What difficulties do anti-aging drugs face before they arrive?

Aging is an eternal topic that human beings cannot avoid. Since ancient times, people have been trying to change the process of aging. Before that, Qin Shi Huang built a lot of civil engineering, superstitiously believed in the art of immortality, and even spent thousands of dollars to send Xu Fu and five hundred pairs of virgin boys and girls overseas to seek immortal medicine. Later, Emperor Wu of Han sent people to ask for immortals and medicines, and built a high platform to undertake the so-called xianlu.

In modern times, in the past decade, the number of people over the age of 65 in developed countries has increased by more than 10%, and it is expected to exceed 20% in 2030, and the aging of the population has gradually become the focus of social attention. Unfortunately, although the biomedical industry has invested a lot of time and resources in the treatment of chronic diseases related to aging, people's methods of anti-aging are still very limited, and the development and promotion of anti-aging drugs is not an easy task.

Senescent cells become the key to anti-aging

Human aging is a complex physiological process, which is a random change in the structure and function of molecules, cells and organisms caused by the passage of time and the interaction with the environment. Aging is characterized by a progressive decline in physiological function and the ability of tissues to stabilize the environment, leading to an increased incidence of degenerative diseases and death.

From the essence of aging, the occurrence of aging generally begins at a small genetic level. This is closely related to chromosomes and chromosomal telomeres. In general, the telomeres of chromosomes will protect the chromosomes, and the shortening of telomeres will lead to the continuous shortening of chromosomes and the continuous loss of genes. This process, from a genetic point of view, is the process of human aging.

In stem cells, the shortening of telomeres leads to reduced expression of lineage and pluripotent markers, reflecting a decrease in the proliferation, regeneration, migration, and differentiation of these cells. As telomeres continue to shorten, so do chromosomes, and "apoptotic bodies" continue to form around the nucleus. As there are more and more "apoptotic bodies", the morphology of the cells changes accordingly. Eventually, the cells will develop an abnormal state. The whole process is what we know as "apoptosis," or programmed cell death.

The aging of genes is finally reflected in the aging of cells, and the aging of cells constitutes the aging of the macroscopic human body. The aging of cells leads to a decline in the health and function of organs. This increases the body's sensitivity to age-related diseases, making the organism's response to injury less pronounced and more likely to die.

In the face of human aging, although modern medicine has also put forward suggestions for preventing aging, including exercise, diet, and changes in living habits. It is clear, however, that these measures are not sufficient to prevent diseases that occur in older persons. And as mentioned earlier, according to the essence of human aging, if we can correct these problems, it will not only delay aging, but also prevent or postpone many aging-related diseases. As a result, many current studies focus on the physiological mechanisms behind the aging process.

Among them, senescent cells, as cells that play a key role in the aging process of humans, have become a potential anti-aging target. Senescent cells are cells in the human body where the cell cycle is stagnant. These cells cannot continue to divide, but they cannot die either.

In addition to stopping growth, another distinct feature of senescent cells is their active secretory capacity. They secrete large amounts of inflammatory cytokines, chemokines, growth factors, and proteases. These pro-inflammatory factors may recruit inflammatory cells, re-engineer the extracellular environment, induce abnormal cell death, fibrosis, and inhibit stem cell function.

The only few senescent cells that have progressed so far are the IMR90 (primary fetal lung fibroblast line) study. The study found that the senescent cells secrete 103 different proteins, many of which have potential direct causal relationships for aging-related chronic diseases.

In addition, the third characteristic of senescent cells is resistance to apoptosis. In vivo, apoptosis plays an important regulatory role, ensuring that the cells within the tissue reach an optimal balance, but senescent cells appear to be unregulated by the relevant pathways. Studies have found that under the stress of these aging stresses, although p53, which affects apoptosis, can accumulate, the level is not enough to induce the occurrence of apoptosis. These "old and immortal" cells stay quietly in the tissue, constantly secreting factors that affect the surrounding cells, causing aging-related diseases.

Target senescent cells

Based on the key role of senescent cells in promoting human aging, strategies for targeting senescent cells were also born. At present, senescent cell lysis (senolysis), immune-based senescent cell clearance, and SASP (aging-related secretion phenotype) neutralization are the three mainstream targeting strategies.

First, senescent cell lysis is the first anti-aging therapy to show potential in preclinical trials in vivo. This strategy activates apoptosis in senescent cells, causing these cells to die. For example, navitoclax and ABT-737 can inhibitively bind to BCL-2, BCL-X, and BCL-W, thereby inhibiting their "anti-apoptosis" function, so that senescent cells can initiate apoptosis.

At present, certain senescent cell lysates have entered clinical trials. For example, on September 18, 2019, scientists published data from an anti-aging Phase 1 clinical trial in EBioMedicine. The trial enrolled 11 patients with diabetic nephropathy and used a 3-day combination of dasatinib and quercetin. The results showed that after 11 days, the senescent cells expressing p16INK4A- and p21CIP1- in the skin of these patients decreased, and the levels of senescent-related cytokines such as IL-1α, IL-6, MMPs-9 and 12 also decreased. This is the first time that Senolytic drugs have been shown in clinical trials that short-term treatment can have a more sustained elimination of senescent cell function.

Second, from the perspective of immune-based cell clearance, a decline in immune function may also cause normal aging. At the same time, because the immune system gradually declines in its ability as it ages, senescent cells can often escape the recognition of the immune system. Based on this, the researchers believe that if the immune system can be remodeled to monitor senescent cells, it is possible to destroy these cells.

《Nature Reviews | In a review in Drug Discovery, the researchers noted that in a mouse model of hepatocellular carcinoma, the expression of p53 caused cellular senescence. This is accompanied by a powerful response from neutrophils, natural killer cells, and macrophages. These natural killer cells can also mediate the clearance of senescent cells, limiting fibrosis caused by chronic liver injury.

But also in stem cells, overexpression of NRAS-H12V can cause "oncogene-induced cellular senescence, which can be cleared by the innate immune system in combination with the adaptive immune system. That is, in different models, the immune system has different mechanisms for clearing senescent cells.

Finally, from the perspective of SASP (aging-related secretion phenotype) suppression strategy, senescent cells secrete pro-inflammatory factors, immunosuppressants, protein digestive enzymes and other substances that have a negative impact on neighboring healthy cells, and as the name suggests, SASP inhibitors can inhibit this process. SASP inhibitors are designed to interfere with the many pro-inflammatory cytokines, chemokines, and growth factors secreted by senescent cells. This strategy can be broken down into three parts: inhibiting the signaling cascade pathways associated with SASP in senescent cells, interfering with SASP secretion, or inhibiting components of individual secretory factors.

At present, SASP inhibitors mainly include various antioxidants, Ganoderma lucidum, Wnt/β-catenin inhibitors, Klotho, ICG-001 and JAK inhibitors. However, although SASP inhibitors have health benefits, they should be carefully considered before application. For example, proper intake of antioxidants may be beneficial to health, while excessive intake of exogenous antioxidants may inhibit the synthesis of endogenous antioxidant enzymes.

And, like many therapies, anti-aging therapies have their own conditions and limitations. Research also needs to build better in vitro and in vivo models, look for age-related diseases that are most likely to benefit from them, identify biomarkers that are potentially relevant to disease treatment, screen for appropriate patient populations, and ensure that these therapies have sufficient safety and specificity without off-target effects.

Anti-aging, not so easy

Of course, although there is a broader anti-aging campaign that is currently gaining momentum, it is an objective fact that it is still a long way from us to rely on taking drugs to delay aging.

On the one hand, if anti-aging drugs are to be used as true anti-aging therapies, they need to go through human trials. In addition to using these drugs in people who already have a disease, rigorous testing is required in healthy people who naturally age. The solution currently being studied is to utilize molecular agents or "biomarkers" of the aging process. These are subtle changes, such as the addition of certain chemical factors to DNA that occur over a shorter period of time and are thought to herald a broader picture of aging.

Another option is to start with dogs, which age about 7 times faster than humans and experience many age-related diseases and declines. They also share living space with humans and are subject to many of the same environmental influences that lead to aging. Therefore, they are excellent models for observing the aging process. But the process of human aging lasts for decades, making the necessary experiments both lengthy and expensive. You know, clinical trials are not cheap, and who pays for the cost of clinical trials?

On the other hand, it is about ethics, which involves the question of how many years human beings can live. In recent years, with the development of more and more large-scale cross-sectional studies on human lifespan and biomarker parameters, biological age based on blood marker changes, DNA methylation, etc. has also been widely used in the prediction and assessment of human age.

Previously, in order to quantify the aging process in humans, the research team of Singaporean biotechnology company Gero, in collaboration with the Rosewell Park Comprehensive Cancer Center in Buffalo, New York, found that the body's ability to recover slows down over time. The recovery ability of the human body between the ages of 30-40 drops sharply, the healthy person of 40 years old takes 2 weeks to recover, the 80-year-old person is up to 6 weeks, and the limit of human life expectancy is between 120-150 years old.

Studies have found that between the ages of 120 and 150, the elasticity of the Dynamic Biological State Index (DOSI) indicator will reach its limit. The self-healing ability of humans and the recovery rate of the disease will reach a critical point and will no longer change, which is the upper limit of human lifespan. It also means that between the ages of 120 and 150, the average person who does not suffer from a major chronic disease will completely lose the ability to recover, and even a small disease has the potential to cause significant harm.

This also explains why the most effective means of prevention and treatment can only increase the average life expectancy, but not the maximum lifespan. Because it is impossible to effectively prolong life by preventing or treating disease without stopping the aging process, which is the root cause of potential inelasticity.

Therefore, according to the current medical paradigm, aging does not need to be treated, it is seen as an inevitable cruel reality in life. Against this backdrop, if the U.S. Food and Drug Administration (FDA) and other regulatory agencies were to approve an anti-aging drug, they would first need to recognize that aging is a preventable condition that can be targeted and treated.

And, even if this effort to prolong human life succeeds, there are still some questions that need to be answered. If we develop anti-aging technologies, who can use them? Will inequality increase further in a post-aging world? It is undeniable that in this era of aging, aging has brought a great burden to society, but anti-aging therapy is still a long way from people, and before that, changing living habits may be a better suggestion for preventing aging.

(The author is Chen Gen, a well-known science and technology writer)