Part 2 of a series of articles covering Unity Biotechnology’s inaugural R&D Day, a special presentation to investors and analysts highlighting the company’s recent progress and future plans. An index of our comprehensive coverage of the event appears in Part 1.
Senescence—a physiological change that occurs in our cells as we get older and drives age-related tissue deterioration—is at the forefront of biogerontology. The academic field has moved rapidly, with the most recent findings implicating senescent cells in diseases as diverse as arthritis and neurodegeneration.
Meanwhile, multiple companies are developing novel ways to eliminate senescent cells from the body, with the hope of preventing the damage they cause and thereby ameliorating or even preventing disease of aging.
But how did we arrive here? How did we come from the first observations in the field, now more than 50 years ago, to the vanguard of longevity science? Answering this question was the first mission of Unity Biotechnology’s inaugural R&D day, a special presentation for investors and analysts held on December 11, 2018. The scientist who began the discussion, following Unity president Ned David’s introduction, was Professor Judith Campisi of the Buck Institute for Research on Aging.
Prof. Campisi, who has devoted her career to elucidating the biology of senescence, was described by Ned David as one of two individuals “most singly responsible for giving birth to the scientific field that Unity now leads.” (The other, Prof. Jan van Deursen, gave the next part of the presentation.) She has been widely recognized as an intellectual leader in the field of aging research, and was recently inducted into the prestigious National Academy of Sciences, an honor often seen as the culmination of an uncommonly brilliant scientific career.
“It was really in puzzling over why a protease would stop cell division, why an inflammatory cytokine would stop cell division, that we thought maybe they're not quite right.”
Judy began by reviewing the founding observations in the field: Leonard Hayflick’s finding that normal cells have a limited capacity to proliferate in culture. After reaching their “replicative lifespan,” he learned, cells enter an irreversible growth arrest—not dying, but forever unable to divide. The irreversibility of the change makes senescence an excellent tumor suppressor, as a damaged or mutated cell that undergoes senescence can never form a cancer. But Hayflick’s intuition took him further.
To his eye, the cells “looked old,” and he posited that senescence is a form of cellular aging in culture that recapitulates the process of tissue aging in our bodies. He hypothesized that by stopping cell division, senescence preventing tissues from regenerating and replacing cells lost to injury (or normal wear and tear), ultimately contributing to a decline in organ function.
Consistent with his hypothesis, cells isolated from old humans had a shorter replicative lifespan than those from younger people—but the difference simply wasn’t large enough to explain the dramatic physiological differences between youth and old age.
To understand the true role of senescence in aging, it was necesary to look beyond the original defining feature of senescent cells—their exit from the cell cycle—and investigate what they were doing after undergoing this change.
“Virtually every major disease of age, ranging from neurodegeneration to age-associated cancer, is driven by inflammation. … We believe it's occurring because senescent cells are attracting those immune cells into a tissue and driving this process.”
Some of the earliest work in this direction hit a wall because of an inaccurate assumption: “They assumed if the gene was turned on, it was stopping cell division…and they were usually pretty wrong,” Campisi said. “They showed that senescent cells express things like proteases—enzymes that cleave other proteins—or cytokines that would attract the immune system to a tissue… And it was really in puzzling over why a protease would stop cell division, why an inflammatory cytokine would stop cell division, that we thought, maybe they're not quite right.”
If not promoting or maintaining the growth arrest, what were these factors doing? “Many of these molecules that senescent cells secrete would have profound effects on neighboring cells,” she explained, going on to describe a body of work by her own laboratory showing that senescent cells produce a suite of inflammatory cytokines, growth factors, and proteases that together conspire to degrade tissue integrity. Collectively, these secreted proteins are called the SASP (senescence-associated secretory phenotype), a term first used in the seminal paper that introduced the phenomenon to the field.
“Many of these molecules that senescent cells secrete would have profound effects on neighboring cells.”
This led to a fundamentally new view of the role of senescence in aging: rather than simply robbing the tissue of regenerative capacity, senescent cells become an ‘enemy within,’ driving chronic inflammation throughout the body. “Virtually every major disease of age, ranging from neurodegeneration to age-associated cancer, is driven by inflammation,” Campisi explained. “This is the infiltration of immune cells that produce damaging molecules for the purpose of protecting against infection. But with age, we have a condition that has been termed sterile inflammation—no pathogen, but the cells are there, and we believe it's occurring because senescent cells are attracting those immune cells into a tissue and driving this process.”
Moreover—and somewhat paradoxically, given the role of senescence as a tumor suppressor mechanism—Campisi’s lab also showed that senescent cells could promote the progression and metastasis of cancer.
“It's these persistent senescent cells that accumulate with age that are the target for drugs to try to clear them. This will then guarantee that we've maintained the good and hopefully eliminate the bad.”
If senescence contributes to both carcinogenesis and aging, then, why not simply target the pathways that lead cells into this state? The reasons are manifold: “We don't want to avoid senescence; that will cause cancer,” Campisi explained. “We want to be able to establish senescent cells, but we want those cells to be only transiently present. And it's these persistent senescent cells that accumulate with age that are the target for drugs, to try to clear them. This will then guarantee that we've maintained the good and hopefully eliminate the bad”—i.e., preventing damaged cells from proliferating, but avoiding the negative consequences of their misbehavior after they become senescent.
Campisi concluded by sketching out a roadmap for the future of the field: “The new horizon is two-fold. One is what Unity is doIng: to try to develop drugs that can do what our transgenes can do,” she explained. (Here, she was referring to transgenic mice that have been genetically manipulated to allow conditional elimination of senescent cells; we’ll hear more about that in our coverage of Jan van Deursen’s talk.)
“The other is to drill down as deeply as we can. This is what drives the basic science in my lab and many other labs: to understand senescence in as much detail as possible so that our drugs can become more and more specific.” In support of this idea, she outlined recent work from her group showing that senescent cells consist of multiple subpopulations, each of which behaves in a distinct manner and may be susceptible to different drugs.
“We don't know if this will extend lifespan, but we're pretty certain that it's going to extend healthspan.”
In Campisis’s view, these efforts will lead us toward the ultimate goal: to find multiple clinically tractable ways to eliminate senescent cells throughout the human body.
“We don't know if this will extend lifespan,” she acknowledged, “but we're pretty certain, based on the list of pathologies that are susceptible to eliminating senescent cells, that it's going to extend healthspan.”
On that optimistic note, Judy handed the microphone to Jan van Deursen, whose talk we summarize here.