Encrypted painting (part 2)

What happens to our genes as we age?

Gene expression changes with age, this has been confirmed by many transcriptomic studies. But are these changes always the age-ralated deteriorations and contribute to the development of hallmarks of aging? You see a picture, deciphering which, you can get closer to answering this question.

The details of the picture encoded the results of a simple analysis. We compared data on age-related changes and the impact of changes in gene activity on the lifespan of animals. All data is obtained from the database Open Genes. We found 16 genes which change their expression with age in humans or macaques and at the same time increase in the lifespan of mammals in all performed experiments. These genes are represented in the picture as plants with leaves, flowers and fruits. Every detail has its own meaning.

Olga Posukh, Ekaterina Rafikova and Misha Batin worked on the painting.

The image can be enlarged

Painting characters

The girls and macaques in the picture represent the organism in which an age-related change in gene expression was measured. We found human data for most of the genes. Changes in the expression of the Klotho gene have been shown in macaques, and we used these data too because among our model organisms, macaques are the most evolutionarily close to humans.

Body ornaments

Patterns on different parts of the body of girls and macaques indicate tissues and cell types in which measurements of gene expression were carried out. For 16 of our genes, changes in mRNA or protein levels were shown in the frontal cortex, arteries, gastric mucosa, serum, CD8+ T lymphocytes, peripheral blood mononuclear cells, endothelium, white matter, skin, buccal epithelium, and muscle.

Body ornaments

Patterns on different parts of the body of girls and macaques indicate tissues and cell types in which measurements of gene expression were carried out. For 16 of our genes, changes in mRNA or protein levels were shown in the frontal cortex, arteries, gastric mucosa, serum, CD8+ T lymphocytes, peripheral blood mononuclear cells, endothelium, white matter, skin, buccal epithelium, and muscle.

Plants

The plants on the left, wrapped around a girl and a macaque with their eyes closed, indicate genes that are downregulated in older individuals compared to younger ones. The plants on the right around the girl with their eyes open symbolize genes whose expression increases with age. If the expression changes vary in different experiments, then the plant symbolizing this gene is on both sides.

Dotted lines

In some lifespan experiments, the activity of a gene is changed not from the beginning of embryonic development and not even from birth, but even later, during the maturation or aging of the animal. The number of dotted lines at the base of the plant indicates the age of the animal (months), in which the activity of the gene has been changed.

Dotted lines

In some lifespan experiments, the activity of a gene is changed not from the beginning of embryonic development and not even from birth, but even later, during the maturation or aging of the animal. The number of dotted lines at the base of the plant indicates the age of the animal (months), in which the activity of the gene has been changed.

Figures on the stems of plants

Gene expression changes in women and men can differ in severity and even be opposite. Sex is indicated by geometric shapes around the stems: triangles mark changes in women and rings — in men. If there is no figure on the stem, then the measurement was carried out on a mixed sample, consisting of women and men.

Flowers and fruits

The flowers symbolize mRNA, and the fruits represent proteins — levels of these molecules are used to estimate gene expression. Flower and fruit size represent the average percentage of age-related change in mRNA or protein levels. Flowers and fruits consist of the same elements, but the number of these elements is different. From the bottom to the top of the flower or fruit, the number of elements denotes the numbers of gene entrez ID from first to last.

Flowers and fruits

The flowers symbolize mRNA, and the fruits represent proteins — levels of these molecules are used to estimate gene expression. Flower and fruit size represent the average percentage of age-related change in mRNA or protein levels. Flowers and fruits consist of the same elements, but the number of these elements is different. From the bottom to the top of the flower or fruit, the number of elements denotes the numbers of gene entrez ID from first to last.

Plant color

The color of the plants indicates which changes in gene activity have extended the life of the model organisms. If the gene is indicated by a red plant, then the activity of the gene must be increased to prolong life. Purple plants are genes whose suppression prolongs life.

Here lies the first clue to unravel the main secret of the picture. Purple plants on the right and red plants on the left indicate age-related changes that enchance the aging process. The purple plants on the left and the red plants on the right, on the contrary, represent presumably compensatory age-related changes.

Yellow balls and glass tubes

The diameter of the yellow balls around the flower and fruit represents by what percentage, on average, life expectancy has increased in a model organism. The light circle at the bottom represents 100%. Glass tubes cover the genes, the activity of which was changed not in the whole organism, but in individual tissues. The elongated ball represents the brain, the cylinder represents the liver, and the thimble represents adipose tissue.

Yellow balls and glass tubes

The diameter of the yellow balls around the flower and fruit represents by what percentage, on average, life expectancy has increased in a model organism. The light circle at the bottom represents 100%. Glass tubes cover the genes, the activity of which was changed not in the whole organism, but in individual tissues. The elongated ball represents the brain, the cylinder represents the liver, and the thimble represents adipose tissue.

Leaves

Another clue to answering the main question is the shape of the leaves. The form of leaves on plant stems depends on whether protective or harmful age-related changes in gene expression were observed. Rounded leaves indicate genes whose age-related changes enhance aging, i. e. changes in the expression of these genes are the opposite of a change in activity that prolongs life. Stems with sharp leaves symbolize genes, whose changes in expression coincide with the effect on the gene, which extended life, that is, compensatory age-related changes occur in the gene expression. Stems with thorns encode genes with inconsistent or insufficient data on changes in expression for an unambiguous conclusion.

The image can be enlarged

“Anti-longevity” age-related changes

The changes in gene activity that prolong life is the opposite of age-related change for 4 out of 16 genes. They are indicated by plants with rounded leaves. An increase in the activity of these genes prolongs life, and with age, the activity of the gene decreases in all available experiments, and vice versa. Although the question of which changes in expression are the cause and which are the consequences of aging still remains open, it can be assumed that age-related changes in the activity of these 4 genes accelerate aging and should be addressed first.

Plants that weave around the macaque represent age-related changes in the expression of the KL gene (Klotho). The ubiquitous activation of KL prolongs life, and its expression decreases in macaques in the white matter of the brain. Klotho exists as a membrane protein and as a circulating hormone. As a hormone, this protein inhibits insulin and insulin-like growth factor signals.

CEBPB (1051)

CEBPB mRNA levels increase with age in human muscle, and the downregulation of this gene prolongs life. This emphasizes the purple flower passing through the girl's leg on the right. This gene encodes a transcription factor that is responsible for the expression of genes associated with the immune response and inflammation — the disruption of these processes and chronic inflammation is one of the key hallmarks of aging.

EPS8 (2059)

The EPS8 gene is responsible for the architecture of the cytoskeleton and is indirectly involved in the cell cycle. Its activity is also necessary for the migration of cancer cells. Suppression of this gene prolongs the life of a mouse by a quarter. Its expression increases with age in CD8+ lymphocytes. The EPS8 flower passes through the lymphocyte-like ornament on the right hand of the girl.

TRPV1 (7442)

The fourth plant symbolizes the TRPV1 gene. The ubiquitous suppression of this gene activity prolongs life by 14%. Both TRPV1 mRNA and protein levels increase in the skin — purple stems pass through the ornament on the girl's hand on the right, which resembles layers of cells in a cross-section of the skin. This gene encodes a calcium channel that responds to chemical and thermal stimuli, is involved in intracellular acidosis of neurons, the transmission of pain signals during inflammation, and has a central neuromodulatory effect. Interestingly, activation of this gene is associated with long-term depression. A TRPV1 receptor antagonist recently is undergoing clinical trials for the treatment of chronic pain.

Compensatory or protective age-related changes

The expression of 4 genes changes with age in the same direction in which it needs to be changed in order to prolong life. Such age-related changes can be compensatory and be the result of negative age-related changes. They are indicated by plants with sharp leaves.

FST (10468)

Enhancing FST (follistatin) in 18 months old female mice increases the lifespan by a third. Its expression increases with age in women's muscles, and even stronger in men — a red flower passes through the ornament on the girl's leg on the right. Follistatin is associated with reproductive function in both sexes.

NFKBIA (4792)

NFKBIA expression is increased in the frontal cortex in humans — a red flower passes through the brain pattern on the girl's head on the right. At the same time, its activation throughout the body prolongs life. The product of this gene inhibits the NFKB complex responsible for inflammation, i.e. NFKBIA has an anti-inflammatory effect.

IGF1R (3480)

Suppression of the activity of IGF1R, the insulin-like growth factor receptor, prolongs the life of mice by an average of 16%. Its expression is reduced in peripheral blood mononuclear cells and CD8+ lymphocytes — it is represented by two plants on the left.

MIF (4282)

MIF is another gene associated with immune function and inflammation. Like other pro-inflammatory genes, it needs to be deactivated and life expectancy will increase. The MIF gene is pictured as a flower growing from an ornament of CD8+ lymphocytes on the girl's hand on the left, which indicates an age-related decrease in its expression in these cells.

Ambiguous age-related changes

For 8 genes, data on age-related changes in expression are ambiguous.

INSR (3643)

The INSR gene encodes the insulin receptor. Reducing INSR expression in adipose tissue prolongs life, but we have no data on what happens with lifespan if this gene is partially suppressed in all tissues. At the same time, in our database, we have data on age-related changes of INSR expression in humans only for the frontal cortex, where insulin pathway plays an important role in the functioning of the blood-brain barrier [1]. Its expression increases with age according to our data. Considering the important role of the insulin in the brain, we cannot say that its decrease in brain tissues plays a protective role.

MTOR (2475)

The mTOR gene, also associated with the insulin and insulin-like growth factor pathway, must be suppressed to increase lifespan. And its expression decreases with age in half, at least in the frontal cortex. However, mTOR regulates many functions in brain, such as proliferation, differentiation, migration, and dendrite formation. In addition, mTOR is important in synaptic formation and plasticity [2]. Therefore, although mTOR suppression prolongs life, we cannot argue that age-related decline in mTOR expression is protective. The gene is depicted as a purple flower on the left, passing through the ornament representing the brain.

For the remaining genes from the “ambiguous” group, both an increase and a decrease in expression were shown depending on the tissue, sex, or experiment. Therefore, these genes can be found in the picture both on the right and on the left.

GHRH (2691)

The expression of GHRH, a protein that stimulates the release of growth hormone from the pituitary, increases in men and decreases in women in the same cells. Suppression of the activity of this gene increases the lifespan of mice. Thus, it is possible that in women we see a protective age-related change in the expression of this gene. GHRH flowers are located at the edges of the picture and indicate a change in gene expression in peripheral blood mononuclear cells (the ornament on the girls' legs).

MYC (4609)

MYC expression is tissue dependent: it increases in muscle and decreases in CD8+ lymphocytes in both sexes. Suppression of the activity of this gene throughout the body leads to an increase in life expectancy. However, we do not have data on changes in the activity of this gene separately in the muscles, where it increases with age. Perhaps suppressing the gene only in the muscles would be more effective. This gene encodes a transcription factor. As we saw in the previous picture, it is important for the expression of many genes, including genes whose activity needs to be increased to prolong life. In a previous article, we suggested that the simultaneous activation of such genes could prevent the possible negative effects of MYC suppression and would lead to even more life extension (Girls, birds, network). By combining data on gene interactions and tissue-specific effects, we can better design gene combinations for aging therapy.

PTEN (5728)

PTEN dephosphorylates proteins, so it inhibits the PI3K-AKT/PKB signaling pathway and can suppress glucose metabolism in adipose tissue. Increasing PTEN activity prolongs life. But the change in the levels of its products is observed in the opposite way in different tissues. mRNA levels decrease in CD8+ lymphocytes, which may accelerate aging. At the same time, the protein level is increased in the gastric mucosa in older people compared to young people by almost 3 times — this is indicated by a plant with a fruit passing through the ornament on the girl's stomach on the right.

SIRT6 (51548)

The SIRT6 gene (sirtuin 6) is involved in many processes: DNA damage repair, telomere maintenance, metabolism, and inflammation. If it is enhanced, the life expectancy of the mouse will increase. In most tissues, its expression is reduced — near the girl on the left, you can find many flowers and fruits that encode SIRT6. However, one flower is located on the right — it symbolizes a doubling of the level of SIRT6 mRNA in peripheral blood mononuclear cells. This change may be compensatory. It may also be more efficient to enhance SIRT6 activity in those tissues where it is most significantly reduced, but we only have data on the activation of this gene in the entire body of the mouse.

UCP2 (7351)

The change in the level of UCP2 mRNA also depends on the tissue: in CD8+ lymphocytes it decreases by 2 times, and in adipose tissue it increases by 3 times. By enhancing the activity of this gene, we can increase lifespan in mice by 16%. The flowers representing UCP2 are surrounded by a ball, since its activity was changed only in brain tissues. We do not know how the expression of UCP2 in the brain changes and how the change in the activity of this gene in other tissues will affect life expectancy, additional experiments would help to answer this question.

VEGFA (7422)

The last gene in the picture is VEGFA, which encodes vascular growth factor. Tissue-specific enhancement of its activity in the liver of mice extended their life, as indicated by the cylinder above the flowers and fruits symbolizing this gene. Both protein and mRNA levels are reduced in the endothelium and muscles, as shown by the two flowers and two fruits on the left, surrounded by a glass cylinder. This change might prevent longevity. However, an 80% increase in VEGFA expression was observed in the frontal cortex, which may be a beneficial protective change.

A map of age-related changes taking into account all the details of experiments and comparing them with life extension experiments and other data, such as associations of genes with longevity, will help identify the most promising combinations of targets for anti-aging therapy.
You can download datasets for analysis with all the details of the experiments in the Download section of the Open Genes website (https://open-genes.com/download).

Beddows, C. A., & Dodd, G. T. (2021). Insulin on the brain: The role of central insulin signalling in energy and glucose homeostasis. Journal of Neuroendocrinology, 33(4). doi:10.1111/jne.12947
LiCausi, F., & Hartman, N. (2018). Role of mTOR Complexes in Neurogenesis. International Journal of Molecular Sciences, 19(5), 1544. doi:10.3390/ijms19051544

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