Gabor Szendi:
Slowing down aging and maintaining health

Who wants to get old? No one. What do we do against aging? Nothing. Why? Can you do something about it? Very much so. One of the lesser known methods out of many is to increase the function and number of mitochondria.

 

 

The secret to eternal youth and good health has long been researched. The central assumption of several theories of aging - such as the theory of oxidative stress, or the wear and tear theory - is ultimately related to mitochondrial dysfunction and to the decrease in the number of mitochondria. Mitochondria are tiny organs of the cells that produce ATP (adenosine triphosphate), an energy molecule that is required for the functioning of cells, among other things. Each cell contains hundreds or even thousands of mitochondria. However red blood cells or ocular cells do not contain such small 'power plants'. Mitochondria have their own DNA (mtDNA), which is bacterial in origin. That is, the first unicellular organisms built mitochondria into themselves at the dawn of evolution. The mtDNA is inherited from the maternal branch, therefore by examining the prevalence of genetic variants, it is possible to deduce where different groups of people have migrated from and to during prehistory.

Oxygen is a prerequisite for life on earth. When it comes to breathing, it's actually about using oxygen in the mitochondria, meaning that the complex system of breathing and oxygen delivery serves the purpose of supplying the mitochondria with oxygen. Mitochondria produce ATP from the nutrients they consume - carbohydrates, fats, and amino acids - using oxygen. In the absence of nutrients or oxygen, mitochondria become damaged. It is easy to see that one of the fundamental processes of aging is the reduction of the body's energy production, partly due to the failure of the vascular network in atherosclerosis, which delivers less oxygen and nutrients to the mitochondria of tissue cells. There are many other ways in which mitochondria can be damaged, and as age advances, their number decreases.

Energy production is a dangerous process, and ATP production produces free radicals that can damage even the mitochondria. This is why a system was developed to prevent oxidative effects, the effectiveness of which decreases with age, partly due to nutritional deficiencies and partly due to the deterioration of the body. If a cell's energy supply deteriorates, its function is impaired and it eventually dies. Just think of what happens when, for example, the activity of brain cells, muscle cells, immune cells is reduced. This is the process of aging that mainly affects tissues which require a lot of energy. These include the heart, the muscles, the brain, the immune system and the retina of the eyes.

Of course, mitochondria are not organic cell batteries, they are organic components of the cells, adapting their energy production to the actual needs of the cell, and they influence the function of the cell as well, including the regulation of cell division and programmed cell death, and they even interfere with the immune function.

Mitochondria and medicine

The importance of mitochondria was discovered by medical science in 1988, when a multifaceted disease, mitochondrial myopathy (muscle dysfunction), revealed that hereditary damage to mtDNA causes muscle weakness, eye damage, epilepsy, deafness and other severe symptoms (Holt et al., 1988). The possibility arose that a variety of mtDNA mutations are behind a variety of diseases, or even some outstanding talents. Mutational variants of mtDNA have been mapped and are referred to as haplogroups (Richards et al., 2002). One of the directions of the research is to associate haplogroups with the risk of diseases. Tibetans in the Himalayas are very likely to have a variant of mtDNA that allows them to adapt to the rarer air at high altitude, but at the same time this version tends to increase the risk of Leber's hereditary blindness, which develops in adulthood (Ji et al., 2002). Elite athletes have shown mitochondrial variants that can produce energy more intensively with increased oxygen uptake, and they are more protected against oxidative damage (Maruszak et al., 2014).

As geneticists searched for the cause of the disease in variants of chromosomes and genes, the search for a link between mtDNA abnormalities and disease susceptibility was accelerated. Today, the proportion of articles related to mitochondria in all medical publications is 1.5%, and in the heyday of genetic research - at the time of the mapping of the human genome - the proportion of articles about genetics was 2%. Research into this issue is complicated by the fact that mtDNA mutations are on the one hand hereditary, while on the other hand they accumulate during the course of life. The mtDNA has no repair mechanisms, but a single cell contains hundreds or thousands of mtDNAs.

The ability of a cell to function also depends on how much mitochondrial DNA is damaged. Because the effects of genetic modifications vary by cell type, mutations may be more likely to accumulate in some organs, whereas this effect may not appear in other organs and tissues, or may be different. This is called the epigenetic effect, whereby the function of certain genes is permanently altered according to external and internal environmental influences. A prominent example of this is the research into people born between 1920-30 in Hertfordshire, UK, and Scotland, showing that fetal malnutrition, indicated by low birth weight, was associated with an increased tendency to diabetes and metabolic syndrome in adulthood (Hales and Barker, 2001).

Genes and lifestyle

It is important to emphasize that diseases associated with mtDNA variants present only a risk. The various haplogroups would not have survived and spread if they had caused disease in the individuals carrying them. It is well known that previously healthy Natural Peoples began to gain weight immediately after switching to Western nutrition, and became diabetic in 30-50% of cases (Szendi, 2009). Children born during the Leningrad Famine, as opposed to the Hertfordshire sample, did not become diabetic later in life, as they did not live better in adulthood (Stanner and Yudkin, 2001). Hence, diseases related to haploid groups or mtDNA mutations, except in rare cases, are caused by lifestyle and the environment (toxins, drugs, etcetera).

Obesity, diabetes and mtDNA

Fetal malnutrition and low birth weight can lead to obesity and type 2 diabetes (hereinafter called diabetes) in adulthood, because the fetal metabolism in the womb is programmed to be in a nutritionally poor environment. Given that abundance has never been a feature of human history, this mechanism has continued to serve successful survival throughout human evolution. Early research has associated this trait with the 'thrifty genotype'.

During the 20th century, developed countries produced a highly energy-rich diet, which poses an increased risk of carbohydrate metabolism disruption in adulthood for people with the 'thrifty genotype'. There are many - genetic and other - causes of low birth weight, but whatever the cause, this poses an increased risk of diabetes (Dunger et al., 2007).

One of the 'thrifty genes' is recognized in the so-called 16189 variant of mtDNA. Infants of mothers bearing this variant, regardless of their mother's nutrition during pregnancy, are born with low weight, that is they are programmed for a nutritionally poor environment. In times of abundance, these infants undergo significant weight gain during the first and second years of their life, and tend to gain weight as they grow up. This is because they have high levels of insulin and we know that insulin is a hormone for nutrient storage, that is, fat storage (Casteels et al., 1999). Because of their high insulin levels, they develop insulin resistance, leading to diabetes in adulthood (Kwak and Park, 2016). Because mtDNA is inherited from the maternal branch, these infants also carry the 'thrifty gene'. These people repeat the fate of Natural Peoples who switched to Western nutrition during the 20th century.

The difference between the fate of Mexican and Arizona Pima Indians is well known. 50% of Pima Indians carry the 16189 variant (Poulton et al., 2002), however while the traditional Mexican branch is not diabetic, the proportion of people with severe diabetes in the Arizona Reserve is very high. Over the age of 45, 65% of men and 71% of women had diabetes (Lee et al., 1995). Among the natives of Polynesia, the 16189 variant has a 93% frequency (Poulton et al., 2002) and diabetes is the most common in them (Kwak and Park, 2016). The evolutionary utility of the 16189 variant is proven by the fact that it is very widespread throughout the world; about 10% of Europe's population also carries it (Kwak and Park, 2016).

Of course, many other genetic and lifestyle factors predispose an individual to diabetes, and in Europe the 16189 variant is responsible for 4% of diabetics. Whoever carries this variant has a 60% greater chance of developing diabetes - compared to those who follow the same lifestyle (Casteels et al., 1999). Diabetes and being prone to obesity should be a warning sign on the mother's branch. Other mtDNA modifications result in low levels of mitochondria in insulin-producing beta cells, resulting in low ATP production and reduced insulin secretion (Kwak and Park, 2016). That is, the beta cells are not damaged but are unable to respond properly to glucose. Many other mtDNA variants have been associated with diabetes over the years (Crispim et al., 2002) and a modification was also found that specifically protects against diabetes (Kokaze et al., 2005).

Diabetes is not a 'genetic fate'. In carriers of the 16189 variant, being overweight poses a 2.14-fold risk, while obesity indicates a 4.63-fold risk for diabetes (Liou et al., 2007). That is, those who are on a 'thrifty' diet that their genes dictate - such as the paleo diet - do not develop diabetes.

These mtDNA variants did not cause diabetes until the 20th century! The question arises whether stimulating the mitochondria could cure type 2 diabetes. There are already promising results for this (Trammell et al., 2016).

The mitochondria and the heart

High blood glucose levels significantly reduce the effectiveness of heart function, as myocardial cells also become insulin resistant and thus mitochondria are deprived of nutrients and become broken. This partly explains the relationship between obesity and heart disease (Zhang et al., 2013). Our heart pumps blood throughout our whole life, so its energy needs are similar to our brain's. Myocardial cells contract 60-90 times per minute, requiring a lot of ATP to be produced by the mitochondria. The most common cause of heart failure, which is characterized by fatigue, shortness of breath, edema of the lower limbs, chest pain, arrhythmia, etcetera, is the dilatation of the left ventricle. According to measurements in such patients, cardiac mitochondria produce 35% less ATP. In hereditary cardiac dilatation, ATP synthesis is reduced by 50%. Because mtDNA mutates 15 times more frequently than the DNA, and since mtDNA damage is not repaired, as life progresses and damaging effects increase, the number of defective or dysfunctional mitochondria increases in the myocytes. The end result is the destruction of myocytes, which is fatal because myocytes are unable to divide, that is to say, only to a very limited extent (Chaudhary et al., 2011).

The damage is caused partly because of the increasing oxidative effects - due to mitochondrial function - and partly because of the lack of various nutrients supporting mitochondrial function, and because of the mtDNA mutations mentioned above. Treatment options will be discussed later, but the well-known Q10 is noteworthy, the production of which decreases with aging, and since it has multiple roles in mitochondrial function, supplementing it improves cardiac performance and slows aging (Hernández-Camacho et al., 2018).

Mitochondria and neurodegenerative diseases

Based on the above, it is not a mistake to say that high blood sugar and insulin levels due to excessive refined carbohydrates are the root of most of the diseases of civilization. The same is true in the case of Alzheimer's disease. Long-standing Type 2 diabetes poses a four-fold risk for Alzheimer's disease (Luchsinger, 2008). Beta-amyloid plaques in the brain are usually said to be responsible for memory decline, although diabetics also display these deposits on the beta cells of the pancreas, which is more likely a sign of the high insulin levels (Akter et al., 2011).

The function of the insulin-degrading enzyme would be to neutralize the continuous production of the beta-amyloid proteins along insulin, but since the amount of the enzyme is the upper limit for the process, this function is insufficient due to the too high insulin levels, and this is how amyloid plaques develop (Xie et al., 2002). To make matters worse, amyloid plaques occupy the insulin receptor, displacing insulin from it (Zhao et al., 2008). In insulin-resistant brain cells, the sugar uptake is reduced and the mitochondria are unable to produce ATP, causing neurons to die. Existing beta-amyloid protein deposits penetrate the mitochondria and impair their function through multiple mechanisms. Being in the H5a haplogroup is an approximate 8-fold risk for Alzheimer's disease, while those in the U and T haplogroups have a reduced risk of the disease. However, again, it is important to keep in mind that Alzheimer's is a modern disease and mtDNA mutations are detectable only in a few percent of patients, meaning that Alzheimer's is predominantly a lifestyle disease (Coskun et al., 2012).

Twenty percents of Alzheimer's patients also have Parkinson's disease, and 60% of Parkinson's patients have dementia. There is a link between Parkinson's disease and insulin resistance, and in some populations between Parkinson's and diabetes (Santiago et al., 2014). Parkinson's disease is caused by the destruction of the dopaminergic neurons of the substantia nigra and the striatum. The disease, like Alzheimer's, silently develops over a period of about 20 years. Symptoms occur only after the death of 70% of the dopaminergic neurons. The role of mitochondria in Parkinson's disease were first observed in the 1980s when it was found that certain nerve poisons (Exner et al., 2012) inhibit mitochondrial respiration. Geographical distribution of insecticide and herbicide use follows the geographical distribution of Parkinson's patients (Wan and Lin, 2016). One area of research for therapeutic options is in stimulating mitochondrial function (Błaszczyk, 2018). Unfortunately, the basic drugs used to treat Parkinson's disease cause mitochondrial damage (Neustadt and Pieczenik, 2008).

Mitochondria and aging

Denham Harman stated in 1972 that the rate of aging correlates with the amount of free radicals produced in the mitochondria (Harman, 1972). Today aging is seen as a programmed process, but its speed depends greatly on the quality and activity of mitochondria. Most often the mitochondria of muscle tissue are examined, as aging decreases muscle mass and strength by 1% annually, and by 4% over the age of 70 years. Of course, this can be significantly altered by regular physical activity, since that stimulates the production of mitochondria throughout the body, and also in the brain. The aging of cells is due in part to a reduction in the quantity and quality of mitochondria. Aging stem cells also diminish the regeneration capacity of the tissues.

Increasing inflammation is also associated with aging. The reason for this is that the mitochondria were originally bacteria, and the damaged mitochondria release substances that activate the innate immune system (Sun et al., 2016).

Of course, the aging process is significantly accelerated by diseases in particular organs and tissues, which then degrade the overall functioning of the body. The activity of sirtuin proteins is linked to life expectancy. In this regard of particular importance are the sirtuins in the mitochondria, of which sirt3 stands out because it stimulates the energy production of the mitochondria. In aging people, the level of sirt3 decreases. Of great interest are studies that have shown that calorie-reduced nutrition that is not associated with malnutrition (for example, vitamin deficiency), increases the amount of sirt3 and thereby the number and function of mitochondria. In contrast, insulin resistance decreases the level of sirt3 (Lombard et al., 2011). The key to slowing aging is thus to preserve mitochondrial health.

Substances that impair the mitochondrial function

Many medications, even those that are commonly used, impair the function of the mitochondria, thereby promoting disease and accelerating aging. Most commonly used drugs (by active ingredients) include statins, aspirin, ibuprofen, diclofenac, paracetamol, naproxen, metformin, beta-blockers, anti-epileptics (barbiturates, valproic acid), antidepressants, alprazolam, and diazepam (Neustadt and Pieczenik, 2008). Highly dangerous antibiotics are quinolones and fluoroquinolones (for example, Ciprofloxacin, Levofloxacin, etcetera) because they can cause multiple organ damage, paralysis, and death (Marchant, 2018).

Boost the mitochondria!

In the mitochondria, energy is produced in the citric acid or Krebs cycle. However it takes a lot of 'additives' to produce ATP from carbohydrates, fatty acids, and amino acids. One of the most important is NAD+ (nicotinamide adenine dinucleotide). 70% of the myocardial NAD+ is found in the mitochondria. There is no ATP production without it and so the cells die. One of the most prominent fatal diseases due to NAD deficiency is pellagra, which is caused by the deficiency of vitamin B3 (nicotinic acid) and the amino acid tryptophan. In the first decades of the 20th century in the southern states of the USA, as a result of one-sided corn-based nutrition, pellagra became epidemic, killing hundreds of thousands of people. NAD+ may be formed from vitamin B3, nicotinamide, tryptophan, NR (nicotinamide riboside) or NMN (nicotinamide mononucleotide) (Stein et al., 2012). Since sirtuins are also big NAD+ users, it is understandable that NAD+ levels in the body are essential not only for the normal functioning of the body but also for a long life. NAD synthesis decreases with aging, but this can be balanced with reduced calorie intake, intermittent fasting, physical activity, and NR and NMN intake. Unfortunately, higher doses of Vitamin B3 and Nicotinamide are not suitable for enhancing NAD synthesis, due to unwanted side effects but there is increasing interest in NR and NMN.

In animal studies, administration of NMN increased NAD+ levels in every tissue and organ, decreased insulin resistance, and increased insulin production. NMN also enhanced the activity of sirt3. NMN improves neurodegenerative processes and heart disease, and increases muscle strength. Similar results were obtained using NR. However, it is important to keep in mind that cancer cells also use mitochondria for energy production, so increasing NAD+ can stimulate tumor growth (Yoshino et al., 2018).

Diseases and aging are partly reversible, but no one should expect success from pills and nutritional supplements that stimulate the mitochondrial function on their own. If we continue to destroy mitochondria with our lifestyle, dietary supplements will not stop the negative processes. So you can achieve most through sports, and with a low-calorie, fully processed-carbohydrate-free diet.

What helps mitochondria function?

Everything that is involved in the Krebs cycle and that protects the mitochondria from oxidative damage can be considered as a nutritional supplement supporting mitochondria. These can only be obtained in uncertain quantities and, incidentally with average nutrition.

Magnesium: It is essential because ATP is only used when bound to magnesium

Vitamin Bs: Not only vitamin B3, known as a precursor to NAD, is important, but almost all vitamins in the vitamin B group are important for mitochondrial function (Depeint et al., 2006).

Vitamin D: It is known that vitamin D levels are closely related to muscle strength, and this is because vitamin D stimulates the formation and activity of mitochondria (Ryan et al., 2016), while protecting mitochondria from the already harmful, increased use of oxygen (Ricca et al., 2018).

Acetyl L-carnitine: Part of the inner membrane of the mitochondria, stimulates mitochondrial function, reduces inflammation, prolonged use has a life-prolonging effect (Patel et al., 2010). ALC introduces fatty acids into the mitochondria of myocardial cells. This is because the heart muscle gets its energy mainly from fatty acids.

Q10: Stimulates electron exchanges in mitochondria and protects against oxidative effects, participates in ATP synthesis. Lack of it causes severe disorders in the function of mitochondria (Saini, 2011). Statins inhibit its synthesis in the body (Langsjoen and Langsjoen, 2003).

Resveratrol: Stimulates the formation of mitochondria, increases the activity of sirtuin genes, protects telomeres, improves carbohydrate metabolism, prolongs life (De Paepe et al., 2017). However, it is poorly utilized and its levels in the blood decrease rapidly, so more active pterostilben is recommended instead (Kauffman, 2017).

Glutathione: The most important antioxidant that protects mitochondria from oxidative effects (Marí et al., 2009). However, it is not useful when taken orally, but N-acetylcysteine is a good precursor.

N-acetylcysteine: A precursor to glutathione synthesis, and free radical neutralizing in itself, prevents the hepatotoxic effects of paracetamol (Mokhtari et al., 2017).

(R)-alpha lipoic acid: Mitochondrial nutrient, coenzyme, protects against oxidative effects, reactivates oxidized vitamin C and glutathione, enhances mitochondrial respiration, improves memory and is effective in neuropathy (Liu, 2008).

Astaxanthin: Protects mitochondria against oxidative effects (Wolf, 2010).

Creatine: Protects mitochondria and thereby reduces age-related muscle mass loss (Barbieri et al., 2016).

Melatonin: Contrary to popular belief, it is not only produced in the pineal gland and is not only a "sleep" hormone, but is actively involved in protecting mitochondria from oxidative effects (Kauffman, 2017).

 

References

Akter, K. et al. 2011. Diabetes mellitus and Alzheimer's disease: Shared pathology and treatment?, Br J Clin Pharmacol, 71(3):365-376.

Barbieri E, Guescini M, Calcabrini C, Vallorani L, Diaz AR, Fimognari C, Canonico B, Luchetti F, Papa S, Battistelli M, Falcieri E, Romanello V, Sandri M, Stocchi V, Ciacci C, Sestili P. Creatine Prevents the Structural and Functional Damage to Mitochondria in Myogenic, Oxidatively Stressed C2C12 Cells and Restores Their Differentiation Capacity. Oxid Med Cell Longev. 2016;2016:5152029.

Błaszczyk JW. The Emerging Role of Energy Metabolism and Neuroprotective Strategies in Parkinson's Disease. Front Aging Neurosci. 2018 Oct 5;10:301.

Casteels K, Ong K, Phillips D, Bendall H, Pembrey M: Mitochondrial 16189 variant, thinness at birth, and type-2 diabetes: ALSPAC study team: Avon Longitudinal Study of Pregnancy and Childhood. Lancet 353:1499-1500, 1999

Chaudhary KR, El-Sikhry H, Seubert JM. Mitochondria and the aging heart. J Geriatr Cardiol. 2011 Sep;8(3):159-67.

Coskun P, Wyrembak J, Schriner SE, Chen HW, Marciniack C, Laferla F, Wallace DC. A mitochondrial etiology of Alzheimer and Parkinson disease. Biochim Biophys Acta. 2012 May;1820(5):553-64.

Crispim, D.; Tschiedel, B.; Souto, K. E. P.; Roisenberg, I. Prevalence of three mitrochondrial DNA mutations in type 2 diabetic patients from southern Brazil. Clinical Endocrinol, 2002, 57(1): 141-142.

De Paepe B, Van Coster R. A Critical Assessment of the Therapeutic Potential of Resveratrol Supplements for Treating Mitochondrial Disorders. Nutrients. 2017 Sep 14;9(9).

Depeint F, Bruce WR, Shangari N, Mehta R, O'Brien PJ. Mitochondrial function and toxicity: role of the B vitamin family on mitochondrial energy metabolism. Chem Biol Interact. 2006 Oct 27;163(1-2):94-112.

Dunger DB, Petry CJ, Ong KK. Genetics of size at birth. Diabetes Care. 2007 Jul;30 Suppl 2:S150-5.

Exner N, Lutz AK, Haass C, Winklhofer KF. Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences. EMBO J. 2012 Jun 26;31(14):3038-62.

Hales, CN; Barker, DJ: The thrifty phenotype hypothesis. Br Med Bull, 2001, 60:5-20.

Harman D. The biologic clock: the mitochondria? J Am Geriatr Soc. 1972 Apr;20(4):145-7.

Hernández-Camacho JD, Bernier M, López-Lluch G, Navas P. Coenzyme Q(10) Supplementation in Aging and Disease. Front Physiol. 2018 Feb 5;9:44.

Holt, I.J., Harding, A.E., Morgan-Hughes, J.A., 1988. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331, 717-719.

Ji, F., Sharpley, M.S., Derbeneva, O., Alves, L.S., Qian, P., Wang, Y., Chalkia, D., Lvova, M., Xu, J., Yao, W., Simon, M., Platt, J., Xu, S., Angelin, A., Davila, A., Huang, T., Wang, P.H., Chuang, L.M.,Moore, L.G., Qian, G.,Wallace, D.C., 2012. Mitochondrial DNA variant associated with Leber hereditary optic neuropathy and high-altitude Tibetans. Proc. Natl. Acad. Sci. U. S. A. 109, 7391-7396.

Kauffman, S: The Kauffman protocol. Amazon Dig Serv, 2017.

Kokaze A, Ishikawa M, Matsunaga N, Yoshida M, Makita R, Satoh M, Teruya K, Sekiguchi K, Masuda Y, Harada M, Uchida Y, Takashima Y. Longevity-associated mitochondrial DNA 5178 C/A polymorphism is associated with fasting plasma glucose levels and glucose tolerance in Japanese men. Mitochondrion. 2005 Dec;5(6):418-25.

Kwak SH, Park KS. Role of mitochondrial DNA variation in the pathogenesis of diabetes mellitus. Front Biosci (Landmark Ed). 2016 Jun 1;21:1151-67.

Langsjoen P.H, Langsjoen, A.M. The clinical use of HMG CoA-reductase inhibitors and the associated depletion of coenzyme Q10. A review of animal and human publications. BioFactors 2003;18:101-111.

Lee, ET; Howard, BV; Savage, PJ; Cowan, LD; Fabsitz, RR; Oopik, AJ; Yeh, J; Go, O; Robbins, DC; Welty, TK: Diabetes and impaired glucose tolerance in three American Indian populations aged 45-74 years: the Strong Heart Study. Diabetes Care, 1995, 18:599-610.

Liou CW, Lin TK, Huei Weng H, Lee CF, Chen TL, Wei YH, Chen SD, Chuang YC, Weng SW, Wang PW. A common mitochondrial DNA variant and increased body mass index as associated factors for development of type 2 diabetes: Additive effects of genetic and environmental factors. J Clin Endocrinol Metab. 2007 Jan;92(1):235-9.

Liu J. The effects and mechanisms of mitochondrial nutrient alpha-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction: an overview. Neurochem Res. 2008 Jan;33(1):194-203.

Lombard DB, Tishkoff DX, Bao J. Mitochondrial sirtuins in the regulation of mitochondrial activity and metabolic adaptation. Handb Exp Pharmacol. 2011;206:163-88.

Luchsinger, J. A. 2008. Adiposity, hyperinsulinemia, diabetes and Alzheimer's disease: an epidemiological perspective, Eur J Pharmacol, 585(1):119-129.

Marchant J. When antibiotics turn toxic. Nature. 2018 Mar 22;555(7697):431-433.

Marí M, Morales A, Colell A, García-Ruiz C, Fernández-Checa JC. Mitochondrial glutathione, a key survival antioxidant. Antioxid Redox Signal. 2009 Nov;11(11):2685-700.

Maruszak, A., Adamczyk, J.G., Siewierski, M., Sozanski, H., Gajewski, A., Zekanowski, C., 2014. Mitochondrial DNA variation is associatedwith elite athletic status in the polish population. Scand. J. Med. Sci. Sports 24, 311-318.

Mokhtari V, Afsharian P, Shahhoseini M, Kalantar SM, Moini A. A Review on Various Uses of N-Acetyl Cysteine. Cell J. 2017 Apr-Jun;19(1):11-17.

Neustadt J, Pieczenik SR. Medication-induced mitochondrial damage and disease. Mol Nutr Food Res. 2008 Jul;52(7):780-8.

Patel SP, Sullivan PG, Lyttle TS, Rabchevsky AG. Acetyl-L-carnitine ameliorates mitochondrial dysfunction following contusion spinal cord injury. J Neurochem. 2010 Jul;114(1):291-301.

Poulton J, Luan J, Macaulay V, Hennings S, Mitchell J, Wareham NJ. Type 2 diabetes is associated with a common mitochondrial variant: evidence from a population-based case-control study. Hum Mol Genet. 2002 Jun 15;11(13):1581-3

Ricca C, Aillon A, Bergandi L, Alotto D, Castagnoli C, Silvagno F. Vitamin D Receptor Is Necessary for Mitochondrial Function and Cell Health. Int J Mol Sci. 2018 Jun 5;19(6).

. Richards M, Macaulay V, Torroni A, Bandelt HJ. In search of geographical patterns in European mitochondrial DNA. Am J Hum Genet. 2002 Nov;71(5):1168-74.

Ryan ZC, Craig TA, Folmes CD, Wang X, Lanza IR, Schaible NS, Salisbury JL, Nair KS, Terzic A, Sieck GC, Kumar R. 1?,25-Dihydroxyvitamin D3 Regulates Mitochondrial Oxygen Consumption and Dynamics in Human Skeletal Muscle Cells. J Biol Chem. 2016 Jan 15;291(3):1514-28.

Saini R. Coenzyme Q10: The essential nutrient. J Pharm Bioallied Sci. 2011 Jul;3(3):466-7.

Santiago JA, Potashkin JA. System-based approaches to decode the molecular links in Parkinson's disease and diabetes. Neurobiol Dis. 2014 Dec;72 Pt A:84-91.

Stanner SA, Yudkin JS. Fetal programming and the Leningrad Siege study. Twin Res. 2001 Oct;4(5):287-92.

Stein LR, Imai S. The dynamic regulation of NAD metabolism in mitochondria. Trends Endocrinol Metab. 2012 Sep;23(9):420-8.

Sun N, Youle RJ, Finkel T. The Mitochondrial Basis of Aging. Mol Cell. 2016 Mar 3;61(5):654-666.

Szendi G: Paleolit táplálkozás. Jaffa, 2009.

Hales CN, Barker DJ. The thrifty phenotype hypothesis. Br Med Bull. 2001;60:5-20.

Trammell SA, Weidemann BJ, Chadda A, Yorek MS, Holmes A, Coppey LJ, Obrosov A, Kardon RH, Yorek MA, Brenner C. Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice. Sci Rep. 2016 May 27;6:26933.

Wan N, Lin G. Parkinson's Disease and Pesticides Exposure: New Findings From a Comprehensive Study in Nebraska, USA. J Rural Health. 2016 Jun;32(3):303-13.

Wolf AM, Asoh S, Hiranuma H, Ohsawa I, Iio K, Satou A, Ishikura M, Ohta S. Astaxanthin protects mitochondrial redox state and functional integrity against oxidative stress. J Nutr Biochem. 2010 May;21(5):381-9.

Xie L, Helmerhorst E, Taddei K, Plewright B, Van Bronswijk W, Martins R. Alzheimer's beta-amyloid peptides compete for insulin binding to the insulin receptor. J Neurosci. 2002 May 15;22(10):RC221.

Yoshino J, Baur JA, Imai SI. NAD(+) Intermediates: The Biology and Therapeutic Potential of NMN and NR. Cell Metab. 2018 Mar 6;27(3):513-528.

Zhang L, Jaswal JS, Ussher JR, Sankaralingam S, Wagg C, Zaugg M, Lopaschuk GD. Cardiac insulin-resistance and decreased mitochondrial energy production precede the development of systolic heart failure after pressure-overload hypertrophy. Circ Heart Fail. 2013 Sep 1;6(5):1039-48.

Zhao WQ, De Felice FG, Fernandez S, Chen H, Lambert MP, Quon MJ, Krafft GA, Klein WL. Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J. 2008 Jan;22(1):246-60.