lifestyle intervention.  In fact one of the most satisfying  aspects of using DXA scans in Lifestyle Medicine is showing patients their early progress, 3-4 months in when the scale has hardly budged.  All too often, we see patients with total weight loss of <5 lbs. who come in frustrated and feeling defeated only to learn that their DXA shows a significant body recomposition (Net loss 5 lbs: lean muscle gain: 5 lbs and bone mass gain: 1 lb; Fat loss: 11lbs).   What is most interesting is the tyranny of the weight scale - these same patients know that their clothes fit differently that they have decreased sizes, yet the absolute number on the scale is what often bothers them the most.  For these people having the DXA results is a major reinforcement of the power of their lifestyle changes. 
​
Reason #5 - DXA scans are very safe and can be repeated multiple times in a year.
But don’t they use x-ray radiation?

• True, but the radiation received by the patient during the scan is less than that of an airline flight from Victoria to Montreal and back. (Reference)

Reason #6 - DXA scans are relatively inexpensive 
DXA for total body composition is not an insured service, so cost will be an issue for some.
However, given the nature of the test and the data they produce for many DXA's are a cost effective investment in their health. ($120 for the first test; $100 for follow-up scans.)

In summary - 6 Reasons Why DXA Scans are so useful 

1. weight and BMI are misleading - they don't tell the whole story
2. understanding to the degree which you have abdominal obesity is vital for metabolic health
3. DXA measures lean muscle mass and bone density which are important for vital longevity and really hard to estimate clinically
4. all the key metrics from the DXA are modifiable by lifestyle intervention
5. the test is very safe
6. the test are relatively inexpensive

At Wellness Garage, we are proud to announce that Bodycomp Imaging is locating a DXA scan within our facility that will be available for our clients as part of our assessments.
We are very excited to see this technology come to the South Surrey/White Rock area.   Clients are free to book with Wellness Garage or Bodycomp at their convenience.

* Wellness Garage and Bodycomp are independent businesses - and Wellness Garage derives no profit from DXA scans done at our facility.  

 Today I am going to provide a list of 7 biomarkers for you health - numbers you should know.   These are all biomarkers that can be improved through lifestyle interventions - they are numbers that can be normalized and optimized - and in doing so you will reduce your risk for heart disease, diabetes, cancer, Alzeimher's dementia, kidney failure, arthritis and many other conditions.  Optimizing these biomarkers will even decrease your risk of premature death.  I think this should be a pretty good investment of 15 minutes of reading!  (If you want to skip the reading - there is a quick summary at the end of this post).

2. Gamma Glutamyl Transferase (GGT) - optimal < 30 U/L
GGT measures a liver enzyme and is commonly described as liver function test most closely associated with the adverse effect of alcohol. GGT is however much more important as it is an indirect measure of the body’s glutathione supply. Glutathione protect cells against the oxidative stress resulting from metabolism. Without this protection the free radicals generated by mitochondria through normal metabolism with oxygen would accumulate, overwhelm and damage the mitochondria and the cell. In normal ageing it has been shown that it is this accumulation of oxidative stress that leads to many of the age-related diseases.
In many ways, glutathione is consider the master antioxidant: working with as part of the enzyme glutathione peroxidase to protect membranes from oxidation, enabling Vitamin E and C in their anti-oxidant capacities as well as working directly.
Glutathione is also a key component of the Phase II metabolism (detoxification) of drugs, hormones and xenobiotics where it works as a component of an enzyme Glutathione s-transferase (GST) that conjugates heavy metals, toxins and other compounds so that they become water soluble and can be excreted in the bile or urine.
Exposure to high levels of toxins that overwhelm glutathione in its Phase II metabolic role will lead to oxidative stress.

3. hsCRP - high sensitivity CRP - optimal < 1.0
Again another topic I have recently blogged about: chronic inflammation.
Chronic inflammation is at the root of 7 of the top 10 causes of death accounting for 80% of all deaths in our society. The most insidious aspect of this type of inflammation is its silent nature that allows for damage to occur without diagnosis.

HsCRP is the gold standard for assessing chronic inflammation - optimizing this number through behavioural change - diet, exercise, stress reduction - decreases the risk for many diseases.

4. Blood Pressure - optimal <115/75 (systolic/diastolic pressures measured in mmHB)
This is the simplest - something that you can do at home, at the local pharmacy and with your doctor. Normal blood pressure is 120/80. Recently there were major headlines in the US, noting a change in the definition of high blood pressure (hypertension), lowering the definition threshold to 130/80 from 140/90. While this change dramatically increases the number of people who will be diagnosed with hypertension - not all will automatically be recommended medications. Those recommendations will depend on a person’s overall risk for cardiovascular disease - anyone with a 10% or greater risk should aim to bring the BP below 130/80.

High blood pressure or hypertension is quantitatively the most important modifiable risk factor for cardiovascular disease (the largest contributor to premature death in our society).

It is also a significant risk factor for both kidney and heart failure.

For every 20 mmHg increase in diastolic blood pressure above 75, the risk of death from heart disease or stroke doubles.

Elevations in blood pressure are caused by dysfunctions within core biological systems

• renin-angiotensin system.
• sympathetic nervous system
• blood vessel constriction and hardening
• kidney fluid and salt balance

Caused by poor behaviours:

• not enough exercise
• excess alcohol
• high dietary sodium
• stress
• Obesity

With genetics alone, accounting for only 2-3% of causes of hypertension

5. Fasting Blood Glucose and or HbA1c: optimal FBS <5.2mmol/L (normal <5.6 mmol/L); optimal HbA1c <5.0%
Maintaining normal blood sugars is one of the most important and tightly regulated functions in your body.

Diabetes mellitus (DM) is the condition when your body cannot maintain normal blood glucose levels. Type I DM is an autoimmune disease where the pancreas stops producing insulin. Type II DM, is characterized by insulin resistance, where the body no longer responds normally to insulin. In order to maintain blood sugars, the pancreas increases production of insulin - leading to elevated insulin levels which in turn trigger inflammatory changes, which in a vicious cycle further worsens insulin resistance. Insulin resistance precedes Type II Diabetes and can remain undetected for years, as glucose levels are maintain as normal until the pancreas begins to fail, which is relatively late in the process.

Diabetes is diagnosed when FBS >7.0 or HbA1c >6.5%

Type II DM is currently at epidemic levels globally having tripled since 2000. Almost 500M people or 1 in 11 have diabetes at an estimated cost of $850M.

The direct complications from diabetes come from damage to blood vessels at two levels:

1. Microvascular
   • Retinal damage (retinopathy) leading to blindness
   • Kidney damage (nephropathy) leading to kidney failure
   • Nerve damage (neuropathy) leading to limb amputation
2. Macrovascular - or cardiovascular disease - resulting in heart disease and stroke.

6. TG/HDL - Triglyceride/HDL ratio - optimal <1.0
Of all the information that can be derived from a lipid panel the TG/HDL ratio provides the best information about risk.

TG/HDL is an excellent marker for insulin resistance and metabolic syndrome

When elevated above 3.5 - this is the simplest test to identify atherogenic dyslipidemia, which is marked by the joint occurrence of elevated TG, low HDL and atherogenic, small, dense, LDL particles. This is highly predictive of cardiovascular disease.

As we have seen above insulin resistance is the precursor to Type II DM and is often silent and undiagnosed, and is also one of the major causes of chronic inflammation.

7. Android:Gynecoid Fat Ratio - optimal <1.0
The major cause of the global diabetes epidemic is the associated obesity epidemic. Over
2B people are overweight with about 600M reaching the definition of obese (BMI >30).

For obese people cardiovascular disease is the leading cause of death and disability, followed by diabetes. Kidney failure and cancer are the other major causes of death.
Obesity, through adipocyte dysfunction leads to a chronic inflammatory state that
predisposes an individual for many diseases. Abdominal or visceral fat contributes
disproportionately to this inflammatory response as compared to peripheral fat.

The best way to measure visceral fat is with a DXA body scan, which provides you with
android:gynecoid fat ratio. The ratio correlates with insulin resistance, showing the clear
link between visceral fat and the pathogenesis of diabetes.

The added benefit of getting a DXA scan is getting understanding your lean muscle mass and bone density. As you age maintaining lean body mass and bone density are both essential for vital longevity avoiding age-related sarcopenia and osteoporosis.

A good alternative (without the extra bone and lean body information) is a waist:hip ratio. The optimal ratio for men in <0.85 and women <0.75.

Abdominal obesity is also a marker for metabolic syndrome - a cluster of conditions that carry risk individually but are collectively carry massive risk:

1. Abdominal obesity
2. High triglycerides
3. Low HDL
4. High Blood Pressure
5. High Fasting Blood sugar​

As you can see, all of the risks for metabolic syndrome have been covered by our 7 numbers.

According to a recent study - almost 1 in 5 Canadians, including 40% of people over 65 have metabolic syndrome .  Unfortunately, many are unaware of it and have placed themselves at massively increased risk for diabetes, heart disease and premature death.

In Summary - 7 Numbers You Should Know

1. ​Vitamin D - optimal level 100 - 150 nmol/L (40-60 ng/ml) ​
2. Gamma Glutamyl Transferase (GGT) - optimal < 30 U/L 
3. ​hsCRP - high sensitivity CRP - optimal < 1.0  
4. Blood Pressure - optimal <115/75 ​
5. ​Fasting Blood Glucose and or HbA1c: optimal FBS <5.2mmol/L (normal <5.6 mmol/L); optimal HbA1c <5.0%
6. ​TG/HDL - Triglyceride/HDL ratio - optimal <1.0
7. Android:Gynecoid Fat Ratio - optimal <1.0

​You can learn your numbers by visiting your family doctor or by contacting us at Wellness Garage.  All of these biomarkers can be normalized or optimized through lifestyle interventions - improvements in diet, exercise, sleep, stress, relationships and purpose.

It is chronic inflammation that represents perhaps the biggest threat to our health and through the epidemic of chronic disease affects the sustainability of our health care systems.

So where does chronic inflammation come from?

1. The Gut:  Harmful products from the microbes in our guts (or mouth) that leak into surrounding tissues, enter circulation and generate an inflammatory response.
2. Mitochondrial Dysfunction - Oxidative Stress:  Mitochondria (the cellular power-houses) create free radicals during the process of oxidation.  When mitochondria become dysfunctional (often as a result of ageing and inflammation), free radicals accumulate and damage DNA, organelles and other cellular components, as well as macromolecules and lipids that become peroxided.  All of this damage elicits inflammatory responses.
3. Metabolic Dysfunction - Insulin Resistance - Diabetes:  Caused by excess nutrients and sedentary lifestyle; metabolic dysfunction results in an accumulation of metabolites that will trigger inflammation. i The list of metabolites that can cause this is extensive and includes extracellular ATP, fatty acids, uric acid, ceramides, cardiolipin, amyloid, succinate, and of course glucose.  Elevated glucose levels in diabetes create advanced glycation products - these inflammatory compounds are a result of sugars sticking to proteins  making them dysfunctional.
4. Self-debris: Damaged cells and macromolecules:  Cells are constantly being damaged and repaired in the normal course of life.  When the damage cannot, or is not repaired self debris byproducts elicit inflammation.
5. Old or Worn-out Cells: Cellular Senescence:  when cells accumulate too much damage they lose function and begin to secrete pro-inflammatory cytokines (messenger compounds) that damage other cells (both locally and at a distance as the cytokines enter circulation).  For chronic disease the most significant source of senescent cells (and their pro-inflammatory byproducts) are the overloaded fat cells found in the visceral fat of obese or people with metabolic dysfunction.
6. Ageing - “Inflammaging":  Senescent cells accumulate with age.  Both the immune and coagulation systems overlap with the inflammation pathways.  Age-related changes in these systems elicits inflammation.

The large variety of stimuli that fuel inflammation converge on a few basic mechanisms and pathways within cells - specifically the activation of the transcription factors NF-κB and Nlrp3 inflammasome which activate gene transcription and the production of inflammatory molecules called cytokines that interact with other cells to elicit a cascading response.

This response leads to increased plasma levels of pro-inflammatory cytokines (Interleukin-6, IL-6, Interleukin-1, IL-1 and Tumour Necrosis Factor-α, TNF-α) as well as increases in the main inflammatory biomarkers such as C-Reactive protein (CRP) and serum amyloid A.

This generalized pro-inflammatory state, interacts with genetic and environmental factors to potentially trigger the onset of inflammation-related diseases:

• atherosclerosis
• metabolic syndrome
• type 2 diabetes
• cancer
• neurodegeneration
• arthritis
• osteoporosis
• sarcopenia and frailty 
• depression
• autoimmune diseases
• allergies

Given the multitude of triggers and profound potential consequences that chronic inflammation has, the logical question (if you have read this far) is:

Am I inflamed?

The standard test for this in the clinic is the high sensitivity C-reactive protein (hsCRP) - anything greater than 1.0 nmol/L suggests a low-grade inflammatory process, with levels greater than 3.0 nmol/L associated with elevated risk for heart disease (atherosclerosis).  Levels greater than 10 nmol/L suggest an acute inflammatory response (infection).

What is an optimal strategy to avoid inflammation?

1.  Maintain optimal gut microbiota health and prevent leakage of gut microbes into the body

• “weed” - this starts with food - eliminate inflammatory foods starting with refined sugars and industrial vegetable oils.  If you have celiac disease or you are gluten sensitive, avoid wheat and gluten.  For many, dairy creates gut issues (generally with symptoms).  Improving your diet will help “weed” out the bad bacteria and allow the body to heal.  (Special consideration can be given to supplements, such as glutamine - but do this after fixing your diet).
• “seed” - try fermented foods - yoghurt, kefir, kombucha, sauerkraut, kimchi, natto, tempeh, miso, and organic pickles.  Fermented foods contain probiotic bacteria that can help “seed” or stimulate good bacteria.  If you cannot tolerate any of these foods - consider a supplement, the challenge is picking the right one.  There are many, many probiotic supplements in the market - most are unlikely to help,because they do not have enough active bacteria.  Select one with at least 50B colony forming units AND that needs to be refrigerated to survive.  If you are having gut issues - you may have to try a few.
• “feed” - increase dietary fibre - non-digestible dietary fibre feeds good bacteria in your GI tract. Garlic, artichokes, leeks, onions all contain excellent sources of the right kind of fibre to improve gut health and decrease inflammation coming from your gut. Prebiotic supplements with inulin can work as well.  
  

​The order here is really important - you do not want to start by feeding your current microbiome without first being sure that you are eating the right foods to encourage the growth of good bacteria and limit the growth of the bad.

If you are having symptoms or have concerns about intestinal permeability - there are tests that we can do to determine whether leakage of microbes from your gut is contributing to your inflammation.

Finally, if you are really interested you can check your microbiome and assess it's overall health - two caveats here: 1) there is huge variability between tests - these tests are really just snap-shots; and 2) there really is very limited data from these tests to direct you to a more specific response then I have outlined.

2.  Minimize cellular damage from oxidative stress

• This is where exercise is so powerful - regular aerobic exercise decreases overall oxidative stress by improving mitochondrial function; resistance exercise (especially in the large muscles of the legs and back) increases mitochondrial density.
• Eating foods with high levels of anti-oxidants - I will blog more on this later - but the point I will make here is to get your antioxidants from food (as much as possible).  The literature on supplements with specific anti-oxidants show potential harm (Vitamin E, beta-carotene) and reflect the fact that some oxidative stress is healthy and triggers cellular clean up (autophagy and apoptosis) and eliminating this signal with high doses of supplemented anti-oxidant may be deleterious.  Just another reason why the food first paradigm makes so much sense.
  

3.  Repair and regenerate damaged cells - autophagy, apoptosis

• this is where the power of intermittent fasting (IR) and time-restricted eating (TRE) comes into play.  The body is really designed for stress and recovery - we are built with a natural diurnal rhythm of stress and recovery follow light and dark cycles; pairing this with an eating strategy that provides nutrients  following exercise and withholds nutrients so that we can signal our cells to clean up the cellular debris makes the most sense.
• In addition, or really prior to, implementing IR and TRE - eliminating refined carbs, industrial farmed animals, and highly processed vegetable oils decreases the damage in the first place.
• As sleep is a major contributor to repair and regeneration - making sure that you are getting adequate sleep is vital.
• There are some supplements (and medications) which stimulate this pathway (increased AMPK, suppressed mTOR) that I am sure I will blog about in the future.
  

4.  Minimize the deleterious effects of high blood sugars and/or high insulin
Our society is in the midst of a diabetes epidemic - it is estimated that between 50-70% of the population has been diagnosed with diabetes, elevated blood sugars (pre-diabetes) or elevated insulin levels (insulin resistance - the precursor to diabetes).  While there are clear genetic risk factors, the overwhelming evidence points to lifestyle:  poor diet - excessive nutrients of poor quality - high carbohydrate, high fat, combined with physical inactivity leads to elevated insulin levels which initially maintain blood sugar levels at the expense of increasing the storage of calories in fat.  This increased fat storage leads to obesity with overloaded fat cells becoming dysfunctional and senescent and secrete pro-inflammatory cytokines which in turn cause insulin resistance - creating a vicious cycle.  The inflammation eventually affects the pancreatic beta cells, decreasing their ability to secrete enough insulin to maintain blood sugars and a person is diagnosed as diabetic.

The frightening part of this scenario is that it often takes 10-20 years to go from insulin resistance to diabetes - during that time levels of chronic inflammation increase as do the associated risks.

For diabetes and insulin treatment and prevention the place to start is with diet as it is the most likely culprit. A whole food, low carbohydrate, healthy fat approach is the way to go.

For diabetics on medication - ketogenic diets have an excellent track record as a therapeutic intervention to decrease or eliminate medications.


As you can see from these strategies to avoid inflammation, the answer lies in your behaviours - especially eating, exercising, sleep and stress.  Your optimal strategy will come from assessing and understanding your current situation and addressing your behaviours in a systematic fashion.

If you are overweight (or simply over 40) you should, at a minimum, know your hsCRP, fasting blood sugar, HbA1c (3 month average of blood sugars), HDL cholesterol, LDL cholesterol, triglycerides and GGT (liver enzyme that also is a key marker of oxidative stress), as well as your waist to hip ratio.  These are tests that every family doctor can (or probably has already) done for you - the important thing is for you to know.  If any of these tests are abnormal (or not optimal), you should develop your own strategy to getting well.  If these tests are normal, you should still review your core behaviours and assess what can still be improved.

At Wellness Garage, we deliver comprehensive lifestyle medicine assessments reviewing all of this data, along with other optional tests that are not routinely offered in the publicly funded system: molecular data (genomics, metabolomics, proteomics, microbiome, and other advanced diagnostic tests), DXA scans (to assess body composition).  We use all of this data to help you build the optimal strategy for your own personal wellness.  We then can match you to a personal coach to help you implement the behavioural changes necessary.