Senescence, An Emerging Industry
A brief review of our conversation with several experts in senescence
If you didn’t have a chance to watch our webinar on senescence last week, you can watch the recording on our YouTube channel.
Overview
Aging is the disruption of the fine balance, or homeostasis, that exists between different elements of the body such as macromolecules, sub-cellular compartments, cells, tissues, extracellular matrix, and organ systems at the molecular composition and function levels. One of the manifestations of aging, cell senescence, is the disruption in balance in a cell’s fate and its ability to function as an integral part of its surroundings.
A few fundamental questions are appropriate to ask here. First: of all the different areas within longevity, why did we decide to zoom in on cell senescence for this webinar, and what led us to choose this panel?
Cell senescence is integral to aging. Several studies have shown that the senescent cell burden increases with age and transplanting even small numbers of senescent cells in animal models has been shown to induce physical dysfunction in younger animals. Regenerative strategies such as heterochronic parabiosis (exchange of plasma between young and old animals) decreases the senescent cell burden in the old animal while increasing the burden in the young animal, indicating how closely the phenomenon of cell senescence is linked to aging and rejuvenation. Transplantation of senescent cells is used as a strategy to create animal models that effectively mimic age-related diseases such as osteoarthritis. Several of the damage types associated with aging can trigger cell senescence: examples are DNA damage, oncogenic mutations, telomere shortening, metabolic disruption, oxidative stress, genotoxic stress, dysfunction of organelles such as mitochondria, and being in the presence of other senescent cells and their secretions.
Each of the panelists brought unique expertise that was relevant to the conversation. Prof Paul Robbins has an illustrious career spanning several decades. He is the Associate Director of the Institute on the Biology of Aging and Metabolism at the University of Minnesota. He was previously Professor of Molecular Medicine at Scripps Institute Florida. He is an established leader in the field of cell senescence and exosomes and has published a large number of scientific papers that have shaped the field.
Marco Quarta is the CEO of Rubedo Life Sciences, which is working on drugs that can work without side effects in the elderly. The first indication they are targeting is idiopathic pulmonary fibrosis and the senescence burden associated with the disease state. He is a serial entrepreneur who gave up his Stanford faculty position to develop strategies to cure aging.
Angele Maki is currently a Vice President of Emerging Technology & Innovation at Eli Lilly and Company where she leads search & evaluation efforts in the Bay Area for Lilly Research Labs. At Lilly she also plays key roles with Lilly Gateway Labs, Lilly’s new incubator-like facility in South San Francisco, and with Lilly New Ventures, Lilly’s corporate VC group.
The panelists were carefully chosen to provide a holistic view of the field. Paul brought rich experience and expertise from donning the hats of both basic and applied clinical researchers. He has catalyzed the development of the field along with the likes of Jim Kirkland. Marco brought in an interesting industry perspective while Angele’s long-standing association with “big pharma” very lucidly alluded to how the pharmaceutical industry views this fast-emerging field and their views on possible M&A deals and the overall investability of the field. Paul’s commitment to studying cell senescence comes from his belief in the geroscience hypothesis, which states: the resolution of all the chronic diseases associated with aging needs to begin with therapeutically addressing aging physiology. Angele Maki argued that cell senescence is a phenomenon that needs to be studied as it affects everyone, unlike several metabolic diseases and genetic diseases that only affect specific cohorts. Marco Quarta began science experiments when he was five years old in his own lab and believes that his technology of converting inactive drugs into active ones utilizing the body’s physiology in a tissue — and compartment-specific way while minimizing side effects is the only way to distinguish between different senescent cell types.
It is important to understand the nature of cell senescence and how the senescent cell burden impacts the balance between health and disease and even healthspan. The concept of senescence and its impact on aging has been around for 50 years, but only in 2011 did evidence begin to show that the elimination of senescent cells can impact diseases. Since then, the field has grown leaps and bounds.
A senescent cell in many ways resembles a cancer cell. Like cancer cells, senescent cells escape apoptosis or programmed cell death and although they do not divide like cancer cells, they persist and become toxic due to their ability to secrete SASP (senescence-associated secretory phenotype) and impact neighboring cells, driving the formation of additional senescent cells termed secondary senescent cells. Senescence is a stable cell state. Paul stated that the major hurdle in the field stems from a lack of ability to understand the differences between different types of senescent cells in vivo — for example, a senescent astrocyte from a senescent neuron from a senescent chondrocyte and how they respond to individual drug molecules. Also, within these individual types, methods to differentiate primary versus secondary senescent cells in developing a therapeutic intervention is highly important. Angele agreed to this and talked about how in the early stages of chemotherapeutic development and how a “throwing a sledgehammer” approach is being replaced by sophisticated drug development approaches. Marco alluded to the approach pursued at Rubedo, where they have a computational tool that precisely takes into account the differences that exist between tissue-specific senescent cells as well as cell-specific states. Since all their drug discovery approaches are based on the underlying data and the computational application, they were able to create a highly effective, specific drug with a lower toxicity profile as their first proof of concept.
Paul mentioned that there are about 20 ongoing clinical trials targeting senescent cells. He is currently associated with several of them including an IPF trial, osteoarthritis trial, and a type 2 diabetes trial. There is also an ongoing clinical trial that is elucidating the role of senescent cells in COVID-19. He explained how, due to the metabolic and physiological similarities between cancer cells and senescent cells, the initial set of drugs tested as senolytics were all repositioned cancer drugs and though they showed efficacy their applicability in a chronic setting is limited. Angele stressed the importance of safety and said that though it is acceptable, although not desirable, to have limited toxicity for an oncologic indication, the same thing is not acceptable for a field such as senescence.
There are many approaches to managing the senescent cell burden within tissues. There are many companies developing molecules/approaches that eliminate senescent cells under the umbrella of senolytics, but there are also senomorphics that block the secretions from senescent cells and also those that in a stage-specific manner convert a senescent cell back to its original state (we need to remember here that the senescent state is associated with morphological changes, chromatin remodeling and metabolic reprogramming and is not normally reversible once the changes are complete). Lastly, there are senoblockers that have the ability to block the formation of senescent cells. Marco talked about having a careful strategy with dosing in the case of senoblockers, as if these drugs are taken earlier in life, they might stop “good senescent cells” (which I will explain in a moment) from forming and carrying out their function. We just do not know everything about the stage and speed of formation of senescent cells in vivo and when they change from their state of transient occurrence to chronic accumulation.
It is important to understand the concept of good and bad senescent cells. These terminologies refer to the functional role the senescent cells (the transient ones) have under normal physiological conditions. The so-called good senescent cells are associated with functions such as wound healing, tumor suppression, and embryonic development.
Paul spoke about how these cells are actively cleared in the younger population by the immune system but that, with the immune decline with age, the active clearance fails and leads to accumulation of senescent cells leading to chronic conditions.
Clearly, given the importance of these cells, a multitude of applications can be visualized. These range from ameliorating chronic disease conditions, to the treatment of organs before transplantation to enhance their function, to increasing the effectiveness of chemotherapy. Paul spoke about how it is enough to clear about 30–40% of senescent cells, as this amount of clearance initiates recovery of function. Paul reiterated that “aging is driven by several pillars which are all linked. When you clear senescent cells, you see stem cell numbers and function being revived, metabolism being restored, mTOR going down. Affecting or lowering the senescent cell pillar impacts all other pillars of aging.”
It is therefore important to understand the developments that are ongoing, especially the clinical developments. Paul summarized a quote from Ned Sharpless, the director of the National Cancer Institute, and said that this is a very fast-moving field, and we will be able to definitively conclude its significance in five years from now.
Angele went on to define the Pharma outlook. Big pharma is very interested in cell senescence and they have dedicated resources that are closely watching this field. One thing that they are cautious about is the necessity for the association of senescence with a therapeutic indication. Cell senescence is a phenomenon of biology, but only when it is effectively linked to a therapeutic indication will anti-senescence technologies become investable. Also, big pharma needs one biotech company to successfully show human efficacy, which will then transform this burgeoning early-stage field into a highly investable one.
Unity Biotech, a company that tested its senolytics indication on osteoarthritis, was discussed and the conclusion was that the setback in Phase 2 readouts of Unity does not set the field back but actually emphasizes the care needed in drug design as well as clinical trial design, dosing strategies and endpoints. All these hold true not only for the field of senolytics, but also for the entire field of longevity.
The overall verdict of the panel was that this is an early but highly exciting and fast-developing field that might hold the key to solving multiple diseases of aging in as little as 5 years.
To wrap up, my cohost Brandon Simmons asked the panel for their recommendations on longevity. Everyone agreed the age-old advice to exercise and eat a balanced diet are the closest thing we’ve got to a panacea at the moment but hopefully, technology will offer more tailored therapies soon!
You can watch the entire conversation on our YouTube channel.
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