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—— TIMEPIE ——
Editor's Note
This article was compiled by the Time School Institute from an interview with Dr. James Kirkland by the American Federation for Aging Research. Cellular aging is one of the nine biomarkers of aging, and it is a phenomenon that may exist in the body of men, women and children. In 2016, researchers found that the removal of senescent cells extended the healthy period of mice, and lifespan was extended by 25%. "If you dare to come, don't be afraid that I will kick you out", which is also the mechanism of action of Senolytics, the most promising anti-aging drug at present.
In this interview, Dr. James Kirkland, the father of Senolytics, will introduce in plain language what cellular aging is, how it relates to aging and health, and the characteristics of the first Senolytics drugs.
Q: What are senescent cells? How do these cells change as we age?
A: Senescent cells are those that were originally able to divide, but now lose this ability. They are like "nail households" in the body, they do not wither on their own, and generally need the immune system to act as a "demolition brigade" to remove them.
As we age, there will be more and more senescent cells in the human body. Some people develop obesity or diabetes at a young age, and they also have senescent cells in their adipose tissue, pancreas, and other locations. Some children have cancers such as leukemia and lymphoma, have taken anti-cancer drugs or received chemotherapy, and they will also have senescent cells in their bodies.
Therefore, whether a cell will age or not is not determined by age alone. In most cases, the triggers of cellular senescence are signals of cellular stress, metabolic damage, cell division, and tissue damage that can age cells in as little as 10 days to 6 weeks.
Q: Can you briefly share with us the process of developing targeted senescent cell therapies?
A: Leonard Hayflick and Paul Moorhead were the first to observe senescent cells in 1961. By the mid-1970s, institutions such as the National Institutes of Health had published some important papers that found that senescent cells may accumulate as people age. In the early 1990s, we also found that senescent cells secrete a substance that causes tissue damage and promotes apoptosis, and TNF-α.
In 2004, Norm Sharpless, now director of the National Cancer Institute, shared several of his findings at the Journal of Clinical Investigation: First, the larger the proportion of senescent cells in mice, the shorter the health period and the lower the health level. Second, as they age, the senescent cells in the mice accumulate more and more. Dietary restriction and induction of Emmy's dwarfing mutations can delay cellular aging and prolong the health and lifespan of mice.
This enlightens us: Since senescent cells are inextricably linked to health, can we get rid of them to prolong our lives? We first tried to make a fusion protein to eliminate senescent cells, but found nothing; then we wanted to use high-throughput screening to find drugs that could selectively remove senescent cells, but there was no suitable screening method, and finally Professor Paul Robbins of the University of Minnesota discovered Senolytics drugs through high-throughput screening.
In May 2013, we began to study why senescent cells themselves are old and do not die, but lead to the death of neighboring cells. We used a large database to find eight anti-apoptotic pathways (SCAP) for senescent cells, which weave a huge protective net to prevent senescent cells from being accidentally injured by their own secreted destructive weapons.
Q: How were the first Senolytics drugs discovered?
A: We first used RNA interference to selectively knock down the node on the protective network of SCAP to see if we could selectively remove senescent cells by temporarily shutting down some of its functions, and the results did work.
Now that the idea works, we start trying to find drugs or compounds that have the same effect. We found that dealing with senescent cells requires a multifaceted effort. The action pathways of different senescent cells are also different, only one of them is blocked, and senescent cells can also find another "death-free gold medal". So we identified substances that could block multiple pathways, and that was the first Senolytics.
For the first Senolytics, we decided to start with natural substances present in drugs and foods circulating on the market because they are safer. At the same time, we also specially selected some biological substances with relatively short half-lives, that is, substances that can disappear quickly after entering the human body, and wanted to see if they could "finish fighting and running" when dealing with senescent cells. After all, the formation of senescent cells takes 10 days to 6 weeks, and it is enough to administer the drug every half a month or a month.
That's what happened with the first Senolytics drugs. Since then, more and more people have developed drugs according to the same idea, including CAR-T therapies, vaccines, etc., for the elimination of senescent cells.
Q: Are there preclinical models demonstrating that Senolytics can prevent, delay, or alleviate age-related diseases?
A: Researchers have conducted experiments on mice, rats, and monkeys. For example, a large number of human diseases were simulated in the mouse trial, and more than 40 of them were delayed, prevented or alleviated. We also found that some Senolytics, while not suitable for young mice without senescent cells, extended the lifespan of older mice with senescent cells; some Senolytics delayed aging-related diseases.
Q: How is Senolytics related to geriatrics (the science of applying aging research to disease intervention)?
A: In the Senolytics trial, the death of mice was caused by a combination of aging-related diseases, rather than a single disease. We also found that if, conversely, even a tiny number of senescent cells were transplanted into healthy, middle-aged mice, aging was accelerated, weakening, shortening lifespan, and eventually dying from multiple rather than one aging-related disease. All of this supports a hypothesis in geriatrics that many chronic diseases, as well as expensive and lethal diseases, are rooted in aging.
Our approach to Senolytics is not like developing drugs such as antihypertensive drugs (with one drug, targeting one target, treating a disease), but trying to combine multiple drugs, or using drugs that can target multiple targets at the same time, to see if they can delay, prevent, or alleviate multiple aging-related diseases.
The Senolytics that have now been identified are basically like this. They can help aging animals alleviate a variety of aging-related conditions, including aging weakness, aging-related muscle loss, mild cognitive damage, etc., and now the research of these conditions has entered the clinical stage.
In addition, Senolytics is also expected to help people with more senescent cells improve their ability to resist infectious diseases, postoperative recovery, and even reduce the risk of vaccination, which is also closely related to the prevention and treatment of new crown pneumonia.
Q: How are clinical trials in Senolytics' research area progressing?
A: Many studies have entered the stage of placebo-controlled, double-blind clinical trials. For example, we recruited a group of patients who suffered from leukemia in childhood and received bone marrow transplants, who are now in their thirties and forties, some of whom are aging faster, some of whom have diabetes, osteoporosis, alzheimer's disease, muscle weakness and even Alzheimer's disease. We asked them to take different Senolytics to see what would change.
Another area of research is organ transplantation. In a study conducted in collaboration with Harvard, we found that after transplanting senescent cells into young animals, young animals also begin to age. Therefore, it is certainly not possible to directly use those organs that have aged and impaired function during organ transplantation, which results in 35,000 donated kidneys every year that cannot be used for transplantation. Therefore, we are trying to restore the function of these kidneys before transplanting them into young patients to improve their postoperative health.
In addition to these previously mentioned studies, clinical trials with Senolytics to intervene in diseases such as renal fibrosis, diabetes, obesity, renal insufficiency, aging-related osteoporosis, osteoarthritis, etc. are also underway, focusing on the safety and tolerability of the drug.
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