Aging: Why People Can’t Avoid Getting Old?
Posted: Dec 07, 2018
"From cradle to crave" is a journey that humans cannot avoid. As we age, our risk of developing various diseases increases. As for the connection between the two, a potential explanation is that the mechanism that causes aging can also cause aging-related diseases. In recent years, with the deepening of biological research, we have gradually realized that senescent cells play a key role in the aging process of human beings and thus become a potential anti-aging target. Today, based on the article published on Nature Reviews|Drug Discovery "Senescent cells: an emerging target for diseases of ageing", we’ll further explore the causes of aging and what measures can be taken to slow down the aging process.
Inevitable aging and death
As early as 1881, the well-known evolutionary biologist August Weismann pointed out in the article "The Duration of Life" that humans die because the exhausted tissues cannot permanently update itself. There are limits to the ability of cells to divide. More than 100 years ago, Weisman’s point of view was clearly too far ahead of the times. This argument was re-examined after more than 80 years.
In 1961, Leonard Hayflick confirmed Weisman's assertion. He found that mammalian cell division ability does have limits, refuting the idea that cells have immortality. This phenomenon is also known as the "Hyflick Limit".
Whether it is Weisman or Hayflick, they all believe that the reason for tissue aging lies in the accumulation of these "non-dividing cells." It is also because of the existence of these cells that the tissue cannot continue to repair itself. But limited to the times, they only touched upon these cells, missing many of their role at the molecular level. And as researchers continue to study these cells, they give these aging cells a new name "senescent cells".
Characteristics of senescent cells
In addition to the inability to repair tissue through division, senescent cells have many characteristics - they secrete cytokines into the surrounding environment, causing inflammation; they remodel the extracellular matrix; they can also cause cell death, or inhibit the function of stem cells.
"Stopping growing" is the most obvious characteristics of senescent cells. With age, many factors such as DNA damage, telomere shortening, activation of cancer genes, deficiency of PTEN, cessation of DNA replication, and unfolded protein responses will cause cells to decide not to grow anymore. Behind the growth stopping, there are two signaling pathways: p53-p21-RB, and p16 INK4A–RB. They stop the cell cycle and stop the cells from dividing.
Another distinguishing feature of senescent cells is their active secretion capacity. They secrete large amounts of inflammatory cytokines, chemokines, growth factors, and proteases. Currently, we have not performed a detailed analysis of SASP (senescence-associated secretory phenotypes) from different cell sources, and only one of the few advances comes from studies of IMR90 (primary fetal lung fibroblast cell line). The study found that this aging cell secretes 103 different proteins, many of which have a potential direct causal relationship to aging-related chronic diseases. This also explains why aging causes a range of inflammation-related symptoms.
The third characteristic of senescent cells is their ability to resist apoptosis. In vivo, apoptosis plays an important regulatory role in ensuring optimal balance of cells within the tissue, but aging cells appear to be unregulated by related pathways. Under the stress of these aging stress, p53, which affects apoptosis, can accumulate, but the level is not enough to induce apoptosis. These "old and undead" cells are quietly staying in the tissue, constantly secreting factors that affect the surrounding cells, causing aging-related diseases.
Senescent cells and aging diseases
In a series of studies, the association between aging cells and aging diseases has been further elucidated. In a mouse model of premature aging, the researchers found a large number of senescent cells that were positive for p16 INK4A in their tissues. They cause a range of aging symptoms, including muscle decay syndrome (sarcopenia), cataracts, and lipodystrophy. However, if the production of p16 INK4A is inhibited, the production of senescent cells can be inhibited and symptoms can be alleviated.
With the support of these findings, scientists began to look for signs of senescent cells in common human aging diseases and successfully established a causal relationship between atherosclerosis and osteoarthritis. In atherosclerosis, plaques composed of fat and protein gradually accumulate on the inner wall of the artery, easily inducing heart disease, stroke, or other serious ischemic diseases. It can be seen that the formation and growth of these plaques is the root cause of the disease.
In animal models, the researchers found many aging macrophages at the site where plaques initially formed on the arterial wall. Over time, other types of aging cells have emerged near these sites. These senescent cells are expressed in a large amount of secretory factors that promote atherosclerosis compared to other control cells. After using these methods to remove these senescent cells, it can inhibit the growth of the lesion and alleviate the condition of this serious disease.
Similarly, in osteoarthritis, researchers have discovered the accumulation of many senescent cells in the affected joints, and the elimination of aging cells can relieve pain, promote the repair of damaged cartilage, and even prevent natural aging. The mouse developed osteoarthritis.
Strategies for targeting senescent cells
A number of studies from 2016 to 2017 found that the elimination of senescent cells does not cause significant side effects, which opens the door to the development of therapies for aging cells. Currently, senescence cell senolysis, immune-based senescent cell clearance, and SASP neutralization are the three major targeting strategies.
Senescence 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 bind inhibitorically to BCL-2, BCL-X, and BCL-W, thereby inhibiting their "anti-apoptotic" function, allowing senescent cells to initiate apoptosis. UBX0101 can also have a similar effect in the treatment of osteoarthritis.
As the immune system ages, its ability will gradually decline, making senescence cells often escape the identification of the immune system. If you can reshape the immune system to monitor senescence cells, you are expected to eliminate these cells. In a mouse hepatocellular carcinoma model, expression of p53 causes cellular senescence. Accompanied by strong responses from neutrophils, natural killer cells, and macrophages. These natural killer cells can also mediate the clearance of aging cells and limit the fibrosis caused by chronic liver damage. But also in stem cells, overexpression of NRAS-H12V causes "oncogenic gene-induced cellular senescence," which can be removed by the innate immune system and the adaptive immune system. These results indicate that the immune system has different clearance mechanisms for senescent cells in different models.
- Some current anti-aging therapies
SASP Neutralization is designed to interfere with the many pro-inflammatory cytokines, chemokines, and growth factors secreted by senescence cells.
This strategy can be further refined into three parts: inhibition of SASP-related signaling cascades in senescent cells, interference with the secretion of SASP, or inhibition of components of secreted factors alone. For the first part, one of the biggest challenges researchers face is directly affecting these signaling pathways, which can lead to cell cancer. To this end, we also need more in vivo experiments to enhance our understanding in this area; the second part of the problem is also that we do not know enough about the secretion mechanism of these factors, so that we can not accurately find the need to target object. At present, researchers believe that protease may play an important role in this. As for the third part, because we have a certain understanding of many related factors and their receptors, it has become possible to develop targeted drugs. For example, we have monoclonal antibodies against IL-6 and its receptors. They are also expected to be used for anti-aging.
The challenges and prospects of anti-aging therapy
Like many therapies, anti-aging therapies have their own limitations. It should be noted that we need to establish better in vitro and in vivo models, find aging-related diseases that are most likely to benefit from it, identify biomarkers that are potentially relevant to disease treatment, screen for appropriate patient populations, and ensure that these therapies have adequate safety and specificity without off-target effects.
If we can solve these problems, the prospects in the anti-aging field will be vast. Aging has brought enormous burdens to society. Anti-aging treatments are expected to keep people healthy while they are getting older and its impact on human society may be revolutionary.
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