The Importance of Autophagy

The human body is an incredibly complex system. Even though we learn new things about it every day, there are still many unresolved questions. Our bodies are prone to many different (specifically age-related) types of damage, but it turns out that we have a repair mechanism that is much more powerful than previously thought.

We are beginning to unravel the potential of biotechnology to treat a vast array of diseases, including aging itself, but many people wonder what they should do now to remain healthy until regenerative medicine is fully mature? This question warrants a thoughtful response. Diet and exercise are both important, but they are not the game-changers that will significantly increase our lifespans. Even the undeniably positive benefits on our healthspan decline as we age. We have to try something new.

The best way to protect ourselves from numerous chronic, age-related diseases is to trigger and boost the natural process of autophagy. Many studies suggest that autophagy is currently the best way to protect ourselves from cancer, diabetes, Alzheimer’s disease, Parkinson’s disease, and many other age-related disorders. While we don’t see the same lifespan increase as we do in rodents, autophagy is still a powerful tool that we can use to combat and slow down aging today.

Here we’ll first define autophagy (it’ll be a little technical) and then go into how you can promote it. 


What is Autophagy? 

The term autophagy comes from two Greek words – “auto” and “phagein”. The first word stands for “self” while the second one stands for “eating.” In other words, autophagy lets eukaryotic cells recycle old and damaged cellular components in response to stress. As a result, your body is getting rid of  cells that no longer have a purpose in the body, including cells that are already malignant or are likely to become malignant. After it recycles them, it uses that newly created energy to grow new and healthy cells. 

We can view autophagy as an evolutionary self-preservation mechanism. Without it, we wouldn’t survive for long. Autophagy helps the body regenerate itself while promoting adaptation and survival against an assortment of internal and external stressors. 

There are several types of autophagy:

  • Microautophagy – this is a process that involves the consumption of cytosolic components by the lysosome directly through the lysosomal membrane
  • Macroautophagy – the most prevalent form of autophagy where cytoplasmic cargo is transported directly through the double membrane and to the lysosome. Lysosome and autophagosome are then fused together and autolysosome is formed
  • Chaperone-mediated autophagy – a process where proteins are translocated across the entire lysosomal membrane in a complex of different chaperone proteins (HSC70 or HSPA8 is one example of that)
  • Micro and macropexophagy – both of these processes involve the selective degradation of peroxisomes
  • Piecemeal microautophagy of the nucleus – a process that occurs in Saccharomyces cerevisiae. The end result is the release of nonessential parts of the nucleus into the vacuole.
  • Cytoplasm-to-vacuole targeting (Cvt) pathway – the only known biosynthetic pathway that promotes autophagy in yeast. The pathway controls the delivery of different hydrolases into the vacuole.


Autophagy Benefits

The impact of autophagy on the aging process has long been neglected, but now we realize the importance that it has on both lifespan and healthspan. Benefits include:

  • Reduced inflammation.
  • Reduced risk of neurodegenerative diseases
  • Improved cardiovascular health 
  • More energy
  • More efficient metabolism
  • Autophagy boosts your immune system and it helps you fight off infectious diseases
  • Prevents the onset of cancer
  • Offers strong protection against metabolic disorders like diabetes
  • Improved muscle performance
  • Loss of unwanted body fat

We have several different ways to kick-start this regenerative process.

Activating Autophagy

Caloric restriction/Intermittent fasting


The easiest way to activate autophagy is by restricting your daily calories or by following a protocol known as “ intermittent fasting”.


Caloric restriction is a dietary regimen in which you reduce your daily caloric intake below normal. The keynote here, however, is that we are not talking about “starvation.” You’re still getting all of your essential nutrients, but you are aiming to consume fewer calories in the long run. Women need to limit their daily caloric intake to 1,200 calories while men can limit their intake to 1,400.


“True” caloric restriction can be challenging for many people which is why intermittent fasting is a much more popular alternative. With this eating protocol, you don’t consume any calories at all for certain periods. Your feeding window is restricted, which puts your body into a fat-burning mode and the state of ketosis. As a result, the longer you fast, the more benefits you will reap.


You have several different protocols that you can follow here. The consensus right now is that a 16-hour fast on a daily basis is enough for most people. That is also the minimal time needed to get the most benefits of autophagy in the long run, but this is not the only way you can fast. 

 

You can also do the 5:2 protocol and fast for 24 hours two days a week. Alternate day fasting is another option. As the name suggests, it just requires that you restrict your calories or fast every other day. Lastly, you can also do periodic fasting and restrict your caloric intake for five days in a row (on a monthly basis). You have full flexibility here and the choice is up to you.

Metformin


The data suggests that an old diabetes drug, Metformin has anti-aging properties. Even more so, Metformin can be used to induce autophagy without any fasting or caloric restriction involved.


Two metabolic pathways are important to understand here as both of them are longevity-related. One of these pathways is AMPK (AMP-activated protein kinase) and the other is mTOR (mammalian target of rapamycin).


The AMPK pathway serves as a central regulator of cellular energy homeostasis. This fuel-sensing enzyme is present in all mammalian cells and its main role is to stimulate energy-generating processes (like fatty acid oxidation). However, AMPK has one more important role – it decreases all processes that consume energy in the body (like protein and lipid synthesis). Growing evidence suggests that boosting AMPK can halt or potentially reverse the most insidious aspects of aging. 


The other important pathway is mTOR. Similar to AMPK, mTOR is also a regulator of cell metabolism, as well as growth and survival in general. Contrary to AMPK, however, studies are showing that mTOR is activated in many age-related pathologies. For instance, we can see it in action during tumor formation and angiogenesis, as well as metabolic disorders like insulin resistance. 


The solution here is obvious – we want to upregulate the AMPK pathway while suppressing the mTOR pathway for maximum benefits. That’s exactly what Metformin does – it activates  AMPK and inhibits mTOR simultaneously. Early data suggests that Metformin could serve as a geroprotector, one with the potential to improve our healthspan significantly. The TAME trial led by Dr. Nir Barlizai will hopefully give us more insight into whether Metformin can be used to combat aging directly.


Metformin was one of the key ingredients that Dr. Gregory Fahy used in a highly-revolutionary TRIIM study. The cocktail regenerated the thymuses of nine volunteers and it reversed their epigenetic age by 2.5 years on average. Yet another (important) proof that using Metformin as an anti-aging drug is a very plausible concept.

Rapamycin


A well-known immunosuppressant, Rapamycin is yet another tool that we can use to trigger autophagy. Some preliminary studies suggest that Rapamycin can inhibit the growth of malignant cells while inducing autophagy along the way. They also suggest that Rapamycin is indeed a very powerful mTOR suppressor.


More data is needed, but this is certainly another drug that can induce autophagy. A recent study has shown it may even slow skin aging in humans.


Autophagy and Telomeres


Researchers at The Salk Institute have recently investigated the relationship between autophagy and telomeres. After a careful examination, they concluded that autophagy can stop cancer before it becomes lethal. The team wanted to see what would happen if they applied different types of DNA damage to the ends of the chromosomes (telomeres) and the middle regions of the normal cells.

 

The results have shown that cells with telomere loss triggered increased autophagy while the other cells activated apoptosis. They also demonstrated that apoptosis is not the only mechanism that can destroy cancerous cells, suggesting a strong link between telomeres and autophagy.


We need more research in this area. but the data suggest that autophagy is an effective safeguard against cancer development resulting from critically short telomeres.

 

The telomerase gene therapy is currently the most powerful tool to combat aging. Bioviva and IHS allow patients in the highest need to get access to the therapy today.


Autophagy and Klotho


Studies have shown that the expression of Klotho increases the lifespan of mice while Klotho deficiency has a negative impact on longevity. Researchers created a special mouse model with induced autophagy to determine whether there are any connections between this regenerative process and Klotho. The results were positive.


The study showed that mice with increased levels of autophagy had a slightly longer lifespan than their counterparts. On top of that, the administration of Klotho induced autophagy. The same effect was later translated to mice who were genetically deficient in Klotho.


This mechanism is fully applicable to humans as well. BioViva and IHS have realized the importance of Klotho and that’s why Klotho gene therapy is one of the most powerful tools in our arsenal in the war against aging today. 


Autophagy and PGC-1α


As we age, both autophagy and mitochondrial biogenesis start to decline and our risk of developing different age-related pathologies increases. Even though the two processes seemed unrelated at first, new research is now challenging this idea. As it turns out, PGC-1α stimulates the expression of the p62 gene which upregulates the natural mechanism of autophagy. This data suggests that by targeting the PGC-1α/p62 pathway we can induce autophagy and potentially prevent or delay age-related diseases like atherosclerosis.


PGC-1α is yet another therapy that IHS offers to patients who need it the most right now.


Autophagy and Follistatin


Research on the connection between autophagy and Follistatin is still limited, but one study, in particular, is very promising. This 2019 study suggests that FSTL1 may have a significant cardioprotective function. Furthermore, it also suggests that myocardial IRI pretreatment induces autophagy and improves cell viability. Therefore, expressing FSTL1 can be a good way to prevent myocardial ischemia and reperfusion injury.


Follistatin gene therapy is also available at IHS for patients who need a more radical intervention today.


Concluding Remarks


We’ve made tremendous progress over the last decade. We are getting closer and closer to understanding how aging works and what can be done to control it. 


Until we develop a more comprehensive solution, autophagy is the mechanism that we can utilize today so that we can live longer and be healthy. Keep all this information in mind the next time you hear that you need to eat five times a day if you want to survive. Use that information wisely, your body will be grateful to you.

 

 

 

 

 

 

 

 

 

 

 

 

Milos Stefanov

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