04 July 2016

Potential targets for aging gene therapy (2)

This list provides selected information about genes, the impact on which may affect the aging process. More complete information can be obtained in the online GenAge database, which includes thousands of genes of various species.

(See the introduction and the beginning of the list of target genes in the first part of the article).

Hepatic transcription factors: A whole spectrum of transcription factors is associated with liver development and regeneration. Researchers have demonstrated that activation of some of them can reduce the severity of liver fibrosis by shifting the priority of dividing cells from the formation of scar tissue to the formation of beneficial liver cells.

Hepatocyte Growth Factor (HGF): currently at the stage of development of compensatory therapy to stimulate remodeling and growth of new blood vessels in ischemic disease.

INDY: The INDY gene, whose name stands for "I'm Not Dead Yet" (from the English "I'm Not Dead Yet"), was one of the first longevity genes identified in fruit flies. A decrease in the level of INDY protein increases life expectancy, which, according to existing data, is due to an increase in the functionality of intestinal stem cells.

Interleukin-21 (IL-21): Scientists have demonstrated that increasing the concentration of interleukin-21 improves the state of the immune system by accelerating the formation of new immune cells. Age-related decline in immune function is an important component of senile decrepitude and even partial compensation for this decline can be very useful.

KLF4: a selective decrease in the concentration of klf4 protein in vascular smooth muscle cells causes positive changes in the behavior of these cells. This is manifested by suppressing their excessive reaction to the entry of damaged lipid molecules into the bloodstream, which slows down the progression of damage and the reaction to these injuries, leading to the development of atherosclerosis.

Klotho: According to available data, Klotho overexpression increases the lifespan of mice, possibly through the same mechanisms as a low-calorie diet. As with many other methods of genetic engineering that slow down the aging of laboratory models, this mechanism is characterized by complex biochemistry, weakly expressed efficiency and there is still a lot to understand in order to figure out how it really works.

Lamins: There are three isoforms of lamin: A, B, and C. The cause of progeria, a rare disease characterized by accelerated aging, is a mutation of lamin A. Much lower concentrations of abnormal lamin A are recorded in aging tissues, although it is unclear whether this contributes in any significant way to the progression of aging. An interesting fact is that for genetically modified mice, in which only lamin C is synthesized in the body, a moderate increase in life expectancy is characteristic. This mechanism is also completely unclear.

LAMP2A: variant A of the membrane protein-2 associated with lysosomes is a receptor involved in autophagy processes necessary to maintain effective cell activity, however, its levels decrease with age and, at least in some species, this is one of the factors responsible for the age-related extinction of autophagy. Already about 10 years ago, researchers demonstrated the possibility of restoring the liver functions of old mice to levels characteristic of a younger organism by adding an additional copy of the gene, which increased the concentration of this protein. Increasing the effectiveness of autophagy manifests itself as a component of many interventions that slow down the aging of animals, however, this example is one of the few that have demonstrated a certain rejuvenation of the functions of the organs of old individuals.

Leukemia inhibiting factor (LIF): A change in the concentration of a leukemia inhibiting factor was used to stimulate the activity of cells of the nervous system in order to increase the effectiveness of repairing damage to the myelin sheath of nerve fibers. Since we all partially lose this shell with age, this mechanism is of general interest and is applicable not only in conditions characterized by the loss of a large part of myelin, such as multiple sclerosis.

Lin28a: Increased expression of Lin28a increases the regenerative ability of mice. This is another gene used in reprogramming ordinary cells into stem cells. As with other potential options for enhancing human biochemical metabolism, in this case it is necessary to take into account the risk of developing cancer, which makes this method more suitable for the development of temporary therapy, rather than irreversible change.

LOS1: LOS1 can be involved in various fundamental cellular processes, ranging from protein synthesis to DNA repair. However, the effect of LOS1 knockout on longevity has been studied only in yeast, so proving its suitability as a target for gene therapy requires a lot more work.

miR-195: miR-195 microRNA interacts with telomerase and its inhibition has the same positive effect on stem cell activity as increasing the level of telomerase. Increased stem cell activity means more active regeneration, however, there may also be an increased risk of developing cancer later in life. Since the activity of stem cells fades with age, a very large number of research groups are developing potential methods of restoring, as an option, even temporarily, this activity to the levels of a young organism.

Mitochondrial complex 1: Scientists have demonstrated that partial disruption of the functioning of mitochondrial complex 1 moderately increases the life expectancy of a number of species. According to the dominant theory, this is due to the effect of hormesis, in which an increase in the formation of reactive oxygen species causes cells to react more actively by activating the processes of eliminating damage and maintaining functionality. An important point is the degree of violation, since too minor or too severe violations may either have no effect or be detrimental to the cell. Similar effects can be achieved by changing the protein synthesis apparatus of this complex or other complexes of the electron transport chain. It is quite obvious that mitochondria play an important role in aging, but the effect on their work in this way looks unproductive compared to the approach proposed by the SENS concept, which implies eliminating the influence of mitochondrial DNA damage by allotopic expression of mitochondrial genes in nuclear DNA.

Mechanical target of rapamycin, or mammalian rapamycin target (mTOR): Researchers have demonstrated that manipulations of the mTOR gene and levels of its protein product moderately increase the lifespan of some species. There are also several synergistic genetic changes involving mTOR and other genes identified in lower animals that provide significantly more pronounced effects. The mTOR protein is involved in many fundamental cellular processes, as well as many longevity-associated genes of laboratory animals, and can cause truly comprehensive changes in cellular metabolism. However, the exact decoding of what is happening inside the cell is still far from over, both for this and for many similar longevity genes.

Myostatin: A decrease in myostatin increases the growth of muscle tissue, which can be a useful compensation for age-related decrease in muscle mass and strength. Due to the existence of a number of natural animal lines with this mutation, to date, knockout of myostatin is the most well-studied and tested of all potential gene therapy approaches. For example, clinical studies of myostatin blockade with the help of antibodies have been conducted, in addition, it is even known about several people with developed muscles with mutations that disrupt the functioning of myostatin.

NAD-dependent methylenetetrahydrofolate dehydrolase-methenyltetrahydrofolate cyclohydrolase (NMDMC): elevated levels of NMDMC moderately slow down the aging of drosophila flies, most likely by improving mitochondrial function.

Nuclear factor "kappa-bi" (NF-kB): inhibition of this gene moderately increases life expectancy in a number of lower animal species, however, given its involvement in immunity, inflammation, apoptosis and other fundamental processes, researchers literally run their eyes when trying to explain the basic mechanisms of this effect. A detailed study of all such globally altered states of metabolism, accompanied by a slowdown in aging, requires a lot of time and effort, so their study is still far from completion.

NRF2 / SKN-1: Elevated levels of NRF2 in mice or its homologue SKN-1 in nematodes lead to a slowdown in aging and moderately increase life expectancy (usually the level of NRF2 decreases with aging). This can be achieved by manipulating the level of other interacting proteins, such as glutathione transferase (gGsta4). It is believed that in this case, resistance to oxidative damage and enhanced quality control of damaged protein molecules are involved in the mechanism of action. An interesting fact is that long-lived naked diggers are characterized by high levels of NRF2.

Oct4: This gene is one of the target genes for reprogramming cells into induced pluripotent stem cells. It has recently been found that Oct4 can stabilize atherosclerotic plaques, reducing the risk of death from this disease. However, such an intervention looks too late. It is much better to remove plaques or prevent their formation than to spend a lot of effort to reduce their danger to life.

P16: Perhaps P16 is best known as an indicator of physiological cell aging – mechanisms that lead to the loss of the ability to divide or self-destruction of damaged cells or cells that have reached the Hayflick limit. The best approach to cells that have entered the phase of physiological aging is their destruction, however, there is evidence that in some cases a targeted reduction in P16 levels can bring net benefits, for example, when it is used to increase the activity of stem cells in old age.

P21: Both MRL mice and mice with knockout P21 are capable of regenerating small lesions without scarring, which is not available to most mammals. Apparently, reduced levels of p21 protein are a common factor for the two mentioned lines of genetically modified mice. P21 is very close to the tumor suppressor gene P53. Tumor growth suppression and enhanced regeneration often turn out to be different sides of the same coin. This makes this gene a difficult target for gene therapy, but researchers working with P53 have found methods to circumvent the issue of increasing the risk of cancer.

P53: the p53 protein plays the role of a suppressor of tumor growth, however, a general increase in the level of p53, in addition to reducing the likelihood of cancer, will accelerate the aging process by suppressing the maintenance of tissue viability due to the formation of new cells. However, there are a number of approaches in which p53 levels can be increased only if necessary. One of them implies a decrease in the level of mdm2, which is a p53 inhibitor. Another approach uses an additional copy of the p53 gene, embedded without interfering with the existing regulatory process that controls p53 levels. In the second case, the life expectancy of genetically modified mice increases moderately due to a decrease in the incidence of cancer.

Parkin: increasing the level of parkin protein is one of the methods that can induce an increase in the efficiency of maintaining cell functioning through autophagy, which leads to improved health and a moderate increase in life expectancy. There is a lot of data in the literature confirming the unquestioning positive role of autophagy in issues related to health and aging. Many methods of increasing the life expectancy of laboratory animals are associated with increased autophagy and in some cases, such as a low-calorie diet, it has been shown that autophagy is a necessary factor for increasing life expectancy.

PCSK9: PCSK9 mutations leading to loss of functionality reduce the risk of developing diseases of the cardiovascular system. It is most likely that this is due to a decrease in the concentration of cholesterol in the blood. Studies confirming this principle were conducted on mice.

PER2: Deletion of the circadian rhythm-associated PER2 gene in mice increases the efficiency of DNA damage repair in stem cell populations related to the immune system. This leads to an improvement in the state of the immune cell population, an increase in the effectiveness of immune function in old age and a moderate increase in life expectancy. An alarming point in this case is that PER2 mutations exist in the human population and are associated with sleep disorders.

PGC-1: Increased levels of PGC-1 in intestinal tissue increase the lifespan of fruit flies, possibly due to improved functioning of mitochondria and stem cells. The functioning of the intestine is especially important as a determinant of aging and mortality of flies, so this organ is the target of many experimental interventions. In mice, the introduction of a certain variant of PGC-1 into the genome provides enhanced growth of muscle tissue, most likely due to its interaction with myostatin.

PHD1: The PHD1 protein acts as an oxygen sensor. Mice lacking this protein are protected from ischemic damage during stroke, they are characterized by the death of fewer cells and a more complete subsequent recovery.

PEPCK: Elevated levels of PEPCK, achieved through genetic manipulation, lead to very energetic mice that eat more and live moderately longer than their unmodified relatives.

PIM1: Mice with PIM1 overexpression in heart tissue live longer by improving the ability of heart tissue to repair and self-sustain.

Plasminogen Activator inhibitor-1 (PAI-1): a decrease in the levels of plasminogen activator inhibitor-1 moderately slows down aging, possibly by eliminating one aspect of the destructive effect of cells that have entered the phase of physiological aging. However, the direct destruction of such cells is probably a better option than trying to safely interfere with the biochemistry of the human body in order to make their presence less harmful.

Pregnancy-associated plasma protein-A (PAPP-A): Knocking out the gene of this protein alters insulin metabolism and provides improved health and increased life expectancy in mice, similar to that achieved using other methods with similar effects.

Phosphatase and tensin homologue (PTEN): Adding an additional copy of the tumor suppressor gene PTEN to the mouse genome not only reduces the incidence of cancer, but also increases life expectancy. This is uncharacteristic for tumor growth suppressors, since most of them reduce life expectancy by suppressing regeneration and maintaining the vital activity of the tissue.

RbAp48: Levels of RbAp48 in the hippocampus decrease with age. The researchers demonstrated that targeted restoration of the levels of this protein characteristic of young age in old mice restores most of the manifestations of age-related memory impairment.

Reticulon-4 receptor (RTN4R): Reduced levels of the reticulon-4 receptor may increase brain plasticity in adult mice, improving the repair of brain damage and increasing the ability to learn new skills. Apparently, this is a component of the mechanism by which brain plasticity is suppressed after leaving childhood.

Rpd3: reducing the level of Rpd3 improves cardiac function and moderately increases the lifespan of fruit flies, but the mechanisms of action have yet to be understood in more detail.

SERCA2a / SUMO-1: Elevated levels of any of these interconnected proteins (SUMO-1 regulates SERCA2a activity) may provide more efficient remodeling of blood vessels of cardiac tissue than occurs under normal conditions. Therefore, this approach is potentially a compensatory therapy that can slow down the progression of many diseases of the cardiovascular and circulatory systems.

Sirtuins: sirtuin genes were loudly discussed as a target of mimetics of a low-calorie diet, but in practice everything turned out to be not so simple. The results obtained in experiments on mice were neither significant, nor reliable, nor easily reproducible. The evidence that changes in sirtuin levels provide convincing positive results is very contradictory, whereas some studies demonstrate marginal or gender-specific effects.

Telomerase: Increased levels of telomerase have been shown to increase the lifespan of mice, as well as reduce the likelihood of developing cancer in representatives of this species. There is still work to be done on a full understanding of the underlying mechanisms, but the most plausible reason is an increase in the activity of stem cells, while the effect on cancer risk may be explained by a higher activity of the immune system, although today this is only a hypothetical theory. A fairly large amount of scientific data indicates the potential usefulness of such therapy, however, the dynamics of the telomeres of mice differs significantly from human ones, which is a serious warning. It would be reasonable to conduct experiments on dogs, pigs and other mammals whose telomere dynamics are closer to human. However, BioViva is already moving forward with a gene therapy approach that targets telomerase. In addition, there are groups in the research environment whose purpose is to conduct clinical studies of more conservative methods of increasing telomerase activity.

Transforming Growth Factor-beta-1 (TGF-β1): The expression of transforming growth factor-beta-1 increases with age, while it is involved in the loss of stem cell functionality. Intervention in this mechanism through any of the proteins involved in it in order to reduce the level of this factor may be a viable method of increasing the activity of stem cells in old age.

Transcription factor EB (TFEB): Increased activation of the transcription factor EB increases the activity of autophagy, thereby increasing the efficiency of maintaining optimal cell condition. Apparently, enhanced autophagy is good news in almost all situations, in addition, it is involved in many methods of moderate increase in the life expectancy of laboratory animals.

Troponin C: Researchers have demonstrated that embedding a modified version of the calcium troponin C receptor into mammalian heart cells can improve heart function and cardiovascular system function.

TRPV1: Knocking out the TRPV1 pain receptor gene is one of a number of methods to slow down aging and increase the lifespan of mice that work by acting on the insulin-mediated signaling mechanism. Another potential mechanism is that knocking out this gene blocks the interaction between pain receptors and chronic inflammation, which, according to modern concepts, has a detrimental effect on aging tissues and organs. As well as for many other interventions that slow down the aging of mice, in this case, in order to understand the mechanisms of action, a lot of work will still have to be done. Moreover, the expediency of the practical application of this intervention is unclear, since pain is a useful mechanism, and irreversible suppression of pain at the receptor level is most likely unreasonable.

Uncoupling proteins (UCP): uncoupling proteins manipulate mitochondrial function to regulate body temperature. As with many other proteins that affect mitochondrial function, changes in concentration or genetic variations can provide improved health and increased life expectancy. Although a compromise is of great importance for uncoupling proteins, since too active uncoupling quickly goes from disastrous to fatal.

Urokinase (uPA): Mice of the aMUPA line have an additional urokinase gene, which provides them with a longer life. The uPA gene is related to the PAI-1 gene, which is positioned as increasing the lifespan of mice through behavioral changes: reducing the amount of food consumed, triggering a reaction to a low-calorie diet. It is very interesting whether such an intervention will be useful for a person, in other words, whether a person will react in the same way to a change in appetite.

Vascular Endothelial Growth factor (VEGF), Gata4, Mef 2c and Tbx5: A significant amount of research and development has been devoted to attempts to use vascular endothelial growth factor to accelerate the regeneration of damage to the cardiovascular system, especially the heart, in the case of mammals with a very limited ability to regenerate. In one of the most successful rodent experiments, researchers used a mixture of VEGF, Gata4, Mef 2c and Tbx5 to stimulate the transformation of scar tissue of the heart into a normal myocardium.

For links to sources, see the original article.

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