Mitochondrial dysfunction is a central point in aging research. Often referred to as the "powerhouses of the cells," the power and efficiency of our mitochondria decline with age. To make matters worse, old mitochondria can no longer be properly broken down and clog the cells until they lose their function. Many of the metabolic pathways associated with aging occur in the mitochondria or involve them. One example would be NAD.
We will show you here what happens in our mitochondria, how aging affects our cell organelles, and what we can do to potentially reverse this hallmark of aging.
The mitochondria – a small wonder of nature
The mitochondria are present in varying numbers in body cells and form one of many structures that contribute to a functioning cell function. Muscle cells, sensory cells, or egg cells are cells with a high energy demand. Accordingly, there are also above-average numbers of mitochondria in these cells. In a heart muscle cell, the volume fraction even reaches an extraordinary 36%. This is already a hint towards the great importance of these cell organelles.
The body's own power plants have a special feature: they possess their own DNA, the so-called mtDNA (from English. mitochondrial DNA), which floats in a circular form inside the mitochondrion.Independent reproduction is not possible in this way. Only 37 genes are included in the mitochondrial genome in humans. In 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 is unprotected in the cytoplasm of the mitochondria. This makes it particularly susceptible to oxidative stress. Our body's own glutathione and antioxidants, which we mainly find in secondary plant compounds .
Respiratory chain, energy provision, and NAD+
It is well known that energy is produced and provided in the mitochondrion.This process is called cellular respiration and occurs through the electron transport chain – a collaboration of 5 protein complexes that form an electron transport chain. Electrons (negatively charged particles) play an important role in the energy production process. At the beginning of the electron transport chain is the molecule NADH, which can donate two electrons in the context of energy production. This ultimately results in ATP and the "waste product" NAD+. NAD+ is nothing more than the molecule NADH, just with one proton (positively charged particle) and two electrons less.
Long story short: The energy production in our cells consists of splitting off the electrons contained in food. This process then releases energy. High NAD+ levels now mean that a lot of NADH is converted to ATP, so the cell is capable of producing a lot of energy. This is 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 z.B. easily determined with a NAD test . The reasons for this are varied, from reduced production to increased breakdown. We have summarized the detailed presentation of current research in our overview article “What is NAD” for you.
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Free radicals – reactive oxygen species (ROS)
A selected theory of aging suggests that the progressive mitochondrial dysfunction that occurs with aging leads to an increased production of free radicals (= reactive oxygen species, ROS from English. reactive oxygen species). This further damages the mitochondria and thus leads to overall cell damage. Antioxidants are of interest in this context.
Numerous studies support this connection, but in recent years there have been increasingly controversial research results regarding this. For example, increased free radicals could extend the lifespan of yeasts and nematodes. Moreover, genetic manipulations that caused oxidative damage did not accelerate aging in mice. The lifespan of mice was also not extended by manipulations that improved antioxidant defense mechanisms.
Similarly, basic research provided solid evidence for the role of free radicals in the triggering of cell division and survival signals in response to stress. In light of these and many other surprising results, the theory came under scrutiny – a reassessment became necessary. Similar to the IGF-1 signaling pathway , it was also possible here to harmonize the seemingly contradictory results under a common framework.
Accordingly ROS are a stress-related survival signal to compensate for the deterioration associated with aging. The number of free radicals thus increases to ensure the survival of cells. At least as long as they do not betray their original purpose and rather worsen the age-related damage due to the massive increase than alleviate it. One could also summarize it differently:
We need the ROS; they can act like training partners for our cells. However, if they become too much, they cause damage to our cells.
Mitochondrial dysfunction and biogenesis
Aging due to mitochondrial dysfunction is not only mediated by free radicals (ROS). We will take a closer look at a whole range of other factors. As with so many processes in the body, the gene family of Sirtuins is also important here. SIRT1 modulates biogenesis through 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 the regulation of the mitochondrion.
Here is a somewhat more tangible example: When small children engage in sports that require endurance, fast muscle fibers (for sprints) are reprogrammed to slow muscle fibers (for endurance). These muscle fibers have a lot of mitochondria to ensure a sustained energy supply.
The amount of mitochondria is determined by PGC-1α – a high level ensures increased mitochondrial production. A certain basic distribution of muscle fibers is genetically predetermined. However, the smaller variable part is influenced by physical demands via PGC-1α. Parents can thus indirectly influence the muscular development of their children through the choice of sport.
Did you know? While exercise can increase PGC-1α levels, inflammation causes PGC-1α to decrease. Typically, during inflammatory processes in the body, Nf-kB is activated, which can directly negatively affect PGC-1α. This again shows that the various Hallmarks of Aging interact with each other and are difficult to separate. Inflammaging, the tenth hallmark, directly contributes to mitochondrial dysfunction.
Back to the longevity pathways. SIRT1 also regulates the removal of damaged mitochondria through autophagy, a type of waste disposal in the body. SIRT3 targets enzymes involved in energy metabolism and can also directly control the rate of free radical production.
From a bird's eye view, these results support the assumption that sirtuins act as a kind of metabolic sensors to influence mitochondrial function and protect against age-related diseases.Since 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 intermittent fasting improve health, as they can prevent mitochondrial degeneration. This is based, on the one hand, on autophagy, which can be effectively triggered by both fasting and endurance training. On the other hand, various forms of fasting activate additional longevity pathways, such as sirtuins,.
Mitohormesis – small stimuli, big effects?
This somewhat mysteriously sounding term is composed of Mitochondrion and Hormesis . According to the concept of Hormesis , mild toxic treatments trigger beneficial compensatory reactions. The compensatory reactions exceed the repair of the triggering damage and thus lead to an improvement in cellular fitness compared to the state before the damage.
This hypothesis traces its origins back to Paracelsus and thus to the 16th century. Over time, this view has been experimentally supported and made medically usable with substances such as Digitalis (heart failure), Colchicine (gout), or opiates (pain).
A number of research lines on aging have also focused on this concept. While severe mitochondrial dysfunction causes illness, only mild disturbances could extend lifespan due to a hormetic response. There is scientific evidence for the view that Metformin and Resveratrol are mild mitochondrial toxins that induce a low energy state and thereby increase AMP levels. The consequence is already known from the discussion on dysregulated nutrient measurement: AMPK is activated and thus slows down aging.
Metformin extended the lifespan of nematodes and mice in some studies.Under normal dietary conditions, resveratrol could not extend the lifespan of mice, but there are significant study results indicating that it protects against metabolic damage and improves mitochondrial function through the increase of PGC-1α. The observation that PGC-1α overexpression extends the lifespan of fruit flies provides further evidence for the role of the protein in longevity.
Summary of the signaling pathways around mitochondria and aging. Mitohormesis, PGC1a, and free radicals are attributed a protective function.
Conclusion – how can mitochondria be strengthened?
Mitochondria are not only the power plants of the cell but also potential sources for healthy aging.The function or rather non-function has a profound impact on the aging process.
The studies show quite clearly that one can exercise z.B. Strengthening mitochondria is possible. Endurance and strength training even into old age form the basis. Furthermore, we must protect the mitochondria from excessive oxidative stress by consuming a diet rich in secondary plant compounds. Resveratrol, for example, has been shown to have a positive effect on the mitochondria.
The health of the mitochondria is always closely linked to the NAD level. As these decrease with age, it may make sense to supplement the precursors, such as those found in regeNAD . The last aspect of strengthening our mitochondria is to ensure that the "disposal" of old mitochondria functions smoothly. The altered (macro-) autophagy represents a hallmark of aging in its own right, which is why we will explore this aspect in more detail in another article.
In conclusion, it can be said that mitochondria are a fascinating aspect of aging research. The goal for the future is to learn even more about why mitochondria are not as efficient in old 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 discuss the seventh hallmark of aging: cellular senescence.
