Mitochondria: the key to longevity

They are called cellular powerhouses – it is in the mitochondria that nutrients taken in from food are converted into energy that powers our entire body. These tiny organelles therefore co-determine our vitality, our body’s willingness to lose weight, but also the speed of our ageing.

A little warning right at the beginning: This article is going to be long. But according to recent research, mitochondria affect our health, aging processes, and physical and mental performance in such a fundamental way that it deserves a more comprehensive text that goes into sufficient depth. It is mitochondria that provide cells with the most essential thing they need to function: energy. Moreover, they differ from other cell organelles (except the cell nucleus) in an important way: they contain their own DNA.

Mitochondria produce energy aerobically, i.e. they oxidise glucose and fatty acids with the help of oxygen. The energy contained in their molecules is then stored in so-called macroergic phosphates (e.g. ATP), which are the only substances that can serve as an energy source for all cells in the body.

Mitochondrial “fitness” is therefore essential, especially for tissues that depend on aerobic energy production – most notably the brain, heart and eyes, where up to 90% of the energy required for these cells to function is produced aerobically. It is therefore these organs that are most vulnerable to disruption of mitochondrial function. The skeletal muscles, the islets of Langenrhans in the pancreas, the kidneys and the liver follow close behind.

It is also interesting to note that a large number of mitochondria are contained in the muscle cells of endurance athletes. This is because in endurance events, muscles obtain most of their energy aerobically, and therefore the increase in mitochondrial numbers is an important part of adaptation to endurance exercise.

A bit of a different DNA

Most of you probably remember that our DNA is stored in the cell nucleus. That may be true, but the nucleus is not the only place where this key substance is found. In fact, the mitochondria also have their own DNA. When a cell divides, the nucleus first undergoes what is called DNA replication, in which the original double helix becomes two new, identical helices. However, the same process also takes place in the mitochondria.

Each mitochondrion contains 2-10 molecules of mitochondrial DNA (mtDNA). Depending on the type of tissue (and the number of mitochondria), each cell usually contains between 1,000 and 10,000 molecules of mtDNA. The exceptions are sperm, where there are only a few hundred, and eggs, where there are up to 100,000.

Like the DNA in the cell nucleus, we inherit mtDNA from our parents, even with negative changes caused by mutations or epigenetic processes that our parents have accumulated on their mtDNA up to the moment of our conception. But there is one major difference: while in the case of nuclear DNA we get half of our genes from our mother and half from our father, mitochondrial DNA is inherited almost exclusively from our mother. There are two reasons for this: first, there are many times more mitochondrial DNA molecules in the egg than in the sperm, and second, the sperm’s mitochondria are almost completely destroyed when it enters the egg. It was the analysis of mtDNA, by the way, that led scientists to the hypothesis that all humans in the world are descended from a single woman who lived in Africa 250,000 years ago.

Thus, paternal mitochondrial DNA is present in our cells only in very minimal amounts, but in case of its damage it can still cause problems – for example, a case of a patient who suffered from myopathy due to mutations in paternal mtDNA has been described.

Mutations everywhere you look

mtDNA has a different structure than the DNA in the cell nucleus. It lacks proteins called histones, which co-create the structure of this substance in the nucleus – it is the histones that the DNA strands are wound on like thread on a spool. But this is also why mtDNA is less well protected, and why mutations occur up to ten times more often than in the cell nucleus. In addition, its functionality is also impaired by epigenetic changes – i.e. through biochemical reactions that decrease or increase the activity of individual genes.

While epigenetic changes are largely reversible (although this usually requires, for example, a major lifestyle change), changes caused by mutations are definitive. They can only disappear if the “mutated” mitochondria, or indeed the whole cell, is destroyed. Moreover, unfortunately, when a cell undergoes division, the mitochondrial DNA is copied alongside the nuclear DNA. Unfortunately, this is because all errors are copied along with it – those caused by mutations and those caused by epigenetic changes. Meanwhile, negative changes in both types of DNA generally increase with age, and because of this the rate of negative changes increases not only in nuclear DNA but also in mitochondria.

Mitochondria and aging

So as the organism ages, the mitochondria change – they become fewer and larger, and various abnormalities arise in their structure, and this also affects their function. In particular, their efficiency in generating energy decreases, so that cells in individual tissues suffer from a kind of “malnutrition”, even though there is plenty of nutrients flowing to them in the blood. However, other processes in the body, such as calcium balance or the permeability of cell membranes, are also affected. Particularly high levels of negative changes then lead to apoptosis, or cell death.

But it also turns out that the link is probably reversed: the more negative changes accumulate in our mitochondria, the faster we age and the greater the risk of many diseases and other manifestations of ageing. In any case, while young individuals tend to have only a small amount of mitochondrial damage, the elderly have an overwhelming amount of damage to these organelles.

Mitochondrial dysfunction is also directly related to the development of a number of diseases – especially those affecting the organs most demanding of aerobic energy production. Typical examples include Alzheimer’s disease, some eye diseases, cardiovascular diseases and diabetes, but also hair loss, osteoporosis and autism. We will provide more details on the connection of various diseases with mitochondrial function in the next article.

Declining mitochondrial function is also one of the reasons why weight gain tends to increase with age. Their primary function is to convert nutrients into energy, and when this process is impaired, nutrients taken in from food are stored in much larger quantities in fat stores.

Watch out for free radicals

Mitochondria are also extremely sensitive to oxidative stress. Increased production of free radicals therefore significantly impairs their function. Moreover, it is often the disruption of mitochondria that causes cell death due to oxidative stress. Peroxide and oxygen radicals are particularly problematic for mitochondria – their accumulation has a similarly devastating effect on cells as radiation exposure, and can even cause apoptosis or cell death.

In addition, the body’s antioxidant defences deteriorate with age, again increasing the risk of mitochondrial damage. In addition, damaged mitochondria also produce a lot of free radicals themselves, creating a vicious cycle that leads to increasing damage to many tissues and systems in the body.

But the problems are far from over. The substances secreted by the damaged mitochondria bind to receptors on immune cells, which then react in the same way as when they encounter a pathogen – they start secreting substances called cytokines that promote inflammatory processes. This inflammation then increases the risk of a number of diseases, including the most serious ones.

According to some hypotheses, peroxide and oxygen radicals may also contribute to the body’s impaired immunity to viral and other infections, because viral particles spread much faster in cells that are damaged by them.

It follows that if we can support mitochondrial function, we can do a lot for the functioning of the whole body.

A hope called plastoquinone

It would seem, then, that the most effective weapon against aging and diseases related to mitochondrial dysfunction is a high intake of antioxidants. For this purpose, for example, vitamin E supplementation was recommended until recently. Unfortunately, it is not that simple. On the one hand, it is true that a low intake of antioxidants speeds up ageing, but the complete destruction of free radicals throughout the body is also not desirable, because these substances are also beneficial to the body in certain amounts. Therefore, the body will not allow the elimination of all free radicals and therefore ruthlessly destroys antioxidants taken in above a certain level. Because of this, however, a certain amount of peroxide and oxygen radicals remain inside the mitochondria, which can cause damage.

The only possible solution to ensure that all free radicals in the mitochondria are eliminated is to get antioxidants directly inside these organelles. Unfortunately, no natural substance has this ability, but several scientific teams from Russia, the USA and Sweden have been working intensively for a few years to develop and test synthetic antioxidants that would be significantly effective in protecting the mitochondria. So far, derivatives of plastoquinone (SkQ), in particular the compounds abbreviated SkQ1, SkQ3 and SkQR1, seem very promising.

Even very small amounts of SkQ1 and SkQR1 were able to completely stop apoptosis caused by peroxide radicals in animal experiments. Larger concentrations were then able to significantly slow down ageing, both in invertebrates and mammals.

In addition, in mammals, administration of plastoquinone derivatives significantly suppressed the development of some age-related diseases, such as osteoporosis, cataracts, glaucoma and retinopathy (a disease that causes damage to the retina). After administration of SkQ1, there was even a reduction in the affected area after myocardial infarction and stroke!

In addition, plastoquinone derivatives can effectively inhibit the formation of senescent cells. These are cells that have already undergone a large number of cell cycles and have lost the ability to divide. However, they do not die but accumulate in the tissues and can cause a number of problems. The process of senescence is considered to be one of the most important mechanisms of ageing (more here https://www.epivyziva.cz/elixir-mladi-klic-mozna-lezi-v-senescentnich-bunkach /). Protecting mitochondria from free radicals can suppress the formation of senescent cells.

So there is hope that we will soon see a real elixir of youth.

Mitochondria and the gut microbiome

However, synthetic antioxidants are not the only way to protect mitochondria and boost their function. Another very powerful weapon is found right inside our bodies. This is the much talked about gut microbiome.

In recent years, disruptions in the balance of the gut microbiome have been linked to the development of an increasing number of diseases, and it is no coincidence that many of these are related to the brain – be it Alzheimer’s disease, depression or even autism. The microorganisms that inhabit our gut are not only involved in digesting food, producing certain nutrients and maintaining an optimal environment and microbial balance within the gut. Some gut bacteria also produce substances that enter the blood and subsequently affect the functioning of processes throughout the body.

Perhaps the most important of these are the short-chain fatty acids, i.e. acetate, propionate and butyrate. Especially the last one, butyrate, is quite essential for the functioning of mitochondria and can even influence the activity of some genes in mitochondrial DNA in an epigenetic way. Butyrate also improves the ability of mitochondria to oxidize nutrients and generate energy from them in the form of ATP. It also increases the sensitivity of the cells to insulin, which also results in an improved ability of the mitochondria to produce energy (and, of course, improved regulation of blood sugar levels). Butyrate also reduces the concentration of oxygen free radicals inside the mitochondria, improving their integrity and generally protecting them from damage.

Another interesting function of butyrate is to promote autophagy, a process in which the cell literally eats itself. Through this process, the cell is able to remove parts of itself that are somehow disturbed, which includes damaged mitochondria.

Moreover, mitochondria can efficiently use butyrate as an energy source, which may be particularly beneficial in Alzheimer’s disease, where brain cells suffer from a lack of energy due to insulin resistance.

How to support mitochondrial function

Therefore, in addition to antioxidant protection, it is certainly worthwhile to take care of the gut microbiome, especially regular consumption of probiotics and prebiotics, in order to protect and support mitochondrial function. Particularly important in this respect is a high consumption of fibre, which serves as food for gut bacteria.

In addition, it is necessary to highlight especially aerobic movement (brisk walking, running, swimming, cycling, etc.) As we have already mentioned in the introduction, for these activities the muscles need to obtain energy in an aerobic way, which is the domain of mitochondria. Therefore, if we engage in aerobic exercise regularly, the body adapts to the load by increasing the number of mitochondria in muscle cells and improving their function. Moreover, this effect also works in the case of the elderly and even a relatively low intensity exercise (at the level of brisk walking) is sufficient.

Increasing the number of mitochondria in muscles and improving their function not only improves athletic performance, but also has the beneficial side effect of improving muscle sensitivity to insulin. This reduces insulin resistance and lowers blood sugar levels, which is important in the prevention and treatment of diabetes and obesity. In most cases, mitochondrial function is fundamentally impaired in obese individuals, which in turn complicates weight loss due to the limited capacity to convert nutrients into energy. This puts obese individuals in a vicious circle, and focusing on regular exercise can help break it.

The high consumption of simple sugars, i.e. glucose, fructose and sucrose, also contributes to mitochondrial damage. These react with proteins and fats in the body to form compounds known as AEGs. These in turn promote the production of NF-kB, which activates a number of inflammatory genes in cells. The result is an inflammatory process that worsens a number of processes in the body and, among other things, damages mitochondria. It is therefore definitely worth trying to limit the content of these simple sugars in the diet.

Restriction of total caloric intake also has a positive effect on mitochondria – this is also related to improved antioxidant protection of these organelles and has a particularly strong protective effect on nerve cells. Starvation also promotes the ability of cellular autophagy, which is the way in which the cell gets rid of damaged mitochondria.

Mitochondrial function is also affected by epigenetic changes, especially in the area of two genes – CGAT and SHMT2. These are responsible for the production of the amino acid glycine inside mitochondria, and glycine significantly supports mitochondrial function.

Useful dietary supplements

Sirtuin activators –sirtuins are enzymes that are associated with longevity and also play an important role in the proper functioning of processes within the mitochondria. Among the best known sirtuin activators is resveratrol, a dye found in grape skins. A similar compound, piceatannol, also found in grapes and, to a lesser extent, blueberries, also has excellent effects.

Butyrate, a short-chain fatty acid, is produced by bacteria that are part of the gut microbiome (see above), but it is also possible to increase its blood levels by taking supplements.

Glycine – this is an amino acid that is a common part of the diet. However, when it was also given to very old people (over 90 years old), they experienced a significant improvement in mitochondrial function.

Vitamin B2 – from this vitamin derives a substance called flavin adenine dinucleotide, which is essential for mitochondrial function.