The pursuit of the length of life, ancient times also have. Qiu Xian asked, alchemy taking medicine, Chang'e running the moon, all revealed the ancients' desire to prolong life. With the continuous improvement of medical standards, the life expectancy of modern humans is also increasing, but aging is still an inevitable thing.
So what exactly causes human aging? Can humanity solve this problem in a targeted manner?
Why do we "age"?
Wrinkles appear, skin sagging is the smell of aging that we feel directly, so what is aging in the end? Why did it come about?
Biologically, aging is a spontaneous and inevitable process of organisms over time. It is a complex natural phenomenon manifested in structural degeneration, functional decline, adaptability and reduced resistance.
Physiologically, aging is seen as a history of ontology from the time of the fertilized egg to old age.
Pathologically, aging is a combination of stress and strain, injury and infection, decline in the immune response, malnutrition, metabolic disorders, and negligent and drug abuse accumulation.
As for the causes of aging, in fact, as early as 1881, the well-known evolutionary biologist August Weismann pointed out that the reason why humans die is that depleted tissues cannot permanently renew themselves, and the ability of cells to divide is also limited. In 1961, Leonard Hayflick confirmed Weissmann's assertion. He found that mammals have limited ability to divide cells, a phenomenon also known as the "Hayfrik limit." Most often, eukaryote cells have about 50 or so mitotic divisions and enter the apoptosis program.
Apoptosis is an active death, a process strictly controlled by multiple genes, with a wide range of biological significance, for example, the removal of excess cells during embryonic development is conducive to the construction of organs; when cells are infected by viruses or cancerous, the body will also be cleared by apoptosis. However, some cells have not completed the full number of division tasks and stopped proliferating, becoming quiescent non-division cells, and the accumulation of these cells has led to a gradual decline in the self-repair ability of tissues. Scientists name this part of the cell senescent cells. Studies have confirmed that senescent cells will stop replicating and dividing themselves, but they will not obediently withto, but just like "zombies" continue to secrete some proteins to resist the arrival of death.
Professor Weissmann
(Image source: Wikipedia Wikipedia)
In summary, senescent cells have the following three characteristics:
The most obvious feature is "stopping growth". As the individual's age increases, various problems from the outside and inside will make the cell make the decision to "stop growing";
The second characteristic of senescent cells is the active secretory capacity. Studies have found that this senescent cell secretes more than 100 different proteins, which can change the cell microenvironment and lead to the occurrence of a variety of pathological conditions, and there is a potential causal relationship with many aging-related chronic diseases;
The third characteristic of senescent cells is the ability to resist apoptosis. Apoptosis plays an important regulatory role in the human body, ensuring that the cells in the tissue reach an optimal balance, but unexpectedly, senescent cells seem to be unregulated by the relevant pathways.
All in all, these "old and immortal" cells stay quietly in the tissue, constantly secreting factors that affect the surrounding cells, causing aging-related diseases.
The road to anti-aging is long
There are many factors that cause aging, food, environment, exercise, drugs, etc. can affect the aging process of human beings, nutritionally balanced food, clean water, pollution-free air, appropriate exercise, and the correct use of drugs can delay aging to a certain extent.
In recent years, research on anti-aging has been promising, including infusion of plasma in young people, stem cell therapy, enhancement of the autophagy process of special species and periods through specific methods, intermittent fasting, promotion of neurogenesis to reverse Elzheimer's disease, and taking of antioxidants and herbs, but these methods may only be confirmed in animal experiments, require clinical trials to evaluate long-term efficacy and side effects, or have not been industrialized because of technical and ethical issues.
In 2013, the journal Cell published research showing that a protein growth factor called GDF11 in the blood of young mice increased the muscle strength of elderly mice, allowing aging brains to be repaired. However, a 2015 study published in Cell Metabolism showed that as they age, GDF11 levels in mice did not decrease, but increased, and inhibited the regeneration of skeletal muscle, which contradicted previous studies. Therefore, in 2019, the U.S. Food and Drug Administration (FDA) issued a warning that plasma transfusion treatment involves a large amount of blood transfusion, and there may be risks such as infection, allergy, respiratory and cardiovascular disease, which has led to plasma infusion treatment never being approved.
There is also a stem cell therapy that has received attention.
Stem cells are a class of multi-potential cells with the ability to replicate themselves. Under certain conditions, it can differentiate into a variety of functional cells, because it has the potential function of regenerating various tissues and organs and the human body, and is called "universal cells" by the medical community. Stem cell therapy is a treatment that uses stem cells or stem cell-derived cells to replace or repair tissue damaged by exogenous injury, disease, or aging. Stem cell therapy can be broadly divided into three different approaches:
(1) Stimulation of ontogenous stem cells through growth factors, cytokines and other molecules to induce the self-repair process of damaged tissues;
(2) Inject stem cells directly into the damaged tissue site to differentiate and replace the damaged tissue;
(3) The third method is the transplantation of cells, organs or tissues derived from stem cells.
Although stem cell therapies have great promise in treating a variety of diseases, there are many ethical, technical, and fundamental scientific questions that hinder the development of stem cell technology.
First of all, the treatment cost of stem cell therapy is very expensive;
Second, the application of oocytes and blastocysts in stem cell therapy has been controversial;
Third, the therapeutic effect is limited by the body's rejection of exogenous cell tissue.
In addition, stem cells have the ability to divide indefinitely, a feature that is the same as tumor cells, so the risk of cancer also limits the application of stem cell therapy in the treatment of diseases.
In addition, humans have also discovered genes that regulate aging. Scientists screen out the gene fragments responsible for regulating aging in mice in the gene ocean, and use certain technical means to knock out these gene fragments. The experimental results showed that knocking out the aging regulatory genes could reduce the proportion of senescent cells in mice, significantly reduce the level of pro-inflammatory factors in the blood, and prolong the lifespan of physiological aging mice and Progeria mice. The biggest advantage of this technology is that these genes can be "manipulated" at the molecular level to delay the aging of the mouse body and achieve targeted manipulation.
Since knocking out genes can be done, is there a relevant drug that can directly kill senescent cells, so as to achieve the purpose of reducing the level of senescent cells?
Promising anti-aging substances and their role in specific aging markers
(Image source: Nature Reviews Drug Discovery)
The answer is gratifying. So far, scientists have found more than 10 drugs such as dasatinib and quercetin to remove senescent cells. Unity Biotechnology has established a large archive to record the correspondence of senescent cells with diseases and related drugs in detail, and this database is now being further expanded with further research.
Although scientists have found more than 10 drugs to remove senescent cells and have achieved certain results in the clinic, in order to reduce side effects, treatment cannot be carried out regularly. The biggest obstacle to anti-aging drug development is that aging is not a single factor.
However, the pace of scientists' exploration has not stopped.
Recently, the world's top scientific journal "Nature Metabolism" released a major research result: the Chinese research team extracted PCC1 (proanthocyanidin C1) from specific grape seeds, which can efficiently and safely remove senescent cells. When the scientists used proanthocyanidin C1 on senescent mice alone, their healthy median lifespan was extended by 64.2 percent.
It sounds powerful, but compared with other drugs that clear senescent cells, what is the special significance of proanthocyanidin C1, which deserves such a sensation in the scientific community?
Screenshot of the article
(Image source: National Library of Medicine)
Anthocyanin C1, what is so powerful?
In search of new compounds that can effectively regulate senescent cells, the Chinese research team conducted an undifferentiated screening of phytochemical libraries (PDMA libraries) composed of 46 plant-derived drugs and found that specific grape seed extracts and proanthocyanidin C1, one of its active ingredients, have a special effect on senescent cells. The reason for choosing grape seed extract as the main research direction is largely because the scientific research team considers that this is an untapped field and has greater hopes of obtaining research results that fill the gap level.
The research team first experimented with specific grape seed extracts, and by analyzing cell survival rates, found that grape seed extracts from a concentration of 0.75 μg ml-1 induce senescent cell death, but do not lead to proliferating cell death. At a concentration of 0.75 μg ml-1, the survival rate of senescent cells drops to about 10%, while the viability of proliferating cells is not affected even at a concentration of 15.00 μg ml1 (this is the highest concentration used in this experimental cell assay). It is fully demonstrated that grape seed extract has significant selectivity and specificity for senescent cells.
But grape seed extract is a mixture, which monomer component works? The team analyzed the composition of grape seed extract and found three broad classes of phytochemicals, including phenolic acids, flavonoids (such as flavan-3-alcohols, proanthocyanidins) and other compounds. Proanthocyanidin C1 c1 caught the team's attention because proanthocyanidin C1 has been shown to induce DNA damage in cells and cause cell cycle arrest. Therefore, the scientific research team continued to carry out a series of studies around proanthocyanidin C1, and was pleased to find that starting from 50 μM, proanthocyanidin C1 has a role in promoting the death of senescent cells, and at this concentration, the proliferating cells are basically unaffected. Proanthocyanidin C1 at a concentration of 200 μM can cause lower survival rates for senescent cells, while at concentrations of 600 μM or higher it shows toxicity to proliferating cells. Thus, it can be determined that proanthocyanidin C1 selectively removes senescent cells in a dose-dependent manner, with no significant effect on non-senescent cells when used at appropriate concentrations.
One of the characteristics of cellular senescence is the secretion of a large number of biologically active substances, which can change the cellular microenvironment, resulting in diseases in the body. The research team found that at low concentrations, proanthocyanidin C1 can inhibit the formation of these active substances.
Through experiments, scientists found that proanthocyanidin C1 can accurately snipe senescular cells, showing a high degree of controllability, and not accidentally injuring normal cells, greatly reducing the side effects of the substance. In addition, the combination of proanthocyanidin C1 and classical chemotherapy can significantly reduce the tumor volume and prolong the survival time of laboratory animals. It has also previously been proven to be a safe dental protector. It can be said that proanthocyanidin C1 is a versatile "all-rounder".
So far, several anti-aging drugs have been reported, including dasatinib and quercetin, fistin, piperin, heat shock protein (HSP)90 inhibitors, and inhibitors of the BCL-2 family, such as ABT-263 and ABT-737. Among them, BCL-2 inhibitors are the most widely used anti-aging drugs, although they were originally developed as a treatment for lymphoma. Both ABT-263 and ABT-737 have some targeted effects, but ABT-737 has lower solubility and oral bioavailability, and ABT-263 often leads to platelet depletion. Fistin is another natural flavonoid, but only at high concentrations has shown a milder effect on aging human embryonic fibroblasts and pre-fat cells. Quercetin is also toxic to senescent cells, but its efficacy is usually lower than that of proanthocyanidin C1. In contrast, proanthocyanidin C1 is a natural product with excellent safety, selectivity, and effectiveness.
However, a thorough assessment of the toxicological effects of proanthocyanidin C1 is critical for clinical application. Data from the Chinese research team show that there is no significant systemic toxicity in high concentrations (20 mg/kg) and high frequency use of proanthocyanidin C1 (once every two weeks). However, the current study has only been confirmed in mice, and further clinical research is needed on whether proanthocyanidin C1 has an effect on human aging, safe dosage range and mode of administration.
Although there is no specific application at present, the discovery of proanthocyanidin C1 has undoubtedly lit a bright light for human beings to prolong life. Perhaps in a few decades, the health and longevity of the whole people will no longer be a dream of nothingness. How far we can go on this road may be far beyond our imagination.
bibliography:
1、August Weismann《The Duration of Life》
2、《The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice》，DOI: 10.1038/s42255-021-00491-8
3、《Procyanidin C1 is a natural agent with senolytic activity against aging and age-related diseases》，DOI:https://doi.org/10.1101/2021.04.14.439765
4、https://www.cyagen.com/cn/zh-cn/community/frontier/information-20171108-2.html
5、https://zhuanlan.zhihu.com/p/441014532
6、https://www.sohu.com/a/216967458_100104174
Author 丨 Teng Tengtai Attending Physician
Reviewer 丨Yuan Shan (Director of Dermatology Department, Beijing United Family Hospital)
The article was launched by Tencent's "All People Love Science" team
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