At this very moment our cells are busy selecting from 22 available amino acids to build a vast array of proteins. Nine of the amino acids cannot be produced in our bodies and must be supplied by our diets, thus they are essential. In these modern times our diet sends a near constant supply of amino acids to our cells. Thus, production continues day and night unabated even when production errors result in proteins that don’t function, that can’t be used, that stick to other proteins and form plaques. Houston we have a problem.
It’s a problem that increases as we age. The junk proteins accumulate in our cells and disrupt regular functions. The damage may not be dramatic enough to trigger cell death via apoptosis, but the cell often goes into early retirement in what is known as cellular senescence. As our bodies clog with senescent cells our organs become impaired and we begin to show all the hallmarks of aging including chronic inflammation.
Our bodies were not designed for perpetual plenty. Throughout mankind’s history we have experienced frequent periods of short-term famine. Hunting and trapping didn’t work out today? Hoping for better luck finding food tomorrow? In the mean time we fasted and moved around on an empty stomach in order to find that next meal.
During periods of fasting the amino acid reserve is depleted. It doesn’t require a prolonged hunger strike to get there. Fasting for 12-18 hours will get our cell’s attention and start a process that is not only healthful but restorative. Faced with continuing demand and a sudden lack of supply, cells look to the only remaining source of amino acids — old, unnecessary, or poorly formed cellular components. A recycling process begins and newly liberated amino acids become the building blocks for new proteins.
The recycling of amino acids was first noted by Belgium researcher Christian de Duve in the 1950s when his team stumbled upon the existence of an acid filled organelle floating around in our cells that he named “lysosome.” That was enough to earn him a Nobel Prize in 1974. The intervening 20 years were not idle for de Duve who continued to uncover the organelles and enzymes of the process that he called “autophagy.” Autophagy means “self-eating” and demonstrates again that sometimes it’s best not to translate medical terms. Japanese researcher Yoshinori Ohsumi worked out many of the mechanisms of autophagy in the 1990’s including identifying genetic components of the process (ATG or autophagy-related genes) and for his work was awarded a Nobel Prize in 2016.
There are different ways to initiate autophagy and some selectively activate genes whose mechanism of action may be different than others, but the result is always the breaking down of amino acid chains into their base components. Here are a select few of these mechanisms:
Macroautophagy is a two-step process and usually what we mean when we say autophagy. The cellular material to be degraded is engulfed and becomes an “autophagosome” which then merges with a lysosome. The lysosome is like a tiny stomach floating around inside the cytosol. It’s membrane contains the more than 60 different enzymes in an acidic environment (pH 4.5-5) and protects the slightly base (pH 7.2) cytosol. Amino acids are unhooked from one another and released back into the cell for building projects.
Microautophagy is more direct in that the lysosome simply engulfs the target and breaks it down.
Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress.
Back to Aging
It would stand to reason that autophagy clears out the junk, returns the cell to a healthy state, reduces inflammation and prevents senescence, which does appear to be true. However, cells can’t go on forever (unless cancerous) so eventually senescence happens and at that point autophagy actually promotes the process. So just like many other biological processes the good or bad effect depends in no small part on timing. If any of that concerns you just remember that numerous studies have shown that autophagy extends lifespan.
You know what inhibits autophagy? Our old frenemy insulin.
PPAR: There are three PPAR pathways and each one alters lipid metabolism in a distinctly different way and generates distinct classes of lipid molecules. PPAR alpha kicks in when we are fasted or cold, and triggers autophagy.
Various medications and supplements have been shown to trigger autophagy. Here are a few:
- Aspirin – not only stimulates PPAR alpha, but upregulates the biogenesis of lysosomes thus further contributing to successful autophagy.
- Coconut oil (MCT)
- Vitamin D
- Omega 3 and 6 fatty acids
- Lithium (much less than a therapeutic dose)
- Metformin – A drug used to treat type 2 diabetes, it works by decreasing liver glucose production and increases insulin sensitivity. Metformin has also shown promise in a small randomized placebo-controlled crossover study for treatment of early Alzheimer’s. Prolonged use can result in Vitamin B12 deficiency.
Activities that promote autophagy include:
- Ketogenic Diet – This high fat/low carb diet is more effective than the above mentioned Metformin at decreasing glucose and increasing insulin sensitivity. The benefits of the ketogenic diet is impressive.
Into the Weeds
I described macroautophay above as a two step process, but technically it’s referred to as complex I-IV. Each complex involves a different classification of genes. Logically ATG1 starts macroautophagy, but complex II is controlled by ATG9a. I’ll stop there.
September 6, 2018 Longer daily fasting times improve health and longevity in mice