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If you have time to visit a pharmacy near a home, it should not be difficult to find a wide range of health products that can “defer aging”. Anti-aging is an eternal topic that humans have had since ancient times. But whether it is the Taoist elixir or the pharmacy’s health products, there are two truths that have never changed, even though these products are known as anti-aging products: they are a good way to make quick money, and there is no solid scientific evidence. Confirm that they are effective on the human body.

 

Even if it took hundreds of thousands of years of hard work, even though advertisers have spared no effort to boast, we still have not found the magic potion that turned the clock back. Many anti-aging treatments that have been similar to injections of human growth factors or transplanted gorilla testicle tissue for many years do not actually produce the desired results. Instead, they often produce unexpected injuries. There are also compounds that resemble Resveratrol, which many doctors believe in their “efficacy.” In fact, scientific research results do not support their commercial propaganda. If even ineffective products are sold so well, anyone who really finds a safe and effective anti-aging product will earn crazy.

Considering the huge market demand, many people will wonder why we have not found any kind of anti-aging drug. The answer is actually very simple, because the aging process is unusually complex. There are thousands of genes involved in the aging process of the human body. Whether we are exercising, fasting, smoking, or anxiety or overeating, these behaviors may more or less cause changes in the human genome and affect the aging process. And every major discovery of biology, whether epigenetics, the discovery of miRNAs, or the microbiome, people will find that they have an impact on the aging process. Anti-aging clinical trials usually take decades to see the effect, and the consequence is that any clinical trial of an anti-aging drug requires a huge investment to complete, so you should be able to understand research in the field of anti-aging research. Workers have pain in their hearts.

Despite countless challenges, those who wish to extend the “healthy life” do not have to be discouraged because hope still exists. Researchers are looking for ways to reverse the aging process, and there are already several drugs already on the market that are undergoing transformation and become potential anti-aging drugs. Players in this arena include companies such as Google that can afford money, and such outstanding biologists as Craig Venter. They hope to combat aging, the most powerful enemy of humans, through such means as genome, big data, and machine learning.

 

Ageing is the most important risk factor for almost all causes of human death. Over the past few centuries, the development of modern medicine and other innovations have doubled the lifespan of human beings. However, these treatments are limited to the treatment of diseases such as cancers and cardiovascular diseases that are easy to occur in the elderly, but rarely lead to the resolution of people. Intrinsic cellular and molecular biology mechanisms that increase the risk of these diseases. People’s life expectancy has increased, but it is difficult to enjoy these life-time extensions due to the development of modern medicine. Many young people have made their lives extremely difficult because they need to take care of the elderly who have been living in bed because of illness.

According to the report of the World Health Organization, in most countries, the proportion of the elderly over the age of 60 in the total population is higher than that of any age group. By 2050, the elderly population will account for one-fifth of the world’s total population, more than double the current figure. It is clear that the search for scientifically based methods that can make the elderly population healthier, and trying to explain why people are aging from the scientific point of view is becoming an urgent problem in the field of scientific research. So why are we aging?

Causes of aging

In the 1950s, Judy Campisi put forward a very interesting point: Antagonistic pleiotropy evolutionary theory. This theory holds that in order to survive to the age of normal reproduction, people will evolve some characteristics that are harmful to people in old age. For example, people with calcium in blood can help the people who hunt to heal quickly after bone injury so that they can hunt as soon as possible. However, by the age of 60, calcium in the blood will be deposited in the arteries, resulting in blockage and hardening of blood vessels. The favorable physiological characteristics of a 30-year old person are not necessarily good for a 60-year-old person.

 

However, researchers in the 1990s discovered that only a single gene mutation can lead to a two-fold, three-fold or even greater prolongation of the lifespan of a nematode, after which a single gene that can prolong the lifespan of fruit flies, mice, and other organisms can be prolonged. Mutations have also been discovered one after another. If genetic changes can affect the lifespan of animals and the length of their lives, then can drugs be designed to influence the function of the proteins expressed by these genes? The seemingly extremely complex physiological processes seem to be easily intervened, which has surprised scientists but has also become extremely exciting. So scientists began to study the function of these genes in the human body. They found that the genes involved in the biochemical signal pathway criss-cross, including regulation of nuclear or mitochondrial function, or overall physiological and metabolic signal pathways.

 

With the increasing number of genes associated with the aging process that have been discovered over the past two decades, the study of the biochemical processes involved in these genes in vivo has become more and more in-depth. For example, studies have found that many aging-related genes are involved in the body’s overall metabolic process. A number of studies in humans and experimental animals have also demonstrated that exercise and diet control can increase longevity and reduce the risk of age-related diseases. Genes that affect aging can also influence the signaling processes involved in human hormones, the ability of stem cells to differentiate into new tissues and blood cells, and the function of mitochondria. And a variety of aging-related genes can interfere with the aging process by affecting the length of telomeres. Based on the above scientific findings, although it may not be easy to prolong lifespan through various interventions, it is feasible to reduce the incidence of aging-related diseases and postpone the occurrence time, thus prolonging the healthy life time (healthy life) of the person.

Although there is relatively reasonable evidence that a healthy lifestyle can affect the aging process by affecting various signaling pathways in the body, taking into account people’s diet, exercise and other behaviors are difficult to change, so researchers hope to combat aging through the use of drugs. To date, scientists have discovered hundreds of compounds that can influence signaling pathways involved in the aging process. But at the same time, it should be noted that it is not wise to intervene in these signal pathways most of the time. The normal physiological processes of cells are usually the balance of fine adjustments of multiple factors. If the degree of intervention is insufficient, it may not have a significant effect. If it is too much, it may cause other problems.

 

Telomeres are a good example. The researchers found that the shorter the telomere, the higher the risk of death and suffering from aging-related diseases, so activation of telomerase to extend the telomere compound may be effective in aging. However, scientists have found that prolonging telomeres by interfering with telomerase activity by small molecule compounds increases the risk of cell cancer. In fact, many interventions that interfere with the physiological processes that affect aging will all face the same problem: Inducing cell carcinogenesis. The more we understand about the physiological mechanisms that affect aging, the more we can discover that the complexity is unimaginable.

Targeting senescent cells

 

Although we do not know much about the molecular basis of the aging process, many people suspect that aging is associated with genomic damage. With age, telomeres are continuously shortened, the chance of DNA exposure to carcinogens increases, and the probability of integration of viral DNA into the human genome increases, resulting in further damage, and the way DNA is integrated into chromosomes is also affected. This will cause cells to enter the aging state, and the aging cells will affect the surrounding cells by secreting cell signaling molecules. Therefore, studying aging cells has become an important branch of the anti-aging field.

 

Perhaps similar to the overall aging of humans, after a long process of evolution, aging cells are beneficial to young organisms, while aging cells in elderly people have many problems. When a person is young, senescent cells stop dividing if they are at risk of becoming cancerous, while senescent cells secrete a variety of molecules to promote regeneration and damage repair. However, as the age increases, more and more cells enter the aging state. Accumulation of signal molecules secreted by senescent cells will increase the formation of inflammation and induce peripheral cells to enter the aging state. These continuously secreting signaling molecules can even cause a variety of aging-related diseases including cardiovascular diseases and certain types of cancer.

 

As the aging cells play an important role in the aging process, the development of drugs targeting senescent cells has become a hot research field. Treatment strategies for targeting senescent cells are mainly divided into the following types:

 

  1. Selective clearance of senescent cells – senolysis (senescence cell lysis?)
  2. Immune system-mediated senescence cell clearance
  3. The senescence-associated secretory phenotype (SASP) neutralizes.

 

If compared, the prospects for the development of senolysis drugs may be better, because the permanent removal of senescent cells will not have the problem of SASP, and theoretically there is no risk of canceration after aging cells are cleared. The biochemical process of senescent cells crosses with other pathological processes, so many drugs that treat other diseases may also become senolysis drugs.

The senolysis drugs currently in the research and development stage are mainly targeted to apoptosis systems, such as BCL-2 family proteins. Unity Biotechnology attempts to use the compound Navitoclax (ABT-263) to remove senescent cells from the kidneys, eyes, arteries, and joints. Domestic Yasheng Pharmaceutical and Unity Biotechnology also established a cooperative relationship to jointly develop anti-aging drugs. Scientists at the Weizmann Institute for Science used a compound similar to Unity Biotechnology, ABT-737. In 2016, they published an article claiming that the compound was able to kill mouse skin cells and cause the proliferation of hair follicle stem cells. . Navitoclax and ABT-737 can inhibit the binding of BCL-2, BCL-X and BCL-W, inhibit their anti-apoptotic function and induce apoptosis in senescent cells.

As people age, the ability of the immune system to clear senescent cells also declines. Therefore, the use of the immune system to eliminate senescent cells is also an important research direction. Recently researchers have also tried to use CART cells to eliminate senescent cells (not into the clinical research stage). The mechanisms by which senescent cells evade the clearance of the immune system include strategies such as decoy receptors and PD-1, so the use of decoy receptor inhibitors and checkpoint inhibitors is also a potential therapeutic strategy (although it does not sound very reliable).

 

Clearing senescent cells is actually not as simple as it seems. First of all, cell aging is not all harmful to the body. Cell senescence plays an important role in inhibiting tumor formation, wound healing, embryonic development, and tissue regeneration. It also promotes the secretion of insulin from pancreatic beta cells during aging. Therefore, we must pay attention to the time, location, and mode of elimination of senescent cells. Second, although many small molecule drugs targeting senescent cells have been reported, the off-target effects of these compounds are widespread. Third, senescent cells in different tissues have different sensitivities to different therapies. Therefore, when designing drugs, it is not only necessary to select the type of targeted cells, but also to enable the drugs to be enriched in specific tissues.

 

In addition to these strategies for inducing the elimination of senescent cells, scientists have also reported an interesting approach: restoring senescent cells to a young state by removing markers from senescent cells. This strategy was inspired by the well-known induced pluripotent stem cell technology. An article in Cell Magazine last year reported the work of the Belmonte Task Force. They remodeled senescent cells by briefly activating four genes that can induce pluripotent stem cells. These four genes are capable of remodeling epigenetic markers of cells, eliminating signs of cellular aging at the cellular level. The experimental mice’s muscles, pancreas, spleen, and skin all returned to a more youthful state, and they live longer. After this they are also trying to use a combination of small molecules to produce similar effects.

Metabolic process

There is a very important feature in the aging process: metabolic abnormalities. Older people usually experience a decrease in the ratio of fat mass to fat mass, a decrease in muscle mass, and a process of fat transfer from subcutaneous to visceral. The fat visceral metastasis was associated with decreased tissue insulin sensitivity and elevated serum insulin levels. At the same time, metabolic abnormalities are also risk factors for many diseases. For example, the degree of obesity is negatively correlated with life expectancy, and young people with high visceral fat content also suffer from hypertension, and the risk of ‘geriatric diseases’ such as heart disease increases.

 

Studies have found that limiting calorie intake in mice and rats throughout life can extend life by up to 50%. Other studies such as yeast, fish, and dogs have also found the same phenomenon, limiting calories without causing malnutrition. Ingestion can delay aging-related biochemical processes. Maintaining a young body can also increase life expectancy.

 

Just adjusting the diet can produce a series of physiological and metabolic changes, and even extend the lifespan, which sounds really attractive. Not only that, the researchers also found that simply limiting the intake of cysteine ​​can also extend the lifespan of nematodes, yeasts, fruit flies, and rodents. However, it should be noted that limiting the impact of cysteine ​​intake on human health remains to be further studied. It has been reported that excessive cysteine ​​intake may lead to health problems such as fatty liver, low body weight, and anemia.

 

Because many people’s dietary programs are more difficult to adjust, researchers are also studying how to simulate changes in the biochemical processes affected by diet control. These drugs are called CRM (Caloric restriction mimetics), which translates to the simulation of caloric restriction. Compound). At present, the strategy for the development of this class of drugs is to find small molecule compounds that can promote the deacetylation of intracellular proteins and thus trigger autophagy. Now there are three strategies to reduce acetylation: reduction of intracellular acetyl-CoA concentration, inhibition of acetyltransferase, or activation of deacetylase.

The purpose of these three methods is to reduce the acetylation level of intracellular proteins, thereby activating the cytoplasmic receptors, activating AMPK, and inhibiting mTORC1. At the same time, the epigenetic regulation in the nucleus is also affected, causing a series of biochemical changes in the cell that eventually trigger cell autophagy.

 

Acetyl-coenzyme A is produced during glycolysis and lipolysis. Since it is an acetyl donor of acetyltransferase, a decrease in acetyl-CoA concentration causes a decrease in intracellular acetylation. Decreasing the level of acetyl-CoA can be achieved by inhibiting its biosynthesis process, such as inhibiting MPC, PDH, CPT1, etc. in its synthesis pathway.

 

There are many types of acetyltransferases, but due to historical reasons, we only have more researches on histone acetyltransferases, so the development of acetyltransferase inhibitors is mainly concentrated in the field of histone acetyltransferases. The reported pan-histone acetyltransferase inhibitors are mainly natural products such as curcumin in ginger, EGCG in green tea, anacardic acid, and some synthetic small molecules such as MB-3, C646.

 

Many deacetylases are zinc-dependent, but another class of deacetylases, including sirtuins, are zinc-independent and NAD-dependent, with SIRT1-mediated deacetylation for protective autophagy. It’s important to start. Resveratrol is generally considered to be the first SIRT1 agonist to be found, but its activation is directly or indirectly controversial. In addition SIRT1 agonists also include quercetin, bisitol, and various NAD precursors including NR and the like. It should be noted that the mechanism of action and anti-aging effects of these compounds have not been confirmed, and most of the relevant experimental data are obtained in invitro or animal models, and clinical studies on the effectiveness of humans are rare. Despite the lack of scientific evidence, there are still many companies selling health products containing NAD precursors due to the regulation of the health product market. Elysium Corporation of the United States is a good example, but because they found seven Nobel Prize winners as the company’s scientific adviser, they have attracted many criticisms.

Magical small molecule

If you think that these studies on anti-aging therapies are all small-scale and far from being listed, the next two types of small-molecule drugs may overturn your understanding of the field.

 

Since the 1950s, metformin has been a commonly used drug for patients with type 2 diabetes due to decreased hepatic glucose production and insulin sensitization. A 2014 study of the long-term effects of the drug found that patients with type 2 diabetes who were taking metformin had a longer life expectancy than those who did not have the disease and did not take the drug. That is to say, as long as people who have diabetes are taking metformin, their life span may be longer than those who do not have the disease. The observational study also found that patients taking metformin had a lower risk of cancer and related deaths and improved cognitive function.

 

Due to the safety of metformin and the above research data related to anti-aging, the American Association for Aging Research (AFAR) supported a metformin anti-aging clinical research project (TAME study). There is no doubt that this clinical study requires huge amounts of money and time, but if the clinical trial is successful, it will revolutionize the development of the anti-aging field.

 

In addition to metformin, another very important drug is rapamycin. Rapamycin was discovered in the soil bacteria of Easter Island in the 1980s and it was used to suppress the immune rejection of organ transplant surgery. Many years ago, scientists discovered that rapamycin can extend the lifespan of mice. In previous years, Novartis scientists pushed anti-aging research to another level: they tested the effect of RAD001, an analog of rapamycin, on human aging-related problems. Novartis Joan Mannick and his colleagues found that RAD001 can restore the elderly’s immune system to a young state.

 

This study is based on a common problem faced by the elderly: the response to influenza vaccine is not high. As people age, the ability of the human immune system to recognize new antigens is gradually becoming inactivated. Based on experimental data from mice, Novartis scientists allowed clinical trial subjects to take Rapamycin analogue RAD001 for six weeks. The drug was then removed from the body for two weeks and the influenza vaccine was given. They found that the patient’s responsiveness to the vaccine was significantly increased, and the body’s production of anti-influenza virus antibodies increased significantly. This work has also aroused many people’s interest in mTOR, the target of rapamycin.

This kinase is a key component of multiple signaling pathways, so drug chemists are also designing new rapamycin inhibitors to adapt to different cellular environments. mTOR can not only affect the immune system, but also can inhibit senescent cells to generate a variety of harmful signal molecules. At the same time, the study also found that the enzyme is also involved in the positive regulation process of dieting.

 

Since rapamycin acts on metabolite-related side effects of mTORC2, and its anti-aging effects are mainly related to mTORC1 inhibition, mTORC1 selective inhibitors may become very promising anti-aging drugs.

Conclusion

Studies in areas related to aging are far more important than we think. In the past 100 years, life expectancy has been significantly extended due to a decline in neonatal mortality. However, while the life span is prolonged, the elderly have not become healthier. Therefore, the prevention of aging-related diseases and the prolongation of people’s health life have a tremendous impact on reducing related social problems and reducing the medical burden.

Because the process of aging is too complicated, our understanding of this process is not deep enough at this stage. But despite this, I still believe that the aging process is reversible. The transient expression of Yamanaka’s factor OSKM can return the mice’s body to a relatively young state. Linking the circulatory system of aging mice and young mice can reduce the signs of aging in aging mice. These experiments are preliminary. The proof of aging mice can return to a young state.

 

But the most critical question is how to intervene in the aging process through drugs or other means while ensuring safety. I believe this will be a big problem for scientists in the new drug development industry. Although there are already many drug development directions in this area, the overall probability of a breakthrough in a short period of time is very low. In addition, the funding and time for clinical trials of anti-aging drugs will be extremely large. Therefore, if drugs such as senolysis or CRM are used as the end point of clinical trials rather than the extension of lifespan, the incidence of aging-related diseases may become extremely serious. Greatly reduce investment in capital and time.

 

Metformin and rapamycin analogs are by far the most promising drugs in the field of anti-aging, but there is still not enough evidence from human trials to support their effectiveness against human anti-aging effects. Recall the overall success rate of clinical trials, how many drugs have complete pharmacological theory, and the preclinical data are exceptionally beautiful, but still die in Phase II/III clinical?

 

At present, the safest potential (potentially latent) anti-aging methods for the general public are still lifestyle improvements such as moderate exercise and proper control of diet. But for ordinary people like me, exercising and eating a diet may be a lot harder than eating one or two tablets of metformin daily.

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