Following a ketogenic diet leads to the appearance of new mitochondria, as well as a low-calorie diet and exercise. Physical activity on the background of carbohydrate starvation (low glycogen levels) is the most powerful stimulator of mitochondrial synthesis. Hormones that stimulate mitochondrial proliferation include thyroxine, estrogens, and glucocorticoids. The appearance of new mitochondria is usually accompanied by suppression of apoptosis, programmed cell death. In the later stages of life, apoptosis of still functional cells is a more serious problem than the inability of malignant cells to self-destruct through apoptosis. In other words, suppressing apoptosis is ultimately beneficial in terms of slowing down aging, but the flip side of the coin is a possible increase in cancer risk.

Coenzyme Q10, or ubiquinone, is an important component of mitochondrial chemistry that transports electrons along their path to ATP molecules, which are the main energy product of mitochondria. This compound is often referred to as an antioxidant, but this is not the main role of coenzyme Q10. It has a consistently good reputation as a food additive. There is plenty of evidence of its positive effect on markers of health status, especially physical endurance, a number of aspects of heart health, as well as erectile function. Coenzyme Q10 is highly indicated for fibromyalgia, as well as for people taking statins. It is also quite promising for chronic fatigue syndrome. However, there is no reason to expect that this compound is capable of extending lifespan. The use of ubiquinone increases the lifespan of worms, but does not have a similar effect on mice and rats. At the same time, worms that do not synthesize ubiquinone at all live 10 times longer than normal individuals. A few years ago, ubiquinol (coenzyme Q reduced) was introduced as a more bioavailable form of ubiquinone. This drug is more expensive, but there is no clear evidence of its increased bioavailability.

Pyrroloquinoline quinone is a useful but not critical component of mitochondrial chemistry. Bacteria synthesize large amounts of this compound, plants produce less, and mammals produce negligible amounts. Mice completely deprived of pyrroloquinoline quinone are characterized by impaired growth, but the amount they need is many times less than its content in dietary supplements. Pyrroloquinoline quinone is a growth factor for bacteria, and the main claim of its health benefits lies in its ability to stimulate the growth of new mitochondria. This conclusion is based on the results of biochemical experiments and experiments on cell cultures. In studies on mice, it has been shown that a lack of pyrroloquinoline quinone leads to mitochondrial insufficiency. However, the results obtained do not indicate that in high doses this compound provides an increase in the number of mitochondria. The positive effects of pyrroloquinoline quinone also include improved sleep quality and the growth of new nerves, which contributes to improved cognitive function. A small amount of pyrroloquinoline quinone can enter the body from plant products, but not from animal products. Much larger doses can come in the form of dietary supplements. 100 g of soy tofu cheese contains only 2 micrograms of pyrroloquinoline quinone. The dose of a dietary supplement is usually equivalent to 5-20 mg, which is hundreds of times higher than the possible intake of the compound into the body when following a vegetarian diet.

These two closely related molecules were first synthesized in Russia in the 1970s, but it was not until the 1990s that their therapeutic value was demonstrated by New Zealand researchers. One of the ends of this molecule is known as coenzyme Q10 (CoQ10), a plant version of the compound that is considered even more effective as an antioxidant. The other end of the molecule is an “electric tug” that pulls the molecule inside the mitochondria. Russian researchers claim that with the help of SkQ, they were able to moderately increase the lifespan of mice, and also that this compound has a pronounced rejuvenating effect on aging eyes. Therefore, in Russia it is sold in the form of eye drops, while in New Zealand SkQ is sold as part of creams and in tablet form. Earlier this year, Russian researchers announced that SkQ significantly increases the lifespan of mice of the line, whose short lifespan is due to a mitochondrial defect. However, these data have not been reproduced by any Western laboratory.

Mitochondria have their own circular DNA encoding only 37 genes. (This does not mean that only 37 proteins are enough for mitochondria. The vast majority of the proteins they need are encoded in the chromosomes of the cell nucleus and transported to the mitochondria if necessary.) Just 16 years ago, the first identified mitochondrial DNA protein was named humanin, as it was shown to improve cognitive function in patients with dementia, partially restoring their “human essence”. In addition to its neuroprotective properties, humanin has the ability to increase tissue sensitivity to insulin. The activity of the humanin molecule is not limited to the mitochondria in which it was synthesized, as this protein circulates in the bloodstream as a signaling molecule. The concentration of humanin in the blood decreases as we age. Humanin’s ability to protect animals from diseases has been demonstrated in experiments on mice. Currently, there are no systems for assessing the impact of humanism on life expectancy. Quote from the report of Pinchas Cohen, MD, at the European Conference on Biogerontology: “To date, it has been demonstrated that humanin and its analogues affect the development of many diseases, including type 2 diabetes, cardiovascular diseases, memory loss, amyotrophic lateral sclerosis, stroke and inflammation. The common mechanisms for many of these age-related diseases are oxidative stress and mitochondrial dysfunction. Mitochondria are the main source of reactive oxygen species, the excess of which can cause oxidative damage to cellular lipids, proteins and DNA. The accumulation of oxidative damage leads to the extinction of mitochondrial function, which, in turn, leads to increased production of reactive oxygen species. This vicious cycle can lead to cell damage, triggering apoptosis and the mechanism of physiological cell aging, which contributes to the development of age-related diseases. Indeed, oxidative stress is closely associated with many human diseases, such as Parkinson’s disease, atherosclerosis, heart failure, myocardial infarction, chronic inflammation, kidney disease, stroke, various types of cancer, and many types of metabolic disorders. It has also been shown by several research groups that the human being plays a critical role in suppressing oxidative stress. Mitochondria are organelles that produce the energy cells need and have their own DNA, which is different from nuclear DNA. The amount of DNA in the mitochondria is much less than the amount of DNA in the nucleus. Thus, mitochondrial DNA encodes few proteins, one of which is humanin. This protein was discovered while searching for factors that contribute to maintaining the viability of neurons in unaffected regions of the brain of patients with Alzheimer’s disease. Humanin prevents the death of neurons in Alzheimer’s disease, and also protects them from exposure to toxic chemical compounds and prions. It has also been found that humanin protects the cells of the inner lining of blood vessels, preventing the development of atherosclerosis. In particular, it has been shown that low doses of humanin in the bloodstream are associated with dysfunction of the coronary artery endothelium. In addition, the humanin’s ability to increase tissue sensitivity to insulin has been demonstrated. Since the concentration of humanin in the blood decreases with age, it is generally believed that this contributes to the development of age-related diseases, including Alzheimer’s disease and type 2 diabetes mellitus.” If humanin were a patent-pending drug, there would be a lot of excitement about it and numerous clinical studies on the treatment of Alzheimer’s disease would be conducted, possibly with a subsequent transition to studying its general “anti-aging” effects.

This compound is another short peptide of mitochondrial origin that has been identified and characterized recently. The results obtained by the researchers are very impressive. The administration of MOTS-c to mice provided an increase in muscle mass, a decrease in the amount of adipose tissue, as well as an increase in physical strength and endurance. MOTS-c ensures the preservation of tissue sensitivity to insulin when animals are kept on a high-fat diet. Studies of its effect on life expectancy have not yet been conducted. Like humanin, MOTS-c is encoded in mitochondrial DNA and is synthesized inside mitochondria, however, it is exported from the cell and travels through the bloodstream as a signaling molecule. The MOTS-c content in the blood decreases with age. This protein is a miniature molecule of 16 amino acids. However, its small size does not allow it to avoid digestion, which makes the compound unsuitable for oral administration. Experts believe that MOTS-c has great potential as a target for the treatment of metabolic syndromes by regulating the physiology of muscle and adipose tissue, as well as possibly as a means to increase life expectancy.

Glutathione is an antioxidant that has no drawbacks. Experiments have shown that genetic modifications that increase glutathione production increase the lifespan of roundworms, fruit flies, and mice. For a long time, it was generally believed that glutathione is useless to take as a dietary supplement, as it is broken down during digestion. However, a number of researchers disagree with this based on the fact that they were able to register a significant increase in glutathione levels in human tissues and blood after adding unmodified glutathione to the diet at a dose of 1 g per day. Liposomal glutathione is a form for oral administration that allows you to bypass the digestive problem, especially when taken together with methyl group donors such as s-adenosyl methionine (SAMe). The use of the herbal preparation silymarin (Silibinin), a complex of milk thistle flavonoids, can increase glutathione levels. By far the most effective supplement stimulating the synthesis of glutathione is its precursor N-acetylcysteine. In the only study whose results are available, the addition of glutathione to the feed significantly increased the lifespan of male mice, but had no effect on the lifespan of females. The ability of N-acetylcysteine to increase the lifespan of roundworms and fruit flies has also been demonstrated. We can hope for the best in the future. In fact, less than 20% of the glutathione contained in the cell penetrates into the mitochondria, where it is most needed. There are molecules that are glutathione esters, which in theory should be attracted by mitochondria. However, they have been tested only on cell cultures and are completely unsuitable for animal experiments so far.

The chemical compounds NAD+ and NADH are alternative cyclic forms of the intermediate product of the mitochondrial energy synthesis process. Levels ABOVE+/NADH decreases with age. Nicotinamide riboside is a precursor of NAD+. Preliminary results of human studies have shown that the use of nicotinamide riboside provides an increase in the NAD+ content in the blood. After some time, we will be able to reliably find out whether this provides an improvement in health or an increase in life expectancy. Nutritional supplements containing this compound are actively promoted by well-known researchers, and many consumers make early claims of positive short-term effects. One study in mice demonstrated a 3% increase in life expectancy, but it is too early to speak about the reliability of these results.

The main role of melatonin is to regulate sleep/wake cycles. Melatonin levels decrease with age, which is accompanied by blurring and shifting periods of increasing its concentration. This leads to a deterioration in the quality of sleep. In experiments on mice, melatonin has demonstrated a moderately positive effect on longevity, but overall the research results are mixed. In 12 of the 20 studies, an increase in life expectancy was recorded, and in the remaining 8, there was no effect or decrease in life expectancy. The possible effect of melatonin on human mortality when used to improve sleep quality has not been evaluated. The concentration of melatonin in mitochondria is 100 times higher than in the body as a whole. It can also be synthesized in mitochondria, independently of the melatonin circulating in the bloodstream, secreted by the pineal gland at night. One of its functions is to act as a mitochondrial antioxidant and neutralize reactive oxygen species. Twenty years ago, Walter Pierpaoli promoted melatonin as a sleep-enhancing hormone with antitumor effects that can improve mood and sex life, while prolonging youth. Russian researchers were also very optimistic. In fact, melatonin is a legal anti-aging hormone, especially useful for people with age-related sleep disorders. It is widely available, inexpensive, and safe. With the exception of jet lag syndrome, it is enough to take 1-2 mg of melatonin before bedtime.

Magnesium is necessary for the synthesis of glatutin. Selenium has its effect in parallel with glutathione. Omega-3 fatty acids can stimulate the synthesis of glutathione. Acetyl-L-carnitine transports fat molecules through the mitochondrial membrane for subsequent cleavage with the release of energy. Alpha-lipoic acid is a component of mitochondrial energy metabolism.

Commercially interested parties can make some messages look more convincing than others. At the same time, medical news delivered to people is equally influenced by two factors: profitability and benefits. Physical activity is extremely important, but it has no commercial value. Of the dietary supplements mentioned in the article, N-acetylcysteine is the compound whose benefits for the state of mitochondria have been most convincingly confirmed. In addition, it has a potential positive effect on life expectancy. The drug N-acetylcysteine is cheap and affordable. Liposomal N-acetylcysteine is definitely much more expensive, but perhaps more effective. Melatonin is even cheaper, while numerous studies in rodents have demonstrated its ability to increase life expectancy, as well as have a wide range of positive effects, in addition to modifying mitochondrial function. Humanin and MOTS-c are still far from commercialization and at the same time look very promising in terms of health benefits, but not in terms of profitability. Josh Mitteldorf, Mitochondria in Aging, II: Remedies