The Biology of Aging

Paul: So many of the drugs used to kill senescent cells are actually anti-cancer drugs, and some of them have side effects. The question then becomes: what is the right dose to avoid those side effects? The advantage of senolytics is that we don't have to take them daily. The thought is we could take them every two weeks or every month to clear senescent cells.

Paul: Then they slowly come back, and we take them again.

Brent: Welcome to The Life Lab by Death Clock. I'm your host, Brent Franson. The mission of Death Clock is to help 100 million people live ten years longer. Today, we speak with Dr. Paul Robbins about the biology of aging. Dr. Robbins is a professor of biochemistry, molecular biology, and biophysics at the University of Minnesota, where he is also associate director of the Masonic Institute on the Biology of Aging and Metabolism.

Brent: Dr. Robbins is a pioneer in senolytics. He's an expert in the biology of aging and all of the different factors at the cellular level that might help us live longer. He's a wonderful guest. I hope you enjoy.

Brent: Dr. Paul Robbins, welcome to the show.

Paul: Very pleased to be here.

Brent: Today we're going to talk broadly about the biology of aging, recent advances in longevity, and ways we can extend lifespan and healthspan. I'm looking forward to chatting about that. Before we begin, can you give us a sense of your background and your day job?

Paul: I am currently the Associate Director of the Institute on the Biology of Aging at the University of Minnesota, and a professor in biochemistry, molecular biology, and biophysics. Previously, I was at Scripps Research Institute in Florida and, before that, the University of Pittsburgh. I am now focused on developing ways to slow aging to extend healthspan.

Brent: Wonderful. I'm interested in the same thing. You're a pioneer in senolytics, a word I had heard a lot but hadn't deeply considered until preparing for this episode.

Brent: Can you tell us what senolytics are and why we should care about them?

Paul: Let me take a step back and start with what a senescent cell is. Cellular senescence is a cell fate—it's what happens to cells that accumulate a lot of damage. For example, exposure to tobacco smoke or mutations that activate oncogenes to stimulate unwanted cell growth.

Paul: These are all types of stress. The cell recognizes this and halts proliferation to avoid becoming cancerous or causing other problems. It exits the cell cycle and releases inflammatory factors that signal the immune system to remove it. When you're young and healthy, your immune system functions well.

Paul: Your immune system clears those senescent cells, reducing cancer risk and inflammation. But as we age, damaged cells accumulate, and our immune system becomes less effective at clearing them. In many individuals, they accumulate to the point where they drive many age-related pathologies.

Paul: There is evidence in mice that clearing senescent cells makes them healthier and, in some cases, extends lifespan. While we can use genetic methods in mice, humans require therapeutic drugs that target and eliminate these damaged senescent cells. That is what senolytics are.

Paul: These drugs target specific pathways in senescent cells to induce cell death. My lab, alongside researchers at the Mayo Clinic, works to identify and optimize these compounds, which are now in phase one clinical trials around the world.

Brent: So as we age, a subset of cells stops functioning normally without dying. They cause inflammation and other problems, similar to gunk building up in an engine. Animal trials show that removing these senescent cells mitigates those negative effects.

Brent: As a result, mice are healthier and live longer. Now we're figuring out how to translate that to humans.

Paul: That's a great summary. An analogy I like to use is a bad apple in a bushel: one bad apple releases factors that cause the rest to decay rapidly. A senescent cell acts like that single bad apple spreading damage.

Brent: Are these cells inevitable? You mentioned UV damage and smoking, but even if someone avoids sun exposure and smoking, will senescent cells still accumulate with age?

Brent: Is it simply part of the aging process?

Paul: That's correct. Both extrinsic factors like UV light or smoke and intrinsic cellular processes contribute. Mitochondria generate ATP for energy, but chemical reactions aren't 100% efficient, producing reactive oxygen species (ROS). These ROS molecules damage proteins, lipids, and DNA.

Paul: As mitochondria decline with age, intrinsic damage causes cells to become senescent. Mutations like activated oncogenes push cells to stop proliferating and signal the immune system for clearance.

Brent: Are senescent cells similar to other aspects of aging where poor diet or lack of exercise accelerates their accumulation? I assume genetics also play a role in how rapidly they build up.

Brent: What drives cells to convert into a senescent state, and what dictates the volume? Is it lifestyle, genetics, or both?

Paul: It's likely a combination of factors. Lower-calorie diets and regular exercise both lower senescent cell burdens. In another project, we're studying centenarians to identify rare genetic variants that delay senescence.

Paul: These genetic variants result in less DNA damage and lower senescence. However, human populations are heterogeneous, so genetic, environmental, and lifestyle differences cause individuals to accumulate senescent cells at different rates.

Paul: We're still determining the exact relative contributions of these factors.

Brent: You mentioned that mouse studies used genetic approaches, whereas human studies focus on drugs. Was CRISPR used to modify DNA in mice?

Brent: Why can't we use those same genetic approaches in humans?

Paul: Instead of CRISPR gene editing, we created transgenic mouse models containing an inducible gene expression cassette. This cassette encodes a toxic protein specifically inside senescent cells.

Paul: The protein remains harmless until an activating drug is introduced, which selectively kills the senescent cells. When we clear these cells in aged mice, their overall health improves significantly.

Paul: We cannot insert transgenes into humans, though researchers are exploring gene therapy methods for clearing senescent cells. Pharmacological drugs remain the most practical near-term clinical solution.

Brent: So activating self-destruction in senescent cells allows the mice to live longer, healthier lives.

Paul: Yes. A decade ago, senescent cells were thought to be uniform, but we now know they are highly heterogeneous. A central goal is determining which specific senescent populations drive pathology in organs like the liver, brain, and kidneys, so we can target them selectively.

Paul: Senescent cells also play beneficial roles during embryonic development, in the placenta, and transiently during wound healing by releasing repair factors.

Paul: Transient senescence can be beneficial, whereas chronic, uncleared senescent cells cause harm. The immune system typically clears beneficial senescent cells after they perform their repair functions.

Paul: This distinction makes cellular senescence more complex than previously understood.

Brent: That's a classic Dunning-Kruger effect—learning more reveals deeper complexity. It sounds similar to bacteria: some strains cause harm, while others are beneficial.

Brent: The goal is surgically targeting harmful senescent cells while preserving beneficial ones, similar to managing the microbiome.

Brent: And thinking about good versus bad bacteria.

Paul: In older individuals, beneficial senescent cells are less common. During wound healing in older subjects, clearing bad senescent cells yields better outcomes than trying to preserve beneficial ones. Older populations generally carry a much higher burden of harmful senescent cells.

Paul: Whether senolytics are beneficial depends heavily on age. Current senolytics selectively kill harmful senescent cells, though verifying whether good senescent cells remain preserved is harder to measure, as those cells appear and disappear naturally.

Paul: And that's actually much harder because these cells come up and disappear naturally.

Brent: How do we measure senescent cell load? Is there a blood test to evaluate my current level at age 44 compared to age-matched baselines?

Paul: Over a decade ago, Ned Sharpless—former director of the NCI and FDA—developed a test isolating T cells from blood to check a specific marker. Though basic, measuring p16 protein levels in blood T cells correlates with healthspan and senescence progression.

Paul: The NIH is funding a $190 million SenNet consortium to map cellular senescence in healthy human aging across different organs.

Paul: This initiative aims to establish biomarkers for organ-specific senescence in the liver, brain, or kidneys, paving the way for targeted treatments.

Paul: Different tissues age at different rates. Mapping cell- and tissue-specific markers will allow more precise interventions.

Paul: Currently, available blood tests offer rough correlations with general senescent cell burden.

Brent: What is the practical value of taking that test today if actionability remains limited?

Paul: A high result indicates elevated senescent cell burden. The best current responses are lifestyle interventions: exercise and diet. Some supplements reduce senescent cell burden in animal models, though I do not prescribe or formally recommend them.

Paul: Optimal human dosing protocols remain unknown. An elevated burden signals that lifestyle changes or future senolytics should be considered to control burden and inflammation.

Brent: And that test is age-adjusted, since a 70-year-old naturally has a higher burden than a 30-year-old?

Paul: Characterizing senescent cell burden is complex. The NIH's $190 million investment will produce refined biomarkers to provide definitive tissue-specific measurements.

Brent: Will tissue-specific senescent cell burdens correlate with chronic organ diseases, like brain senescence with dementia or heart senescence with cardiovascular disease?

Brent: So you've got higher risk of heart disease. Is that ultimately where it's going to lead. Do you think.

Paul: That is the goal. Tony Wyss-Coray published a study on serum proteins indicating that immune system aging drives systemic aging. Mouse studies from my lab several years ago showed that aging the immune system alone causes non-lymphoid tissues to age prematurely.

Paul: In the brain, aging astrocytes correlate with health decline. We are searching for biomarkers linked to senescence in immune cells and astrocytes.

Paul: Increased senescence in astrocytes or microglia may elevate risk for Alzheimer's and Parkinson's diseases.

Brent: When discussing immune health and inflammation, standard tests like high-sensitivity C-reactive protein (hs-CRP) come to mind. Does high chronic low-grade inflammation directly correlate with a higher senescent cell burden?

Paul: In theory, yes. However, standard markers don't easily distinguish between senescence-driven inflammation and active viral or pathogen responses, as both release overlapping cytokines.

Paul: We need biomarkers specifically secreted by senescent cells, such as activin A, TGF-beta, and osteopontin, to measure senescence-induced inflammation accurately.

Paul: Human trials are beginning to evaluate whether senolytics successfully reduce these specific inflammatory markers and clear senescent cells.

Brent: For an everyday person, testing seems premature without clear actionable steps, and phase one clinical drugs aren't available from a primary doctor yet.

Brent: Phase one trials are an impressive milestone, but full approval takes time. What practical steps should people take right now, and what do you do personally based on your findings?

Brent: Is it best to stay patient and wait for further clinical data?

Paul: The field has moved faster than expected—progressing from initial discovery in 2015 to dozens of clinical trials today. Measuring long-term health benefits requires extended study periods.

Paul: Trials target specific surrogate conditions linked to senescence, including Alzheimer's, Parkinson's, and inflammatory bowel disease, before assessing overall healthspan and frailty reduction in broader aging populations.

Paul: Personally, I try to exercise and eat healthily, and I take a supplement shown in models to lower senescent cell burden. I started taking it during COVID-19 after publishing a *Science* paper demonstrating that clearing senescent cells in mice reduced mortality from viral infections like SARS-CoV-2.

Paul: I remained asymptomatic throughout that period. Many researchers take supplements that reduce senescent cell burdens in mice, though human efficacy remains unproven.

Paul: Is it doing? Are there any benefits? We don't know.

Brent: Which supplement is that?

Paul: Fisetin, a flavonoid found in apple skins and other fruits. It acts as an antioxidant and weakly reduces senescent cell burden. Controlled clinical trials are currently evaluating fisetin.

Paul: It is widely available over the counter, but optimal dosing remains unknown—some take high doses biweekly, while others take daily doses.

Paul: I don't advise self-medicating yet. We are still learning how to use these supplements and repurposed FDA-approved drugs effectively.

Brent: It's notable that experts in your field use these compounds. Typically, wellness trends rely on unregulated supplements while scientific fields maintain strict skepticism due to FDA standards for safety and efficacy.

Brent: FDA approval requires rigorous clinical testing, which supplements lack. Supplements often lack verified purity or efficacy compared to prescription drugs.

Brent: It's very hard, you know, to get something as approved as a prescribed medication. That's a very, very high bar. And, you know, supplements don't have that bar. And so we don't know what's in them. And they tend not to be that efficacious, because if they were that efficacious, well, then we'd be putting them through trials and we'd be making a bunch of money and we'd be prescribing them.

Brent: This compound seems to enjoy greater trust within the scientific community than typical supplements.

Paul: When sourcing fisetin for clinical trials, finding suppliers meeting 95%+ purity was difficult. Many commercial brands tested at only 50% to 90% purity, introducing unknown contaminants. Mass spectrometry helps identify clean sources, but fisetin remains a suboptimal candidate overall.

Paul: That is why we are working on developing better targeted drugs. Cellular senescence acts as an anti-tumor mechanism where cells activate pathways similar to tumor cells to arrest growth.

Paul: Senescence is often an initial step toward tumorigenesis: oncogenes activate, cells enter senescence, and a fraction may acquire mutations that bypass arrest to proliferate.

Paul: Consequently, many senolytics are repurposed anti-cancer drugs, which can carry side effects depending on dosage.

Paul: The advantage of senolytics is intermittent dosing—taking them every two to four weeks clears senescent cells as they slowly re-accumulate, reducing overall toxicity. Our goal is developing safe, well-tolerated senolytics suitable for older adults.

Paul: High-dose chemotherapy protocols cannot be easily tolerated by individuals in their 70s or 80s.

Brent: So the therapeutic strategy uses intermittent clearance to minimize side effects while keeping senescent cell levels low. Are current phase one trial candidates distinct from fisetin?

Brent: It's something it's something totally different.

Paul: Some trials use fisetin, but early trials paired dasatinib—a leukemia medication targeting specific cell surface receptors—with quercetin, a flavonoid similar to fisetin.

Paul: The combination of dasatinib and quercetin (D+Q) targets a broader spectrum of senescent cell types and leads current phase one clinical trials.

Paul: Running trials with over-the-counter supplements is difficult because regulatory standards require documented purity, origin, and potency testing from the ground up.

Paul: Using dasatinib in trials was easier than using quercetin or fisetin because dasatinib had decades of established FDA safety data. Fisetin trials are now actively underway across various age-related conditions.

Paul: There are well controlled studies being done for multiple age related conditions.

Brent: Are longevity figures like Bryan Johnson experimentally adopting these senolytic combinations ahead of full approval?

Paul: Bryan adjusts his protocol based on continuous diagnostics, so I won't speculate on his exact regimen. Many researchers in the aging field favor specific interventions that appeal to them.

Paul: Metformin is widely taken to optimize metabolism and indirectly reduce senescent cell burden in animal models. GLP-1 receptor agonists are also gaining attention, though their direct effects on senescence are still being evaluated in our ongoing studies.

Paul: NAD+ precursors like NMN are popular despite debate over age-related NAD decline, as elevating levels offers distinct biological benefits.

Paul: Taking unstudied combinations of multiple supplements risks unforeseen drug interactions or neutralizing effects.

Brent: Do you take metformin or low-dose GLP-1 agonists like tirzepatide?

Paul: No, mainly because I dislike taking pills. I take a low-dose blood pressure medication, and I used fisetin intermittently during the pandemic.

Paul: I still take fisetin occasionally when I think of it, but I generally avoid complex drug regimens.

Brent: Are you optimistic about GLP-1 agonists and metformin long-term for general healthspan expansion in healthy adults?

Paul: Metformin is beneficial for individuals with insulin resistance or pre-diabetes, but its preventative value in healthy 40-year-olds remains unproven.

Paul: GLP-1 agonists show promising effects, but long-term outcomes over 5 to 10 years need observation, particularly regarding muscle mass retention.

Paul: Optimizing GLP-1 microdosing may help limit muscle loss and weight rebound after cessation. While some view GLP-1 agonists as true anti-aging therapies, conclusive evidence requires time.

Paul: The jury is still out.

Brent: Longevity research seems split into two categories: disease prevention (e.g., statins, screenings) and cellular reprograming/rejuvenation (e.g., senolytics, Yamanaka factors).

Brent: The first category uses traditional medicine like statins and colonoscopies to prevent specific chronic conditions.

Brent: The second category targets fundamental cellular aging mechanisms to reset cells to a younger state, as seen with Yamanaka factors.

Brent: What is your assessment of Yamanaka factors and cellular reprogramming?

Paul: Shinya Yamanaka discovered four transcription factors that convert somatic cells (like skin cells) into induced pluripotent stem cells (iPSCs).

Paul: In aging research, brief, transient expression of Yamanaka factors (for 3 to 5 days) rejuvenates cells, restoring youthful gene expression, chromatin structure, and cellular function without resetting them all the way to stem cells.

Paul: The goal is safe in vivo partial reprogramming. David Sinclair's Life Biosciences is launching a gene therapy trial targeting optic nerve regeneration to restore lost vision.

Paul: Having proven effective in mice and non-human primates, their viral vector therapy was administered to human patients to stimulate tissue repair. The primary safety concern is avoiding oncogenesis caused by over-reprogramming.

Paul: He's shown this works in mice and it works in non-human primates. So I think they've treated the first patient with a viral vector to deliver these Yamanaka factors to the eye. They use a certain approach to then turn on expression and turn off expression, and they'll see if these patients can see. So a very direct immediate readout. And then the questions about safety a lot of times if you make a cell healthy or you may actually making it more of a cancer cell if you go too far or make changes.

Paul: Many companies are seeking small molecules for partial reprogramming. Some compounds in our screening libraries suppress senolytic markers while partially restoring youthful characteristics.

Paul: Significant capital is flowing into partial reprogramming, including Altos Labs ($3.5 billion in funding). Finding a safe, effective clinical approach will take time, but the potential is substantial.

Brent: Are you aligned with the conservative perspective expecting a modest +10 healthspan extension through basic prevention, or the aggressive view suggesting human lifespans will extend to 150+ years?

Brent: Camp one focuses on adding an extra healthy decade through conventional preventative measures and lifestyle optimization.

Brent: Camp two advocates radical life extension, arguing that cellular interventions will allow humans to live past 150 years.

Brent: Looking forward 100 years, do you expect radical extension claims to prove accurate, or is standard biological lifespan capped closer to 115–120 years?

Paul: I remain skeptical about humans living to 160. Demographic studies by researchers like Jan Vijg indicate natural human lifespan peaks around 115 years.

Paul: Our primary target is extending healthspan by 10 years for general populations who lack the resources or ability to maintain strict athlete-level regimens.

Paul: Socioeconomic factors and chronic stress accelerate senescence. Therapeutic interventions can help bridge health disparities for individuals facing high daily strain.

Paul: Improving overall healthspan may yield a modest 5 to 10 year lifespan increase, compressing late-life morbidity into a brief window near age 115.

Paul: Compressing morbidity allows individuals to remain active until shortly before death, rather than spending a decade in decline.

Paul: No single pill or intervention can fix every failing system in the human body, but keeping people healthy for longer is achievable.

Brent: Is over-promising life extension counterproductive? Bryan Johnson shares useful self-experimentation and highlights healthy habits, but extreme immortality claims can overshadow valid research.

Brent: Promoting radical life extension alongside commercial products creates skepticism, potentially undermining reliable health messages.

Brent: How far out ahead of current science are extreme longevity claims? Has research on senolytics or Yamanaka factors provided enough evidence to justify 160-year lifespan projections?

Brent: Bold claims often originate from high-profile figures. Where do these projections diverge from current clinical reality?

Paul: Grandiose claims frequently come from corporate executives marketing products. Scientists must avoid overstated claims. High-cost, rigid protocols are unfeasible for the vast majority of people.

Paul: Extremely rigid lifestyles are difficult to sustain. If prominent figures making bold claims suffer premature health events, public trust in broader longevity research risks being damaged.

Paul: If public figures promising extreme longevity fail to reach expected outcomes, it could set back scientific credibility across the field.

Brent: Adopting healthy lifestyle changes remains challenging for most people. The core challenge is compliance rather than basic awareness.

Brent: Sustaining optimal diet and exercise habits daily is difficult. Highly processed foods are convenient, making long-term dietary discipline hard to maintain.

Brent: GLP-1 agonists succeeded because they offset willpower demands, making appetite management far easier.

Brent: Relying on extreme personal discipline is not a scalable public health strategy for the general population.

Paul: That drives the need for medical therapeutics. Healthy food preparation and exercise require significant time and financial resources, which long work schedules often prevent.

Paul: Demanding work shifts and family responsibilities create practical barriers to ideal health habits, even when people understand the benefits.

Brent: Your research aims to deliver therapeutic options that reduce cellular damage even when lifestyle changes fall short.

Paul: Yes. We must identify which of the 12 recognized hallmarks of aging (epigenetic alterations, DNA damage, stem cell exhaustion, mitochondrial dysfunction) drive decline in a given patient.

Paul: Individual aging profiles vary: one person may experience primary mitochondrial dysfunction, while another presents with high DNA damage or cellular senescence.

Paul: Clearing senescent cells positively affects other hallmarks, but precise diagnostic profiling is needed to match individual patients with senolytics, antioxidants, or stem cell therapies.

Brent: It resembles a dashboard with 12 health gauges, where each individual shows distinct warning lights requiring personalized targeted responses.

Paul: Diagnostic testing must be quick, non-invasive, and affordable. Complex or costly diagnostic procedures won't achieve widespread clinical adoption.

Brent: How is the broader political landscape affecting biomedical research funding and scientific progress?

Paul: US scientific research faces significant pressure through budget cuts and increased restrictions. Proposals introducing political reviews for grant funding threaten scientific objectivity.

Paul: Major breakthroughs—such as CRISPR gene editing, rapamycin, and Taxol—emerged from open-ended basic science research rather than rigid, top-down directives.

Paul: Restricting basic research risks shifting leadership in scientific innovation to Europe and China, driving talented students away from scientific careers in the US.

Paul: Uncertainty surrounding research funding deters early-career researchers, leaving long-term impacts on the scientific pipeline.

Brent: To consider the counterargument: were there inefficiencies or misaligned public health priorities that justified institutional reform?

Brent: Given high rates of chronic metabolic disease, were earlier research guidelines partially responsible for poor public health outcomes?

Brent: Were prior scientific efforts hampered by self-inflicted mistakes, or are current challenges driven by policy changes?

Paul: While public institutions can refine efficiency, restricting basic biological terminology in grant proposals hinders essential research. Biological aging and senescent cell burdens differ significantly between biological sexes.

Paul: Restricting studies on sex-specific metabolic and cellular differences undermines research intended to improve health outcomes across all demographics.

Brent: Restricting standard biological variables like sex in grant applications seems detrimental to fundamental medical research.

Paul: Including those terms can lead to grant rejection regardless of scientific context.

Brent: Even when used purely as basic biological variables?

Paul: Yes. Therapies like rapamycin show distinct efficacy profiles between male and female mice, an effect that translates directly to human clinical trials.

Paul: Ignoring population variations and key biological variables risks missing critical insights necessary for effective clinical treatments.

Brent: Looking ahead, what upcoming developments in your research excite you the most?

Brent: Which milestone are you most eager to see realized?

Paul: I am focused on translation from animal models to human clinical trials. Human trial data will allow us to refine compounds and improve targeting in the lab.

Paul: I am optimistic about developing safe methods for partial cellular reprogramming to achieve meaningful extensions in healthspan.

Paul: Establishing safe partial reprogramming protocols will mark a major leap forward in healthspan extension.

Paul: That area holds the greatest potential for expanding human healthspan, which is why so many research teams are actively pursuing it.

Brent: Dr. Paul Robbins, thank you for your leadership in cellular senescence research and for taking time to join us today.

Paul: I really enjoyed the conversation, Brent. Thank you for having me.

Brent: The Life Lab by Death Clock is recorded in Boulder, Colorado, and San Francisco, California. Produced by Patrick Guardino, with music by Patrick Lee. Hosted by Brent Franson, founder and CEO of Death Clock.