Longevity Therapeutics 2019 [Opening session]: Senescence, Senolytics, and Aging Therapeutics

Part of our coverage of the 2019 Longevity Therapeutics summit. An index of all articles about the event appears here.

Fluorescence micrograph of a senescent fibroblast, with nucleus in blue and mitochondria in red. Credit: NICHD/U. Manor

Fluorescence micrograph of a senescent fibroblast, with nucleus in blue and mitochondria in red. Credit: NICHD/U. Manor

Session chair John Lewis of Oisin Biotechnologies, a Seattle-based company currently working on developing senotherapeutics, gave opening remarks and introduced the speakers.

Ned David (Unity Biotechnology): Advances in Senolytic Approaches for Disease of Aging


Unity co-founder and president Nathaniel E. (Ned) David began, as he often does, with a definition of healthspan: the period of life when we are functionally young. Although his company is primarily devoted to senotherapeutics at the moment, Ned is already looking ahead: he considers Unity to be a healthspan company, rather than a senescence company—signaling the idea that future development efforts will not be limited to senolytics.

“Aging is a flexible, malleable thing,” David argues, with “control knobs” that nature itself has twisted and turned over the course of evolution, creating 10-fold differences in lifespan within taxonomic orders (e.g., mice vs naked mole rats) and 100-fold differences within orders (e.g., mammals: shrews, which live less than a year, vs. bowhead whales, which can live to be 200 or even more).

Unity is pursuing multiple pathways to impact the aging process, but began with cellular senescence because the mechanisms by which this phenomenon contribute to aging are quite well understood: senescent cells secrete a potent brew of cytokines, proteases, and other factors that drive age-related decline in tissue function.

We know from mouse models that clearing senescent cells can delay the onset of disease, extend healthspan, and even restore youthful cognition and behavior patterns. Unity is developing drugs that can do the same thing in human beings.

The first drugs tested in Unity’s therapeutic paradigm will be senolytic molecule that are delivered into affected tissue, selectively eliminating senescent cells, decreasing the burden of senescence, and creating a functionally younger tissue. Later approaches will move from local senolysis to systemic senolysis—factors that can be administered in the circulation or orally that attack senescent cells throughout the body. Eventually, the company hopes to target other pathways, including pathways affecting mitochondria and other aspects of cell signaling.

Unity’s first disease target is osteoarthritis (OA), which David describes as “the primary reason why it hurts to be old.” Their hypothesis is that senescent cells accumulate in the cartilage of the knee and other joints, secrete inflammatory factors, and ultimately give rise to chronic pain and loss of cartilage tissue. Their drug candidate UBX0101, currently the subject of an early-phase clinical trial, has already been shown to destroy senescent cells and promote cartilage regrowth in explants from OA patients. Importantly, the frequency of senescent cells in disease tissue is correlated with pain, implying that senolysis will alleviate one of the most devastating symptoms of OA.

Next, Unity hopes to engage age-related retinal degeneration, specifically targeting vascular cells at the back of the eye that become senescent, driving vision loss. In mice, the drug UBX1967 can partially reverse diabetic retinopathy—even after the disease is already underway.

Judith Campisi (Buck Institute for Research on Aging): Aging & Drug Discovery – The Next Frontiers in Senolytics


Judy’s talk began by acknowledging Ned David’s critical role in founding Unity and, in her words, “pushing the scientists” to expand the limits of our knowledge about cellular senescence and its role in aging.

She emphasized that senescence is not the only phenomenon driving aging, but the evidence is clear that it is a key contributor to the exponential increase in disease risk as we get older.

In her introduction to the concepts underlying senescence, Judy raised an important question: why do we need senescence at all? The body already has an effective way of preventing damaged cells from forming tumors—apoptosis, which has the advantage of completely eliminating the affected cells and preventing it from (e.g.) secreting inflammatory factors later in life. One answer for this question is that senescent cells make positive contributions to important physiological processes, such as wound healing.

In aging, however, senescent cells are “smoking guns”, present at the right time and place to drive aging and multiple age-related disease. But how do they do it?

Critically, the cytokines and other factors secreted by senescent cells drive sterile inflammation: invasion of innate immune cells (which Campisi describes as the “less intelligent part of the immune system”) in the absence of an infectious agent, interfering with tissue function and negatively affecting stem cells that would ordinarily provide a source of new cellular material to repair damage.

She then quickly reviewed evidence that senescent cells cause or contribute to diverse age-related diseases, ranging from Alzheimer’s and Parkinsons to cardiovascular dysfunction, diabetes, arthritis, and others. Thus, cellular senescence begins to provide a grand unifying theory of aging— again, it’s not the only cause of age-related decline, but it seems to affect almost every disease of aging, raising the possibility that targeting this one core phenomenon could help to ameliorate a vast range of illnesses.

What are the next challenges in developing senolytics? Campisi identified N things:

  1. Achieving greater specificity: Given that senescence has some benefits for the body, it may be that some senescent cells are beneficial and should not be targeting. To this end, she proposes doing deep phenotyping of senescent cells from embryos, placentas, healing wounds, etc. in order to figure out what’s happening in a detailed way.

  2. Developing animal models and human biomarkers (especially cell surface biomarkers): Mice aren’t humans, and in order to assess the benefits of senolysis in human beings, it essential to be able to measure the senescent cell burden in our own tissues.

  3. Understanding heterogeneity: Senescent cells are surprisingly heterogeneous, even in culture. To explore the inter-cell differences, the Campisi lab has characterized the transcriptomes of individual cells from the same culture dish. The results reveal that senescent cells consist of discrete subpopulations, some that may be more important for age-related changes and others that may be beneficial.

  4. Understanding dynamics: The senescence-associated secretory phenotype (SASP) may be involved in both promoting and resolving fibrosis, and these effects may occur at different times.

  5. The role of the immune system: Senescent cells produce factors that both promote and suppress their own clearance by natural killer (NK) cells. How are these cells signaling to the immune system, and how can we modulate these signals in order to make sure that we eliminate the appropriate cells?

Keynote Panel: “A Therapeutic Revolution Against Aging – Bridging the Gaps & Opportunities”

  • Aubrey de Grey, CSO, SENS Foundation & VP of New Technology Discovery, AgeX Therapeutics

  • Judith Campisi, Professor, Buck Institute for Research on Aging & Lawrence Berkeley National Laboratory

  • Nir Barzilai, Professor & Director, Institute for Aging Research, Albert Einstein College of Medicine

Aubrey began with a reminiscence about how much the field has changed over the last 20 years, recalling the first report that senescent cells accumulate in the cartilage of OA patients. Those results were so preliminary that they were barely noticed, but now dozens of companies are seeking to develop senotherapeutics to prevent or reverse age-related disease.

Nir: “We are not competitors here. It’s a small field, and there’s room for everybody.”

Judy: “The field of aging is on the cusp of making a huge difference fo humanity, and I’m proud to be part of that movement.”

Session chair John Lewis: “Are there any black boxes in aging?" (that is, what are the holes in our knowledge?)

  • Judy: Why do humans and mice have such dramatically different lifespans? We have no idea.

  • Nir: A 70-year-old man’s sperm can fertilize a 50-year-old woman’s egg. These cells have accumulate age-related damage, but the resultant blastocyst is 0 years old. Our bodies have figured out how to erase cellular aging, but we have no idea how to do this.

  • Aubrey: Although there is a great deal we don’t understand, there’s quite a lot that we do understand. The overall paradigm established 20 years ago hasn’t undergone significant revision.

Judy: “How do we explain what Yamanaka has done”? [i.e., reprogramming of somatic cells]

  • Nir: There’s a company trying to apply this to aging already.

  • Aubrey: It doesn’t count as age-related damage. There’s aging, and there’s development.

  • Judy: I disagree with that.

  • John: It makes sense to ask which cells in the body would benefit from reprogramming.

  • Judy: Manuel Serrano can conditionally express the Yamanaka factors. Some cells undergo senescence, driven by the oncogene Myc. The SASP of those cells helps the reprogrammed cells undergo proper development.

  • Nir: Our maximum lifespan as a species is 115, but we die at the age of 80. There’s already 35 years we can realize without resetting our cells to zero. A modest improvement in healthspan that we could realize in the next decade would be great, because we can build form there.

John: Should we treat aging as a bunch of different diseases, or as one thing?

  • Aubrey: It is clear that there is a smaller number of things going on than the number of age-related diseases.

  • Nir: I went to the FDA, and it’s surprising how reluctant people are to call aging a disease. The AARP would never let us call it that. For an FDA indication, if you can prevent a cluster of age-related diseases, that’s as much as we want, and maybe people will come around. It’s a mistake for us to engage at this level because we’ll alienate the public.

John: What are the key challenges?

  • Aubrey: Discovery and delivery. Many of the things we’d like to do are genetic, and at the moment we’re not very good at somatic gene therapy.

  • Nir: Until aging becomes an indication, what we’re all trying to do is find a disease that we can target.

  • Judy: It would be useful to create better organoids with human tissue.

  • Aubrey: We need more diverse animal models, sure, but the experiments are really hard. At the moment, one really simple way to get better models would be to test late-onset interventions. Some of these studies are underway, but it’s been a long time coming. The rapamycin study started at 20 months of age, but that was an accident—and it didn’t set an adequate precedent, and this represents a missed opportunity.

  • Nir: “It’s never too late to target aging, especially with senolytics.”

John: Thinking about aging as an endpoint, biomarkers are really important.

  • Aubrey: We’re going to have an excellent session this afternoon on the use of AI to identify biomarkers. Previous efforts to identify biomarkers were a bust. If you were able to reverse aging, you could use cruder biomarkers over shorter periods of time.

  • Nir: It’s one thing to say that you want a biomarker that reflects biological vs chronological age, but another if you want to biomarker to change if you’ve altered the rate of aging. The Horvath clock is the most interesting biological marker now, but we don’t know whether it’s reversed if you reverse or delay aging.

  • Judy: There’s not going to be a biomarker, but a panel, and we’ll need statisticians to help interpret the data.

  • Nir: Longitudinal proteomic studies in humans revealed a bunch of proteins that we had no idea about. Historically we’ve searched “under the light,” but unbiased approaches will open up whole new unexplored territories.

John: What about upcoming commercial models?

  • Aubrey: There doesn’t need to be one solution, commercial or otherwise. There are companies, academic institutions, philanthropic support…and “the size of the checks is growing.”

  • Nir: I always thought that old people would be the ones to fund us, but it turns out they think it’s too late. The funders of Lifeforce, Calico, etc. are all young. “There are lots of people with lots of means that ‘get us’ much better…”

John: In your minds, what are the next research breakthroughs? What excites you about the future?

  • Judy: As I said, there are many black boxes. In terms of gene editing, I agree with Aubrey: we haven’t solved the delivery problem. Maybe nanoparticles will solve the problem? I don’t know.

  • Aubrey: There are a lot of different steps: you need to get agents into cells, but then once you’re in the cell you need to safely and programmably introduce DNA into the genome.

  • Nir: Regeneration and stem cells are areas where we want to see more breakthroughs. There are a lot of tools I’d like to see out there.