As a recent Ph.D. graduate in tissue engineering, I was fortunate enough to be given a ticket for EARD2020, an online conference focused on aging research, particularly on developing technologies that target the aging processes directly in order to cure age-related diseases. Today, I want to share some of my experiences of the conference with you along with the area of research that interests me the most: cellular senescence.
Fortunately, cellular senescence was on the top of presenters’ and attendees’ minds alike at EARD this year. Although several speakers touched on the topic, Dr. Judith Campisi of the Buck Institute for Research on Aging delved deep into cellular senescence. Dr. Campisi, a pioneer of aging research, is well-known for her role in discovering the link between cellular senescence and aging.
Dr. Campisi defined senescent cells as sharing three key characteristics: 1) irreversible growth arrest (no longer dividing/proliferating), 2) multi-faceted secretory phenotype (the SASP), and 3) resistance to apoptosis (avoidance of cell death).
These cells, and particularly the factors they secrete, have been shown to play a role in nearly all age-related diseases along with aging itself. This inflammatory senescence-associated secretory phenotype (SASP) is highly variable over time, by both tissue type and cause of senescence.
However, Dr. Campisi’s group has identified 135 core proteins common to most senescent cells. While their initial strategies attempted to suppress the secretion of these proteins, several beneficial effects of the SASP have also been identified, including tumor prevention and wound repair, resulting in negative side effects if suppressed entirely. Instead, the intermittent clearance of senescent cells via senolytic drugs has shown greater promise.
The “Targeting aging with interventions” session showcased more of that promise. Dr. Lewis Gruber of SIWA Therapeutics discussed his company’s lead therapy, a humanized monoclonal antibody dubbed 318H. This antibody attacks senescent and cancer cells simultaneously by targeting cells that exhibit aerobic glycolysis. In a mouse model, they have been able to reduce p16ink4a expression, increase muscle mass, and reduce breast cancer tumor size.
Moving forward, the company is setting its sights on kidney disease and preventing the relapse of aggressive cancers such as pancreatic cancer and triple negative breast cancer. As cells with a high viral load also exhibit aerobic glycolysis, SIWA is also actively looking for a strategic partner to utilize 318H as a broad spectrum antiviral – something which is sorely needed in the midst of the current COVID-19 pandemic.
Dr. James Kirkland of Mayo Clinic discussed a bioinformatics approach that identified the first senolytic drugs, dasatinib and quercetin, back in 2015. Senescent cells have multiple pathways for resisting apoptosis and are very heterogeneous both within and across cell populations. Because of this, very few, if any, drugs are able to broadly target all senescent cells, hence the utility of this “D+Q” combination approach. These drugs have been researched as senolytics by many groups, as they have shown significant promise in an impressive range of age-related diseases in mice.
This has included protection from radiation, increase in bone mass, alleviated insulin resistance, decreased frailty, hair loss prevention, decreased cognitive decline, and increased median lifespan. In humans, they have been shown to reduce senescent cell load in obese patients and patients with kidney disease, as well as improve frailty among patients with idiopathic pulmonary fibrosis. For Alzheimer’s disease, a small, three-site clinical trial is also currently getting underway.
Dr. Marco Quarta of Rubedo Life Sciences rounded out the senolytics portion of the program. Rubedo aims to develop a platform technology which will modify senolytic drugs to increase their potency and specificity. The safety of senolytic drugs will be of paramount importance if they are to be used for preventative purposes. This is a major concern with first-generation senolytics, which are mostly repurposed cancer drugs and systemically toxic.
The company’s lead therapeutic, RBO-1000, was able to remove senescent cells caused by chemotherapy in mouse livers and also reversed other side effects, such as loss of body weight. In naturally aged mice, RBO-1000 reduced senescent cell load, increased physical activity levels, decreased frailty, and increased muscle strength.
Like with many targets in the longevity field, targeting cellular senescence holds great potential to simultaneously treat a wide variety of age-related diseases while increasing both healthspan and lifespan.
Despite the recent disappointing results from Unity’s clinical trial, guarded optimism was a unanimous theme even from speakers not focused on cellular senescence. After a quip about Unity co-founder Ned David’s hair, keynote speaker Aubrey de Grey remarked how the company still overwhelmingly deserves support and stated, “this in no way challenges the validity of removing senescent cells as a therapeutic strategy.”
Others, such as Alexandra Bause of Apollo Ventures, pointed to the study’s main endpoint as a possible issue for the lack of a positive outcome. The WOMAC score, while commonly used in osteoarthritis trials, is a self-reported score of pain. This makes it highly susceptible to the placebo effect and very far downstream of the potential therapeutic effects that the senolytic treatment may have had.
Nonetheless, it was also suggested that the benefits of clearing senescent cells may be primarily realized in increasing healthspan rather than lifespan, with several studies reporting increases in median lifespan but not maximal lifespan in mouse models. In closing her presentation, Dr. Campisi stated, “there is great promise for extending healthspan, but when it comes to lifespan, we have a lot to learn.”