Potential targets for aging gene therapy (1)
A Short List of Potential Target Genes for Near-Future Gene Therapies Aimed at Slowing Aging or Compensating for Age-Related Damage and DeclinePosted by Reason
Translated by Evgenia Ryabtseva
Based on the materials of a large number of publications on Fight Aging! a list of potential targets for gene therapy in the near future was compiled. This article focuses on the validity of the use of such approaches as compensatory therapy of aging, therefore, the list does not include a wide range of hereditary diseases caused by a mutation in a single gene, which in the next few decades will account for a large share of the gene therapy sector of the medical industry. Moreover, Fight Aging! only selectively provides information about ongoing research and does not note all areas of work. More complete information can be obtained in the online GenAge database, which includes thousands of genes of various species.
In addition, many methods of gene therapy have a temporary effect intended for short-term improvement of the situation in pathological conditions, like the action of pharmacological drugs. Most of these approaches were also not included in the list. And finally, almost all potential gene therapy approaches are currently, at best, aimed at maximizing compensation for aging-induced damage or at very moderate slowing down the progression of these injuries by influencing metabolism using mechanisms that have not been fully studied to date. Based on several cases in which we can compare the same genetic manipulations performed on mice and humans, only mice have an obvious increase in life expectancy. This is because when it comes to changing metabolism, the life expectancy of representatives of short-lived species is much more plastic.
The arrival of the era of gene therapy
It is obvious that the era of enthusiasm for genetics and gene therapy is now coming, in which it will be possible to edit genes in certain tissues economically at certain times and in certain circumstances. Genes encode proteins produced by the cell during gene expression. Genes can be deleted, modified or doubled, and the level of their expression and, accordingly, the number of proteins produced can also be selectively increased or decreased. The activity of the cell changes in response to an increase or decrease in the levels of various proteins. The components of this control system are interconnected, and the system itself is extremely complex and poorly understood. However, the ability to change protein levels in principle makes it possible to change the behavior of the cell. To date, in order to find out the effect of each specific change as quickly as possible, it must first be tested in animal experiments, and subsequently confirmed in clinical studies. To select the most promising targets, theoretical predictions can be made in advance, however, for the reason that in cellular biochemistry all components are interconnected, no change occurs in isolation. It will have secondary and even more distant effects, changing the mechanisms and levels of gene expression of other proteins, which as a result may or may not lead to theoretically expected results.
The rapid development and cheapening of gene editing technologies in recent years has opened the doors for research. Whereas previously the work was carried out only in the most convincing directions, today changing any gene is a viable start for research.
Potential targets for gene therapy of the future, hypothetical and not
Angiotensin Converting Enzyme (ACE): There is evidence that reduced ACE levels increase the average lifespan of nematodes. ACE inhibitors are used in medicine to treat hypertension, however, the mechanism providing an increase in the life expectancy of nematodes that do not suffer from increased blood pressure has yet to be clarified.
Adenylate Cyclase (AC5): knockout of adenylate cyclase increases the lifespan of mice, most likely due to increased resistance of the cardiovascular system to various manifestations of aging. Many other features of mice with knocked-out adenylate cyclase resemble the features of animals contained in a low-calorie diet.
AMP-dependent kinase (AMPK): selective overexpression of AMPK in the gut of fruit flies provides an increase in life expectancy. This protein is an energy sensor involved in the reaction to a low-calorie diet, which manifests itself by more effective maintenance of cell activity, improving health and a moderate slowdown in the aging process. Several methods using it to improve the activity of stem cells in the intestines of fruit flies have also demonstrated an increase in life expectancy.
Angiopoietin-like protein-4 (ANGPTL4): The results of a recent study indicate that a rare variant of the gene encoding this protein, available in less than 1% of the European population, reduces the risk of myocardial infarction by 50%. The proposed mechanism of this implies changes in cholesterol metabolism. This protein is an excellent example of a potential target of gene therapy, which still needs a lot of work to validate the initial data, but has quite a lot of human carriers, which indicates safety.
Type 1 receptors for angiotensin-2 (Agtr1a): reducing the levels of Agtr1a protein protects the functioning of mitochondria and moderately increases the lifespan of mice, although, as with many methods that allow to slow down aging a little, in this case, many other changes in metabolism that have not been studied to date can also occur.
Apolipoprotein A-1: an increase in the amount of this protein can be used for positive changes in cholesterol metabolism, slowing the progression of atherosclerosis by removing some of the damaged lipids that accumulate in the walls of blood vessels.
Apolipoprotein E: one of the exclusively human genes, variants of which are stably associated with a longer lifespan. At the same time, the effect it exerts is not so pronounced as to provide such an association. Perhaps the chance of reaching the age of 100 for some people increases from 1% to 1.2%. From the author's point of view, this gene is not a worthwhile target for gene therapy.
ARID1A: According to a recent accidental discovery, knockout of the ARID1A gene increases the regenerative potential in mice, especially liver tissue. To date, it is too early to talk about the mechanisms by which this effect is realized, since the activation of regeneration is directly opposite to the initially predicted effect of this genetic manipulation.
Activating Transcription Factor-4 (ATF4): elevated levels of ATF4 in the liver are detected using many methods to slow the aging of laboratory organisms, although it is unclear whether this makes this protein a worthwhile target.
Atoh1: increased concentrations of atoh1 protein were used to accelerate the growth of hair sensory cells in guinea pigs, which makes this manipulation one of the promising approaches to influencing the direct cause of the development of forms of age-related deafness developing due to the death of these cells, but not for other reasons.
Azot: The azot gene in fruit flies is a component of the mechanism by which cells interact to identify damaged or inadequately functioning "neighbors", marking them for destruction and replacement. Adding an additional copy of the azot gene to increase the concentration of its protein product increases the efficiency of destroying cells with reduced viability and increases life expectancy, at least in fruit flies. The gene itself and the quality control mechanism associated with it have been preserved in the mammalian genome, but to date there have been practically no studies devoted to attempts to test this approach on mice or other organisms.
BCAT-1: Inhibition of bcat-1 protein increases the lifespan of roundworms, possibly through some variant of hormesis or the effect of a low-calorie diet through blocking the processing of certain nutrients.
Beta-2-microglobulin (B2M): the level of B2M increases with age, while a decrease in the concentration of B2M in elderly mice partially restores the manifestations of cognitive decline accompanying aging. The underlying mechanism has yet to be studied, but it is known that the role of B2M is associated with an adaptive immune system.
BubR1: mouse models with increased expression of BubR1 are characterized by a low incidence of cancer, an increased ability to tolerate physical activity and a moderate increase in life expectancy. The effect on cancer incidence makes sense in the context of what is known about BubR1, which is involved in important control mechanisms of cell replication, while the second effect is less clear.
C-Myc: It is interesting that this list includes most of the genes involved in cell pluripotency induction recipes, such as c-myc. Studies have shown that reduced levels of c-myc can moderately slow down aging and increase the lifespan of mice. There is evidence that this is due to the effects of insulin metabolism, although many more studies are needed to obtain convincing evidence.
C1Q: The C1Q gene plays an important role in the functioning of the immune system. Its removal from the mouse genome increases the efficiency of regeneration through a signaling mechanism mediated by Wnt. The concentration of C1Q in the brain increases with aging, and its elimination improves the state of cognitive function in the later stages of life of mice.
Catalase: Gene therapy aimed at increasing the levels of the antioxidant catalase in mitochondria has brought contradictory results, however, some studies have demonstrated improved health and increased life expectancy. Other approaches using mitochondrial-specific antioxidants have yielded similar results. According to the prevailing theory, this reduces the severity of mitochondrial damage caused by reactive oxygen species formed in these organelles, in which antioxidants neutralize reactive molecules before they cause damage.
CLK1: A decrease in CLK1 activity may increase the lifespan of mice due to changes in mitochondrial function and a subsequent decrease in the formation of reactive oxygen species. There are many potential ways to influence the functioning of mitochondria, but it is quite possible that attempts to combine them can provide a decreasing effect.
CRTC1: A decrease in CRTC1 levels may increase the lifespan of nematodes and may be involved in the development of a reaction to a low-calorie diet. This protein is very similar to AMP-dependent kinase, and manipulations of these two compounds are likely to make similar changes in metabolism.
Cyclin A2: There is evidence that increasing the level of cyclin A2 increases the regenerative capacity of heart tissue. This protein is one of a complex of proteins that can be used as a basis for regenerative gene therapy of heart diseases. Such methods can be used long before the onset of old age to slow down or delay the degeneration of cardiac tissue.
Fibroblast growth factor (FGF21): hyperexpression of fibroblast growth factor develops against the background of a reaction to a low-calorie diet and artificial induction with the help of gene therapy can increase the lifespan of mice. This approach is one of many methods of moderate slowing down of aging, interconnected with a well-studied signaling pathway mediated by growth hormone/insulin-like growth factor-1.
FKBP1b: gene therapy that increases the level of FKBP1b to concentrations characteristic of young age can eliminate age-related disorders of calcium metabolism in the brain of rats. This is manifested by an improvement in cognitive functions, assessed using spatial memory tests.
Follistatin: Increasing follistatin levels stimulates the growth of muscle tissue, which is a potentially useful compensation for the decrease in muscle mass and strength accompanying aging. This is the reverse side of the action of myostatin, since an increase in the level of follistatin blocks the activity of myostatin. In animal experiments, an increase in follistatin levels and a decrease in myostatin levels provide similar effects, manifested by an increase in muscle mass. Interventions and the use of follistatin have not been studied as well as interventions using myostatin, however, BioViva chose to increase the level of follistatin to develop a therapeutic approach.
FOXO3: According to available clinical data, a certain variant of FOXO3 is associated with a significant reduction in the likelihood of developing cardiovascular diseases and mortality. FOXO3 is involved in many mechanisms involved in aging, so there is a lot of room for discussion of causes and consequences and very few unambiguous answers.
FOXN1: An increase in the level of FOXN1 has its effect in the aging thymus. The thymus (thymus gland) is an organ of the immune system in which immune cells mature, so this intervention improves immune function in the later stages of life by stimulating the appearance of new immune cells. Aging and impaired functioning of the immune system are partly the result of a decrease in the number of immune cells forming, so a new method of activating this mechanism may be useful.
Growth and Differentiation Factor-11 (GDF11): Researchers have demonstrated the ability of elevated levels of growth factor and differentiation-11 to improve many aging indicators in mice, such as heart function, exercise tolerance and olfactory sensitivity. This is most likely due to the increased activity of stem cells, but until today there are a number of disputes about what exactly researchers observe when conducting such studies. Identification of growth factor and differentiation-11 is one of the results of the increase in interest in parabiosis observed over the past years.
GHK: The concentration of GHK in the blood and tissues decreases as we age. This is involved in a number of changes, manifested by the deterioration of wound healing in old age. Since the introduction of GHK demonstrates positive results, the use of gene therapy to restore the levels of this protein can partially restore this loss of regenerative abilities.
Glycine-N-methyltransferase (Gnmt): in drosophila flies, elevated levels of glycine-N-methyltransferase inhibit the use of methionine in protein synthesis, which reproduces some parameters of the effect of a low-calorie diet on health and life expectancy. The reaction to a decrease in methionine levels is a key trigger of the reaction to a low-calorie diet.
Growth hormone/growth hormone receptor/insulin-like growth factor/insulin receptor: The longest-lived genetically modified mice do not have a functional growth hormone receptor. They are small in size and sensitive to cold, but have no other health problems. Many similar approaches, violations of the well-studied action of growth hormone and insulin metabolism also increase the life expectancy of mice to varying degrees. Some of these approaches affect the entire body, while the rest are tissue-specific. There is a small population of people with Laron syndrome caused by mutations that disrupt the functioning of the growth hormone receptor. They do not live longer than other people, which is a warning against extrapolating the results obtained in mice to humans, and have a number of health disorders associated with a specific form of dwarfism, but may be resistant to some forms of age-related diseases. Currently, data is still being collected on this issue and it is very interesting to consider all possible effects of gene therapy affecting the metabolism of growth hormone and insulin in adulthood.
Histone deacetylase-2 (HDAC2): genetically modified mice characterized by low levels or complete absence of histone deacetylase-2 demonstrate improved memory and neural plasticity.
Heat shock proteins: Heat shock proteins (chaperones) are involved in cellular processes that ensure the elimination of damaged or incorrectly folded protein molecules. Their activity increases under the influence of high temperature, toxins and various other forms of cellular stress. An increase in the activity of heat shock proteins slows down the aging of laboratory animals. Many of these methods involve changing the levels of other proteins interacting with heat shock proteins or regulating their activity.
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30.06.2016