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INSIGHTS | 11. Autophagy in Major Human Disease
Autophagy is the natural degradation of cells or proteins which are either unnecessary or dysfunctional.
Article: Autophagy in major human diseases
As a child I could not understand why people would undertake prolonged periods of fasting. Whether it was for Ramadan or a lifestyle choice, the idea of starving yourself did not seem appealing.
Since then, I have come to appreciate and understand the nature of ancestral wisdom as well as the scientific underpinning of fasting.
To appreciate the implications of this article, I want to provide a framework that may be helpful.
The cells of your organs start out as pluripotent stem cells, and differentiate based on their location & function. Once fully formed, they exist in collaboration of other cells of their type. They have a shared environment from which they extract nutrients, generate waste, produce signals & metabolic functions.
Sometimes, the cells or their individual components become dysfunctional. Other times, they become obsolete - the environment which informed their development has changed. Disease can be defined as the dysfunctional state of an organ (or collection of organs). Either dysfunctional or obsolete cells must be cleared & recycled into other cells & proteins.
If dysfunctional cells are not properly removed & recycled, they accumulate and use up precious nutrients, or destabilize the cellular signalling by their very presence.
Aging, and longer life, is associated with chronic disease. Autophagy is the natural degradation of cells or proteins which are either unnecessary or dysfunctional.
Autophagy is a health-modifying agent, with a large body of evidence supporting its role in longevity. In contrast, loss of effective autophagy contributes to aging & illness. Autophagy refers to the combination of cellular pathways in which different parts of the cells are transported to lysosomes - lysosomes are organelles inside the cell which degrade and recycle.
There are several types of autophagy: macroautophagy, microautophagy, chaperone-mediated autophagy. The difference lies on the scale & specificity of the recycling. Anywhere from a large population of cells to specific proteins within a cell.
Several lifestyle changes which are now in vogue (caloric restriction or fasting, and exercise) share a common capacity to stimulate autophagy. Diseased states manifest when dysregulation of autophagy occurs.
Autophagy typically proceeds at a baseline rate in almost all your cells - a part of the cell's housekeeping functions. A surge can occur with a disturbance of the intracellular or extracellular environment.
Autophagy equips your cells with the ability to strive under nutrient-restricted conditions, conferring a competitive advantage over cells that cannot. This assertion is supported by whole-body autophagy-deficient mice who die at birth, because they cannot tolerate post-natal starvation.
Most of the research on autophagy has been performed on animal models, but several of the proteins involved in these disease states have been found defective in cases of human disease as well. Here we will discuss some of the more common diseases, and the role of autophagy.
A large proportion of neurodegenerative diseases are associated with the accumulation of certain proteins - these aggregates then disrupt cellular function & survival. In addition to its role in clearing protein aggregates, intact autophagy can reduce inflammatory neural reactions. Mice that lack autophagy have a short lifespan and develop early-onset neurodegenerative diseases.
Alzheimer's disease is the most common dementia in humans, and is believed to be caused by protein aggregates (Tau or Beta amyloid). Accumulation of Tau fibrillary tangles disrupts transport of autophagosomes in neurons.
Beta Amyloid is targeted for autophagy-dependent degradation within lysosomes. This is demonstrated in rodent models that result in reduced Amyloid plaques upon activation of autophagy.
Ischemia of cells results when they are deprived of oxygen, often due to lack of blood perfusion. This results in a shortage of nutrients and production of reaction-oxygen species (ROS) - a maladaptive state for the cell. So maladaptive, in fact, that even if you re-introduce blood & oxygen, the cells can become even more damaged. This is termed reperfusion injury - and can be so severe that the infarcted tissue can bleed.
Often, this is discussed in the case of heart attacks or strokes (of the brain). In reality, this can happen to almost any organ which experiences an interruption of blood supply. Mouse models demonstrate that autophagy equips cardiomyocytes with a capacity to sustain ischemic shock, compared to their non-autophagic counterparts.
Overindulgent lifestyle choices undermine autophagy. Therefore, it should come as no surprise that excessive calorie intake impairs cardiovascular autophagy.
Autophagy is a major factor in several phases of atherogenesis - the process of forming atherosclerotic plaques in your arteries. Stimulation of autophagy by macrophages (immune cells) limits plaque buildup in the blood vessel, and favors the removal of fat from the plaque. Autophagy promotes the delivery of lipid droplets to lysosomes - where cholesterol esters can be broken down and converted to free cholesterol.
Autophagy is an essential component and function of osteoblasts and osteoclasts - the cells which form and remove bone, respectively. These cells operate antagonistically to maintain the bone, and help it to adapt to changing stressors.
Autophagy of bone is also directly modulated by hormones and other signalling molecules. This is why osteoporosis is often a concern in post-menopausal women, who have a significant alteration in their hormone signalling.
Therefore, it is not surprising that conditions which directly or indirectly disturb these cellular processes are involved in osteopetrosis (hardening), osteopenia (softening), and osteoporosis (really soft).
Not all Good News
Autophagy isn't always good. As you can imagine, if autophagy gets out of hand, it can start destroying your organs. This is precisely what is believed to happen in cigarette smokers who develop chronic obstructive pulmonary disease (COPD).
In COPD, cigarette smoke is believed to damage your alveoli (functional sacs of the lung that exchange gas with your blood). Damaged alveoli lose their walls, and start to form larger air-sacs - as you can see below. The loss of the wall surface-area of the alveoli, ultimately results in the reduced capacity for gas exchange.
Less surface area = less gas that can be exchanged at any given time.
In animal models with a partial deficiency in autophagy, we observe reduced signs of emphysema (the clinical manifestation of COPD) after 3 months of exposure to cigarette smoke.
Mice with deficient autophagy exposed to cigarette smoke exhibit improved lung function compared with normal mice counterparts.
Additionally, it has been observed cigarette smoke causes death of neutrophils (immune cell), which release elastase upon their death. Elastase is an enzyme that can chew up parts of your lungs, promoting the emphysematous changes characteristic of COPD.
We live in a time of abundance, and it should come as no surprise that abundance is a common cause of disease. Whereas we can juggle this idea metaphorically, the reality is that it's a valid assertion all the way down to the cellular level.
The life of a cell can be conceptualized as follows:
Use nutrients & signals to differentiate and grow
Adapt to your local environment, and optimize to perform your functions
Communicate with other cells near, and far
Maintain the integrity of your internal machinery
An essential component of this process is the removal and recycling of dysfunctional parts. But, autophagy is more than that. When your orthodontist re-aligns your teeth, he is not physically moving your teeth. The stress applied by the hardware causes your teeth to die in some parts, and grow in other parts.
Look at this macrophage (an immune cell) consume other things:
The 'movement' of the cell is an illusion. It is not moving. It is dying on one end, and growing at another. The cell is responding to external and internal signals to mobilize its machinery. The machinery is consuming some parts of the cell to grow other parts of the cell.
Autophagy is everywhere, in everything, all the time. It is critical for life.
In an environment in which nutrients are abundant, however, there is less need for the cell to destroy dysfunctional parts to make new parts. Why waste the energy? Instead, you can just make new parts from the abundant nutritional environment.
Nutritional and caloric overabundance results in reduced clearance overall. But, the consequence of this reduced rate of autophagy means that dysfunctional and diseased cells will also survive.
Your body must recycle its cells and proteins. Just as you must change the used oil in your car's engine. One of the simplest ways to force your body to decide which cells are worth keeping, and which need to be recycled is fasting
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