Anti Aging Therapies

Bare digger



Aging is the biggest killer on earth — hundreds of thousands of people die every day. Most people do not want to die, and would be happy to live another couple of years, or another 10-15 years. At the very edge of death, people understand how they love life. People change their habitual diet, quit smoking, lose weight, stop drinking as soon as health damage becomes apparent. Medicine treats mostly elderly people. And if the healthy longevity of millions of people were to be prolonged, the economic effect would be impressive.



It is no secret that mature workers have indisputable advantages over their younger colleagues, first of all, rich experience and knowledge. At the same time, we live in a unique time - science is at the height of its power, and the amazing conveniences of life are available to us. What is more spurs the taste for life for all and the reluctance to die in the near future. We know for sure that if aging is not abolished, then human life can be significantly prolonged, at least there are people who look younger than their age and those who live to be 90-100 years old. We also know that there are animals that are aging differently than we are (this is well described in the two previous articles on giktimes - “Alternatives to death: how to overcome aging” “Why aging can be avoided: excerpt from the book Hacking the code of aging” ).

Eternal Hydra, 30 years of naked digger, 200 years of Greenland whale, 180 years of turtles, 30 years of Brandt's night-light. Animals age differently and if they do not cancel aging, then slowing it down seems to be a feasible task. You can even expect to overcome the species barrier in 120 years.



The biggest argument that this is possible (to increase healthy longevity) is that we already know a lot of changes that occur with the body at the molecular level. At the cell level, aging is marked by such disorders as DNA damage in the nucleus and mitochondria, mitochondrial dysfunction, leading to an increase in the formation of reactive oxygen species (ROS) and reduced ATP production, oxidative damage to proteins and other macromolecules, improper folding of proteins and their aggregation, protein glycation , activation of the synthesis of proinflammatory cytokines, telomere shortening, cessation of cell divisions and a sharp decline in the stem cell population, genome instability, growth of the senescent population s cells.

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At the level of organs - over 300 changes .

Geroprotectors

Substances prolonging life, of which the most famous is rapamycin, found in soil samples on Easter Island in the 70s of the 20th century. It has extended the life of mice by 25%, but it is unsafe to use it for a person due to its immunosuppressive properties. They will test its safer analog, rapalog.

A network of geroprotectors www.geroprotectors.org has appeared in the network.

It would be good if it was supplemented with substances that shorten the life of fruit flies and nematodes.

The most promising experience that awaits us, the Screening project is the testing of 1000 medicines and bioadditives on 15,000 thousand mice conducted in America by Alexei Ryazanov with funding from Alexander Chikunov. Prior to publication, it became known that magnesium significantly extended the life of mice.



Further, from the unpublished book of Dmitry Dzhagarov, “Aging and promising ways to longevity”.

Rapamycin

It is important to note that the development of treatment methods that focus on mTOR signaling, in order to delay aging, will require an understanding of the tissue specificity of mTOR signaling in different organs. Thus, the violation of mTORC2 signaling in the liver and muscles leads to a diabetic phenotype, whereas in adipose tissue the loss of mTORC2 does not cause diabetes. The drug rapamycin used to prolong life and protect against cancer gives side effects such as immunosuppression and diabetes, which limits its usefulness.

Acarbose

Hypoglycemic drug, an alpha-glucosidase inhibitor that inhibits the digestion and absorption of carbohydrates in the small intestine and, as a result, reduces the growth of glucose concentration in the blood after eating carbohydrate-containing food. (p <0.0001), while women's only 5% (p =, 01). The maximum lifespan increased by 11% (P <0.001) in males and by 9% (P = 0.001) in females.

Metformin

An anti-glycemic drug used to treat type II diabetes. The mechanism of action of metformin is not associated with an increase in insulin secretion. The use of this drug reduces the ratio of bound insulin to free and increases the ratio of insulin to proinsulin, which is accompanied by a decrease in insulin resistance. It is assumed that metformin prolongs life by influencing the process of mitochormesis (mitohormesis) - an adaptive mitochondrial reaction, accompanied by an increase in stress resistance

Sirtuins

In experiments with yeast, it was found that a small activation of the SIR2 gene by polyphenolic molecules (resveratrol, pica-tanna, pterostilbene, batein) leads to a significant extension of life, while overexpression of this gene can cause toxicosis.

Glucosamine

The widely used dietary supplement glucosamine has contributed to the prolongation of the life of aging mice by about 10%. In addition, statistical studies of 7,000 Americans showed that the use of glucosamine was associated with a significant reduction in the risk of death from cancer and respiratory diseases.

Hormetins (hormetins)

Some gerontologists suggest that by exposing cells and organisms to mild stress (insufficient for the manifestation of harmful factors) caused by radiation, toxins can activate an adaptive, hormetic response, leading to improved health. The hormetins are obviously carbon nanotubes, some of which (MWCNT 41) do not inhibit MTOR, and yet significantly activate cellular autophagy. The number of hormetins should also include fullerene C60

Omega-3 polyunsaturated fatty acids

Back in the 1970s, it was discovered that the Eskimos of Greenland, consuming large amounts of fatty fish, practically did not suffer from cardiovascular diseases and did not have atherosclerotic damage. In studies conducted in Italy, it was found that people who ate fish at least twice a week, much less likely to get cancer than those who eat fish less than once a week. In 2004, it was officially recognized that the consumption of fish oil containing omega-3 polyunsaturated fatty acids such as Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA) can reduce the risk of developing coronary heart disease



Senolitiki (eng. Senolytics from the words senile - decrepit and lytic - lysing, destructive) is the conventional name for a class of drugs whose distinctive feature is the ability to selectively initiate the death of aged cells. Some of these cells undergo mutational changes, which allows them to re-enter a state of proliferative activity.



If the body does not destroy such cells in time, they can turn into malignant cells and cause cancer. In addition to the fact that aged cells cope worse with their functions, they also acquire senile secretory phenotype SASP (senescence associated secretory phenotype) and, releasing into the extracellular environment a multitude of soluble factors causing inflammation and changes in the extracellular matrix, negatively affect the tissue microenvironment and whole body.



The fundraising for the test of the combination of senoliths in mice has recently been completed, $ 52,000 has been collected for the experience with the senolithists of Dasatinib and Venetoclax, Quercetin . Another experience that was already completed showed a 25% increase in the lifespan of mice .



A drug has been developed that effectively destroys aged cells in mice and consists of two drugs: antitumor (antineoplastic) chemotherapeutic agent Dasatinib, which is an inhibitor of protein tyrosine kinases, and Quercetin, which, according to the authors, eliminates aging human endothelial cells.

What programmers can do in the fight against aging

Science has already found a huge accumulation of facts about which therapies prolong life, which genes and mutations

they contribute to longevity. You can find a selection of studies in a review of life extension studies .

Programmers can help with computer simulation of the synergy of these studies. Because sometimes one disease weakens the negative effect of another, a computational computer model is predicted to predict the effects of geroprotectors, gene therapy, gerostatics in the body of both healthy and sick people.



Computer simulation of aging is divided into two areas: modeling of cell aging and modeling of the whole organism. Cell modeling is represented by the system by the human aging scheme Furber from the company LegendaryPharma.com. In Russian, you can see the system diagram of human aging here .

Now the task is to check this model in the dynamics and in personal medicine - so I advise the kit given by the snider ( expression study, metabolom, one person’s genome for 18 months ).



Another approach to computer modeling of a human cell is to train deep neural networks and their ensembles, on a cell of some human tissue (for example, red blood cells, liver cells). In order to later test drugs for geroprotective properties, toxicity, water solubility, other properties. The architecture of a neural network is such as transcriptome and meta-transcriptome data at the input, and the output is a toxicity indicator for this type of cell.

Someone if he wants to experiment on his own, then here is the database for that. (expression of the main genes in the response of the tissue to the drug compound) LINCS .

Computer simulation of the body

We can determine the aging of an organism either by cumulative aging of all organs, or by the weakest (aged) organ. To do this, it is desirable to develop a test that transcripts, blood metabolome determined the biological age of each tissue (organ). In order to calculate how old the body would be, it would be useful to make a model of the human body, which, based on the main indicators of the work of all organs, read their biological age and predicted survival, and the onset of age-related diseases.



Age-dependent body changes for the brain look like the thymus involution, the aging hypothalamus,

violation of synapse formation, iron absorption, lipid and monoamine metabolism, changes in the concentration of extracellular calcium. All the main factors of aging are relevant for the brain: inflammation, impaired protein synthesis, and mitochondrial dysfunction.





Hydra

Aging biomarkers

Age of chronological notes how old we are on the passport, and the biological age determines our youth and health. What are biomarkers of aging for? A person lives in developed countries up to 80 years, this is already a very long time, compared to the average lifetime of 100 years ago. We can’t test how the therapy worked on a person during clinical trials, whether she prolonged his life or not, if we don’t have a panel of good markers, for example, according to blood tests (metabolic or transcript), they say that the person is healthy or has lived for 37 average years. And as far as therapy has slowed down the rate of aging (another indicator is the rate of aging). Also a good indicator is the response to therapy (If we have cohorts and we can compare with other patients). Therefore, aging biomarkers are a strictly necessary indicator for assessing the results of geroprotectors.



- The established biomarkers of aging today are: leukocyte telomeres length, creatinine clearance, high-density lipoprotein cholesterol, total cholesterol, white blood body count, highly sensitive C-reactive protein, hs-CRP, Triglycerides, urea nitrogen, Apolipoprotein B Apolpoprotein, Apolipoprotein B \ Apolipoprotein, Ps-CRP, Triglycerides, urea nitrogen, Apolipoprotein Body mass index, Glycated hemoglobin, or glycohemoglobin, Mean arterial pressure



Also well proved to be in predicting chronological age with an error of only 2 years epigenetic 353 DNA methylation markers Steve Horvath

The change in human gene expression (transcript) during aging can be found here .

- Now if we have data of a transcriptome ($ 100 price of a blood transcriptome) or a blood metabolome, there are two good algorithms to derive a biological age. To train the network for deep learning - in this study, out of 60,000 samples of data from typical blood biochemistry, the biological age and gender are derived. 6 years, the average spread of the results obtained. The DNN ensemble brought out the five most significant indicators - albumin, glucose, alkaline phosphatase, urea and red blood cells.



Go bruteforcing and choose from 20 blood tests 20 of the most similar to ours, then calculate the average age of these 20.

Combinatorial explosion: how to turn many small therapies into one powerful one.

We already know a lot about aging, and about therapies that can slow it down.

At the molecular level, membrane lipid peroxidation occurs, non-enzymatic glycosylation, cross-linking between membranes, mutations in DNA — we can CRISPR correct the most frequent mutations , invent non-toxic molecules that break glucosepane. Or a means of smoothing the toxicity of the disintegrator glucosean.



CRISPR can also help make changes to the human genome to make it more similar to the genome of the long-livers .



The study of the nuclear genome of long-livers (at the age of over 90 years) revealed a connection between life expectancy and the alleles of the APOE and EBP1 genes. The rs4420638 variant in the ApoE gene, which regulates the ratio of bad and good cholesterol in the blood, dramatically increases the risk of mortality from all age-related causes. In contrast, carriers of a single-letter replacement of rs2149954 (T) in the EBP1 gene, which is involved in the transfer to the inside of the cell of signals from hormone-like proteins - growth factors, have a reduced risk of mortality from cardiovascular diseases.

It is possible to get rid of garbage inside cells by developing new enzymes that remove garbage from cells.



At the cell level, aging manifests itself by a shift in gene expression .

It can be treated by altering gene expression to a young state of a small molecule hurricane. (Testing of individual molecules for expression changes is performed by programs such as LINCS).

Damage to mitochondria - restore powerful antioxidants such as ions Skulacheva .

Lipofuscin accumulation - Can be treated by synthesizing low molecular weight activators of lysosomal enzymes to break down lipofuscin

PI3K, nf-kb, mTOR hyperfunction - suppressed by geroprotectors



At the Tissue level, aging manifests itself through Cellular Aging, Excessive Apoptosis, Intercellular Communication Disruption, Loss of Stem Cell Reproduction

- be treated with stem cell therapy and senolithic.



Blood clots in the vessels are treated and is prevented by the magnetothrombotic system here.

Loss of sensitivity of hypothalamic cells to homeostatic signals. - The hypothalamus is a small neuroendocrine brain that connects the functionally sensory inputs of the nervous system with the endocrine system and controls the processes of growth, metabolism and reproduction. Undergo cell stem cell therapy.



At the level of the body, aging expresses itself through chronic inflammatory processes - which can be treated with aspirin and other drugs of the same class . And also a hormonal shift, a lower level of testosterone and estrogen, Disruption of circadian rhythms - is solved by hormonal therapy and proper sleep.



The conclusion is that we already know a lot about the processes inside the cell and the body, and how to influence them. It remains very difficult to build an organism model on which combinations of therapies can be investigated, but if there is a statistically significant number of people receiving anti-aging therapies and regularly donating blood to aging biomarkers, we can monitor the response to treatment from thousands of people. Moreover, the response to therapy itself is also a biomarker of aging.



The problem is that there is too much data - and it is necessary to somehow develop a comprehensive successful therapy. But unfortunately, it is impossible to calculate the effectiveness of such therapies as the use of induced stem cells. Therefore, all hope for effective biomarkers of aging and large-scale clinical trials of complex therapies in humans. There are 25 ideas for life extension, including a set of promising geroprotectors. Imagine what will happen if you simultaneously test all geroprotectors (there are those that are not in the geroprotectors.org database, that is, they turned out to be not statistically significant (less than 5% extension of life). But this does not mean that if you add up even 1-3% the increase in life expectancy given by ghrelin + estrogen for females does not mean that they will not work) described in this monograph.

Life Activists in the US and Russia

Meanwhile, a biomedical innovation conference for healthy longevity was held in St. Petersburg; all the leading anti-aging specialists from around the world, including Brian Kennedy \ Alex Zhavoronkov, were invited.

RAAD festival will be held in San Diego August 4-7. This is the largest collection of enthusiasts of radical life extension.

In Russia, activists are represented by the Foundation for Life Extension . By the way, they organize the first ever clinical trials of the geroprotector. What you can read below. The blog fightaging.org is updated almost every day - there is a lot of information on the latest scientific discoveries, commenting on scientific articles, in general, they support the SENS program Aubrey de Grey. There is also the prize of the Methuselah mouse - which is awarded to the researcher who most prolongs the maximum lifespan of a laboratory mouse.



The transhuman community has its own crowdfunding site with successfully completed two fundraising : Testing senoliths in mice and transferring the mitochondrial genome into the nucleus of the cell



- This is a journal Longevity Reporter , there is relatively rarely publish articles on diseases associated with aging.



Recently, Liz Parrish came to Moscow and caused a wave of controversy over her adopted gene therapy, if she took the hTERC gene necessary for telomerase completion, if the percentage of telomere length increase is 9% enough for the test carried out in the same laboratory 10% of the test for the test by different methods and laboratories.

She herself claims that her genes have rejuvenated and the likelihood of cancer has decreased.

There is an umbrella organization for all parties extending life in the world - longevityalliance.org

In particular, in Russia there is a group of the Life Extension Party with 2.5 thousand participants.

Recently, the next books of Professor Moskalev were published: Potential geroprotectors and biomarkers of aging.

And this excerpt from the book 120 years of life - only the beginning. How to overcome aging? Older species are neglected - that is, those animals whose probability of dying does not increase with age.

The list of negligently aging species now legally includes the Greenland whale - whose maximum life expectancy (NRM) reaches 211 years, the Aleutian sea bass - the MFA 205 years, the Florida box turtle –138 years, the sea hedgehog of the Red Sea - 205 years, the bivalve Icelandic cyprine - 507 years.

Daniel Martinez, in his 1998 work, showed that freshwater hydras (Hydra sp.) Have potential immortality.



Hydra are small freshwater polyps, distant relatives of corals, sea anemones and jellyfish. Individuals breeding by budding during the four-year experiment grew steadily, their reproductive ability did not decrease and they did not die. However, as another scientist, Stephen Ostad, has shown, the process of sexual reproduction of hydras does cause age-related mortality and the physiological signs of aging.







A list of startups whose goal is related to the fight against aging or healthy longevity. Of these, one with Russian roots: insilicomedicine . And also the completely Russian GERO , which develops a theory of 4 main effects on aging: effective genome size, effective genome connectivity, protein turnover rate, degree of DNA repair. Here is their recent article, arxiv.org/abs/1502.04307 , on the Gompertz law - Accelerating the probability of death of an organism with age.

For life extension investments, contact ivao.com .



And if you want to take part in the clinical trials of geroprotectors (primarily metformin), then contact the Foundation - "Science for the extension of life . "