Mitochondria in aging, part 2

Healing methods

Josh Mitteldorf, Mitochondria in Aging, II: Remedies
Translated by Evgenia Ryabtseva
Part I is here.
For links, see the original article 

The free radical mitochondrial theory of aging developed a generation ago turned out to be too superficial. Aging is not the result of diffuse damage – on the contrary, diffuse damage is the result of a decrease in the body's defenses in old age. Despite this, mitochondria play a certain role in the aging process, mainly due to the work of signaling mechanisms and apoptosis. Antioxidants acting on mitochondria may be an exception to the rule that antioxidants do not increase life expectancy. Other dietary supplements and strategies that promote the production of new mitochondria or increase the efficiency of their work demonstrate the possibility of a moderate increase in life expectancy.

Growing new mitochondria

Following a ketogenic diet leads to the appearance of new mitochondria, as well as a low-calorie diet and exercise. Physical activity against the background of carbohydrate starvation (low glycogen levels) is the most powerful stimulator of mitochondrial synthesis.

Stimulating mitochondrial proliferation hormones include thyroxine, estrogens and glucocorticoids. The appearance of new mitochondria is usually accompanied by the 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 the risk of cancer.

Ubiquinone = coenzyme Q10

Coenzyme Q10, or ubiquinone, is an important component of mitochondrial chemistry, transferring electrons along their path to ATP molecules, which are the main energy product of mitochondria. This compound is often called an antioxidant, however, this is not the main role of coenzyme Q10.

It has a consistently good reputation as a dietary supplement. There is a lot of evidence of its positive effect on markers of health, especially physical endurance, a number of aspects of heart health, as well as erectile function. Coenzyme Q10 is very 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 increasing life expectancy. 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 in which ubiquinone is not synthesized at all live 10 times longer than ordinary 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.

Pyrroloquinolinquinone

Pyrroloquinolinquinone is a useful but not critical component of mitochondrial chemistry. Bacteria synthesize a large amount of this compound, plants – less, and mammals – negligible. Mice completely devoid of pyrroloquinolinquinone are characterized by a growth disorder, but the amount they need is many times less than its content in dietary supplements.

Pyrroloquinolinquinone 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 pyrroloquinolinquinone leads to mitochondrial insufficiency. However, the results obtained do not indicate that in large doses this compound provides an increase in the number of mitochondria.

The positive effects of pyrroloquinolinquinone also include an improvement in the quality of sleep and the growth of new nerves, which contributes to the improvement of cognitive function.

A small amount of pyrroloquinolinquinone 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 tofu soy cheese contains only 2 mcg of pyrroloquinolinquinone. 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.

SkQ and MitoQ

These two closely related molecules were first synthesized in Russia in the 1970s, but it was only in 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, considered even more effective as an antioxidant. The other end of the molecule is an "electric tug" that pulls the molecule into the mitochondria.

Russian researchers claim that with the help of SkQ they managed 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.

Humanist and his relatives

Mitochondria have their own ring DNA encoding a total of 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 its ability to improve cognitive function in patients with dementia was shown, partially restoring their "human essence". In addition to neuroprotective properties, humanin has the ability to increase the sensitivity of tissues to insulin. The activity of the humanin molecule is not limited to the mitochondria in which it was synthesized, since this protein circulates in the bloodstream as a signaling molecule. The concentration of humanin in the blood decreases with aging.

In experiments on mice, the humanist's ability to protect animals from diseases was demonstrated. To date, there are no systems for assessing the impact of a human being 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 mellitus, cardiovascular diseases, memory loss, amyotrophic lateral sclerosis, stroke and inflammation. Common mechanisms for many of these age-related diseases are oxidative stress and mitochondrial dysfunction. Mitochondria are the main source of reactive oxygen species, an 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 circle can lead to cell damage, triggering apoptosis and the mechanism of physiological aging of the cell, 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 humanin has a critical role in suppressing oxidative stress.

Mitochondria are organelles that produce the energy needed by cells, having their own DNA, different from nuclear DNA. The amount of DNA in mitochondria is much less than the amount of DNA in the nucleus. Thus, mitochondrial DNA encodes a few proteins, one of which is humanin. This protein was discovered while searching for factors that contribute to maintaining the viability of neurons in the 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 was also 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 endothelial dysfunction of the coronary arteries. In addition, the humanin's ability to increase the sensitivity of tissues 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."

If humanin were a patent-pending drug, there would be a lot of excitement about it and numerous clinical studies were conducted on the treatment of Alzheimer's disease, possibly with a subsequent transition to the study of its general "anti-aging" effects.

MOTS-c

This compound is another short peptide of mitochondrial origin, identified and characterized more recently. The results obtained by the researchers are very impressive. The introduction 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 diet with a high fat content. Studies of its effect on life expectancy have not yet been conducted.

Like humanin, MOTS-c is encoded in mitochondrial DNA and synthesized inside mitochondria, however, it is exported from the cell and moves through the bloodstream as a signaling molecule. The content of MOTS-c 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 use.

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/N-Acetylcysteine (NAC)

Glutathione is an antioxidant that has no drawbacks. Experiments have shown that genetic modifications that increase glutathione production increase the life expectancy of roundworms, fruit flies and mice.

For a long period, it has been considered that glutathione is useless to take as a dietary supplement, since it is broken down during digestion. However, a number of researchers disagree with this on the basis 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 donors of methyl groups, such as s-adenosyl methionine (SAMe).

The use of the herbal preparation silymarin (Silibinin), a complex of flavonoids of milk thistle can increase the level of glutathione. To date, 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.

Nicotinamide Triboside and other stimulants OVER+

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 triboside is a precursor of NAD+. Preliminary results of human studies have shown that the use of nicotinamide riboside provides an increase in the content of NAD+ 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. Dietary supplements containing this compound are actively promoted by well-known researchers, and many consumers make early statements about positive short-term effects. In one study on mice, an increase in life expectancy by 3% was demonstrated, but it is too early to talk about the reliability of these results.

Melatonin

The main role of melatonin is to regulate sleep/wake cycles. The level of melatonin decreases 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 in general, the results of studies are ambiguous. In 12 of the 20 papers, an increase in life expectancy was recorded, and in the remaining 8, there was no influence or a 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, regardless of the melatonin circulating in the bloodstream, secreted by the epiphysis 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 means to improve sleep, a hormone with antitumor effect 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 cases of time zone change syndrome, it is enough to take 1-2 mg of melatonin before going to bed.

Also worthy of mention

Magnesium is necessary for the synthesis of glatutin. Selenium exerts its action in parallel with glutathione. Omega-3 fatty acids can stimulate glutathione synthesis. 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.

Resume

Commercially interested parties can make some messages look more convincing than others. At the same time, medical news delivered to people is equally affected by two factors: profitability and benefits. Physical activity is extremely important, but it has no commercial value. Of the food additives mentioned in the article, N-acetylcysteine is the compound whose benefits for the state of mitochondria have been confirmed most convincingly. In addition, it has a potential positive effect on life expectancy. The N-acetylcysteine drug is cheap and affordable. Liposomal N-acetylcysteine is definitely much more expensive, but perhaps more effective. Melatonin is even cheaper, while numerous studies on rodents have demonstrated its ability to increase life expectancy, as well as to 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 from the point of view of health benefits, but not from the point of view of profitability.

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