Senolytics are a powerful new class of longevity therapeutic. They selectively kill disease-causing senescent cells that accumulate in our bodies as we age. In this project we will test a class of drugs we identified called cationic amphipathic drugs (CADs) that we’ve shown in preliminary studies to have powerful senolytic activity. Based on the drugs’ chemistry we propose this class acts like an intracellular soap to ‘clean out’ these ‘old’ senescent cells from the body. Because many of the drugs we’re testing are already in use in humans and are inexpensive, and we will make our results publicly available, our goal is to accelerate the longevity field by providing immediately useful therapies.
What are Senolytics? And how do they relate to longevity?
Aging is the #1 risk factor for many common diseases, such as cardiovascular disease, cancer, Alzheimer’s, etc. Meaning, the older one is the more likely one is to have one of these conditions. There are several molecular explanations for this increased risk, but senescent cells that accumulate as we age are emerging as a key contributor.
Senescence refers to cells that are no longer dividing. Senescent cells are particularly important in the context of stem cells. Over our lifespans our stem cells throughout our body need to continually proliferate in order to replace damaged cells to replenish our tissues. As we age, damaged cells outpace healthy cells and the resulting increase in senescent cells results in decreased function. Moreover, senescent cells secrete pro-inflammatory and other destructive signals that can add insult to injury.
Eliminating senescent cells – akin to taking out our body’s trash – is now well-established as effective in a variety of aging-related disease models. A first therapeutically tractable approach to eliminate senescent cells was discovered by James Kirkland and colleagues at the Mayo Clinic in 2015. The term ‘senolytics’ was coined to describe the drugs they identified that ‘lysed’ or killed senescent cells. They prototype senolytic they discovered, dasatinib, was interesting because it had previously been used as a cancer therapeutic. Since then, researchers have identified others including navitoclax.
Despite this progress, the field has been limited in its search for senolytics because they don’t fit in the predominant paradigm of drug development. In drug development one typically needs a protein to target a drug against. In this paradigm researchers design a drug to fit in a molecular ‘pocket’ in a protein in a lock-and-key-like mechanism where the drug binding to the pocket either inhibits or activates the protein. With senolytics, however, the drug target is a cell and not a protein. The field therefore has been bottlenecked by not knowing what an effective senolytic should ‘look’ like. Senolytic identifying assays still involve the time and labor-intensive screening experiments Kirkland et al first developed. To date, only a few reproducibly effective senolytics have been developed.
More importantly, fewer yet are in the hands of researchers around the world. Because of the exploding interest in senolytics numerous companies rushed to the space. Perhaps most well know is the Jeff Bezos-backed Unity Biotechnology. Unfortunately, initial senolytic clinical trials haven’t been successful. This is a problem for the field because with companies one can’t know what drugs are being developed so the field doesn’t benefit from their insights and failures. This slows progress.
The field is need of concerted public efforts for identifying senolytics. This is why we started Open Senolytics.
Backstory on Open Senolytics
The work that led to our approach of identifying was a classic example of following the science. During the COVID pandemic we set out to understand what human genes might be commonly implicated in host responses across pathogens. Such a gene set could be a starting point as a target for a broad-spectrum prophylactic as well as be informative in the event of future pandemics. We performed meta-analyses of 15 genome-wide screens and 31 transcriptomic profiles involving diverse pathogens including viruses (e.g., SARS-CoV-2), bacteria, fungi, and parasites. Interestingly, the clear unifying signature from this analysis were factors related to sphingolipids and senescence.
We next sought to identify drugs that might target similar gene sets to those we identified with pathogens. Such drugs might represent a therapeutic for multiple pathogens. We performed analogous unbiased experiments and discovered drugs with cationic amphiphilic chemical properties (CADs) had a striking gene overlap (75%) to those we found for pathogens in also centering on sphingolipids and senescence. One notable example CAD we found is fluvoxamine, which is showing promise in multiple COVID-19 trials.
That we found CADs to specifically relate to both pathogens and senescence was interesting in light of senolytics. Senolytics selectively kill pathogenic senescent cells compared with healthy proliferating cells, but it is unclear what their molecular target is that provides this selectivity. Without this rationale, it has been hard to make progress in identifying new senolytics. In this proposal, we hypothesize drugs that possess cationic amphiphilic properties chemically resemble sphingolipids and are a defining class of senolytics. We will test this hypothesis in the following specific aim:
Specific Aim 1: Establish CADs senolytic capabilities across senescence-inducing insults and cell types
Many insults can induce cell senescence, yet their effects can vary by cell type. The same is true for senolytics.
Objective 1: Determine the efficacy of CADs as senolytics in the context of various senescence-inducing insults. In addition to pathogens, we will use commonly used senescence-inducers such as irradiation to determine to what extent each CAD’s senolytic activity is agnostic to the source of the induction or whether different CADs have different inducer specificities.
Objective 2: Determine the efficacy of CADs as senolytics in various cell types. To maintain feasibility in this objective, we will focus on pathogens as our senescence-inducing insults.
We have preliminary evidence this aim should succeed as expected. We identified several CADs performing as strongly as dasatinib, which notably is also a CAD (Figure 1). Interestingly, many of the CADs we identified are psychiatric medications. This aim is an in vitro aim. Depending on the resources available we would be interested in testing our results in vivo.
Who is the team behind Open Senolytics?
Our team is led by Tim Peterson, Ph.D. and Sandeep Kumar, Ph.D. Dr. Peterson is an Assistant Professor at Washington University School of Medicine in St. Louis in the Departments of Medicine and Genetics. “WashU” is a perennially top five medical school in the U.S. in terms of publishing and funding. Dr. Peterson did his Ph.D. at MIT where he published multiple papers in Nature, Science, and Cell journal on one of the major aging pathways, mTOR, and the drug, rapamycin, that targets it. Dr. Peterson did his postdoctoral fellowship at Harvard University where he continued his work on longevity drug mechanisms focusing on the most commonly used drugs for osteoporosis, bisphosphonates and diabetes, metformin. Dr. Kumar similarly has a deep background in aging research most notably performing several seminal lifespan studies in worms.
Dr. Morten Scheibye-Knudsen at the University of Copenhagen will be assisting us with his AI-driven senescent cell detection algorithms (see below). These algorithms are helpful because they allow us much greater throughput in our experiments. Thus, we can test many more CADs.