Changed (Macro) Autophagy or somewhat more visually changed cellular waste disposal is the twelfth and final Hallmark of Aging. This is understood by science as our cells no longer manage to get rid of cellular waste. This can affect large molecular complexes or entire cell organelles – hence the prefix "macro" – but also the smallest deposits, such as those found in Alzheimer's dementia . For simplicity, we will refer to it as autophagy for the remainder of the article.
Why does cellular waste disposal play such a significant role now? To answer this more precisely, we will take you on a little journey through the body and introduce you to the various components of your waste disposal system. Don't be intimidated by complicated names like autophagic-lysosomal system or chaperones , we will explain everything to you step by step. Additionally, we will take a look at the research and explain why sleep and the supplementation of spermidine can be a booster for a struggling recycling system.
What is autophagy?
Autophagy describes the cellular recycling. It is completely normal for proteins or other cell components to eventually lose their function or no longer be needed. After all, our requirements change over time. Even our cellular power plants – the mitochondria – do not last a whole human lifetime. The task of autophagy is to ensure that these remnants are correctly broken down and the components are reused afterwards.
The faulty breakdown of, for example, proteins – the loss of proteostasis – has already been identified as a hallmark of aging .Here, incorrectly folded proteins can no longer be unfolded. This poses the risk of clumping. Since the disposal of proteins is only a small part of cellular waste management, the hallmarks of aging have been expanded. Altered autophagy has become an independent hallmark since the last update. What exactly happens with this in aging, we will show you here.
From scissors to acid traps – how is waste disposed of in our cells?
Before we take a look at what no longer works properly in aging, we should first take a closer look at our recycling system. It is quite elegantly designed and does its job day after day without us noticing.
Roughly speaking, there are two major systems in the waste disposal of cells.The first one has the cumbersome name Ubiquitin-Proteasome System (UPS) and has two main tasks. On one hand, the marking (ubiquitination) of misfolded proteins, and on the other hand, the proteasomes ensure that these misfolded proteins are broken down into their individual amino acids.
You can imagine the proteasomes as a kind of filter, inside which there are highly specialized scissors. Everything that enters the proteasomes in the form of proteins is neatly separated and is then available to the cell as a new building block.
The second major system has the no less complicated name autophagic-lysosomal system. This is more complex than the UPS, as here not only individual proteins are broken down, but in doubt entire cell organelles are dismantled into their building blocks and these are then returned to the cellular metabolism.
The 4th Hallmark of Aging is largely based on a malfunction of the ubiquitin-proteasome system. Now we are talking about autophagy.
Just as garbage piles up frequently in nature, this also happens in old age in humans.
The Autophagic-Lysosomal System
In our cells, not only faulty proteins are a problem, but also cell organelles that no longer function.About the role of ATP and the mitochondria we have already written detailed articles, which reveal little about what happens when old mitochondria need to be broken down. This occurs through macroautophagy.
Also simplified here: A shell forms around the old mitochondrion, which is referred to in its entirety as autophagosome . Now we have a protected environment. This is necessary so that the breakdown inside the cell does not immediately destroy the entire cell.
In the next step, the autophagosome connects with the lysosome. This is a type of small stomach – it contains many digestive enzymes, that we need to break down complex molecules. Within this protected environment, everything is now broken down and, as always in biology, there is now a new name. The autolysosome is the combination of the autophagosome and the lysosome.
After digestion, all reusable materials are supplied to the cell and waste products are transported away with the lymph fluid.
Lipofuscin – when you can literally see age
In old age our highly specialized recycling system can no longer keep up. If we stay with the lysosomes, this is impressive to see. In addition to their role as "waste shredder", these cell organelles can also take up large proteins that no longer have a function in the cell but are too large to be transported away with the lymph or through the bloodstream. This "special waste" is stored in the cell in small capsules called "granules".
When looking at old nerve or muscle cells under the microscope, many of these dark spots can also be seen. For the most part, these are lipofuscin. It mainly consists of damaged mitochondria that can no longer be properly broken down. The cell waste "clogs" the cell and thus restricts its function.This is probably one of the reasons why there is a mitochondrial dysfunction in old age.
Age spots are not only seen under the microscope in nerve cells but also in aging skin.
Alzheimer's – one of the most prominent examples of faulty waste disposal
Another condition associated with faulty waste disposal is Alzheimer's dementia. Here, there is a deposition of so-called Amyloid plaques. Due to faulty breakdown, these complexes accumulate in the nerve cells and "clutter" them .
Additionally, in Alzheimer's patients, the Tau protein is altered – a protein that is important for cell stability. The result is an unstable cell and the death of neurons.
Alzheimer's has become a common disease over decades. The risk factors are partly genetic and partly related to lifestyle. Faulty waste disposal definitely plays an important role in the development of this currently incurable disease.
Sleep – a long underestimated remedy
There are many ways to help our body with autophagy. One very promising way is to get enough sleep. While we peacefully slumber, our brain is being cleaned up.The so-called glymphatic system ensures that the waste products of the day are transported away.
For a long time, sleep was treated somewhat neglectfully in medicine, but now it is known that sleep is extremely important for our health . If we do not get enough sleep for months or years, the cellular waste cannot be properly transported away, and the risk of Alzheimer's increases.
Mitochondria and autophagy – when strength is lacking in old age
We have already seen with age spots, the lipofuscin , what happens to old mitochondria that can no longer be properly broken down.Defective mitochondria and their deficiency are associated with typical signs of aging such as heart failure, but also one of the drivers for age-related muscle loss. One of the most important molecules in the mitochondrion is NAD. This is involved in countless metabolic processes – above all, it is central to energy production. Just like the mitochondria, the NAD content decreases with age. This can be determined through NAD tests, which measure the NAD concentration in the blood.
Studies have now shown that the administration of NAD precursors, as found in NAD boosters , not only corrects NAD levels but also increases autophagy. In animal experiments, this even extended lifespan.
regeNAD is an innovatively formulated complex to increase NAD levels - with Luteolin and Apigenin.
Fasting – an autophagy boost
Abstaining from food in the form of fasting can also be beneficial for our body. We have already written about the different forms of fasting and the molecular effects in a separate article, so here is just the summary.
When we are in a fasting state, it seems to be a kind of starting signal for our body to recycle old material. After all, no food is currently coming in. Therefore, the chaperones are activated within a very short time. Chaperones are specialized proteins that mainly take care of the correct folding of proteins. However, they also play a role in autophagy by transporting proteins that they can no longer fold correctly, to the lysosomes, thus ensuring their breakdown. True gentlemen, indeed.
Fasting ensures, through various means, that our body reactivates its own recycling system. Whether through the activation of the Sirtuins, via which Dr.David Sinclair has researched, or through the chaperone system. A similar approach has fasting mimetics, as you can find in the fasting bundle .
Spermidine – a promising molecule
Another very exciting approach to boost autophagy in aging is supplementation with the body's own molecule Spermidine. This molecule has already been successfully tested in several animal studies and increased cellular recycling there. In particular, Spermidine seems to be beneficial for the health of heart cells, which is why studies are also being conducted in humans.In mice, the supplementation of spermidine has already been shown to bring about a life extension of up to 25% . A spermidine-rich diet in humans has also been associated with better health.
The natural substance spermidine is closely linked to autophagy according to research - a process whose discovery was honored with the Nobel Prize a few years ago.
Conclusion on Autophagy
Our cellular waste disposal system is highly complex and seems to be overwhelmed by the amount of waste products as we age. This is reflected in the emergence of some age-related diseases. However, we are not entirely powerless. There are ways to increase autophagy as one of the Hallmarks of Aging again, whether through fasting, exercise, buying spermidine or NAD precursors.
We can be curious about what new approaches will come to market in the coming years and whether we can eventually prevent diseases like Alzheimer’s.
This was the last article in the series Hallmarks of Aging.
