In the last decade, significant steps have been taken to gain a better understanding of the process of aging and mechanisms to slow it down. One of the most promising developments that surfaced recently is a new class of drugs called senolytics. These drugs not only have the potential to slow down the aging process but as a consequence can be a solution for many age-related conditions such as diabetes, neurodegenerative disorders, osteoarthritis, chronic pulmonary disease, cognitive impairment, renal diseases, and others.
Replicative senescence, a limitation in the number of times that cells can divide, was historically thought as an underlying problem in aging leading to a decline in tissue homeostasis, repair and regeneration. Over time, or due to damage, cancerous mutation or stress-related changes, decrease cells’ ability to divide. A cell that has no ability to renew itself is called a senescent cell (SnC).
The role and consequences of senescent cells
Even though the senescence seems to be at first a mutation, the replicative limitation of the cell has its role, and it has been viewed as a protection against cancer, as it stops cancer cells from replicating. SnCs play a beneficial role in embryonic development, wound healing, and insulin secretion by pancreatic β cells. When not needed, SnCs should destroy themselves through a programmed cell death called apoptosis and be removed by the immune system. The old or weakened immune system loses the ability to remove these cells, and an increasing number of them accumulate in organs. Consequently, accumulated SnCs block space for the new cells, preventing tissue rejuvenation. Additionally, SnCs secrete toxic signals that can alter the structure and function of the neighboring cells and tissues.
Scientists discovered a way to remove the SnCs and the current research results indicate a potential for clearing up the space for rejuvenating tissue stem cells which eventually might lead to extended health span. The removal is facilitated by a new class of drugs, called senolytics. Senolytics induce programmed cell death (apoptosis) so the “dead” cells can be cleared up by the immune system.
SnCs play a beneficial role in embryonic development, wound healing, and insulin secretion by pancreatic β cells.
Encouraging results
Senolytics have already been tested on animal models. Studies on mice indicated restored fitness, fur density, kidney function, improvement in lung disease and even repaired damaged cartilage. In the study conducted in 2016, it was found that the drugs dasatinib and quercetin induced apoptosis of SnCs in mice, increasing their life span. The effect was sustained over time.
Both dasatinib and quercetin are already approved by the U.S. Food and Drug Administration (FDA) for human use - dasatinib is a drug to treat leukemia and quercetin is an antihistamine, available as a supplement. This means that both of these medications can be quickly adopted for geriatric conditions. In fact, the steps to introduce senolytics for human use have been already taken. A researcher from the University of Texas Health, San Antonio, collaborating with the Mayo Clinic and the Wake Forest School of Medicine, recently published results from a study on a small sample of patients with progressive lung disease. This was the first human study on senolytics. A pilot test for further research was conducted on 14 older patients with varying levels of idiopathic pulmonary fibrosis (IPF), a progressive fibrotic lung disease which leaves many, especially, older patients, with a low prognosis of survival. The results indicated an increase in mobility, which had not been achieved with previous types of treatment and as such, this might be a paradigm shift in the treatment strategy of IPF.
Currently, there is one more ongoing study on human subjects and senolytics. A research facility coordinated by the UNITY Biotechnology Inc. recently initiated a safety and tolerability study of a drug named UBX0101 in patients with osteoarthritis of the knee.
The steps to introduce senolytics for human use have been already taken. The results indicated an increase in mobility, which had not been achieved with previous types of treatment.
If the effects of these drugs achieved in animal models are replicated in humans, they might be a transformative method of treating age-related problems as they would address a group of symptoms instead of focusing on specific effects of aging. Another advantage is that the treatment would include only a single dose or periodic short treatments, potentially reducing the risk of side effects of this medication. Additionally, as SnCs do not divide, drug resistance should not be a problem. Researchers are planning to improve this method even further by combining senolytics with stem cell therapy.
Caution advised
The research on senolytics is not without challenges. Defining biomarkers of senescence for each type of cell and finding nontoxic apoptosis inducers is still a very complicated process. Additionally, just as in cancer therapy, caution is needed while removing more significant quantities of these cells. The high number of these cells in the bloodstream can potentially be toxic and hence lethal.
While senolytics show a massive potential to fight age-related conditions and disorders, people should not try to experiment with them on their own. Trials to test potential side effects of these substances used in the context of destroying SnCs have not been conducted yet. Therefore, we do not know what the long-term effects of using senolytics as an antiaging agent in humans are.
