The mitochondrial dysfunction is a central point in aging research. Often referred to as the “power plants of the cells”, the strength and efficiency of our mitochondria diminishes as we age. To make matters worse, old mitochondria can no longer be broken down properly and clog the cells until they lose their function. Many of the metabolic pathways associated with aging occur in or are involved in the mitochondria. An example would be NAD.
Here we'll show you what happens in our mitochondria, how age affects our cell organelles and what we can do to possibly reverse this hallmark of aging.
The mitochondria – a small miracle of nature
The mitochondria are found in different numbers in the body's cells and form one of many devices that contribute to proper cell function. Muscle cells, sensory cells or egg cells are cells with a high energy requirement. Accordingly, there are an above-average number of mitochondria in these cells. In a heart muscle cell the volume fraction even reaches an extraordinary 36%. This is already a pointer to the great importance of these cell organelles.
The body's own power plants have a special feature: They have their own DNA, the so-called mtDNA (from English. mitochondrial DNA), which floats around in a ring shape inside the mitochondrion. However, independent propagation is not possible. The mitochondrial genome in humans only contains 37 genes. For comparison: the DNA in the cell nucleus contains the information for 20,000-25,000 genes.
Did you know? In contrast to our DNA in the cell nuclei, mtDNA lies unprotected in the cytoplasm of the mitochondria. This makes them particularly susceptible to oxidative stress. Our body's own glutathione and antioxidants, which we find primarily in secondary plant substances , have a protective effect.
Respiratory chain, energy supply and NAD+
As is well known, energy is produced and provided in the mitochondrion. This process is called cellular respiration and takes place via the respiratory chain – an interaction of 5 protein complexes that form an electron transport chain. Electrons (negatively charged particles) therefore play an important role in the energy production process. At the beginning of the respiratory chain is the molecule NADH, which can donate two electrons as part of energy production. This ultimately creates ATP and the “waste product” NAD+. NAD+ is nothing more than the molecule NADH, only one proton (positively charged particle) and two electrons poorer.
Long story short: Energy production in our cells consists of splitting off the electrons contained in food. Energy is then released during this process. High NAD+ levels now mean that a lot of NADH is converted into ATP, meaning the cell is able to produce a lot of energy. That's a good sign. NAD+ subsequently activates Sirtuins, a group of genes associated with longevity. More on that later.
Did you know? As we age, NAD levels decrease. This can be done e.g.b simply determine with a NAD test . The reasons for this are varied, from reduced production to increased mining. We have summarized the detailed presentation of current research for you in our overview article “What is NAD”.
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Free radicals – reactive oxygen species (ROS)
A selected theory of aging proposes that the progressive mitochondrial dysfunction that occurs with aging leads to increased production of free radicals (= reactive Oxygen species, ROS from engl. reactive oxygen species). This further damages the mitochondria and leads to general cell damage. Antioxidants are of interest.
Numerous studies support this connection, but in recent years there have been increasingly controversial research results. For example, increased free radicals could extend the lifespan of yeast and nematodes. Additionally, genetic manipulations that caused oxidative damage did not accelerate aging in mice. The lifespan of mice was also not increased by manipulations that improved antioxidant protective mechanisms.
At the same time, basic research provided solid evidence for the role of free radicals in triggering cell division and survival signals in response to stress. In view of these and many other surprising results, the theory began to falter and a reassessment became necessary. Similar to the IGF-1 signaling pathway we were able to harmonize what at first glance seemed to be contradictory results under a common umbrella.
Hence ROS are a stress-related survival signal to compensate for the deterioration associated with aging. So the number of free radicals increases to ensure cell survival. At least until they betray their original purpose and worsen rather than alleviate the age-related damage due to the massive increase. You could also summarize it another way:
We need the ROS; they can act like training partners for our cells. But if they become too much, they cause damage to our cells.
Mitochondrial dysfunction and biogenesis
Aging caused by mitochondrial dysfunction is not only mediated by free radicals (ROS). Of a whole range of other factors, let's take a closer look at a few. As with so many processes in the body, the sirtuin gene family is also important here. SIRT1 modulates biogenesis via a protein called PGC-1α. This protein is the “master regulator” of mitochondrial biogenesis and a direct link between external physiological stimuli (such as exercise) and mitochondrial regulation.
A somewhat more tangible example: If small children participate in sports that require endurance performance, then fast muscle fibers (for sprints) are reprogrammed into slow muscle fibers (for endurance). These muscle fibers have a lot of mitochondria to ensure sustained energy supply.
The amount of mitochondria is determined by PGC-1α - a high level ensures increased mitochondrial production. However, a certain basic distribution of muscle fibers is genetically predetermined. However, the smaller variable part is controlled by physical demands via PGC-1α. Parents can therefore indirectly influence the muscular development of their children through the choice of sport.
Did you know? While exercise can increase PGC-1α levels, worry Inflammation causes PGC-1α to decrease. Typically, Nf-kB is activated during inflammatory processes in the body and this can have a direct negative effect on PGC-1α. This shows once again that the various Hallmarks of Aging act with one another and are difficult to separate from one another. Inflammaging, the tenth hallmark, thus directly contributes to mitochondrial dysfunction.
Back to Longevity Paths. SIRT1 also controls the removal of damaged mitochondria through Autophagy, a type of waste disposal in the body. SIRT3 targets enzymes that are involved in energy metabolism and is also able to directly control the rate of free radical production.
Viewed from a bird's eye view, these results support the idea that Sirtuins act as a type of metabolic sensor to influence mitochondrial function and protect against age-related diseases. Since the mitochondria have their own small genome, corresponding mutations in the genetic information naturally also disrupt functionality.
From theory to practice
So much for the molecular mechanisms in the mitochondrial structure. What do these findings bring us for our everyday life? Studies have shown that endurance training and alternating fasting improve health, there they can avoid mitochondrial degeneration. On the one hand, this is based on autophagy, which can be potently triggered by both fasting and endurance training. On the other hand, different forms of fasting activate additional longevity pathways, such as sirtuins.
Mitohormesis – small stimuli, big effect?
This somewhat mysterious-sounding term is made up of mitochondrion and hormesis. According to the concept of hormesismild toxic treatments trigger beneficial compensatory responses. The compensatory responses exceed the repair of the initiating damage and thereby lead to an improvement in cellular fitness compared to the state before the damage.
This hypothesis has its origins in Paracelsus and thus in the 16th century. century back. Over time, this view was substantiated experimentally and made medically useful for substances such as digitalis (heart failure), colchicine (gout) or opiates (pain).
A number of lines of research on aging have also focused on this concept. Although severe mitochondrial dysfunction causes illness, only mild disorders could extend lifespan due to a hormetic response. There is scientific evidence to support the view that metformin and resveratrol are mild mitochondrial poisons that induce a low energy state and thereby increase AMP levels. We already know the consequence from the paper on deregulated nutrient measurement: AMPK is activated and thereby slows down aging.
Metformin extended the life of roundworms and mice in some studies. Under normal nutritional conditions, resveratrol failed to extend the lifespan of mice, but there is strong study evidence that it protects against metabolic damage and improves mitochondrial function via increasing PGC-1α. The observation that PGC-1α overexpression extends the lifespan of fruit flies provides further evidence for the protein's role in longevity.
Summary of signaling pathways surrounding mitochondria and aging. Mitohormesis, PGC1a and free radicals are considered to have a protective function.
Conclusion – how can the mitochondria be strengthened?
Mitochondria are not only the power plants of the cell, but also potential sources for healthy aging. Function, or rather non-function, has a profound influence on the aging process.
The studies show quite clearly that through sport e.g.b Strengthen mitochondria can. Endurance and strength training, even into old age, form the basis. Additionally, we need to protect the mitochondria from excessive oxidative stress by consuming a diet rich in phytochemicals. Resveratrol, for example, has been shown to have a positive effect on the mitochondria.
Mitochondria health is always closely linked to NAD levels. Since these decrease with age, it can make sense to supplement the precursors, such as those contained in regeNAD t6>. The final aspect of strengthening our mitochondria is to ensure that the “disposal” of old mitochondria works smoothly. However, the altered (macro) autophagy represents its own hallmark of aging, which is why we will examine this aspect in more detail in another article.
In conclusion, mitochondria are a fascinating aspect of aging research. The goal for the future is to find out more about why mitochondria become less efficient as we age and how we can reverse this. The first steps have already been taken.
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The next article in this series will focus on the seventh hallmark of aging: Cellular senescence.
