Prof. Paul Robbins, Senomorphics, Senolytics, and Longevity

Author(s): Scott Douglas Jacobsen

Publication (Outlet/Website): The Good Men Project

Publication Date (yyyy/mm/dd): 2025/03/03

Prof. Paul Robbins is a renowned biochemistry, molecular biology, and biophysics professor at the University of Minnesota. He is Associate Director of the Institute on the Biology of Aging and Metabolism (iBAM). He is a leading researcher in aging science, pioneering gene therapies for autoimmune diseases and developing chemotherapeutics, including senolytics and senomorphic, to target senescent cells. With a Ph.D. from UC Berkeley and postdoctoral training at MIT’s Whitehead Institute, Dr. Robbins has held prominent roles at Scripps Research and the University of Pittsburgh. His groundbreaking work advances healthspan and lifespan science, aiming to improve aging-related health worldwide. Robbins discusses chemotherapeutics, targeting senescent cells, and advancing healthspan and lifespan science. He explains how senolytics kill harmful senescent cells while senomorphics suppress their damaging effects. Highlighting the importance of immune function, Robbins notes that improving immune health can help clear senescent cells and enhance resilience to aging-related diseases. He emphasizes the need for rigorous, well-controlled clinical trials to validate treatments for slowing aging, such as senolytics and NAD precursors. Robbins remains optimistic about the field’s progress, predicting a future of combination therapies addressing various hallmarks of aging for healthier, longer lives.

Scott Douglas Jacobsen: Today, we are here with Dr. Paul Robbins, a professor of biochemistry, molecular biology, and biophysics. He also serves as the Associate Director of the Institute on the Biology of Aging and Metabolism (iBAM) at the University of Minnesota. His work has advanced healthspan and lifespan science globally. What inspired the transition from studying gene regulation and transcriptional enhancers to senescence and longevity research?

Prof. Paul Robbins: Right. I started at the University of Pittsburgh in the gene therapy field, where I ran a gene therapy core facility. We developed viral vectors for various investigators on campus, working on approaches to treat numerous diseases. As I collaborated with these researchers, I realized that the same molecular pathways and targets were implicated across multiple diseases. The same things going wrong in one disease were going wrong in others.

I quickly embraced the concept of geroscience: the idea that aging is the greatest risk factor for disease and involves common pathways linked to various conditions. By developing ways to target aging, I could reduce the risk, mitigate the severity, or even prevent the onset of many age-related diseases. This realization led to a transition from focusing on treating individual diseases to addressing the root cause of many—aging itself. Whether it’s cancer, osteoarthritis, Alzheimer’s, Parkinson’s, or muscle wasting, the biggest risk factor is the aging process itself.

Jacobsen: How do chemotherapeutic compounds reduce senescent cell burdens, and what are the mechanisms involved?

Robbins: There are now two types of chemotherapeutics, and we coined terms for these categories. First, there are drugs called senolytics, which preferentially kill senescent cells. Second, there are compounds called senomorphic, which suppress the adverse effects of senescent cells.

Cellular senescence is a cell fate that evolved in mammals and other vertebrates. It primarily acts as a cancer prevention mechanism. When cells are damaged or at risk of acquiring mutations that could lead to cancer, they activate pathways that induce senescence. This halts their proliferation and prompts them to release inflammatory factors that signal the immune system to clear them. A healthy individual’s immune system likely clears these senescent cells daily. A young, healthy immune system efficiently removes thousands of these cells regularly.

Since senescence is an anticancer mechanism, many cleared cells exhibit changes that could make them pre-tumorigenic or precancerous. Interestingly, many senolytics that target senescent cells also target pathways active in tumour cells. These pathways are upregulated in senescent cells because they are precancerous. Essentially, senolytics target similar pathways to those addressed by anticancer drugs.

Conversely, senomorphic targets the factors released by senescent cells, which are responsible for the adverse effects of these cells on surrounding tissues. These compounds can suppress senescent cells’ inflammatory and damaging signals without necessarily killing them.

They’ll target activated pathways leading to this inflammatory response. Many of them are anti-inflammatory, suppressing the chronic inflammation caused by the increase in the senescent cell burden with age, as the immune system does not clear these cells as effectively. So, senomorphic drugs are, in most cases, suppressing inflammatory factors. Senolytics target the same pathways that anticancer drugs target.

Jacobsen: Side question. Does this mean one could chart, across age, two lines of best fit? One from 0 to, let’s say, 80—a decrease in healing factors and an increase in inflammatory response over time. Is that generally the picture?

Robbins: That’s the hypothesis. I didn’t mention earlier that there is evidence for “good” senescence. For example, in wound healing, there’s evidence that senescent cells transiently accumulate at damage sites. These cells release beneficial factors, such as growth factors, that promote healing, especially in the skin. However, this likely applies to other tissues as well. Then, these senescent cells are cleared, presumably by the immune system or possibly other mechanisms. So, these are the “good” senescent cells.

Then there are the senescent cells that accumulate in older individuals, which chronically release factors that cause harmful effects. Though experimental methods vary between labs and age models, the data supports this idea. When you’re younger, the senescence you see in many cases is “good” senescence. Those cells appear, serve their function, and disappear. They are not a response to extensive damage or mutations that might lead to cancer. Instead, this is a natural process to promote wound healing.

The question is: Is a good senescent cell the same as a bad senescent cell? The answer is no. Drugs targeting bad senescent cells will not necessarily affect good senescent cells. There is ongoing discussion about whether senolytics might have adverse effects on processes like wound healing or even development in pregnant women, etc. These questions are still being investigated, but the consensus is that there are different classes of senescent cells—good and bad—and that the developed drugs aim to target only the subset of bad senescent cells.

Jacobsen: Regarding clinical trials, what are the mechanisms and the prospects for increasing health span and lifespan via a chemotherapeutic compound?

Robbins: This field took off in 2012 with pioneering work. It’s considered pioneering because nobody expected it to work. They created transgenic mice that could selectively kill cells expressing certain senescence markers. They used a marker that regulates the cell cycle called p16. When p16 is activated, it stops cells from growing, and many senescent cells express this marker. These transgenic mice were engineered so that if given a drug, it would kill p16-positive cells.

That study showed that clearing these cells could extend the median lifespan of mice. It delayed the onset of many age-related pathologies and the onset of cancer. However, it didn’t necessarily lead to a significant extension of lifespan—perhaps a minor increase.

A paper published this past year by a faculty member we recruited to the University of Minnesota, Ming Xu, demonstrated that clearing a different type of senescent cell—those positive for another cell cycle regulator called p21—led to mice being healthier and living about 10 to 15% longer. This suggests that targeting specific types of senescent cells could both increase health span and extend lifespan.

The hypothesis is—and these experiments are ongoing—that eliminating both p16-positive and p21-positive senescent cells would have a pronounced effect. Many of the chemotherapeutics that we’re developing appear to target both p16-positive and p21-positive cells. However, we don’t believe our approaches eliminate all types of senescent cells. Instead, we’re reducing their overall numbers but not clearing every subtype.

We still don’t know which senescent cell types in the body are the most critical to target. Is it senescent cells in the liver, brain, muscle, or cartilage? We don’t yet know which types to focus on with our senolytics. We’re reducing the total burden of senescent cells, but the specific subtypes remain uncertain. There’s still much work to be done. If we identify the senescent cell types that are most detrimental, we could develop more effective therapeutics, resulting in clearer benefits like extending the median lifespan, increasing the maximal lifespan, and improving healthspan. How much we can achieve remains to be seen.

Jacobsen: Imagine you have a dumpster pile. It’s as if one company only deals with cardboard waste—they clean that up. Similarly, by identifying specific genetic markers of senescent cells, you might work with another company specializing in copper waste, reducing the overall load but still leaving a significant pile of unknowns. 

Robbins: That’s a good senology. In the last few years, the NIH recognized the importance of senescence across all its institutes. Whether it’s heart, blood, and lung; cancer; allergy and infectious diseases; or aging, senescence has been acknowledged as a significant factor. The NIH Director’s Common Fund has been supporting the SenNet Consortium in addressing this. You can find it online at sennet.org or sennet.gov. This consortium comprises hundreds of scientists working to identify, characterize, and spatially map senescent cells across 18 tissues during normal human and mouse aging.

We’re trying to determine what senescent cell types emerge with age, where they accumulate, and their roles. In the second phase of the grant, we plan to conduct perturbation studies to determine which of these senescent cells are the most important to target. We’ll also have molecular characterizations of these cells, allowing us to leverage bioinformatics, AI approaches, and other techniques to identify compounds that can selectively clear them. At this stage, we know senescent cells accumulate with age, but we don’t know all their types or which drive disease pathology. This may vary depending on the disease, which raises additional questions that must be addressed.

Not all senescence is the same. The concept we’re introducing—and there’s a Nature Magazine perspective under review—is called genotypes. We think there are many different genotypes, much like many tumour types. Understanding these differences will be crucial for developing therapeutics that extend healthy aging and possibly increase lifespan.

Jacobsen: What challenges arise in translating chemotherapeutic research in mouse models to human clinical trials? People who may not know much about this might wonder why researchers work with organisms like Drosophila or mice. They might think, “Those are completely different from humans—why are they even relevant?” Can you explain the connection between clinical trials and these model organisms?

Robbins: Yes. Unfortunately, those working with mice often use genetically homogeneous strains. In theory, all the mice are genetically identical, though there are always slight variations in practice. Because of this, genetic uniformity makes their lifespans and molecular processes fairly consistent. Even then, we see variability—for example, some mice treated with senolytics live longer than others.

When you transition to humans, the situation becomes far more complex. There are likely subsets of people with a higher senescent cell burden and would benefit most from senolytics. Conversely, others may be aging more healthfully or whose diseases are driven by different hallmarks of aging rather than senescence. One of the first challenges we face is identifying the right population of patients to treat—the right diseases, conditions, dose, and timing. The process becomes an even bigger black box when treating people without a specific disease to extend their lifespan.

What we need are biomarkers to assess the burden of harmful senescent cells. Biomarkers could also help us determine which type of senolytic to use, as there isn’t a single drug that can effectively eliminate all senescent cell types. Ideally, we’d like to predict the most effective senolytic for a given biomarker profile. However, not everything that works in mice works in humans. For example, a senescent mouse cell doesn’t have identical molecular characteristics to a senescent human cell. Drugs that kill senescent mouse fibroblasts don’t always work on senescent human fibroblasts, even in cell cultures. These are some of the hurdles we’re dealing with.

That being said, the initial evidence is promising. In early-phase clinical trials, the first-generation senolytic drugs we’ve developed appear to reduce senescence markers, at least for inflammatory markers. Whether this translates to improved health span or reduced disease severity is unclear. Still, initial trials suggest some target engagement with the current drugs.

Jacobsen: That raises an interesting question about the opposite approach. Could there be conditions under which the accumulation of certain senescent cell types counterintuitively extends lifespan or health span?

Robbins: That’s a great question. Suppose you had asked me that five years ago, I would have said, “Of course not. All senescent cells are bad.” But now, the picture is more nuanced. As I mentioned earlier, transient senescent cells can be beneficial. Some senescent cells, as we currently define them with specific markers, may secrete factors that have positive effects.

These cells likely evolved to provide benefits during our evolutionary history. Most people think of senescent cells as part of an anti-tumour mechanism, and that’s true. However, senescent cells, or at least the senescence process, contribute to antiviral or anti-pathogen responses. For example, we know that cells infected with viruses often enter a senescent state. It’s possible that senescence evolved to prevent cancer and reduce the risk of infection.

The problem arises because, thousands of years ago, humans didn’t live to be 80 or 90 years old. Senescence was doing its job in individuals during their teens, twenties, or thirties—not in their eighties. That’s where the issue changes completely. While there’s clear evidence of beneficial senescence in younger individuals—where these cells emerge, perform their function, and disappear—what happens when people live far longer than our species evolved to? Some of these senescent cells persist, and their prolonged presence likely contributes to the negative effects we see in older individuals.

Robbins: That’s where these cells might start causing problems. Something beneficial when you’re 30 may not be beneficial when you’re 80. That’s the concept of antagonistic pleiotropy—traits advantageous at one stage of life might become detrimental at another. There are many examples of this. What you said is likely correct, but we don’t have definitive proof yet.

Jacobsen: How might chemotherapeutic compounds prevent age-related diseases compared to the treatment of existing conditions?

Robbins: If it’s a senolytic, in theory—not every disease is driven by senescence. There may be diseases where senescence accumulates due to disease rather than being the driver. That’s always the issue: Is senescence the driver, or is it the consequence? For example, if you have much inflammation, that inflammation can drive more senescence.

Each disease might be different. Using a senolytic is something you could do intermittently. You wouldn’t need to give it all the time. It’s like treating a bacterial infection—you take antibiotics to kill the bacteria. Then you’re done unless the bacteria return. Similarly, the thought is that senolytics could be administered intermittently, possibly in combination with standard treatments. It doesn’t have to be one or the other.

An example of this is a trial conducted by Unity Biotechnology for macular degeneration. The standard care involves regular injections to prevent angiogenesis in the eye, which helps stop degeneration. Unity Biotechnology found evidence of senescent cells in the back of the eye. It injected a senolytic compound directly into the eye. They observed improvements comparable to the standard care but with a single injection. That single injection provided benefits for a year, whereas the standard treatment requires injections every 1-2 months.

This suggests that senolytics might not need to be administered as frequently, and they could provide an additive—or, in some cases, a synergistic—benefit with standard treatments. However, not every disease will respond to a senolytic. While senescence may be present in every disease context, it might not play as significant a role in some diseases as in others.

Jacobsen: As an aside, this seems like an important question to address in interviews, and it’s worth reiterating ad nauseam. What is your expert perspective on the viability of the multi-billion-dollar industry around supplements, pills, injections, and, as some claim, practices like taking the blood of a young person to rejuvenate themselves? For example, famous individuals taking extraordinary amounts of supplements or adopting practices that make them seem like, for lack of a better phrase, “IV Draculas.”

Robbins: That’s a great question. I always get asked this. I keep my answers PG, but I’ll give it a go. Most of those supplements, and most of the clinical protocols you can go to some foreign country to get, have no clinical evidence from well-controlled trials. There’s no evidence that they work. That’s not to say that some might not work, but there’s no evidence regarding the right dose, timing, or patient population. This is why all these things need well-regulated and controlled clinical studies.

For example, one of the supplements we’ve worked with—and are now trying to test in FDA-approved clinical trials—is a natural product called fisetin. It’s a flavonoid found in the skins of many fruits and vegetables. At higher doses, it appears to have some hemolytic activity. We’re trying to determine if this weak senolytic, being a natural product and safe, could be effective. It doesn’t work at the low doses people typically take—it requires a much higher dose.

As part of the process, we tried to find the right source of fisetin. Our colleagues at the Mayo Clinic conducted mass spectrometry on various commercially available fisetin sources. Some were 50% pure, others 60%, and a few were 95%, which is the FDA’s standard. The FDA requires something over 95% pure. The concern is, if you’re taking something 50% pure, what’s in the other 50%? That raises questions.

No one knows what the right dose is. While some of these supplements may have positive effects, there’s no regulation, quality control, or reliable information about dosing or who should take them. They’re often marketed on late-night TV or in ads in the back of magazines. People buy them, but the products include everything from jellyfish extracts to stem cells from apple seeds. You could go through a long list of unproven substances. Some of these may have effects, but no clinical studies have been done to confirm it. That’s where the field is moving—toward scientific validation rather than unregulated supplements.

Jacobsen: Doubtless, much money is being made off supplements, but I’m paraphrasing here. ‘There’s no clinical trial evidence for most of it.’

Robbins: Yes, exactly. It’s sad, but true.

Jacobsen: Well, let’s move on to other topics. How will current therapies integrate with senescence-targeting treatments in longevity science?

Robbins: That’s still an unanswered question. No one approach will be 100% effective in extending everyone’s health span and lifespan. It will involve cocktails of treatments.

If you look at the aging literature now, there’s this concept of the hallmarks of aging. These include changes in the epigenome, stem cell function, mitochondrial function, the microbiome, inflammation, cellular senescence, etc. These hallmarks are all interconnected and influence each other. However, some people may have one hallmark that’s more prominent than another.

Because of this, future treatments will likely use a cocktail of compounds. Senolytics will likely play a critical role but won’t be the only intervention. In 10, 15, or 20 years, the approach to staying healthier for longer—and potentially living a bit longer—will involve a combination of therapies. It’s going to be a cocktail.

We need to know whether some of these treatments are working in an additive or synergistic way—or are they cancelling each other? For example, how do you proceed if you choose senolytics targeting the same senescent cell without an additive effect? These things will require more preclinical and clinical studies to determine. 

Jacobsen: What is the role of inflammation and immune system decline in the aging process? This has been alluded to multiple times in our discussion.

Robbins: Yes, exactly. We published, and others have also reported, that if you age the immune system in mice—at least using a genetic trick—it leads to systemic aging. Conversely, if young immune cells are returned to an old mouse, it seems to slow aging. This happens partly because the functional immune cells can now clear senescent cells. So, we believe that immune aging can drive systemic aging.

The question is: what drives immune aging? Is it senescence? There’s evidence that immune cells can become senescent-like cells. Immune aging is important because improving immune health could help clear other senescent cells and eliminate dysfunctional immune cells. Our team is investing more effort into understanding ways to improve immune function with age. This could be an indirect method to clear senescent cells, improve resilience to pathogen infections, and reduce the negative effects of aged immune cells on the rest of the body.

If you think about it, senescent immune cells—like T cells—can infiltrate into every tissue in the body. Let’s say you have a senescent liver cell, like a hepatocyte. It’s liver-specific but can release factors into the bloodstream, affecting the rest of the body. However, a senescent T cell can infiltrate any tissue in the body. If it’s releasing inflammatory factors and not functioning correctly, it can cause local adverse effects in multiple tissues.

When immune cells are young and healthy, they perform essential functions. But when they become dysfunctional, they start causing problems. They can invade tissues, release inflammatory factors, and contribute to damage across the body. Targeting immune aging—either with senolytics or other classes of drugs—will be a critical area of focus.

One example that has been published and is being developed for clinical application is CAR T cells. These engineered T cells were originally designed to clear cancer cells by targeting specific tumours. Researchers are now using CAR T cells to target senescent cells directly. In mice, this approach has been shown to clear senescent cells, improve health span, and extend lifespan.

Directing immune cells to clear senescent cells has clear benefits. However, there are challenges in translating this to the clinic. One issue is figuring out how to safely target senescent cells, as there isn’t a single protein on the surface of a unique senescent cell. This raises concerns about accidentally killing normal cells alongside senescent cells. Many safety studies still need to be done, but improving immune function will undoubtedly be an important target for the future.

Jacobsen: That was a long answer. Yes, immune function is something we need to be targeting. Now, for the concluding sentence, as is the case with every single paper and poster presentation, what early results could influence future research directions?

Robbins: Yes. Well, the field is now poised for solid, quality-controlled clinical data. Many studies in the clinic are now being conducted under FDA Investigational New Drug (IND) applications, ensuring quality control, proper statistical powering, and other rigorous standards. These studies include trials with certain senolytics, NAD precursors, and other factors. While most stem cell studies are still being done in other countries under conditions that may not provide the best evidence, legitimate stem cell clinical trials are underway. There’s also ongoing work with antioxidants and other compounds.

The field needs evidence of success. It doesn’t have to be a home run—it doesn’t have to make us live longer. There is a need for proof that these approaches can slow aging or positively impact an age-related disease or condition. That’s where the field is right now. And it doesn’t necessarily have to involve treating a disease; it could target a condition or a biological process.

For example, clinical trials are beginning to test whether senolytics can allow older organs to be transplanted. If you take a liver from an 80-year-old donor and clear all the senescent cells from it, does that organ engraft and function better following transplantation? That’s not the same as treating an individual directly. Still, it demonstrates that clearing senescent cells could improve tissue function after transplantation.

Another area involves trials we’ve been associated with initially focused on COVID-19. We contributed to some of the preclinical work for those studies. Unfortunately—or fortunately—the development of vaccines changed the landscape, slowing down those trials. However, there’s a trial underway to see if senolytics can improve survival in sepsis patients.

A lot is happening, and within the next year or two, we should know whether these approaches provide meaningful benefits. This will pave the way for the field to develop better drugs. The drugs we’re currently using are first-generation senolytics, senomorphic, and other compounds targeting the hallmarks of aging. They are far from optimal. We’re scratching the surface, but with a few wins in the clinic, the field will gain momentum and progress toward more effective treatments.

There are no setbacks, no poorly designed trials, and no evidence showing that older patients are more susceptible or at greater risk of dying from the treatment. Safety is a large priority. The question is: would you treat your grandmother with these drugs? That’s the standard—you have to prove to yourself that they’re safe enough for your grandmother to take, or, in my case, I would take them myself.

These are the things the field needs. It’s going to require some clinical success. There are a lot of clinical studies starting—some well-controlled, others not—but clinical successes are what will push the field forward. A few wins will also bring big pharma into the picture. Pharma has been hesitant because aging is not officially classified as a disease. As a result, developing drugs to slow aging hasn’t been a priority for them. However, they are interested, and a few successes will let the biotech field take off.

That’s a good enough answer for you. I’m optimistic—I’ll conclude with that. I’m optimistic about the field, where it’s going, and the quality of the science. There are going to be some wins.

Jacobsen: Anyways, thank you so much.

Robbins: Thank you so much. Enjoy yourself and stay warm in Canada. It was nice meeting you, Scott.

Jacobsen: Nice to meet you, too. You take care.

Robbins: Bye.

Jacobsen: All right.

Last updated May 3, 2025. These terms govern all In Sight Publishing content—past, present, and future—and supersede any prior notices. In Sight Publishing by Scott Douglas Jacobsen is licensed under a Creative Commons BY‑NC‑ND 4.0; © In Sight Publishing by Scott Douglas Jacobsen 2012–Present. All trademarks, performances, databases & branding are owned by their rights holders; no use without permission. Unauthorized copying, modification, framing or public communication is prohibited. External links are not endorsed. Cookies & tracking require consent, and data processing complies with PIPEDA & GDPR; no data from children < 13 (COPPA). Content meets WCAG 2.1 AA under the Accessible Canada Act & is preserved in open archival formats with backups. Excerpts & links require full credit & hyperlink; limited quoting under fair-dealing & fair-use. All content is informational; no liability for errors or omissions: Feedback welcome, and verified errors corrected promptly. For permissions or DMCA notices, email: scott.jacobsen2025@gmail.com. Site use is governed by BC laws; content is “as‑is,” liability limited, users indemnify us; moral, performers’ & database sui generis rights reserved.