Insulin-like Growth Factor 1

IGF-1 also provides feedback with the hypothalamus and pituitary gland along the somatotropic axis: the secretion of somatotropin-releasing hormone and somatotropic hormone depends on the level of IGF-1 in the blood. With a low level of IGF-1 in the blood, the secretion of growth hormone-releasing hormone and growth hormone increases, while at high it decreases. Also, IGF-1 regulates the secretion of somatostatin : a high level of IGF-1 leads to an increase in the secretion of somatostatin, low - to its decrease. This mechanism is another way to regulate the level of growth hormone in the blood. But the action can be inhibited by malnutrition, insensitivity of growth hormone, lack of reaction of the receptors, or unsuccessful, below the required minimum signaling pathway, communication of receptors. In experiments on rats, it was found that the amount of IGF-1 and RNA in the liver is positively associated with a lack of casein and negatively associated with a lack of protein in food ^[5] . It was also found that with a lack of IGF-1 in the blood, it can be produced in the muscles themselves.

The level of IGF-1 in the blood depends on the effect on the liver of not only growth hormone, but also sex steroids and thyroid hormones , glucocorticoids , insulin . In this case, insulin, androgens , estrogens increase the secretion of IGF-1 by the liver, and glucocorticoids reduce it. This is one of the reasons for the synergism of insulin, growth hormone, sex and thyroid hormones in relation to the processes of growth and development of the body, tissue growth and differentiation, and one of the reasons for the characteristic inhibitory effect of glucocorticoids on the processes of linear growth, puberty, etc. IGF-1 affects development throughout life, but its level in the blood is not constant: the lowest level of IGF-1 production in childhood and old age, and the highest - during adolescence.

IGF-1 as such was opened in 1978 and 10 years later it was used by athletes as an element of training. He gained immense popularity due to the fact that he absolutely does not need additional recharge (steroid courses, insulin, etc.). But recently, side effects have also been removed: an increase in the liver, spleen , and the number of malignant cells .

The GR / IGF1 cascade is highly conserved in various groups of animals (vertebrates and invertebrates). In general terms, it means that IGF1, through its receptor, triggers a cascade of reactions leading to inhibition of transcription factors (DAF-16 in C. elegans or FOXO1 in mice). These transcription factors probably regulate the expression of genes that increase life span ^[6]

If insulin / IGF1 is the only path in invertebrate animals, this pathway is divided into two in higher vertebrates, including mammals. These two pathways have overlapping functions, but insulin is mainly involved in the regulation of metabolism, and the GR / IGF1 pathway plays an important role in the processes of growth, development and, possibly, longevity. ^[7]

It was the IGF cascade genes that became the first open “ aging genes ” - that is, genes whose damage led to an increase in life expectancy ^[8] .

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Various animals (vertebrates and invertebrates) are convenient models for studying aging, due to their relatively short lifespan, the possibility of genetic manipulation, and the study of their lengths of life.

Caenorhabditis elegans

A cascade that regulates both increased life expectancy and diapause ^[9] . was first investigated for the nematode Caenorhabditis elegans . In response to adverse external conditions, this worm transforms into a juvenile form, which is called ("sleeping"). In this form of Caenorhabditis elegans , development, reproduction does not occur. This form becomes resistant to oxidative stress ^[10] . Fat accumulates in the body to store energy. When environmental conditions are restored, the nematode returns to the state of fertile adults. In dauer, only a young individual who has not reached puberty can go over the form.

Restoring environmental conditions stimulates the activation of the insulin / IGF-1 signaling pathway. If the insulin receptor / IGF-1, mutated (or later components of the cascade, PI3-kinase / PDK / Akt ), then Caenorhabditis elegans transforms into a dauer form even under satisfactory environmental conditions. The insulin / IGF-1 cascade is aimed at inhibiting the DAF-16 protein, which is a transcription factor of a block of genes that stimulate the transition to the dauer form ^[9] . Mutations in the pathway that lead to an increase in life expectancy should be weak. With strong mutations and inadequate activity of the insulin / IGF1 cascade, a young individual can “get stuck” in a dauer form.

It has been shown that in addition to life expectancy, the described cascade of reactions also affects fertility and movement of individuals. Some daf-2 mutants went into juvenile form and lost their ability to move. However, such manifestations cannot be associated with life expectancy, since there are long-lived daf-2 mutants whose mobility and fertility are normal (compared to the wild type). The insulin / IGF1 pathway can regulate the body's hormonal signaling. In organisms with daf-2 gene mutations only in certain lines, an increased lifespan of the whole organism was observed. ^{[10] [11]}

Drosophila sp.

Drosophila (fruit fly) has several advantages for studying aging: this animal is a well-studied model organism with developed genetic engineering methods for working with it and also a good object for genetic knockout . Fruit flies have more similarities with humans (with mammals) than Caenorhabditis elegans (nematode) - they have a brain, heart, and homologs of the kidneys. Drosophila also has complex behavior. However, most biological processes have been studied at the embryotic stage and before metamorphosis. The adult fly, a model object of gerontology, has been studied worse than the embryonic stage. Despite this, Drosophila is one of the main model organisms in the study of aging.

As with Caenorhabditis elegans , for Drosophila mutations that reduce the effectiveness of the IGF1 cascade lead to an increase in life expectancy. This was shown by reducing the amount of insulin-like proteins and knocking out the substrates of the IGF receptor (chico and Lnk) ^[2] . At the same time, an increase in the expression of the DAF-16 FOXO homolog ( transcription factor regulated by the IGF cascade) also leads to an increase in the life span of the flies. With a decrease in the expression of another inverse regulator FOXO (14-3-3ε), the duration of flies also increases.

The Drosophila nervous system and fat body are involved in the regulation of longevity. So, some insulin-like proteins (IPBs) are produced by neurosecretory cells. Under stress, a Jun-N-terminal kinase ( kinase ) is activated, which leads to a decrease in the expression of some of these proteins (IPB2 and IPB5), and, as a result, to a decrease in the efficiency of the IGF1 cascade. When this kinase is activated by molecular methods, an increase in the life expectancy of flies is observed.

In the adipose body (equivalents of white adipose tissue and liver in mammals), a reduction in the IGF1 cascade occurred. However, in 2004 it was shown that an increase in the expression of FOXO can increase the life span of an organism. The mechanisms of this effect require further study ^[2] .

In all cases of inhibition of the IGF1 cascade, it was noted that the activity of genes involved in cascades of cellular detoxification increases.

In previous experiments, it was shown that inhibition of the IGF1 cascade increases lifespan, however, does this inhibition slow down the aging process?

A decrease in the activity of the IGF1 cascade leads to a decrease in female fertility, which is not surprising, because this cascade plays one of the key roles in regulating the growth, proliferation, and survival of stem cells , the precursors of eggs. However, while restricting the nutrition of wild-type flies, which leads, inter alia, to limiting the operation of the IGF1 cascade, it increases the number of germ cells.

On the other hand, with a decrease in the efficiency of the cascade (in conjunction with the reduction of the TOR signal chain ), the decrease in cardiac functions slows down, and negative geotaxis is less often observed. For flies serving as models for the study of Alzheimer's disease, it was shown that the reduction of the components of the IGF1 pathway led to a decrease in the pathology progression. Similar results have been shown for a number of other neurodegenerative diseases (e.g., Parkinson's disease). ^{[2] [12]}

Mammals

Evidence of the effect of IGF1 cascade on life span has been shown in various mammalian models. A good example would be dwarf mutant mice deficient in growth hormone . Such mice not only live long, they have slowed down the aging of the immune system ( cell aging ), cross-linking of collagen, slowed down the aging of lethal diseases and random pathological processes such as arthritis. ^{[8] [13]} .

Also, in rodents that were put on a diet (limited diet), a decrease in insulin and IGF1 levels was observed. The amount of stored fat decreased, the immune system was stimulated. Life expectancy increased by 30–40% ^[7] . Genetic models have also shown the effect of IGF1 cascade on life expectancy.

Mice Alzheimer's Study

To create a system for studying Alzheimer's disease, β-amyloid was expressed in mice. A healthy person expresses this protein, and normally this protein is not toxic, however, β-amyloid can form dimers and oligomers that are neurotoxic and cause Alzheimer's disease. During the reduction of the IGF1 cascade in mice, aggregation of β-amyloid into larger ensembles was observed, which reduced their toxicity and slowed down the development of the disease ^[14] .

By analogy with other animals, in mammals, the IGF1 cascade negatively regulates FOXO gene translation factors. FOXO is a highly conserved mammalian family of genes necessary for the body to survive under stressful conditions. Moreover, when the IGF1 signal was reduced, the mice showed greater resistance to oxidative stress. Thus, in mice simulated to study Alzheimer's disease, the complex effect of the IGF1 cascade on the body's defense systems was shown ^[14] .

The role of the cascade in human aging

In 2009, a study was conducted on a group of elderly Caucasians. 30 genes of the insulin / IGF1 signaling pathway were examined. In the course of this study, SNPs reliably associated with life expectancy were found. One of these SNPs was found in the AKT1 gene. And two more SNPs in the FOXO3A gene were associated with life expectancy in women.

AKT1 is one of the tyrosine kinases that is able to phosphorylate FOXO3A. Phosphorylated protein cannot penetrate the nucleus and activate the genes of the FOXO family . FOXO3A is one of three human homologues to the DAF-16 translation factor in Caenorhabditis elegans . Interestingly, SNPs affecting longevity were found in introns whose functions are not yet known. ^[15]

For humans, the ratio of GR / IGF1 plays an important role. With a relatively large amount of growth hormone (with a lack of IGF1), symptoms such as obesity, mental retardation, glucose intolerance ( Laron's syndrome ) can develop ^[7] .

Cancer susceptibility

The IGF signaling pathway has a pathogenic role in cancer development. Studies have shown that with elevated levels of IGF, cancer cell growth is enhanced. ^{[16] [17]} In addition, people with Laron syndrome have a significantly lower risk of developing cancer. ^{[18] [19]} Changes in diet, in particular, a vegan diet, which reduce the activity of IGF-1, may be associated with a reduced risk of cancer. ^[20] However, despite significant research, anticancer therapies affecting IGF-1 have not shown impressive results in clinical trials. ^{[17] [21] [22] [23]}

Stroke

The efficacy of IGF-1 in stroke in mice in combination with erythropoietin has been shown. Behavioral and cellular improvements were recorded. ^[24]

Neurodegenerative diseases

Клинические испытания вещества ибутаморен , которое повышает уровень ИФР-1 у пациентов, не продемонстрировало улучшений симптомов болезни Альцгеймера . ^[25] Другое исследование продемонстрировало отсутствие замедления прогрессирования болезни у пациентов с БАС , однако другие исследования показали значительные улучшения при ИФР-1-заместительной терапии у пациентов с БАС, ^[26] поэтому ИФР-1 имеет потенциал для лечения БАС. ^[27] Однако, в целом исследования показали противоречивые результаты. ^[28]

Пациенты с тяжелым первичным дефицитом ИФР-1 могут лечиться либо ИФР-1, либо ИФР-1 вместе с IGFBP3 (ИФР-связывающий белок типа 3). ^[29] Мекасермин (выпускается под брендом Инкрелекс) — синтетический аналог ИФР-1, утверждённый для лечения нарушений роста. ^[29] ИФР-1 производится в промышленных масштабах с использованием дрожжей или E. coli .

1. https://www.ncbi.nlm.nih.gov/gene/3479
2. Ageing in Drosophila: the role of the insulin/Igf and TOR signalling network, Partridge L, Alic N, Bjedov I, Piper MD, 2011
3. Endocrine regulation of ageing, Russell SJ, Kahn CR, 2007
4. Drosophila melanogaster in the Study of Human Neurodegeneration, Frank Hirth, 2010
5. Reduced IGF-1 signaling delays age-associated proteotoxicity in mice, Cohen et al, 2009
6. The insulin/IGF-1 signaling in mammals and its relevance to human longevity, Rincon M et al, 2005
7. Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity, Pawlikowska L, 2009
8. A Conserved Regulatory System for Aging, Cynthia Kenyon, 2001
9. Genetic pathways that regulate ageing in model organisms Leonard Guarente & Cynthia Kenyon .
10. Role of the GH/IGF-1 axis in lifespan and healthspan: lessons from animal models, Berryman DE, Christiansen JS, Johannsson G, Thorner MO, Kopchick JJ., 2008
11. Dwarf mice and the ageing process, Brown-Borg HM, Borg KE, Meliska CJ, Bartke A. 1996
12. В. Н. Анисимов «Молекулярные и физиологические механизмы старения» — Спб: Наука 2003 — ISBN 5020261998