Cardio-Vascular Disease: Cause & Prevention

Click here for Time lapse over 30 mins of macrophage swallowing other cells

Macrophage cells with yellow lipid droplets: the specialist scavenger of the immune system

(click here for video of macrophage devouring dying immune cells)

Mindboggling but almost totally overlooked by health care professionals is the fact that every second almost 4 million of our own worn-out cells are consumed by scavenging cells of our immune system. The process is called efferocytosis and the immune cells that do most efferocytosis (aka phagocytosis) are macrophages and they are vital to maintain normal function of all body systems. Cells of the macrophage lineage are present in every tissue, amount for around 15% of body mass, and at 10kg would be one of the largest organs in the body, responsible for recycling around 800g of dead/expired cells every day. Most of the material that phagocytes ingest can be recycled except for cholesterol (cholesterol makes up 3.5% of wet cell mass where 70% is water). Cholesterol deposits accumulate wherever more cells die than can be recycled and most cholesterol deposited in arteries comes from dying cells, including macrophages, than from cholesterol (LDL particles) in the blood stream. The important point here is that cholesterol from LDL particles is not deposited directly in arterial walls, it is first taken up by macrophages and poorly functioning macrophages (foam cells) die and leave behind cholesterol residues.

The root cause of arterial sclerosis (artery narrowings)

Our number one killer, heart attack is caused by buildup of dead and dying cells in the walls of arteries, so called "foam cells". All 60 trillion blood vessel lining cells (aka endothelial cells, ECs) are replaced within 3 years. But cells in some places in our arteries have a much shorter life such as low flow areas, exactly where blockages grow. Cell turnover can be around 1% per day and massively increased with hypertension and aging. These disturbed flow areas are littered with dying cells where other areas in arteries with normal flow have absolutely none. Dying ECs migrate into the vessel walls and are swallowed up by macrophages. Macrophages must clear thousands of dying cells per minute to prevent the blockages that cause heart attacks. Around 3.5% of a cell is cholesterol and cannot be broken down by macrophages, instead excess cholesterol must be transferred to carrier particles in the blood stream, the so called “good” cholesterol, high density (HDL), that is eventually taken up by liver cells that recycle or excrete cholesterol into the gut as bile salts. HDL protein (apoA) is made by macrophages along with much of the HDL in the circulation. The ability of macrophages to efficiently clear dead cells is the key to prevention of not only heart attacks but inflammation in other locations where high cell turnover is involved such as arthritis, inflammatory bowel disease, neurodegeneration, and auto-immune diseases. Therefore the question "do macrophages die from too much circulating LDL cholesterol or defective processing of hundreds of thousands of dead cells per day?" must be answered.

Can we Improve Scavenging Function of Immune Cells?

Macrophage function is key to all sorts of diseases associated with inflammation. The process is complex involving “find me” and “eat me” signaling from dying cells to the phagocytes. Once ingested the dead cell must be digested and excess cholesterol offloaded to allow a phagocyte to quickly move on to engulf another dying cell. This metabolic function of phagocytes is highly variable and regulated by many lifestyle factors

Fasting Enhances Autophagy to Improve Macrophage Function

Autophagy accomplishes multiple vital life functions and during periods of fasting autophagy is increased to recycle redundant protein, mobilizing glucose from glycogen stores and free fatty acids from lipid droplets in fat cells. Autophagy is essential for immune cells to digest and recycle 4 billion human cells per second. Autophagy is also responsible for maintaining efficient energy production by mitochondria by recycling all mitochondrial proteins inside a week.

Evidence at present points to low glycemic carbohydrate (even ketogenic) but not excessive protein with high fibre intake combined with time restricted feeding (TRF) to optimize autophagy, immune cell function and gut derived inflammation.

Cell Signaling involving feasting and fasting

It is vital for survival that the body can distinguish feasting from fasting and regulate metabolism accordingly. For example, athletic performance is poor following a meal and vastly improved after 2 hours, or better 4 hours. The main signal to identify a feasting state is blood glucose whereas high free fatty acid levels occur during fasting. Absent the glucose spike, the body still "thinks" it's fasting. Hence fasting mimicking diets are low in glucose/carbs rather than fat. Feasting triggers mechanisms to store energy while fasting triggers mechanisms to release fat and conserve glucose for work and athletic performance.

Why low carb

· Starch and sugar increase blood glucose to massively increase insulin production and initiate a cascade of cell signaling affecting all of our body systems. Low glucose shuts down insulin production and stimulates glucagon which mobilizes energy from fat cells and glucose production from glycogen and protein stores.

· Both glucose and insulin affect immune cells & decrease efferocytosis (eating dying cells)

· Glucose had a marked inhibitory effect on the capacity of macrophages to engulf dying cells.

· Glucagon promotes efferocytosis

· Insulin inhibits efferocytosis

Why Moderate Protein

· Excessive protein has well documented adverse outcomes as well as theoretical risks of suppressing autophagy.

· Excess protein also stimulates insulin secretion and high amino acid levels directly suppress autophagy via the master controller of autophagy, mTOR.

Why high fibre

· Fibre is key to gut health, intestinal barrier integrity, immune function, and hunger.

· Fibre is fermented in the hind gut to produce Short Chain Fatty Acids of which butyrate is an essential player in all the above concerns.

· SCFAs in the hind gut can amount to 60 grams and provide 420 Calories between 4 and 20 hours after a meal and during this time frame SCFAs increase hormones that suppress hunger (GLP1 & PYY) and suppress hormones that cause hunger (ghrelin).

· SCFAs create an acidic milieu of around pH 5.5 which largely determining the makeup of the microbiome in the hind gut. Preventing “dysbiosis”, which is invariably linked to suppression of butyrate producing bacteria.

· High Fibre Diet strengthens gut lining via SCFA and GLP incretin hormones

· High Fibre Diet suppresses appetite and improves ability to comply with fasting/time restricted feeding.

· Regulatory T cells (tregs) play a part controlling macrophages and both types of immune cells are influenced by SCFAs.

· Gut barrier dependent on direct effects of butyrate and signaling via FFAR2 to strengthen tight junctions and mucin production from goblet cells.

· SCFA anti-inflammatory effects on immune cells systemically via FFARs and HDACi

Why Time Restricted Feeding

· TRF extends periods of fasting and increased the effects of a low carb (fasting mimicking diet) in that it creates a low glucose & insulin signaling that stimulates autophagy, efferocytosis and reverse cholesterol transport. Where Insulin inhibits cholesterol efflux from macrophages.

· The hormone of fasting, “glucagon” activates autophagy and efferocytosis in macrophages.

Bottom Line: These lifestyle changes which improve metabolic health and immune function are many times more effective at preventing premature death & heart attacks than reducing cholesterol. The very modest association between cholesterol levels and heart attacks is likely not causal but downstream of the real culprits.

Click on figure for link to original study