Nutrigerontology

Nutrition vs. aging

Margarita Pertseva, "Biomolecule"

Life expectancy and the number of people over the age of 60 is steadily increasing worldwide. Along with this, the level of age-related diseases also increases. However, a balanced nutrition system that allows delaying the development of diseases and slowing down aging has not yet been developed. Stop. And is it possible to influence the aging process with the help of food? Nutrigerontology deals with these issues. Well, nutrigenomics was discussed in the first part of this article.

Introduction

Aging manifests itself as a gradual deterioration of physiological functions: the protection of the immune system is weakened, muscle mass decreases, and disorders of the brain and cardiovascular system occur. Until recently, it seemed that the aging process could not be controlled. However, in recent decades, a number of important discoveries have been made in biogerontology – the science of aging. Scientists have long guessed that the signs of aging available to the eye are the consequences of imperceptible changes at the level of cells and molecules, but it was only recently possible to find out what kind of molecular changes these are [1]. At the moment, there are nine cellular and molecular signs of aging common to various organisms. These signs include (Fig. 1):

• increasing genome instability;
• telomere shortening [2-4];
• epigenetic changes [5];
• changes in intercellular communication;
• violation of protein homeostasis;
• depletion of stem cells;
• cellular aging [6];
• mitochondrial disorders;
• deregulation of cellular signaling pathways that sense the level of nutrients.

Figure 1. Molecular signs of aging. Figure from [7], adapted.

Experiments in the field of biogerontology and analysis of human populations of centenarians have revealed curious relationships between the type of nutrition and life expectancy. And now research is being conducted around the world aimed at selecting the optimal diet that could slow down the aging process and the development of age-related diseases. In this regard, a new branch of science has emerged – nutrigerontology. Let's take a closer look at the molecular mechanisms of aging and consider how food and its bioactive components affect these processes. Well, in a more general way, the question of the connection of nutrition with our health and, moreover, with the work of genes is touched upon in the first part of this article: "Nutrigenomics: nutrition vs. diseases" [8].

Molecular signs of aging and food

Signaling pathways of energy balance

In biogerontology, two cellular signaling pathways are widely known, the weakening of which leads to the prolongation of life in many organisms [9]: the insulin/insulin-like growth factor (IIS) signaling pathway and the mTOR* signaling pathway.

* – The practical aspects of studying such signaling pathways as mTOR, as well as substances that potentially prolong life, can be read in the Longevity Cookbook strategy book, prepared with the assistance of the Science for Life Extension Foundation. The first chapter of the book has already been published on the Internet (although so far only in English): "Longevity Cookbook: Pharmacological Extension of Lifespan". – Ed.

These signaling pathways are closely intertwined and "probe" the level of nutrients in the cell (Fig. 2).

Figure 2. The relationship of IIS- and mTOR-signaling paths. The signal from the insulin receptor (aka the growth factor receptor) spreads through the cell and activates the mTOR protein, which leads to the assembly of two functional complexes: mTORC1 and mTORC2. In turn, the mTORC1 complex can inhibit the insulin receptor substrate (IRS). mTOR is also activated by amino acids, so a high concentration of amino acids in the blood reduces the sensitivity of cells to insulin. Drawing from the website the-scientist.com .

The mTOR and IIS pathways are activated by food components: carbohydrates (activate the IIS pathway to a greater extent) and amino acids (trigger mTOR signaling). Attenuation of signals from these pathways at various stages prolongs the life of a variety of model organisms, and at the moment there is no doubt that the regulation of these pathways is the main lever of the diet's impact on health and longevity.

The IIS signaling pathway (insulin and IGF-1 signaling) informs the cell about the presence of glucose through the level of insulin in the blood. The IIS pathway originates from the membrane receptor*, which recognizes insulin or insulin-like growth factor (IGF1), and then spreads through the cell, stimulating its growth and division and inactivating FOXO transcription factors (regulate stress response, DNA repair, cell death, autophagy [10], etc.). Carbohydrates contained in food, depending on the structure, affect the level of insulin in the blood differently. The simpler the structure of the carbohydrate, the faster it is digested and enters the bloodstream, initiating the production of insulin.

* – It's funny that a receptor related to it plays a completely different role – it feels alkali in the environment: "A receptor of "non-traditional orientation"" [11]. – Ed.

Complex carbohydrates (fiber, starch) are digested gradually, without causing a strong increase in blood sugar levels and sudden insulin emissions, while simple carbohydrates (sucrose, glucose) lead to a jump in blood sugar within 10-15 minutes after consumption, which provokes the production of insulin. In order to assess how much the blood sugar level increases after consuming a particular product, parameters such as the glycemic index and glycemic load were introduced. For example, pastries and sweets have a high glycemic index, as they contain a large amount of simple sugars. A diet with a high glycemic load stimulates the IIS and mTOR signaling pathways, which adversely affects health in the long term. According to studies, a diet with a high glycemic index/load increases the risk of age-related diseases such as type II diabetes and heart attacks [12]. While following a diet with a low glycemic load (for example, a diet based on vegetables), on the contrary, has a beneficial effect on health and can even reverse type II diabetes. And caloric restriction for a long time (while maintaining all the substances necessary for the body at a normal level) significantly slows down the aging of the cardiovascular system and skeletal muscles in humans [13].

The mTOR protein is a key regulator of cell growth and metabolism. mTOR is located in the cytoplasm, it is activated by amino acids and functions in two different complexes: mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2). The mTORC1 complex is well studied, it is collected when signals from nutrients and insulin receptors, growth factors are received. mTORC1 promotes protein synthesis, suppresses autophagy and regulates glucose metabolism (Fig. 3). mTORC2 is also collected at the start of IIS and mTOR, but leads to the inhibition of transcription factor FOXO3. Since mTOR is activated by amino acids, their low content in food can increase life expectancy. For example, mice on a low-protein diet live much longer than mice on a high-protein diet (150 weeks versus 100 weeks) [12].

Figure 3 (from [52], adapted). Scheme of mTORC1 and 2 complexes and their functions in the cell.

Limiting the use of only essential amino acids also affects longevity. So, in rats, the restriction on methionine increases the life span, and a diet with a high concentration of this amino acid accelerates the aging of blood vessels. How can this knowledge be used in relation to people? In many cultures, red meat is an important source of protein in the diet. Recent studies have shown that there is a relationship between the degree of meat consumption and the level of cardiovascular diseases, type II diabetes, cancer and mortality from all cases. However, it should be recognized that not only the protein component contributes to the increased mortality rate from meat consumption. The fact is that meat, especially fried or smoked, contains a fairly large amount of various substances that negatively affect health. But no correlation was found between the consumption of plant proteins and the mortality rate, which is due to the amino acid composition of plant proteins, which contain less methionine and cysteine [12]. Studies have also revealed that people who consume little protein (less than 10% of daily calories) have low IGF1 levels and a reduced risk of cancer and death from all cases [12]. However, elderly people over 65 years of age are recommended to increase the amount of protein in their food to prevent weight loss and excessive reduction of IGF1 and other important factors [14].

How does the activation of the IIS and mTOR pathways contribute to the aging phenotype? Constant stimulation of IIS and mTOR leads to a shortened life and a high risk of age-dependent diseases through a decrease in autophagy, mitochondrial dysfunction, increased protein aggregation (since TOR leads to protein formation) and the level of inflammation (Fig. 4) [12].

Figure 4 (from [13], adapted). The effect of calorie and protein restriction in the diet on the physiology of cells and the body.

Therefore, excess carbohydrates and proteins in the diet contribute to atherosclerosis, osteoporosis, neurodegenerative diseases, cancer, insensitivity to insulin. Such mechanisms fit into the paradigm according to which the aging process is a consequence of excessive stimulation of cells in the adult body through constant "bombardment" of nutrients, growth factors and mitogenic stimuli.

Loss of protein homeostasis

Protein homeostasis in the cell is maintained due to two multidirectional processes: the mechanisms of correct assembly of proteins (and their subsequent stabilization) and the mechanisms of degradation of proteins with a disturbed structure (proteolysis). If these processes fail, the proteins aggregate, which leads to the development of neurodegenerative diseases [15]. Heat shock proteins restore the disturbed structure of proteins, and under stress (thermal or chemical), the level of BTSH in the cell increases (Fig. 5). The synthesis of BTSH induced by stress decreases significantly with age [16], and this affects life expectancy. The SIRT1 protein in mammalian cells initiates the synthesis of BTSH [17], and the activity of SIRT1 increases resveratrol contained in cranberries and grapes.

Figure 5 (from [7], adapted). Maintenance of protein homeostasis. Stress in the cell (thermal or chemical) leads to disturbances in the structure of proteins. Normally, such "broken" proteins either restore the lost structure with the help of chaperone proteins, or are disposed of in proteasomes/autophagosomes. But if there is a failure in the recycling-assembly systems, then the proteins aggregate and worsen the work of the cell. This contributes to aging and the development of neurodegenerative diseases.

The effectiveness of the two main proteolytic systems – autophagosomal (or lysosomal) and proteasomal – also decreases with age. Activation of autophagosomes slows down cellular aging and prolongs the life of a number of model organisms. Spermidine, contained in mushrooms, whole grains and legumes, triggers autophagy processes, and its addition to food contributes to longevity in worms, flies and mice [18, 19].

Violation of protein homeostasis and increased proinflammatory processes provoke the end products of glycation (non-enzymatic reaction of addition of carbohydrates to amino acids in the protein composition). A high level of glycation end products (advanced glycolation products, AGEs) in tissues causes oxidative stress and inflammatory processes, since AGEs bind to surface cell receptors, trigger the inflammatory NF-kB signaling pathway, and also alter the structure and functions of proteins [20, 21]. The data obtained show that reducing the amount of AGEs in food slows down the development of chronic diseases and aging in animals and, apparently, in humans. Vegetables, fruits, grains, legumes, milk and bread contain little AGEs, while in hard cheeses, beef, pork and poultry the amount of AGEs is high [21].

Genome stability

Accumulated DNA damage during life is one of the basic signs of aging. The integrity and stability of the genome are constantly under threat due to the influence of both external (chemical and biological agents) and internal factors (errors in DNA doubling, reactive oxygen species). Genetic damage can affect important biochemical pathways in the cell and disrupt their work, which is especially critical in the case of stem cells. In maintaining genomic stability, the diet plays a more significant role than previously thought. B vitamins (B3, B9, B12), zinc and magnesium are necessary for the normal synthesis of DNA, its methylation and error correction, so even a slight lack of these substances in the body affects genomic stability and leads to an increase in the level of spontaneous chromosomal damage [22]. However, modern norms for vitamins and minerals are established to prevent deficiencies, and not to minimize damage to DNA [22]. The use of these vitamins is especially important for defects in their absorption / metabolism, which are usually observed in old age. Therefore, after fifty years, it is recommended to eat food with a high content of B12 and B9 [22]. People who follow a vegan diet also need special vitamin supplements, since B12 is found only in animal products.

Telomere length

Telomeres are the end sections of chromosomes whose length is shortened with each cell division. Telomeres are associated with a multi–protein complex - shelterin, which prevents them from sticking together. Shelterin does not give access to DNA repair systems that would recognize the ends of chromosomes as breaks in DNA and connect them to each other. Due to limited repair, telomere lesions are relatively stable and capable of inducing cell division arrest and/or cell apoptosis [23, 24]. Vitamins B3 and B9 are needed to prevent damage and maintain normal telomere length [25]. The use of omega-3 polyunsaturated fatty acids positively correlates with telomere length [25, 26].

Epigenetic changes

During life, epigenetic changes occur in the cells of our body*, which affect DNA methylation, histone modifications and rearrangement of the chromatin structure (Fig. 6) [7].

* – These changes can be passed on to the next generations and affect the phenotypes of children and grandchildren. For more information about what epigenetics is, what epigenetic modifications are and whether there are drugs for the treatment of epigenome, see the articles: "Aging and longevity: epigenome reveals secrets", "Epigenetics: the invisible commander of the genome" and "Pills for the epigenome" [5, 30, 31]. – Ed.

Figure 6 (from [7], adapted). Epigenetic changes that occur with age.

This leads to a weakening of DNA repair and an increase in chromosomal instability. But unlike mutations, epigenetic processes are reversible: the activity of enzymes involved in the creation and maintenance of epigenetic labels can be regulated. With the help of changes in histone modifications, scientists increased the life expectancy of progeroid mice (mice with accelerated aging) [27] and restored cognitive abilities in old mice [28]. Many substances have been found in fruits, vegetables and greens that affect the activity of enzymes involved in epigenetic reconstruction [29].

Genistein isolated from soy induces the establishment of certain histone modifications (methylation of H3K27 and H3K9), the level of which decreases with age [29]. And one of the effects of resveratrol contained in cranberries, blueberries, grapes and red wine is an increase in the activity of the SIRT1 protein involved in histone modification. Sirtuin proteins, which belong to the family of NAD-dependent deacetylases (i.e. they remove the acetyl label from histones), are widely studied as potential factors that prevent aging. Increased expression of SIRT1 in mammals improves health indicators in old age (life expectancy does not increase) [32]. In addition, convincing evidence has been obtained for SIRT6 for its activity on the length of life in mammals [33]. And recent experiments have shown that free fatty acids (oleic, linolenic, myristic) in physiological concentrations increase the activity of SIRT6 [34].

Mitochondrial disorders

Mitochondria are the main energy stations of the cell, they oxidize incoming nutrients, converting them into energy in the form of ATP [35]. During the oxidation of substances in mitochondria, oxygen radicals (reactive oxygen species – ROS) are inevitably formed, which damage cellular structures [36, 37]. Previously, it was believed that mitochondrial damage contributes to aging precisely because of increased ROS production. However, the data of recent years call this hypothesis into question. Disorders in mitochondria, regardless of the level of ROS, lead to cell apoptosis and increased inflammatory reactions [38]. Mitochondrial dysfunction occurs with age for several reasons. Firstly, the formation of new mitochondria (mitochondriogenesis) decreases due to DNA damage and telomere shortening. In addition, mutations accumulate in mitochondrial DNA due to the ROS-rich environment and the limited efficiency of repair systems in mitochondria (compared to the nucleus) [7]. The same SIRT1 protein activates mitochondriogenesis, increases the antioxidant protection of the cell [39] and promotes the removal of damaged mitochondria through the process of autophagy [40]. There is another way to improve the functioning of mitochondria. It is known that soft toxins provoke protective reactions in the cell, which is why it is less susceptible to various adverse factors. In response to weak mitochondrial poisons, including resveratrol [41] (contained, recall, in grapes, blueberries and cranberries), mitochondrial control genes are activated in the cell, ensuring the integrity of mitochondria and their functionality [42].

Cellular aging, changes in intercellular communication and depletion of stem cells

Depletion of stem cells and changes in intercellular communication are the main "culprits" of the aging phenotype: bone fragility, muscle mass reduction, weakening of the immune system, etc. One of the reasons for the development of these signs of aging is cellular aging or stopping division. Cellular aging is induced by telomere shortening, DNA damage, or disturbances in cell division signals. At the same time, aging cells secrete specific molecules (proinflammatory cytokines and metalloproteinases) that accelerate the aging of surrounding cells, as well as initiate inflammatory reactions [43, 44]. Due to the depletion of stem cells, the level of immune cells decreases and defects in their activation are observed [45]. In sum, this leads to a weakening of the immune defense, an increase in pro-inflammatory reactions and the launch of the inflammatory signaling pathway NF-kB.

But some functions of the immune system can be restored with the help of nutrition. Thus, increased doses of vitamin E can enhance the functions of T cells in the elderly; the intake of the amino acid tryptophan and fiber along with food has a beneficial effect on the structure and functions of the intestinal microflora and, accordingly, on the secretion of factors that regulate a variety of inflammatory and metabolic pathways (Fig. 7) [13].

Figure 7 (from [53], adapted). The effect of microflora on immunity and inflammation. Microflora reduces the level of inflammation in several ways. Firstly, the intestinal microbiota produces short-chain fatty acids (SCFA), which contribute to the division and maintenance of regulatory T cells. SCFA also stimulate the production of mucus by goblet cells; enhance the integrity of the epithelial barrier. Secondly, the normal microflora displaces pathogenic bacteria, preventing them from multiplying. Thirdly, segmented filamentous bacteria promote the development of T-helper 17 involved in protection against extracellular pathogens.

The intestinal microflora produces special molecules that help the division and differentiation of regulatory T cells (and regulatory T cells play an important role in controlling inflammation and autoimmune reactions) [46, 47]. Population analysis revealed a strong relationship between diet and the composition of microflora, and between the composition of microflora and morbidity, as well as the level of inflammation in the elderly [48]. Manipulations with the composition of the intestinal microflora seem to be another effective way to increase life expectancy and improve well-being in old age [48, 49].

Conclusion

Further research in the field of biogerontology will help in the future to develop a comprehensive system of measures aimed at increasing life expectancy and prolonging youth. An important point of such a strategy will undoubtedly be the compilation of adequate nutrition recommendations. Perhaps, in the future Methuselah diet, carbohydrates, proteins and fats will be delivered to the body in a form that minimally activates the IIS and mTOR pathways, or they will find substances that "simulate" the effect of starvation. But to date, the original causes of aging are still not clear, and the most proven types of nutrition are the Mediterranean and Okinawan diets [26]. The general aspects of these diets are as follows: high consumption of whole grains, legumes, fish and seafood, fruits and vegetables; moderate consumption of dairy products (mainly cheese and yogurt) and wine; low consumption of red meat, poultry and sweets (Fig. 8). Many studies have confirmed the relationship between compliance with the Mediterranean diet and longevity, as well as a reduced risk of developing pathologies [50, 51], and the inhabitants of Okinawa Island are distinguished by the highest life expectancy.

Figure 8. The Mediterranean diet. Cereals, legumes, vegetables, olive oil and seafood are the main components of the Mediterranean diet. An equally important aspect is the enjoyment of walking and eating with friends. Drawing from the website eatalia.ru .

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Portal "Eternal youth" http://vechnayamolodost.ru  09.03.2016