Regeneration

Why is regeneration important?

Our body is a true marvel. Every day, the millions of mitochondria provide energy for our body in the form of ATP. You can think of this as a universal energy currency that we can use to pay for everything that costs energy. A heartbeat, solving a difficult mental task or maintaining our body temperature. All these processes require energy in the form of ATP. To appreciate this feat even more, you can consider that our body produces as much ATP every day as we weigh. All these processes are highly complex and prone to errors. Even at 25 years of age, the mitochondria show the first signs of fatigue and the metabolic processes no longer run optimally. We will delve a little deeper into metabolic physiology with you and show you how cellular energy is produced and why its regeneration is not always optimal.

Mitochondria and energy

Before we take a closer look at the topic of regeneration, we need to take a brief look at how we produce our energy. To do this, let's take a closer look inside the cell, or to be more precise, inside the mitochondria. These little powerhouses are found in almost every cell in our body. As an analogy, you can imagine a factory and the manufactured product is ATP. We can generate ATP, carbon dioxide (CO2) and water from sugar (glucose) and oxygen via several intermediate steps, such as the citrate cycle or the respiratory chain. You may remember the individual steps from your biology lessons. If not, you can read about them in our articles on the respiratory chain and mitochondria.

You don't have to memorize or understand all the steps. However, there are two molecules where it is worth taking a closer look: alpha-ketoglutarate and NAD.

Alphaketoglutarate and the energy metabolism

There are different spellings for alpha-ketoglutarate: Alpha-ketoglutarate or 2-oxoglutarate, AKG or Ca-AKG. Alpha ketoglutarate plays a decisive role in energy production within the mitochondria. It is part of the citric acid cycle (citrate cycle), which is one of the intermediate steps in ATP production.

Similar to NAD, it is built up and broken down again and again. The older we get, the lower the levels. Depending on the study, AKG levels fall by up to 50% in old age. Interestingly, alphaketoglutarate is not found in food, yet we need it for cellular regeneration, especially in energy metabolism. For this reason, this study investigated what happens when people are given alpha-ketoglutarate. The result was a reduction in biological age by a whole 8 years in the epigenetic test.

Nicotinamide adenine dinucleotide (NAD) - the coenzyme of energy production

The name nicotinamide adenine dinucleotidemay sound complicated, which is why we will use the abbreviation NAD in the following. There are other abbreviations for the molecule. You will find NAD+, NADH or NAD+/NADH in the literature. These abbreviations describe the different states of the molecule. For the sake of simplicity, we will stick with NAD.

In simple terms, NAD is both an electron donor and an electron acceptor. This means that it can accept and release electrons. During energy production, NAD takes up electrons, transports them into the mitochondria and releases them there again. In this way, an electron imbalance can be created, which then operates a small "enzyme pump" that turns ADP back into ATP. So without NAD we would not be able to generate any energy at all.

Did you know? NAD is a coenzyme, which means it serves as an aid for biochemical reactions in our body. NAD is a real all-rounder and is involved in over 500 different reactions in the body. However, just like alphaketoglutarate levels, NAD levels fall with age - in both men and women. This means that we have significantly less of this important coenzyme at our disposal.

Where does the loss of NAD come from?

There are about 3 grams of NAD in our entire body. However, this supply is constantly being depleted and built up again. There are three possible ways in which we can produce NAD in the cell:

• Recycling pathway: NAD can be produced via the precursors nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN)
• Preiss-Handler pathway: Here, vitamin B3 precursors (niacin) are the starting substances
• de novo pathway: This is the longest pathway and begins with the amino acid tryptophan as the starting point

There are several theories as to why NAD levels decrease with age. On the one hand, we produce less NAD from the precursors and on the other hand, the breakdown of NAD is increased. If you want a deeper insight into the science behind this, you can read our article on nicotinamide adenine dinucleotide.

Strengthening NAD levels - but how?

According to the theory, there are several ways: 1) Supplement NAD precursors 2) Boost key enzymes 3) Inhibit degradation.

There is a wide range of different precursor molecules, all of which can lead to improved NAD production. The effectiveness depends on the study and the group studied. As a rule, the precursors are vitamin B3 derivatives, such as niacin.

In addition to the precursors, you can try to support the key enzymes in the metabolic pathway. For example, the epigallocatechin gallate (EGCG) contained in green tea epigallocatechin gallate (EGCG) can stimulate the key enzyme NMNAT, which catalyzes the final step in NAD synthesis. Green tea, like matcha, could therefore contribute to strengthening the NAD metabolism. Or the plant flavonoid luteolin can activate the key enzyme NAMPT, which converts NAM into NMN.

The last point is to inhibit the breakdown. There is an enzyme that plays a particularly important role in old age. It is called CD38 and is activated, for example, by inflammatory processes(inflammaging) in old age. More CD38 means less NAD. Here, too, there is a secondary plant substance that inhibits the activity of CD38. Apigenin.

Did you know? Would you also like to measure your NAD level? With Europe's first NAD test, you can do this easily from home. In collaboration with Vilnius University, we at MoleQlar have developed a precise and easy-to-perform test. Curious to find out? Find out your NAD levels and find out which method can help you achieve an optimal NAD level.

NAD - more than just cellular energy

Now that we have seen how important the small molecule NAD is for our energy production, let's turn to another aspect. Before we do that, a quick note. The three approaches to boosting NAD levels are explained in much more detail in our article on the product regeNAD. There we go into more detail about the biochemical background and the studies and show why the combination of niacin, L-tryptophan, EGCG, apigenin, luteolin and vitamin B6 in regeNAD is so effective at boosting NAD levels.

Now back to our coenzyme NAD. NAD not only helps with energy production, but also plays a role in cell repair and protection. It is involved in processes that ensure cells stay healthy and function properly by helping to repair DNA damage and supporting the activity of enzymes that protect cells from stress.

Regeneration - of longevity genes and cellular energy

Nicotinamide adenine dinucleotide(NAD) is a coenzyme that helps our body to repair and protect cells. But how exactly? Every day, minor damage occurs in our cells. Imagine the whole thing like an oversized factory. Somewhere there will be a misfire, or sparks will damage the environment. It's similar in our body. Our energy production in the mitochondria alone creates a potential source of danger, because the production of ATP is nothing other than the oxyhydrogen reaction - only without the bang, if everything goes well.

Nevertheless, free oxygen radicals are constantly being produced, which can be potentially harmful to us. They damage the DNA or the structure of our cells. Collagen can be attacked or other molecules in the cell structure. In order to either eliminate this damage or keep it to a minimum, our body has several compensatory mechanisms. One is the radical scavenger glutathione, which we can strengthen with alpha-ketoglutarate and GlyNAC (more on this later), and the other is our repair mechanisms. First and foremost, the sirtuins and PARPs.

Sirtuins and PARPs - regeneration proteins for longevity

The PARP family is the much larger family. The PARP1 and PARP2 subclasses require NAD to repair our DNA, for example.

The sirtuins are somewhat better researched. This family, often referred to as "longevity genes", (currently) consists of seven members. In particular Sirt1, which is activated by resveratrol, and Sirt6, are the focus of researchers through animal experiments. Harvard professor David Sinclair is one of the pioneers in this field and has concentrated on the interaction between the sirtuins and lifespan. He has discovered that activating the sirtuins can lead to a longer life. They achieve this effect by....

• promote DNA repair: Sirtuins help to repair damage to DNA, which increases genetic stability and improves cell function.
• Reduceinflammation: Sirtuins counteract anti-inflammatory processes that are often associated with ageing and disease.
• Improve energy efficiency: Sirtuins improve the efficiency of mitochondria, the energy powerhouses of cells, which contributes to better energy management and longevity.

Did you know? PARPs are needed to repair DNA. To do this, they need a lot of energy and NAD as a coenzyme. With age, more and more DNA damage occurs(genomic instability), partly due to inflammaging. The PARPs are upregulated and "consume" more NAD. This is one possible theory as to why NAD levels decrease with age

How can you boost NAD and sirtuin activity?

• Nutrition: Foods rich in niacin (vitamin B3) support NAD production. Polyphenols, such as those found in dark chocolate, green tea and red wine, can also support sirtuin activity.
• Calorie restriction and intermittent fasting: Both have been associated with increased NAD levels and increased sirtuin activity.
• ExerciseRegular physical activity promotes mitochondrial health and supports higher NAD levels.

Fasting - a way to boost regeneration

Fasting has a firm place in many religions, but researchers such as Valter Longo and David Sinclair have been able to decipher the molecular processes behind the fasting process. Fasting can contribute to the regeneration of our cells. For example, when we do not eat for a period of time during intermittent fasting (16:9), our cells are exposed to a "hunger" signal. The cells are put into a state of autophagy so that they recycle their own components. In animal studies in particular, calorie restriction has successfully extended the life of animals.

There is also evidence that fasting is associated with health benefits in humans. For example, people in the so-called Blue Zones often practise a form of calorie restriction.

On a molecular level, fasting activates sirtuins and this effect is considered to be one of the main reasons for the positive health effects, not only on our metabolism. Certain diets, such as the Sirtfood diet - made famous by the singer Adele - also try to make use of this effect.

Oxidative stress and cellular regeneration

We have already seen from energy production in the mitochondria that the process of ATP production can also cause some damage to the cell. This is in the form of oxidative stress. To help you better understand the connections, we need to briefly explain what science understands by oxidative stress and why it is so important for our cellular energy and regeneration.

Oxidative stress is a condition in which there is an imbalance between free radicals and antioxidants in the body. Imagine our cells as a factory. During energy production, sparks (free radicals) are constantly being produced. In the worst case scenario, these can start a fire, which would destroy the entire factory. For this reason, there are "guards" (antioxidants) that neutralize the sparks before they become dangerous.

What are free radicals?

Free radicals are molecules with an unpaired electron that are highly reactive. They are normally produced in the body during various processes such as energy production in the cells or in response to environmental stressors such as smoke or UV radiation. Free radicals are not inherently bad, as they can perform certain beneficial functions, such as fighting infection. So we always need a delicate balance between free radicals and antioxidants.

What are antioxidants?

Antioxidants are the "guards" in our cells that can neutralize free radicals before they cause damage. These molecules donate an electron to the free radicals without becoming unstable themselves, thus breaking the chain of destruction. Antioxidants are found in abundance in many fruits, vegetables and other foods. Our body also has molecules with a strong antioxidant effect, such as glutathione.

The consequences of oxidative stress

When there are too many free radicals and not enough antioxidants to neutralize them, they begin to attack important cellular components such as proteins, lipids and DNA. This can lead to a number of problems, including:

• Cell damage and premature ageing
• Inflammatory conditions
• Increased risk of chronic diseases such as heart disease, diabetes and cancer

Inflammatory processes increase particularly in old age, which is why one of the hallmarks of ageing is inflammaging.

How to reduce oxidative stress

There are various ways to get oxidative stress under control:

• NutritionEat plenty of fruit and vegetables rich in antioxidants, such as blueberries, spinach, carrots and tomatoes.
• Avoid environmental stressors: Smoking, excessive alcohol consumption, UV radiation and air pollution should be avoided as they can promote the production of free radicals.
• ExerciseRegular physical activity helps to strengthen the body's own antioxidant defenses.
• Stress management: Chronic stress can increase the production of free radicals, so it is important to practice effective stress management strategies.

Oxidative stress and GlyNAC

In order for our cells to generate optimal energy, there must always be a balance between oxidative stress and antioxidants. One of the most important molecules for this is glutathione. If we take a closer look at the liver, we can see why. Every day, our liver filters our blood and removes toxins. One of the mechanisms for this is glutathione. If our glutathione levels are depleted (as with an overdose of paracetamol), our liver can no longer cope. We can't really supplement glutathione very well because every cell in the body needs different amounts of glutathione.

However, it is better to add molecules that indirectly increase the glutathione level. These include alphaketoglutarate and GlyNAC. GlyNAC was tested in a randomized clinical trial on humans and was able to positively influence some of the hallmarks of aging. It also improves insulin sensitivity and blood pressure.

Conclusion on regeneration

The cells in our body do an enormous amount of work every day to generate enough energy. At the same time, the ability to regenerate decreases with age. As described by the Hallmarks of Aging, among others, our mitochondria no longer function as they once did. For this reason, part of longevity research focuses on the maintenance of regeneration and cellular energy. Molecules such as alphaketoglutarate, NAD, GlyNAC, or apigenin are promising candidates in ageing research.