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3. Hallmark of Aging: Epigenetic changes
Longevity Magazin

3. Hallmark of Aging: Epigenetic changes

Epigenetics is one of the most exciting fields of research. While it was previously thought that everything was in the genes, Today we know that only about 20% is directly inherited and the remaining 80% of our lifespan is determined by epigenetic changes.

The average adult consists of an immense number of approximately 100,000,000,000,000 cells. With only a few exceptions, such as mature red blood cells, all of these cells have a nucleus containing the human genome. We already know this term from the first Hallmark of Aging – the genomic instability. The genome is a term that, in simple terms, describes the entirety of an individual's heritable information. This is information for the production of proteins that determine and change the body's appearance.

So what does epigenetics do? Put simply, epigenetics determines which information is read and which is notHere we show you what effects epigenetics can have and what epigenetic changes have to do with age.

MoleQlar ONE combines the potential of 13 different longevity ingredients to promote health and longevity at the molecular level. The complex has positive effects on all twelve hallmarks of aging.

What does epigenetics do?

Every cell contains the same genetic information. How is it that some cells become muscle cells and others skin cells? The answer lies hidden in the cell nucleus.

We humans not only have a genome, but also an epigenome. The epigenome is a collection of chemical changes in DNA that essentially functions like a switchMany genes have such a switch. When the switch is ON, the gene is "expressed," meaning the blueprint is implemented, producing the desired protein. When the gene is switched off, it is considered silent, and no protein is produced.

Perhaps to better illustrate this, imagine your DNA is the text in a book. However, you never read the entire book because it's much too large; instead, you read only sections. To help you remember which sections you want to read, you've stuck little Post-It notes to the beginning and end of the passage. These Post-it notes are your epigenetic markers.

Chemically speaking, these are methylated sites on your DNA. They don't change your DNA itself, but rather determine which sections are read—and which aren't. To make things even more complicated: The text sections change throughout your life. Sometimes you read passages from one chapter and sometimes passages from the other chapter.. And it also depends on which cell you are looking at.

Did you know? Epigenetics is used to the biological age to eatUsing proteins in your cheek cells and modern algorithms, it is now possible to calculate quite accurately how old a body cell is compared to its chronological age. This is exactly the technology that is used in our Epiproteomics test for use.

The diversity of genes

Each gene contains the blueprint for one or more proteins. This is made possible by a process called "alternative splicingThis means that not all of the information on a gene is always read or used, but for some proteins only parts of it.

Accordingly, the number of proteins significantly exceeds the number of genes: If science today assumes 20,000 to 25,000 human genes out, the Number of proteins in humans is 80,000 to 400,000 More precise statements are currently difficult to make because research is still far from decoding all proteins.

A groundbreaking development by the company DeepMind will certainly help here. They have developed software with the help of a neural network called AlphaFold that can predict the 3D structure of proteins.

The role of epigenetic fixation

The role of epigenetic fixation

Epigenetics, also epigenetic fixation or epigenetic imprinting is the reason why different cell types develop from cells with the same conditionsThey all have the same genome, but different epigenomes that tell them which proteins need to be produced and what kind of cells they ultimately have to be.

In addition, epigenetics is partially hereditary, at least according to current research. Epigenetics research is still a relatively young field, but there are already some exciting results.

Did you know? After discovering that we can determine biological age with the help of epigenetic changes, the question remains how we can influence this. sport and Fast There are also some molecules that can help us reduce our biological age. At the forefront is Calcium alphaketoglutarate (Ca-AKG)In human studies, it has been shown to reduce biological age reduce by up to 7 years! In addition, it helps with muscle and bone building and supports our Mitochondria.

The combination with calcium ensures better AKG bioavailability in the organism.

Is epigenetics partly responsible for the obesity epidemic?

According to WHO figures, the rate of overweight people has tripled since 1975. Worldwide, 1.9 billion people were overweight in 2016 have been.

Obesity, especially severe obesity with high visceral fat content, represents a risk for many age-related diseases, such as diabetes mellitus and cardiovascular diseases.

But where does this sharp increase in obesity come from? Much of it is caused by poor eating habits and too little exercise. but epigenetics also has a hand in this.

Several animal experiments suggest that children of overweight parents inherit epigenetic patterns that predispose them to gain weight more quickly. The key point in the experiments was: It is often not the inherited genetics, but the inherited epigenetic pattern.

The good news, however, is that this pattern can be broken, for example, by replacing harmful epigenetic markers with new, more beneficial ones through proper nutrition. However, further research is needed to determine exactly how this might work in humans.

Epigenetic changes and aging

The epigenome, unlike the rigid DNA template of the genome, changes throughout life. Changes occur, for example, during physiological development, but environmental factors such as stress, disease, or nutrition also have an impact and not all changes are for the best.

Different epigenetic mechanisms cause these changes. This complexity is also the reason why we focus our attention on only one, but very important, epigenetic mechanism: DNA methylation.

This foreign term refers to the transfer of special chemical molecules, the methyl groups, to DNA. We'll omit the remaining chemical subtleties for the sake of clarity. As a result of the attachment of these chemical groups, the architecture of DNA changesWhereas stability suffers in the construction of a house, DNA can only be read in a modified form. To return to our analogy from the beginning. The DNA methylations are the colored post-it notes that tell you whether you want to read the text behind them or not.

Chemical reactions in the body, and thus also the transfer of methyl groups, usually require the presence of enzymes, as these create the optimal conditions. Accordingly, enzymes are also required here, the so-called DNA methyltransferases (Enzymes that transfer the methyl groups to DNA.) What does this rather complicated input have to do with aging?

Recent studies have shown that as time goes on, more and more methyl groups bind to the DNA. Epigenetic changes therefore increase with age – a fact that the Horvath Clock takes advantage of.

Progeria and DNA methylation

As a reminder: Progeria is a group of diseases with a dramatic (up to 10-fold) increase in the rate of aging. For example, it is possible for a ten-year-old girl with progeria to have a biological age of 70. You can find more details about progeria in the first Hallmark of Aging, which genomic instability.

In these people and also affected mice, researchers found in large parts similar methylation patterns as in healthy individuals of advanced ageA connection between DNA methylation and age is already present. Direct experimental evidence that lifespan can be extended by altering DNA methylation patterns is still pending.

DNA methylation

Epigenetic changes – outlook

Unlike DNA mutations, epigenetic changes are reversible. This opens up opportunities for the development of new longevity treatments. The totality of current scientific evidence suggests that understanding and manipulating the epigenome holds promise for improving age-related pathologies. This is inextricably linked to extending healthy lifespan.

However, if one considers the enormous complexity of epigenetics on the one hand and the current state of research on the other, one realizes that that efforts, especially with regard to humans, are still in their infancyThe coming years and decades will demonstrate the extent to which this can lead to tangible approaches for anti-aging and prevention. Ultimately, research is not a one-way street toward success—but it is certainly a one-way street toward understanding and education.


The next article in this series will cover the fourth hallmark of aging: Loss of proteostasis.

Sources

Literature

  • López-Otín, Carlos et al. “Hallmarks of aging: An expanding universe.” Cell vol. 186,2 (2023): 243-278. Link
  • Kleinert, Maximilian et al. “Animal models of obesity and diabetes mellitus.” Nature reviews. Endocrinology vol. 14,3 (2018): 140-162. Link
  • Ouni, Meriem, and Annette Schürmann. “Epigenetic contribution to obesity.” Mammalian genome : official journal of the International Mammalian Genome Society vol. 31,5-6 (2020): 134-145. Link
  • Durairaj, Janani et al. “Uncovering new families and folds in the natural protein universe.Nature  622,7983 (2023): 646-653. Link

Grafiken

The images were purchased under license from Canva.

Table of contents

12. Hallmark of Aging: Altered autophagy

Altered (macro-) autophagy or something more descriptive altered cellular waste disposal is the twelfth and final Hallmark of Aging. Among them  Science understands that our cells can no longer get rid of the cellular wasteThis 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 the sake of simplicity, in the rest of the article we will only refer to the autophagy speak.

Why does cellular waste disposal play such an important role? To answer this question in more detail, we will take you on a little journey through the body and introduce you to the different components of your waste disposal systemDon’t be put off by complicated names like Autophagic-lysosomal system or chaperone Don't be intimidated, we'll explain everything to you step by step. We'll also take a look at the research and explain why Sleep and the supplementation of spermidine can be a booster for a weak recycling system.

What is autophagy?

Autophagy describes the cell's own recyclingIt is quite normal that proteins or other cell components eventually lose their function or are no longer needed. After all, our requirements change over time. Our cell power plants – the mitochondria – do not last a whole human life. The task of autophagy is to ensure that these remnants are broken down correctly and the components are then reused.

The faulty degradation of, for example, proteins – the loss of proteostasis – we have already Hallmark of Aging can be identified. Incorrectly folded proteins can no longer be unfolded. This carries the risk of clumping. However, since the disposal of proteins is only a small part of cellular waste disposal, the hallmarks of aging have been expanded. Altered autophagy has been a separate hallmark since the last update. We'll show you exactly what happens to it as we age here.

From scissors to acid traps – how is the waste in our cells disposed of?

Before we look at what goes wrong as we age, we should first take a closer look at our recycling system. It is elegantly designed and does its job day after day without us noticing.

Roughly speaking, there are two major systems in the waste disposal of the cellsThe first has the cumbersome name Ubiquitin-proteasome system (UPS) and has two main tasks. On the 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 see the Proteasomes can be thought of as a kind of filter with highly specialized scissors inside. All proteins that enter the proteasomes are carefully separated and are then available to the cell as new building blocks.

The second major system bears the no less complicated name Autophagic-lysosomal system. This is more complex than the UPS, as it not only splits individual proteins, but in case of doubt entire cell organelles are broken down into their building blocks and these are then returned to the cellular metabolism.

The 4th Hallmark of Aging is largely due to a malfunction of the ubiquitin-proteasome system. This is now about autophagy.

Just as mountains of garbage often accumulate in nature, the same thing happens to us humans as we age.

The Autophagic-Lysosomal System

In our cells, it is not only faulty proteins that are a problem, but also cell organelles that no longer function. The role of ATP and the mitochondria We have already written detailed articles, but they reveal little about what happens when old mitochondria have to be broken down. This happens through the macroautophagy.

Here again, simplified: A shell forms around the old mitochondrion, which can be seen in its entirety autophagosome Now we have a protected environment. This is necessary so that the degradation inside the cell does not destroy the entire cell.

In the next step The autophagosome connects with the lysosome. This is a Kind of small stomach – it contains lots of 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 connection between the autophagosome and the lysosome.

After digestion, everything that can be reused is returned to the cell and the waste products are transported away with the lymph fluid.

Lipofuscin – when you can literally see your 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 "garbage shredder“, these cell organs can also absorb large proteins that no longer have a function in the cell, but are too large to be transported away via the lymph or bloodstream. This “hazardous waste“ is stored in the cell in small capsules called “granules”.

If you look at old nerve or muscle cells under the microscope, you can also see many of these dark spots. A large part of this is lipofuscin. It consists mainly of damaged mitochondria that can no longer be broken down properly. The cellular waste basically "clogs" the cell and thus limits its function. This is probably one of the reasons why mitochondrial dysfunction comes with age.

Age spots can be seen under the microscope not only on nerve cells, but also on aging skin.

Alzheimer's – one of the most prominent examples of faulty waste disposal

Another disease that is associated with One disease associated with improper waste disposal is Alzheimer's dementia. This is where the deposition of so-called amyloid plaques. Due to faulty degradation, these complexes accumulate in the nerve cells and “clutter” them.

In addition, in Alzheimer patients, tau protein changed – a protein that is important for cell stability. The result is an unstable cell and the death of neurons.

Alzheimer's has become a widespread disease over the decades. The risk factors are partly genetic and partly lifestyle-related. Incorrect 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 to help autophagyA very promising one is sufficient SleepWhile we sleep peacefully, our brain is being cleaned up. The so-called glymphatic system ensures that the day's waste products are removed.

For a long time, sleep was treated somewhat stepmotherly in medicine, but We now know that sleep is extremely important for our healthIf we do not sleep enough for months or years, the cellular waste cannot be properly removed and the risk of Alzheimer's increases.

Mitochondria and autophagy – when strength is lacking in old age

We have already discussed age spots, lipofuscin, we have seen what happens to old mitochondria that can no longer be broken down properly. Faulty mitochondria and the lack of them are associated with typical signs of aging such as heart failure, but also one of the Drivers of age-related loss of muscles.

One of the most important molecules in the mitochondrion is NAD. This is involved in countless metabolic processes – but above all central to energy supply. Just like the mitochondria, the NAD levels decrease with ageThis can be done by NAD tests, which measure the NAD concentration in the blood.

Studies have now shown that the administration of NAD precursors, as in NAD boosters are included, not only correct the NAD levels, but also increase autophagyIn animal experiments, this even extended life.

regeNAD is an innovatively formulated complex to increase NAD levels - with luteolin and apigenin.

Fasting – an autophagy boost

The abstinence from food in the form of Fast, can be helpful 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 short version.

When we are in a state of fasting, this seems to be a kind of starting signal for our body to recycle old material. After all, there is currently no food coming in. The chaperones are therefore 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 removing proteins that they can no longer fold correctly. to the lysosomes and thus ensure degradation. True gentlemen, then.

Fasting ensures that our body restarts its own recycling system in various ways. Be it by activating the sirtuins, about the Dr. David Sinclair researched, or through the chaperone system. A similar approach has been fasting mimeticsas you see in fasting bundle find.

Spermidine – a promising molecule

Another very exciting approach to To stimulate autophagy in old age, supplementation with the body’s own molecule spermidine. This molecule has already been successfully tested in several animal studies and increased cellular recycling. Spermidine appears to be particularly beneficial for the health of heart cells, which is why studies are also being conducted in humans. In mice, spermidine supplementation has already shown a life extension by up to 25% bring. Also a spermidine-rich diet in humans has been linked to better health.

According to research, the natural substance spermidine is closely linked to autophagy - 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 development of some age-related diseases. However, we are not completely powerless. There are ways to increase autophagy as one of the hallmarks of aging, be it through fasting, Sport, Buy Spermidine or NAD precursors.

We can look forward to seeing what new approaches will come onto the market in the next few years and whether we will be able to use them to prevent diseases such as Alzheimer's at some point.

This was the last article in the series Hallmarks of Aging.

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11. Hallmark of Aging: Dysbiosis

For several years now, the microbiome increasingly at the centre of public interest. The billions of bacteria, that live in our bodies have a previously underestimated influence on whether we are healthy or sick. The exact relationships are not yet fully understood, but one thing is certain:  We live in a narrow Symbiosis with our bacteria.

The better we understand this interaction, the better we can use it to our advantage. For example, if we eat a lot of plant-based fiber our intestinal bacteria can convert these into short-chain fatty acids which are associated with several health benefits. Maintaining as much diversity as possible in the microbiome is also beneficial to health.

In old age, this symbiosis seems to increasingly become a dysbiosis to become. Fewer and fewer of the “good” bacteria live in our intestines and the “bad” ones take over. This cannot be easily broken down into one type of bacteria, as each microbiome is highly individual and depends on many factors (e.g. ethnic origin, living conditions, food choices, lifestyle, etc.). Changes in the microbiome are associated with some chronic diseases, such as diabetes, cardiovascular disease and cancerHere you can find out everything about the topic.

More than just bacteria – our microbiome

About the microbiome Entire books can be filled with this topic. Hardly a day goes by without a new study being published on the subject. And the research interest is more than justified. The microbiome depends on us and vice versa. How exactly this symbiosis works is gradually being revealed. Roughly speaking, we need the microbiome to get some nutrients from foodOur body does not have the right enzymes to break down every nutrient. And this is where the microbiome comes into play.

What would normally be considered “waste” for us, such as fiber, can be digested by our microbiome. The bacteria even depend on us to “feed” them. In return, they produce some substances that are beneficial to our health. These include secondary bile acids, vitamins, amino acid derivatives and short-chain fatty acids.

In addition, the microbiome appears to be closely linked to our intestinal nervous system – a gigantic network of nerve cells that surround our intestines along their entire length. If you like, our second brain or our “gut feeling“And this enteric nervous system is of course also in communication with our central nervous system.

As you can see, the microbiome is complex and its connections and effects are even more complex. This does not always make it easy to conduct studies. Nevertheless, scientists have been able to find out a lot about aging. More on that in a moment.

Diversity is what matters – symbiosis instead of dysbiosis

Before we look at what happens when the microbiome does not work to our advantage, we have to ask ourselves what a healthy microbiome isThis question is more difficult to answer than one might think at first glance. There are countless studies on the subject and the findings can be defined as follows: The microbiome is very individual. What bacteria did we carry with us from early childhood? In which country were we born? What genes do we carry? What did our diet look like in childhood? Did we have serious intestinal infections? What do we eat? Do we eat a lot of fiber? And so on.

It is widely recognized that we develop our microbiome in early childhood and that it usually remains stable throughout our adulthood remains (unless you radically change your lifestyle or environment).

The older we get, the more the diversity of bacteria in our intestines decreases. The researchers see this as one of the main reasons for age-related diseases. A one-sided microbiome makes us susceptible to an excess of “bad” bacteria.

This can be seen impressively in the example of Clostridium difficile This small bacterium lives in our intestines and initially does not cause much of a stir. If we have a more serious infection, requires special antibiotic treatment,  However, this bacterium has a survival advantageWhile most of the bacteria in our intestines die, C.difficile survives and begins to multiply rapidly because there are suddenly no more competitors. The result is a severe intestinal infection that often requires hospital treatment.

Dysbiosis can be triggered by an overpopulation of the bacterium Clostridium difficile. This is often caused by antibiotic therapy.

Dysbiosis using p-Cresol as an example

There are hundreds of metabolic processes, all of which have a potential impact on our health. To simplify things a little, we'll show you an example of a fairly well-researched metabolite: p-Cresol

In the ELDERMET study 500 people, all over 65, were tested for their microbiome and possible metabolites. It was found that participants with higher stool concentrations of p-cresol had increased frailty.

So what is p-cresol? This molecule is formed by the Fermentation of the amino acid tyrosine in our intestines. The sulfated version of the molecule is excreted through our kidneys. As long as our kidneys are healthy, this does not seem to be a problem. However, when the filtration rate decreases and the p-cresol level in our blood increases, it seems to become problematic.

High p-cresol levels are associated with the development of cardiovascular diseases and they have a toxic effect on the filter system in our kidneys. This seems to be a vicious circle.People with poor kidney function often have dysbiosis of the microbiomeThere is an increase in aerobic bacteria that promote the production of toxic metabolites, including p-cresol. Perhaps this is a possible starting point for the future.

Tryptophan Metabolism: From Symbiosis to Dysbiosis

Another important metabolic process in our intestine is the tryptophan pathway. Tryptophan is an amino acid that we absorb through food, for example. Our intestinal bacteria have various ways of metabolizing this amino acid. We will show you the three most important ones:

  • kynurenine pathway (Kyn): About the enzyme I DO (indoleamine-2,3-dioxygenase) tryptophan is broken down to kynurenine
  • serotonin pathway: Our intestinal bacteria can convert tryptophan into the “happiness hormone” serotonin. A full 90% of our serotonin is found in the intestines! Via this axis, tryptophan can also be melatonin, the sleep hormone
  • indole pathway: The third way of tryptophan degradation is the indole pathway. Higher indole concentrations in older people could be increased fitness In mice, too, lifespan was increased by increasing indole metabolites

Dysbiosis as a Hallmark of Aging: It's all about balance

Some studies on tryptophan metabolism conclude that Disturbance of balance can contribute to illness. For example, the above-mentioned enzyme IDO (to be precise, the subclass IDO-1) is overactivated, We find more kynurenine compared to serotonin than is normal in the body. This excess of kynurenine is associated with some diseases. It has been shown that Depressed people often have overactivation of IDO-1, which results in lower serotonin levels. One of the hypotheses is that this contributes to depression.

Note: The hypothesis, long accepted in science, that low serotonin levels are the trigger for depression is not entirely correct. Serotonin plays a role in the disease, but it is not so easy to break down.

Chronic inflammation can increase IDO activity and thus the assumption can be formulated that inflammations In this way, they also contribute to the dysbiosis of our microbiome.

Inflammaging and dysbiosis – two hallmarks with close links

As we have just seen, a chronic inflammation can have a negative impact on our microbiomeBut it also seems to work the other way around, at least that is what experiments on mice suggest. Two populations of mice were used for this purpose.Once young and healthy mice and once older, sick mice. Now the microbiome of the older mice was transferred to the younger miceThe result was that the younger mice showed significantly more signs of inflammation, i.e. higher inflammatory markers.

Conclusion

The microbiome is one of the most exciting fields of research and the disruption of its balance seems to contribute to some diseases in old age. We are losing the diversity of bacteria that keep us healthy and that is why dysbiosis has been included as one of the Hallmarks of AgingIn the future, we will certainly see some therapeutic approaches that reverse precisely this dysbiosis.

The next article in this series is about the twelfth hallmark of aging: Altered autophagy.

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