The Optispan Podcast with Matt Kaeberlein

In this episode with our guest Dr. Thomas Seager, we delve into the transformative power of cold plunge therapy and its profound effects on resilience and longevity. We explore real-life case studies, including lessons learned from infrastructure failures like Hurricane Katrina and the Oroville Dam crisis. Discover how psychological resilience shapes our responses to stress, the importance of hormesis in health, and the role of brown fat in metabolism. We also discuss the impact of fasting, caloric restriction, and the relationship between mitochondrial health and aging.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Health effects of voluntary exposure to cold water – a continuing subject of debate - PMC

This review paper evaluates 104 studies on the effects of cold exposure. The authors highlight several limitations with the existing research studies including small cohort size, lack of standardized outcome measures, and acute cold exposures with limited follow up. Of the studies that evaluated health outcomes, several reported health benefits including improved insulin sensitivity, reduced inflammation, body fat and self-reported pain. Despite this initial promise, larger, more rigorously designed studies including standardized protocols and measures are needed to validate the health benefits of cold water exposure

Physiological hormesis and hormetins in biogerontology - ScienceDirect

Thomas and Matt talk about a fundamental concept called hormesis, which may be mediating the physiological benefits of cold exposure. Hormesis is a mild and acute stress that elicits homeostatic response mechanisms and biological adaptations that make cells more resilient to future stressors. Exercise is an example of a hormetic stressor that causes micro tears to muscle, increases the production of damaging reactive oxygen species and intiates a proinflammatory response. Following exercise, the body repairs muscles so they are stronger than they were before and increases gene expression and activity of antioxidant and anti-inflammatory molecules that may help combat age-related damage accumulation. Thomas proposes that cold exposure is a type of hormetic stressor that enhances antioxidant, immune, and metabolic function.

Nina Teicholz at TEDxEast: The Big Fat Surprise

Nina Teicholz’s TEDx talk, The Big Fat Surprise, challenges decades of conventional wisdom on dietary fat. She argues that saturated fats—found in foods like meat, butter, and cheese—are not harmful but essential for health. Teicholz critiques the flawed science and vested interests that shaped low-fat dietary guidelines, which she claims have contributed to poor health outcomes. By revisiting historical data and exploring dietary studies suggesting benefits of whole fats, she advocates for a reevaluation of nutrition policies

Antifragile: Things that Gain from Disorder

In their discussions on stress and how it affects human biology, Thomas talks about the concept of “antifragility”, initially proposed by Nassim Taleb. In this lecture, Taleb extrapolates on the concept of antifragility, which describes systems that improve when exposed to stressors, volatility, and chaos. In comparison to resilient systems that merely resist stressors, antifragile systems thrive on them, gaining strength and new capabilities from challenges. Taleb suggests this principle applies across various domains, including biology, economics, and personal development. Taleb argues that embracing failure and intentionally engaging with stress and challenges can lead to growth, suggesting that we should design our lives and systems to be antifragile.

Impact of Intermittent Fasting and/or Caloric Restriction on Aging-Related Outcomes in Adults: A Scoping Review of Randomized Controlled Trials

The act of eating and fasting in confined windows of time, known as time restricted eating (TRE), has become a hot topic in the longevity field due to promising literature of its effects for health optimization and disease prevention. Whether TRE is uniquely beneficial for healthy aging compared to caloric restriction itself is controversial. Matt discusses the data suggesting that the potential benefits of TRE are primarily mediated through caloric restriction (CR) rather than the biological influence of the timing of an individual’s fasting window itself. This systematic review evaluated thirty studies on intermittent fasting (IF) and CR (12 IF, 10 CR, and 8 combined IF and CR interventions) and their associated effects on various healthspan metrics. Within this review, the authors included TRE as a fasting modality that is part of the broader domain of IF. CR and IF were both associated with weight loss; however, IF studies tended to report greater adherence compared with CR. Overall, IF and CR were equivalently effective across cardiometabolic, cancer, and neurocognitive outcomes. The authors suggest that IF has health benefits in a variety of conditions and may be better accepted and tolerated than CR, but more comparative research is required.

In part two of Matt’s interview with Kim Celmer, they explore practical strategies for gut health, covering topics like the "four R's" of gut restoration, prebiotics vs. probiotics, microbiome testing, and nutritional recommendations. They also discuss healing peptides, insulin-degrading enzymes, SIBO testing, and the FODMAP diet, offering actionable insights for improving digestion and overall wellness.

Kim Celmer, ND, is a naturopathic doctor specializing in primary care. After earning her doctorate from Bastyr University, she completed a residency in naturopathic medicine at the Institute of Complementary Medicine in Seattle, focusing on integrative approaches to hormone health, digestive wellness, and chronic disease management.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Translating microbiota analysis for clinical applications | Nature Reviews Bioengineering

Matt and Kim discuss the strengths, challenges, and actionable insights gained from the clinical application of gut microbiome analysis. They conclude that while it's a useful supportive tool for disease diagnosis, it's most effective when used alongside comprehensive health analysis.

This article explores the crucial characteristics of microbiota analysis systems, their clinical applications, and the challenges inherent in high-throughput sequencing technologies used for analyzing microbial DNA composition.

Key challenges include:

1. Lack of functional insights: Microbiome composition often doesn't indicate functional roles, as bacteria can have various functions depending on physiological context, gut localization, and the surrounding microbial ecosystem (biofilm).
   
   

2. Inability to detect microbial location: Certain microbes may promote health in the large intestine but play a pathological role in the small intestine, making spatial tracking crucial.
   
   

3. Difficulty distinguishing live from dead bacteria: This limitation can skew interpretation of microbial presence and activity.
   
   

The authors emphasize that microbial composition analysis should ideally be performed alongside multi-omics and functional analysis to better understand how microbes influence host physiology through their postbiotic secretions.

The gut microbiome as a modulator of healthy ageing | Nature Reviews Gastroenterology & Hepatology

This review explores targeted studies of the gut microbiome in aging individuals across geographically distinct populations, evaluating how changes in microbial composition and function correlate with age-related diseases and adverse health outcomes.

Analysis of both composition and function of the gut microbiome across age reveals a loss of microbial diversity and overlapping, yet distinct functional changes. These changes are involved in the secretion of factors associated with chronic inflammation, metabolic dysfunction, and dysfunctional intercellular signaling.

The authors highlight that age-related alterations in the gut microbiome are influenced by a complex array of factors, including:

Genetics:

1. Environment
   
   

2. Progressive physiological deterioration (e.g., gut barrier function and anatomy)
   
   

3. Lifestyle-linked factors such as diet, medication, and reduced social contact.
   
   

The study concludes by suggesting that while a single universal healthy microbiome configuration does not exist, specific gene expression and metabolomics profiles are strongly associated with healthy aging outcomes. Furthermore, gut microbiome-based therapeutics for aging individuals will require combinatorial approaches, including dietary intervention and restoration of lost strains through supplementation or fecal matter transplant.

Platelet-Rich Plasma Applications, The Past 5 Years: A Review Article - European Medical Journal

Matt and Kim discuss the current application potential and unknowns of platelet-rich plasma (PRP) therapy, with a focus on gut health and regeneration following injuries. This review article summarizes PRP applications in randomized controlled trials over the past five years for diverse conditions, including dermatology, wound healing, orthopedics, and pain management. The authors find the results inconclusive, with outcomes ranging from positive to no effect compared to placebo. Several key limitations exist:

●      Small sample sizes

●      Short follow-up durations

●      Lack of standardization in PRP preparation methods

This article also discusses classification systems for different types of PRP and underscores the need for controlled studies and standardized protocols, including optimal preparation and administration methods. Future studies are needed to better understand the components of PRP (e.g., growth factor composition) that influence clinical outcomes for its various applications.

Brain-gut Axis and Pentadecapeptide BPC 157: Theoretical and Practical Implications - PMC

This paper reviews preclinical evidence on the effects of BPC 157 for various conditions including gastrointestinal disease, periodontitis, liver and pancreatic lesions, and healing of various tissues and wounds. Notably, the authors propose that BPC 157 may also have neuroprotective effects including nerve regeneration in response to traumatic brain injury. Interestingly, based on various studies evaluating its mechanism of action, the authors suggest that BPC-157 may be exerting its effects through modulating signaling at the gut-brain axis.  At present, BPC 157 is being studied in clinical trials of inflammatory bowel disease and multiple sclerosis. Initial studies suggest it is safe, but more studies are needed to validate both safety and efficacy for the diverse range of age-related conditions it demonstrates potential to address in animal models.

Critical appraisal of the SIBO hypothesis and breath testing: A clinical practice update endorsed by the European society of neurogastroenterology and motility (ESNM) and the American neurogastroenterology and motility society (ANMS) - Kashyap - 2024 - Neurogastroenterology & Motility - Wiley Online Library

Matt and Kim discuss the utility of the lactulose breath test (LBT) for diagnosing SIBO and its clinical implications in treating chronic GI conditions. They conclude that while the breath test can provide useful information, it should be used selectively after considering its limitations and other comprehensive gut health measures (e.g., stool tests, functional tests, and imaging) which may provide more information for disease diagnosis. This review provides an overview of the history of SIBO diagnosis, possible overuse of antibiotics due to the overdiagnosis of SIBO, and the importance of assessing microbial composition and function as opposed to overgrowth alone. The authors explain how the LBT works for SIBO diagnosis and highlight challenges in using it as a surrogate for localization of bacteria, primarily due to variable lactulose transit times between individuals. Consequently, they propose that LBT has relatively low sensitivity and specificity for diagnosing SIBO. The authors conclude that further studies are needed to better understand the impact of bacterial communities, their metabolites, and diet-host interactions to move away from diagnostic criteria for SIBO that solely focus on absolute numbers of microbes.

In this episode, Matt sits down with Thomas Seager, an Associate Professor at Arizona State University (ASU), to explore the challenges and future directions of healthcare. Drawing from his background in environmental engineering and public health, Thomas discusses the pressing health issues affecting longevity in Americans and a potential shift from a reactive healthcare model to one that emphasizes proactive health management. Together, Matt and Thomas examine the complexities of early disease detection, the promise and limitations of AI in analyzing biomarkers, and the difficulties of separating reliable information from misinformation in today’s digital landscape. Thomas shares his personal experiences with biomarkers and resilience practices, such as cold exposure therapy, while he and Matt discuss biases in medical research and differing approaches to health.

Thomas is an Associate Professor at ASU in the School of Sustainable Engineering and the Built Environment. His research focuses on sustainable engineering and resilience, addressing topics such as infrastructure resilience, sustainable energy systems, and environmental ethics. He is also the co-founder of Morozko Forge, a company that promotes cold immersion therapy as a means of supporting metabolic resilience.

Check out the links below for further information and reading about some of the topics we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings but present them as supplementary material to deepen your understanding of the subject. This list is in no way exhaustive but offers a good starting point.

How scaling interventions can improve the lives of those with brain health conditions. | McKinsey

Matt and Thomas discuss the influence of mental health, suicide, and drug overdose as a “hidden mortality risk factor” contributing to the recent decline in life expectancy in the U.S., particularly among young adults. This article by McKinsey Health Institute and Healthy Brains Global Initiative highlights how mental health and substance use disorders account for 15% of the global disease burden, ranking alongside cardiovascular disease as one of the top three most burdensome conditions in society. The authors use interactive graphs to demonstrate that no “silver bullet” exists for mental health disorders. Effective treatment typically requires a personalized and integrated approach combining psychotherapy, behavioral modifications, pharmacotherapy, and social support. Breaking down barriers like stigma and accessibility while strengthening support systems is critical.

From “Sick Care” to Health Care: Reengineering Prevention into the U.S. System - PMC

Matt and Thomas explore the rising incidence of chronic age-related diseases and how the U.S. healthcare system’s “repair shop mentality” often impedes progress. This system addresses diseases and symptoms as they arise rather than adopting a preventative approach. This review article outlines several systemic challenges, including unsustainable healthcare costs, poor outcomes, medical errors, and worsening health disparities.

The authors attribute these issues to:

1. A task-based healthcare model reimbursing for “sick visits” aimed at addressing acute conditions or symptoms of chronic conditions.

2. Economic incentives that prioritize procedures and drugs over lifestyle and behavioral counseling.

3. A preference for specialty care over primary care.

The authors propose that integrating prevention into the healthcare system will require a comprehensive approach emphasizing homeostasis and overall health, rather than focusing solely on disease and diagnosis.

https://www.morozkoforge.com/post/biological-age

Thomas authored this blog post about his experience undergoing a comprehensive health assessment at Optispan HQ. He discusses how this experience changed his perspective on his own health and aging journey. Particularly, Thomas focuses on reviewing the different theories of aging and his intrigue with the metabolic theory of aging and the importance of mitochondrial health for longevity. He concludes by examining evidence for fasting, caloric restriction, exercise, and cold therapy for improving mitochondrial health and how this may translate to improvements in human longevity.

Cold temperature extends longevity and prevents disease-related protein aggregation through PA28γ-induced proteasomes - PMC

This study demonstrates that exposure to cold temperature enhances proteasome function and the clearance of toxic protein aggregates by activating a molecular pathway (PA28y) conserved in nematode worms (C. elegans) and human cells. The authors go on to show that this pathway is required for both cold-induced lifespan benefits and reduction of protein plaques in worm models of neurodegenerative diseases including Huntington’s and amyotrophic lateral sclerosis (ALS). Cold temperature and/or drugs that activate PA28y may hold potential for the treatment of neurodegenerative diseases like Alzheimer’s, but clinical trials are needed to validate these findings in humans.

Do Ice Baths Increase Testosterone? | Morozko Science

Thomas authored this blog post outlining anecdotal evidence from case studies he’s collected over the years suggesting that cold plunge therapy increases testosterone levels, with associated improvements in emotional health, perceived pain, energy and quality of life. Thomas also talks about his own experience boosting his low testosterone levels and reducing his high prostate-specific antigen levels (associated with prostate cancer risk) which he believes is due to his ice bath regimen. Despite the potential promise, well designed clinical trials have not been conducted to validate the effects of cold therapy on testosterone levels. However, such studies are warranted given the favorable risk-to-benefit ratio of cold therapy, preliminary data from aggregate n-of-1 studies, and supporting preclinical evidence.

In May 2024, Matt delivered a talk at the 2024 Glenn AFAR Grantee Conference in Santa Barbara, California and met with several people doing interesting work in the longevity field.

One of these was Aditi Gurkar, an assistant professor in the University of Pittsburgh's Aging Institute, Division of Geriatric Medicine whose lab focuses on the downstream effects of DNA damage on aging. Prior to setting up her lab at the University of Pittsburgh, Aditi conducted research on the impact of DNA damage on aging at Scripps Research. She also completed postdoctoral training at Massachusetts General Hospital/Harvard Medical School and the Broad Institute of MIT and Harvard, where she focused on the tumor suppressor p53 as well as on autophagy regulation. Aditi received a PhD and a B.S. from the Boston University School of Medicine and Florida International University in Miami respectively.

Matt and Aditi spend much of this episode chatting about senescent cells: how Aditi developed a focus on cellular senescence and found its relevance to aging, potential therapeutic benefits of senescent cell clearance, and the much-debated question of how to define a senescent cell. They also discuss the importance of "zooming out" from narrow areas of focus in the geroscience field to find new solutions and of breaking your own models on your way to productive new directions in science.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Gurkar lab

Aditi's lab at the University of Pittsburgh is broadly interested in molecular drivers of aging, and specifically tackles DNA damage and heart disease, DNA damage in post-mitotic tissue, and DNA damage-dependent metabolic reprogramming. If you might want to work with Aditi as a research specialist, technician, postdoctoral fellow, or simply want to learn more about what she works on, check out this page to find papers that have come out of the Gurkar lab, the lab's funding sources and affiliations, and more.

Cellular Senescence: The Trojan Horse in Chronic Lung Diseases

This paper, which Aditi coauthored, likens senescent cells to Trojan horses: harmless at first appearance, but potentially dangerous contributors to disease. This review discusses various known markers of senescent cells, including senescence-associated beta-galactosidase and the senescence-associated secretory phenotype, as well as potential drivers of cellular senescence. It also reviews the potential role of cellular senescence in lung disease pathogenesis and why lungs might be particularly susceptible to cellular senescence.

Cellular Senescence: Defining a Path Forward

What even is a senescent cell? As Matt notes, there doesn't seem to exist a single clear definition of a "senescent cell" even within the cellular senescence research community. This paper attempts to offer some clarity about how we might define and characterize cellular senescence, with its broadest description of the phenomenon matching Aditi's: "a prolonged and generally irreversible cell-cycle arrest". It also goes over the challenges of studying cellular senescence in humans.

Cellular senescence in aging and age-related disease: from mechanisms to therapy

This is one of the literature’s key reviews linking cellular senescence to diseases of aging. It discusses the context-dependent and heterogeneous nature of senescent cells and the resulting challenges of standardizing senescent cell markers in vivo, speculative mechanisms for how senescent cells might cause age-related tissue dysfunction, and diseases of aging in which senescent cells may play a causal role.

Aging, Cellular Senescence, and Cancer

This paper discusses various ways that cellular senescence may drive pathologies of aging, particularly in cancer. It also goes over various general characteristics of senescent cells, drivers of cellular senescence, and ways in which cellular senescence can actually be beneficial.

After Matt and Nick's successful visit to the home of MYOXCIENCE Nutrition founder and content creator Mike Mutzel to give saunas and cold plunges a try, it was our turn to host Mike at our stomping grounds. In this episode, Matt chats with Mike about a wide range of healthspan topics, including nutrition, supplements, environmental exposures, and the interconnectedness of different aspects of health such as sleep, stress, and social connection. They also discuss the use of DEXA scans and other biological age tests, with Mike and Matt sharing their perspectives on the strengths, limitations, and appropriate uses of these tools. They emphasize the importance of not over-interpreting single data points and instead looking at trends over time as well as the need for individualized, holistic approaches to wellness rather than one-size-fits-all prescriptions.

Prior to his work at MYOXCIENCE, a nutritional company aimed at helping people optimize their metabolic health and body composition, Mike served as a sales representative in the natural product space and worked closely with doctors to implement clinical nutrition into their practice. In 2014, he published his first book, "Belly Fat Effect: The Real Secret About How Your Diet, Intestinal Health, and Gut Bacteria Help You Burn Fat". Mike holds an M.S. in Human Nutrition from the University of Bridgeport and a B.S. in Biology from Western Washington University.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start

Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73)

Mike mentions the Minnesota Coronary Experiment (MCE) in his discussion of cholesterol. The MCE, which ran from 1968-1973, was a double-blind, randomized controlled clinical trial to test the "traditional diet-heart hypothesis" that lowering cholesterol via replacement of saturated fat with vegetable oil would reduce cardiovascular disease and mortality risk. The experiment found that while the group that replaced saturated fat with linoleic acid from corn oil and corn oil polyunsaturated margarine did indeed experience reduced cholesterol compared to controls, the group did not experience lower mortality risk from cardiovascular disease or other causes.

Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis

Mike also mentions the Sydney Diet Heart study in this episode when he describes what he calls the "reigning dogma": that higher cholesterol, which is often the result of high dietary saturated fat consumption, leads to increased risk of stroke, heart attack and other cardiovascular diseases. The 1966-1973 Sydney Diet Heart Study (SDHS) was a randomized controlled trial that replaced saturated fatty acids with omega-6 linoleic acid, a type of polyunsaturated fatty acid. The group that received omega-6 linoleic acid died of cardiovascular disease and other causes at higher rates than controls.

Vitamin D insufficiency in southern Arizona
It seems reasonable to assume that people who live in sunny places are less likely to suffer from vitamin D deficiency. But that isn't necessarily the case, according to Mike, who mentions a study demonstrating vitamin D insufficiency in a population living in Arizona. Arizona's residents experience an average of 300 days or more of sun per year, and Arizona houses three of the United States' sunniest cities (Yuma, Phoenix, Tuscon)—yet this study suggests that a large portion of Arizona's adults, especially women and people of Hispanic and black ethnicity, are deficient in vitamin D.

Considerations When Choosing Supplements

Matt and Mike discuss some of the negative practices prevalent in the supplement industry, particularly around labeling and packing loopholes. So how do you figure out which supplements actually do what they say on the tin? This article provides a framework for choosing supplements, which includes assessing safety and efficacy, monitoring dosage, and taking note of a supplement’s chemical form.

Examine.com

Examine is an independently-funded (no gifts, donors, sponsors, consulting clients, advertisements, or affiliations) database of supplements research that provides information about benefits, dietary sources, dosage, side effects, and more for pretty much any supplement you can think of. The website provides further references from the primary literature about each supplement it discusses.

Matt and psychiatrist Jon Berner discussed the potential of rapamycin and ketamine for treating severe depression and chronic pain, focusing on their impact on microglia and brain inflammation. They touch on how microglia, a type of immune cell found in the central nervous system that help protect the brain against infections, clear debris, and respond to injuries, shifts from an inflammatory to a reparative state in response to rapamycin and ketamine treatment. They also dive into clinical case studies of ketamine and rapamycin combinations and the complicated topic of how regulatory reform and AI collaboration might advance medical innovation.

Jon has been in solo psychiatric practice at Woodinville Psychiatric in Washington since 1997. He spent several years working at the Monroe Correctional Complex, a Washington State Department of Corrections prison. His specialties include brain disorders, particularly bipolar and psychotic illnesses,  complex pain, addiction, and "undiagnosed" neuropsychiatric syndromes, and other general psychiatric disorders such as anxiety and depression. Jon has published multiple scientific papers about various topics in the realm of mood disorders and treatments for them. He holds an M.D and a PhD in neuroscience from the University of California, Los Angeles and a B.A. in psychology from Harvard University.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

mTORC1 activation in presumed classical monocytes: observed correlation with human size variation and neuropsychiatric disease - PMC
Rapamycin and ketamine hold significant promise for addressing neurodegenerative disease, neuropsychiatric disorders, and inflammation-driven pathologies. Optimal use of these medications requires identification of biomarkers that specify dose requirements and predict clinical effectiveness of each intervention on an individual level. This study, which Jon coauthored, measured a biomarker of mTOR activity (phosphorylated S70S6K or pS6K) in the blood of 27 women with psychiatric disease and found that baseline levels of pS6K predicted clinical effectiveness of ketamine and rapamycin—and interestingly enough, also predicted body size features like height, pupil distance, and head size in relation to body. Though the cohort size was small and randomized controlled trials are needed for validation, this study sheds light on a simple assay that may provide a cost-effective solution for the personalized prescription of putative gerotherapeutic interventions that may extend healthspan and enhance quality of life.

Cerebrospinal fluid metabolomes of treatment-resistant depression subtypes and ketamine response: a pilot study - PMC

Depression is an extremely heterogeneous disease that can be classified into different subtypes based on biological drivers, experiential risk factors, and clinical manifestations. Ketamine has been shown to be strikingly effective for remedying many cases of treatment-resistant depression, but research on the optimization of ketamine utilization towards specific, responsive subtypes of depression is sparse. This retrospective study used metabolomics and machine learning to analyze the metabolomic signatures of 29 treatment-resistant depression patients’ cerebrospinal fluid. The machine learning model utilized 151 metabolites to define two subtypes of patients that may have different biological drivers of depression, thus requiring differential treatment regimens. One subtype was characterized by markers associated with a glial hyper-inflammatory phenotype, while the second subtype was characterized by markers associated with mitochondrial dysfunction. Interestingly, the mitochondrial dysfunction phenotype of depression was more strongly associated with responsiveness to ketamine treatment. The authors even go on to suggest in this paper that such sub-typing based on metabolomic signatures may allow for the more precise selection of FDA-approved drugs tailored towards an individual’s unique aging signature (“ageotype”).

Rapamycin Augmentation of Chronic Ketamine as a Novel Treatment for Complex Regional Pain Syndrome - PMC

A growing body of real-world data demonstrates that low-dose rapamycin administration substantially improves symptoms in individuals afflicted with varying types of pain. This case study chronicles the treatment history of one of Jon’s patients, a woman suffering with debilitating complex regional pain syndrome following a series of car accidents. She struggled for 16 years taking anti-depressants, opioids, benzodiazepines, spinal cord stimulators, and other interventional modalities to resolve her pain, but these interventions brought her long-term disability associated with suicidal behavior and did little to relieve her symptoms. When she started taking ketamine and rapamycin dual therapy, her pain reduced significantly days after administration.  After 10 months of administration, her pain decreased by 50 percent, she increased the number of daily steps she could take from 400 to 14,000 steps a day, and she was able to reduce the number of medications she was taking. The mechanism of action underlying how rapamycin and ketamine synergize to reduce pain is unknown, but Jon and colleagues hypothesize that the chronic pain is likely driven by a nervous system component including glial hyperactivation and neural inflammation that both drugs have been demonstrated to mitigate in mouse models.

Pro-inflammatory monocyte profile in patients with major depressive disorder and suicide behaviour and how ketamine induces anti-inflammatory M2 macrophages by NMDAR and mTOR - eBioMedicine

Sub-analgesic doses of ketamine have demonstrated remarkable efficacy for ameliorating treatment-resistant depression, but the mechanism of how these doses work is not well understood. While ketamine is often thought of as an experiential medicine, emerging research  suggests that it has some very real effects on the molecular reprogramming of cells of the immune and nervous system, specifically on reprogramming cellular profiles into a more anti-inflammatory state oriented towards tissue repair. This study demonstrated that patients with major depressive disorder had increased plasma levels of pro-inflammatory cytokines (IL-12 and IL-16) and monocytes than individuals without depression. Further, the authors conducted in vitro and in vivo mouse studies and demonstrated that ketamine binds to N-methyl-D-aspartate receptors on immune cells in the spleen and brain to activate mTOR signaling and shift the ratio of macrophages towards the M2c type (anti-inflammatory/tissue repair). Though this study only provided a snapshot of the state of inflammatory mediators within the body, it adds to a growing body of evidence explaining how a single dose of ketamine may reprogram immune signaling to support rapid and sustained antidepressant effects in individuals with treatment-resistant depression.

Mitochondrial complex I activity in microglia sustains neuroinflammation - PMC
Hyperactivation of microglia is a feature of chronic neurological diseases like multiple sclerosis and neurodegenerative disease. It can be characterized as a state of sustained inflammation within the central nervous system. This research study used a multi-omics approach to characterize the catalysts of the “molecular forest fire” of inflammation initiated in the brain in several different model systems and pathological contexts. The research group found a shift towards disease-associated, hyper-inflammatory microglia with increased mitochondrial complex I activity, reverse electron transport, and the production of reactive oxygen species and oxidative stress. Further, blocking mitochondrial complex I (e.g. with metformin) in hyper-inflammatory microglia protected the nervous system from neurotoxic damage and improved functional outcomes in an animal disease model.

Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression | New England Journal of Medicine

Few people would opt for electroconvulsive therapy (ECT) as a first choice to treat their depression. Nevertheless, ECT has long been considered one of the most efficacious interventions for treatment-resistant depression. Ketamine is a more recent contender.

This large, randomized study compared the effectiveness of ECT to sub-anesthetic doses of IV ketamine over three weeks for individuals with treatment-resistant depression. Compared to the ECT group, more responders in the ketamine group (55.4 vs 32.3 percent) demonstrated an improvement of greater than 50 percent on the standardized depression scale, and a greater percentage of individuals experienced complete remission (32.3 vs 20 percent) after just three weeks of treatment. Further, individuals in the ketamine group performed better in memory assessments post-treatment compared to the ECT group. The study also included a six-month follow up period on responders and found that relapse occurred in only 34.5 percent of ketamine patients compared to 56.3 percent of ECT patients. This suggests that just six sessions of ketamine treatment over three weeks was superior to ECT for treatment-resistant depression and had sustained effects that lasted at least six months post-treatment.

We had a great time hosting Buck Institute for Research on Aging Assistant Professor Jennifer Garrison on the podcast to talk about her areas of expertise: reproductive aging and neuropeptide signaling. Jennifer and Matt go over the fascinating and chronically under-researched science of menopause, misconceptions about hormone replacement therapy, and the importance of considering the endocrine function of the ovaries alongside their role in reproduction. They also chat about evolutionary questions around menopause, changes they would like to see in medical school curricula, and more.

In addition to her role at the Buck, Jennifer serves as co-founder and director of Productive Health, formerly the Global Consortium for Reproductive Longevity & Equality, and holds appointments at the University of California, San Francisco and the University of Southern California. She is also a Founding Director of the Marine Biological Laboratory (MBL) Woods Hole Biology of Aging (BOA) Advanced Training Course. She has received numerous awards, including a National Institutes of Health Maximizing Investigators’ Research Award (MIRA) for Established Investigators, a Glenn Medical Foundation Award for Research in Biological Mechanisms of Aging, an American Federation of Aging Research Junior Faculty Award, and a National Academy of Medicine Healthy Longevity Catalyst Award. Jennifer conducted postdoctoral research at Rockefeller University and received a PhD and a B.A. from the University of California, San Francisco and the University of California, Berkeley respectively.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Prof. Jennifer Garrison- "Reframing women’s health and aging"
Jennifer presented this talk in 2023 at The Longevity Summit's third annual event. In it, she provides a broad overview of the ovaries' role as pacemakers for aging and how the precocious aging of the female reproductive system affects broader aging in other tissues. She also discusses other issues such as myths and misconceptions around women's health, problematic language used to describe women's health, and whether or not menopause is a biological imperative.

Delaying Menopause: Understanding the Ovary

The You Are Not Broken podcast hosted Jennifer to talk about menopause, declines in women's ovarian function, and current work attempting to address both. The discussion also touches on the importance of highlighting ovarian function for healthy female aging, healthspan inequalities between men and women, and more.

A critique of the Women’s Health Initiative hormone therapy study

Matt and Jennifer discuss the effects of hormone therapy on all-cause mortality as well as the impact of an early study that arose from the Women's Health Initiative on perceptions of hormone therapy in this podcast episode. This paper offers several criticisms of the study's experimental design, and argues that its conclusions about the risks involved with administering hormone therapy to menopausal women should not be viewed as definitive.

No need to fear menopause hormone drugs, finds major women’s health study

This article in the Washington Post covers a Journal of the American Medical Association paper arguing that the large-scale negative reaction to a Women's Health Initiative study about the risks of hormone therapy for menopausal women was unfounded. It describes the events that led to the study being discontinued, and provides a helpful summary of a follow-up study demonstrating the safety and benefits of hormone therapy for women under 60 experiencing menopause.

'Tis but a scratch: a critical review of the Women's Health Initiative evidence associating menopausal hormone therapy with the risk of breast cancer

This is another review presenting arguments and evidence questioning the validity of the Women's Health Initiative study reporting adverse effects of hormone therapy for menopausal women.

Matt recently attended the 52nd annual meeting of the American Aging Association (AGE) in Madison, Wisconsin and met with several people doing fascinating work in or adjacent to the geroscience field.

His last guest from the AGE meeting is David Scieszka, a longevity entrepreneur with a unique background that includes work as a PsyOps specialist for the US Army. David is currently working on Vertical Longevity Pharma, a senolytics company that he spun out from his postdoctoral work. He previously lead multi-omics efforts at the biotech startup Norvoc Biosciences. David holds a PhD in biomedical sciences from the University of New Mexico School of Medicine, which he did concurrently with an MBA at the UNM School of Management.

In this episode, Dave and Matt give us a peek into the drug development process (TL;DR: it isn't straightforward or cheap), from facing investor skepticism to considering endpoints, dosage, and potential side effects to collecting rigorous preclinical data that will satisfy requirements for U.S. Food and Drug Administration (FDA) approval. They also chat about further opportunities for the drug's use in companion animals, a demographic that would also enable a potentially faster path to FDA approval.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Cellular senescence and senolytics: the path to the clinic - PMC

What is cellular senescence and why is it one of the most heavily targeted hallmarks of aging in longevity biotech? When cells encounter stressors and accumulate cellular damage, they have a critical decision to make: resolve the damage, commit cellular suicide, or enter a cell fate called cellular senescence in which they stop dividing, become death resistant, and release alarm signals known as the senescence associated secretory profile, or SASP. The SASP recruits the immune system’s aid and initiates an inflammatory response. Cellular senescence is thought to be beneficial in certain contexts such as pregnancy, wound healing, and preventing tumorigenesis—as long as the senescent cells are cleared away when the damage is resolved. But as we age, damage occurs at an accelerated rate and our immune system loses its ability to clear away senescent cells, leading to senescent cell accumulation. As senescent cells accumulate, the SASP drives chronic inflammation, fibrosis, and the conversion of more cells into the senescent state, giving them the infamous title of “zombie cells”.

In preclinical trials, senescent cells are demonstrated to accumulate at the site of aged/diseased organs. The clearance of senescent cells with senolytics has been shown to mitigate the progression of certain age-related diseases and biological processes associated with aging (e.g. cardiac hypertrophy, neurodegenerative disease, and insulin resistance).There are several different strategies to address senescent cell burden including killing senescent cells (senolytics), targeting the SASP (senomorphics), and boosting the immune system's innate ability to clear senescent cells (immunomodulators). The latter methodology is the focus of Vertical Longevity Pharma’s (VLP) platform technology. There are over two dozen clinical trials studying the effects of senotherapeutics on diseases as diverse as osteoarthritis, COVID-19, Alzheimer’s, and kidney disease currently in progress. One major challenge in the field is finding reliable biomarkers that are specific to senescent cells to improve senescent cell targeting, diagnostics, and prognostics.

Stop the Clock: New Therapeutic Strategy Targets “Old” Cells to Prevent Aging

Matt and David talk about VLP’s unique approach to targeting senescent cells, namely a senolytic vaccine that trains the immune system to recognize and clear senescent cells. This article covers the Suda et al. (2021) paper published in Nature Aging that serves as the foundational research for VLP’s platform technology. This research group identified a cell surface protein called GPNMB/osteoactivin that is specific to senescent cells and developed a vaccination that educated the immune system to target and clear osteoactivin-expressing senescent cells in three different mouse models. They found that a single treatment with their senolytic vaccine extended the lifespan of mice prone to atherosclerosis in a mouse model of accelerated aging. Interestingly, they also found GPNMB to be highly expressed in endothelial cells of patients with atherosclerosis, a senescent cell-driven pathology. David mentions that atherosclerosis may be the target indication for their proof of concept clinical trial.  If effective, VLP’s senolytic vaccination holds promise to mitigate the progression of one of the leading causes of death in the US.

Clinical Trials and Clinical Research: A Comprehensive Review - PMC

Matt and David talk through the rigors of the drug development process and how VLP is preparing to run the necessary mouse safety/toxicology studies and scaling development of a GMP (good manufacturing practice) batch of their senolytic vaccination in preparation for an Investigational New Drug application, the first major interaction with the Food and Drug Administration before phase one safety and dosing trials. This paper reviews the stages of the drug development process, including Pre-IND preclinical toxicology and drug manufacturing, IND submission including clinical protocols, administrative preparation and regulatory compliance, phase one safety and dosing trials in healthy volunteers (n = 20-100), phase two safety and efficacy trials (n = few hundred), phase three efficacy trials (n = several hundreds to thousands), and post-approval which consists of ongoing monitoring after a drug is in the market. Phase two trials are typically the major bottleneck for a drug's success.

How much do clinical trials cost?

This study evaluated costs data collected from seven high-revenue biopharma companies on 726 clinical trials from 2010 to 2016. The median cost of conducting a study from protocol approval to final clinical trial report was 3.4 million for phase one studies, 8.6 million for phase two, and 21.4 million for phase three trials. The largest influence on variability in cost was the number of subjects, sites, and visits required in the clinical trial. Add this to David’s estimation on the podcast of $5 million to prepare for IND submission, bringing the total to $38.4 million. A significant fundraising campaign for a new startup in the longevity space, but a small price to pay for the potential gains of healthy longevity and prevention of multimorbidity.

How does a cancer vaccine work?

Senolytic vaccines are not a completely novel idea— they are inspired by the development and growing success of cancer vaccinations. This review goes over the different strategies for developing cancer vaccines, as well as the challenges and promises of each. Each methodology involves identifying antigens unique to a given tumor and exposing them to a patient’s immune cells to help them recognize and clear the specific antigen-expressing cancer cells from the body. One potential challenge to overcome is the cancer cells' adaptive evasion tactics, which involve downregulating expression of the antigen or producing immunosuppressive molecules. Attempts to target senescent cells may not face the same challenges of cancer cell evasion, as senescent cells do not undergo cell division and have less adaptive, mutagenic capacity. That being said, targeting senescent cells has its own unique challenge: the immense heterogeneity of senescent cells within the body. Further, the biological aging process compromises the immune system’s ability to respond to vaccinations. Cancer vaccinations have demonstrated success in small pilot studies for pancreatic cancer, melanoma, and lymphoma, but the development of cancer vaccinations personalized towards a given patient’s tumor is extremely expensive. The advent and increasing popularity of machine learning platforms and big data is a major catalyst for the evolution of personalized vaccinations designed to target pathological cell types. Companies like VLP developing senolytic vaccinations can learn from the logistical hurdles, successes, and failures of cancer vaccinations.

In this episode, Matt sits down with naturopathic doctor and primary care provider Kim Celmer to discuss the distinct approach naturopathic doctors (NDs) bring to patient care, addressing common misconceptions about complementary and alternative treatment modalities and explaining how NDs treat prevalent issues like digestive problems, food sensitivities, and nutrient deficiencies. They dive into the distinctions between food allergies and sensitivities and how NDs manage these through a holistic lens. Celmer provides practical advice on managing heartburn and other digestive concerns, along with insights on nutritional insufficiencies and the impact of common medications on gut health. This episode is a practical guide for anyone interested in a holistic approach to health.

Kim Celmer, ND, is a naturopathic doctor specializing in primary care. After earning her doctorate from Bastyr University, she completed a residency in naturopathic medicine at the Institute of Complementary Medicine in Seattle, focusing on integrative approaches to hormone health, digestive wellness, and chronic disease management.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysis
Several years ago, this paper made the news for claiming that vitamin D supplementation was ineffective for improving musculoskeletal health. After analyzing 81 randomized controlled trials, the authors argued that vitamin D supplementation did not reduce fractures or falls, nor did it improve bone mineral density.

The health effects of vitamin D supplementation: evidence from human studies
This review summarizes recent randomized control trials on vitamin D supplementation such as the VITAL, ViDA, and DO-HEALTH trials. The authors suggest that vitamin D supplementation beyond normal levels does not present clear benefits, as it does not appear to impact global health, falls or fractures, or the incidence of diseases such as cardiovascular disease, type 2 diabetes, and cancer. They note, however, that vitamin D supplementation does improve conditions such as rickets and could be moderately beneficial for individuals suffering from vitamin D deficiency.

Considerations When Choosing Supplements

Kim notes in this episode that the costliest supplements are the ones that don't actually contain what they say they do and thus don’t work. So how do you figure out which supplements actually do what they say on the tin? This article provides a framework for choosing supplements, which includes assessing safety and efficacy, monitoring dosage, and taking note of a supplement’s chemical form.

Food allergy, intolerance, or sensitivity: What’s the difference, and why does it matter?
Kim discusses the importance of clearly differentiating between food allergies and sensitivities in this episode. This article discusses food intolerances, allergies, and sensitivities and how to distinguish between them. In short, food intolerances refer to an inability to digest specific foods; food allergies typically involve an allergic reaction such as breathing difficulty following consumption of food; and food sensitivities bring about symptoms, possibly as a result of an immune reaction, from eating certain foods.

Efficacy and safety of the probiotic Saccharomyces boulardii for the prevention and therapy of gastrointestinal disorders
Kim often recommends the tropical yeast Saccharomyces boulardii for reducing negative effects of antibiotic consumption on the gut microbiome. This paper reviews potential mechanisms of action as well as the evidence for the efficacy of S. boulardii as a biotherapeutic agent for addressing gastrointestinal issues.

Matt and psychiatrist Jon Berner chat about the potential of lithium, a generic drug typically used as a mood stabilizer in illnesses such as bipolar disorder, as an Alzheimer's disease and/or life extension drug. They discuss the data supporting lithium's potential effectiveness in preventing premature dementia, practical considerations and challenges around lithium dose optimization, and possible biological mechanisms that explain lithium's effectiveness. They also delve into the various challenges of studying lithium's effects on humans as well as useful further directions for lithium research.

Jon has been in solo psychiatric practice at Woodinville Psychiatric in Washington since 1997. He spent several years working at the Monroe Correctional Complex, a Washington State Department of Corrections prison. His specialties include brain disorders, particularly bipolar and psychotic illnesses, complex pain, addiction, and "undiagnosed" neuropsychiatric syndromes, and other general psychiatric disorders such as anxiety and depression. Jon has published multiple scientific papers about various topics in the realm of mood disorders and treatments for them. He holds an M.D and a PhD in neuroscience from the University of California, Los Angeles and a B.A. in psychology from Harvard University.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Lithium treatment extends human lifespan: findings from the biomedical database UK Biobank

According to this study, lithium supplementation correlates with an over threefold decrease in mortality among people suffering from affective disorders such as mania and bipolar depression, compared to those who use other anti-psychotic drugs. The study does not go into the likely molecular mechanisms by which lithium might extend human lifespan.

Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial

In a randomized, double-blind trial, 45 patients suffering from mild cognitive impairment received either lithium or a placebo over the span of a year. The trial found a correlation between lithium use and lower cerebrospinal fluid (CSF) concentrations of phosphorylated tau (p-tau), an Alzheimer's disease biomarker. Researchers speculate that lithium may be more beneficial for individuals suffering from mild, as opposed to severe, cognitive impairment.

A triple drug combination targeting components of the nutrient-sensing network maximizes longevity

This study suggests that the combination of trametinib, rapamycin, and lithium increases longevity in flies by nearly 50 percent. Combining the drugs (combinations: lithium + rapamycin, lithium + trametinib, rapamycin + trametinib) extended lifespan by an average of 30 percent, compared to an average lifespan extension effect of 11 percent for each drug in isolation.

Gene-expression differences in peripheral blood between lithium responders and non-responders in the Lithium Treatment-Moderate dose Use Study (LiTMUS)

There exists considerable variability in the clinical response to lithium. This study identified a specific pattern of gene expression in individuals who responded to one month of lithium treatment, with the gene expression changes being related to mechanisms including autophagy regulation, neurite outgrowth, and mitochondrially-mediated apoptosis. The researchers identified differential regulation of 62 genes in people who responded compared to those who didn't respond to lithium treatment.

Lithium treated mood disorders, paroxysmal rhinorrhea and mesial temporal lobe epilepsy

Jon authored this paper presenting evidence for the effectiveness of lithium in mood stabilization via two case studies of mood disorders. In the first, lithium helped control shoplifting and major discrete cycles in a woman suffering from bipolar II disorder. In the second, lithium contributed to mood stabilization in a prison inmate suffering from chronic depression, though the drug also brought about side effects such as diarrhea and sudden attacks of rhinorrhea.

Amyloid-Tau-Neurodegeneration (ATN) Profile

This is the blood biomarker for Alzheimer's disease pathology that Matt and Jon discuss in the podcast episode.

Matt and City of Hope Alfred E. Mann Family Foundation Chair of Diabetes and Cancer Metabolism Charles Brenner have had several public disagreements on social media. We love a good conversation between two distinguished scientists whose views may not entirely align, so we were pleased to host Charles on the Optispan Podcast for a discussion of topics in geroscience ranging from whether sirtuins are actually longevity regulators to the clinical utility of epigenetic age tests to the incentive structures around clinical trials. We also spent a chunk of time on NAD+ boosters, one of Charles' areas of expertise, and their relevance to aging and other conditions such as COVID-19.

Prior to his City of Hope appointment, Charles served on the faculties of Thomas Jefferson University, Dartmouth College and University of Iowa, where he was Roy J. Carver Head of Biochemistry for 11 years. He currently serves as the Chief Scientific Advisor of the biotechnology company ChromaDex, which uses his nicotinamide riboside (NR) intellectual property. He is also a cofounder of Alphina and Juvenis, companies in the NAD+ booster space. Charles conducted postdoctoral research at Brandeis University and received a PhD and a B.A. from Stanford University and Wesleyan University respectively.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans

This 2004 paper, which Charles coauthored, is a foundational paper in the NAD+ literature that describes the NR pathway in yeast and humans.

Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+
Charles coauthored this paper describing two NR pathways that boost NAD+ and demonstrating that NR increases yeast sir2 activity and lifespan without caloric restriction.

Targeted, LCMS-based Metabolomics for Quantitative Measurement of NAD(+) Metabolites
This paper describes methods that Charles' group developed as well as technical challenges for quantifying targeted NAD+ metabolites.

Sirtuins are Not Conserved Longevity Genes
Matt and Charles spend some time on a nuanced discussion of sirtuins in this episode, and Charles expresses his grave doubts about claims in the sirtuin literature outside of yeast replicative aging. In 2022, Charles published this paper documenting issues in the animal sirtuin literature as well as providing a working definition of conserved gene function.

RAPAMUNE labeling document
In discussing his concerns with human off-label rapamycin use, Charles cites this RAPAMUNE labeling document along with Blake Rasmussen's randomized clinical trial showing that rapamycin inhibits skeletal muscle protein synthesis after exercise. Charles does consider the premise of the geroscience hypothesis—the idea that the biological processes underlying aging are the root cause of many chronic diseases and conditions commonly associated with aging such as cardiovascular disease, diabetes, Alzheimer's disease, and cancer—to be proven in mice based on the activity of rapamycin.

The papers below discuss the effects of dysregulated NAD+ metabolism on various conditions:

Type II diabetes: Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice

Alcohol-Related Liver Disease: Nicotinamide Adenine Dinucleotide Metabolome Is Functionally Depressed in Patients Undergoing Liver Transplantation for Alcohol-Related Liver Disease

Postpartum conditions: Maternal Nicotinamide Riboside Enhances Postpartum Weight Loss, Juvenile Offspring Development, and Neurogenesis of Adult Offspring

Heart failure: Nicotinamide Riboside Preserves Cardiac Function in a Mouse Model of Dilated Cardiomyopathy

Mitochondrial Myopathy: Niacin Cures Systemic NAD + Deficiency and Improves Muscle Performance in Adult-Onset Mitochondrial Myopathy

Coronavirus infection: Coronavirus infection and PARP expression dysregulate the NAD metabolome: An actionable component of innate immunity

Charles cites a number of positive NR human trials that, in his view, strongly support the use case of NR in healthy aging. We list some of those trials below:

Trials showing anti-inflammatory effects of NR: A Milestone Clinical Study Reveals that Elevating Nicotinamide Adenine Dinucleotide (NAD+) with Nicotinamide Riboside (NR) Supplementation Effectively Reduces Inflammation in Both Healthy Subjects and Immune Cells Derived from Psoriasis Patients(Charles serves as Chief Scientific Advisor of Chromadex)

The NICE trial for peripheral artery disease: Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial

The NADPARK trial for Parkinson’s disease: The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson's disease

Matt recently attended the 52nd annual meeting of the American Aging Association in Madison, Wisconsin and met with several people doing fascinating work in or adjacent to the geroscience field.

One of these was Cristal Hill. Cristal is an Assistant Professor of Gerontology at the University of Southern California Leonard Davis School of Gerontology, where she runs a lab focused on how dietary protein might affect adipose tissue (body fat) function, metabolic, and endocrine health during aging. Cristal received postdoctoral training at the Pennington Biomedical Research Center of Louisiana State University, a PhD in molecular biology from Southern Illinois University, and a B.S. in Animal Sciences from Tuskegee University.

In this episode, Matt and Cristal discuss fibroblast growth factor 21 (FGF21), a hormone produced mainly in the liver that helps regulate metabolism and control how the body uses sugar and fat for energy. They also chat about FGF21's influence on food preferences, role in healthy aging and longevity, potential as an obesity treatment, and more, as well as the broader impact of protein restriction on health- and lifespan as we age.

Some definitions: the term "wildtype" refers to the typical form of an organism or gene as it occurs in nature, and represents the standard or normal genetic makeup and phenotype against which mutants or genetically modified organisms are compared. A "knockout" is an organism in which a specific gene has been completely disabled or "knocked out" to study the gene's function by observing the differences between the knockout organism and a wildtype one. Finally, a "transgenic" organism is one that has had a gene or genes introduced into its DNA to give the organism new traits or abilities, such as resistance to diseases, or to study the effects of the introduced gene.

As far as we can tell, FGF21 tests are not yet commercially available.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

The Hill lab

If you're an aspiring undergraduate researcher, PhD or MD student, postdoc, potential collaborator, or even just someone who wants to know more about what Cristal and her team get up to, here's where you can go to learn all about Cristal's lab at the University of Southern California. On this page you'll find a comprehensive list of the Hill lab publications, some of which deal with the topics that Cristal and Matt discuss in this podcast. You can also read a summary of the Hill lab's research interests.

The starvation hormone, fibroblast growth factor-21, extends lifespan in mice

This paper presents data showing a fairly impressive lifespan extension of ~30% and ~40% in male and female mice respectively after overexpression of fibroblast growth factor-21, or FGF21. Caloric restriction brings about a similar lifespan extension. The authors suggest that the mechanism behind this effect could involve the growth hormone/insulin-like growth factor-1 signaling axis. FGF21 administration may produce some adverse effects, such as reduced bone mass.

FGF21 is required for protein restriction to extend lifespan and improve metabolic health in male mice

Cristal and Matt discuss this research in the podcast episode. Cristal is the lead author on this paper demonstrating the effects on protein restriction on male mice, which include lower frailty, functional decline, body weight, and adiposity; improved physical performance and glucose tolerance; altered biomarkers in the liver, adipose tissue, and blood; and longer lifespan. The paper demonstrates the essential role of FGF21 in bringing about the lifespan extension effect of protein restriction in mice: mice without FGF21 do not respond favorably to protein restriction.

FGF21 prevents low-protein diet-induced renal inflammation in aged mice

In this paper, Cristal and colleagues demonstrate how a low-protein diet impacts aging kidneys as well as the degree to which FGF21 mediates those effects. Mice lacking FGF21 had greater kidney damage and inflammation as a result of protein restriction than mice with FGF21, suggesting that FGF21 may help prevent kidney pathology. Interestingly, protein restriction does not seem to have adverse effects on aging kidneys in humans.

FGF21 Signals Protein Status to the Brain and Adaptively Regulates Food Choice and Metabolism

This study, also from the Hill lab, presents data about the role of FGF21 in energy metabolism and nutrient preferences, or feeding behavior, in mice undergoing protein restriction. FGF21 is responsible for changes in protein appetite, growth, glucose intolerance, and more in response to a low-protein diet.

Matt recently attended the 52nd annual meeting of the American Aging Association in Madison, Wisconsin and met with several people doing fascinating work in or adjacent to the geroscience field.

One of these was Kevin White, physician at longevity-focused clinic Prime Health Associates in Oklahoma City, Oklahoma. Kevin spent two decades in emergency medicine before obtaining fellowship training in integrative and functional medicine, nutrition, and age management. He complete residency training in emergency medicine and trauma at Washington University in St. Louis, and received his M.D. from the University of Oklahoma College of Medicine. Matt describes him as "one of the few longevity docs who actually comes to the science meetings to learn more about the science of aging."

Ultimately, the geroscience field is nothing without the medical professionals who bring new discoveries to bedside. So we really enjoyed sitting down with Kevin and hearing his thoughts on interventions such as stem cell therapy as well as his questions about the geroscience field, which prompted a wide-ranging discussion of rapamycin, the hallmarks of aging, body composition, and more.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Testing Efficacy of Administration of the Antiaging Drug Rapamycin in a Nonhuman Primate, the Common Marmoset
Adam Salmon, whom Matt mentions in the podcast, is a coauthor on this paper about rapamycin administration in the common marmoset, a small-sized nonhuman primate. Marmosets received rapamycin for a short time period (3 months) and a long time period (14 months). The marmosets did not appear to suffer from clinical anemia, fibrotic lung changes, or mouth ulcers as a result of rapamycin dosing, and death rates did not differ from expected death rates given the marmosets' ages.

Long-term treatment with the mTOR inhibitor rapamycin has minor effect on clinical laboratory markers in middle-aged marmosets.
This study, which Adam Salmon also coauthored, examined the effects of rapamycin administration on marmoset blood biomarkers, with a view to understanding how rapamycin might affect marmoset aging. Nine months of rapamycin dosing had little impact on cellular blood counts, and rapamycin concentrations were higher in male marmosets compared to female marmosets. The authors concluded that this particular dose and duration of rapamycin administration likely does not produce detrimental effects on hematological biomarkers in marmosets.

Evaluation of off-label rapamycin use to promote healthspan in 333 adults
Matt and colleagues, including Optispan Chief Medical Officer George Haddad, collected self-reported data from over 300 adults with a history of off-label rapamycin use to capture data about the drug's potential side effects. The only side effect that was significantly more prevalent in rapamycin users compared to non-users was the presence of mouth sores, and several side effects typically associated with rapamycin use such as eye pain and anxiety occurred less frequently in rapamycin users than in non-users.

Rapamycin (AY-22,989), a new antifungal antibiotic I. Taxonomy of the producing streptomycete and isolation of the active principle
Published in 1975, this landmark paper describes the discovery of a new antifungal antibiotic called rapamycin, and characterizes rapamycin's morphological, physiological, and cultural properties and the streptomycete strain that produces it. It details the isolation of the streptomycete strain AY B-994 from an Easter Island soil sample as well as the strain's antimicrobial activity.

A masked, placebo-controlled, randomized clinical trial evaluating safety and the effect on cardiac function of low-dose rapamycin in 17 healthy client-owned dogs
Matt coauthored this paper exploring the effects of rapamycin administration on canine heart function. Seventeen healthy dogs received low-dose rapamycin over a six-month period. The researchers found no significant change, positive or negative, in the dogs' cardiac function, and no adverse effects. Some dog owners reported "positive changes" in their dogs' behavior with rapamycin administration, but these changes were subjective and difficult to characterize.

Matt recently attended the 52nd annual meeting of the American Aging Association (AGE) in Madison, Wisconsin and met with several people doing fascinating work in the longevity field.

One of these was Berenice Benayoun, an Associate Professor (recently tenured!) of Gerontology, Biological Sciences, Biochemistry, and Molecular Medicine at the University of Southern California Leonard Davis School of Gerontology. Berenice delivered the keynote speech at the 2024 AGE meeting, where she received the 2024 Vincent Cristofalo Rising Star Award in Aging Research. Her research focuses on the influence of genomic regulation mechanisms, environmental stimuli, and factors such as biological sex on vertebrate aging and healthspan. Berenice was named a 2020 Pew Biomedical Scholar and a 2021 Nathan Shock new Investigator, and also received the 2019 Rosalind Franklin Young Investigator Award in Mammalian Genetics, an American Federation of Aging Research Junior Faculty Award, and a Global Consortium for Reproductive Longevity and Equality GCRLE Junior Scholar Award.

In this episode, Matt and Berenice chat about the ovaries as a vehicle for understanding aging, the difference between estropause and menopause, and the controversies associated with hormone replacement therapy, and how Berenice made her way into the lab of her dreams. They also discuss the African turquoise killifish, a new vertebrate model organism for longevity research, and address a couple of questions about research we have recently featured on this podcast (how pregnancy affects aging, and sex-specific differences in the effects of estradiol on mouse aging).

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

The Benayoun Lab
The Benayoun lab at the University of Southern California Leonard Davis School of Gerontology is looking for postdoctoral fellows, PhD students, undergraduate researchers interested in uncovering the molecular regulation of vertebrate aging. If you might be one of them, or simply want to learn more about what Berenice and her colleagues do, check out this page to find papers that have come out of the Benayoun lab, the lab's funding sources and affiliations, courses that Berenice is teaching, and more.

Microglia undergo sex-dimorphic transcriptional and metabolic rewiring during aging
This paper, which Berenice coauthored with colleagues, demonstrates that aging of the microglia—a type of immune cell located in the brain—occurs differently in male and female mice. More aging-associated changes happen in the microglia of female than in those of male mice, and these differences are particularly evident in old microglia compared to young microglia. The study outlines potential mechanisms that underpin these microglial changes.

Protection against APOE4-associated aging phenotypes with the longevity-promoting intervention 17α-estradiol in male mice
In this preprint, Berenice and colleagues examined the effect of 17α-estradiol, a type of estrogen, on outcomes in male mice with an age-accelerating allele called apolipoprotein E4 (APOE4). This allele is a major genetic risk factor for Alzheimer's disease and age-related cognitive impairment. The researchers found that 17α-estradiol administration to APOE4 mice conferred healthspan benefits across various systems. You may recall our discussion of the Interventions Testing Program’s finding that 17α-estradiol extends lifespan in male mice.

Estropausal gut microbiota transplant improves ovarian function in adult mice
Transplanting things—blood, ovaries, poop—can have surprising beneficial effects on aging. This preprint, which Berenice coauthored, found that mice receiving gut microbiota transplants experienced better fertility and ovarian health. They also identified clear differences between the gut microbiota of young and old mice as well as specific gut microbes that may be responsible for the improvements observed with transplants.

Menopause Is More Than Just Loss of Fertility

Berenice and Benayoun lab PhD Clayton Baker co-wrote this article reviewing the surprising negative effects of menopause on cognitive function, bone mass, and cardiovascular disease risk. They make the case for paying attention to biological differences between men and women and the resulting differences in drug pharmacokinetics in both genders, and for addressing limitations in women's health such as a lack of female representation across the age spectrum in interventional clinical trials.

Matt recently attended the 52nd annual meeting of the American Aging Association in Madison, Wisconsin and met with several people doing interesting work in the longevity field.

One of these was Mark McCormick, an Assistant Professor at the University of New Mexico (UNM) Department of Biochemistry and Molecular Biology. At UNM, Mark runs a lab that investigates age-delaying drug targets, develops machine learning tools for studying aging, and identifies conserved aging mechanisms and pathways in model organisms and humans. Mark previously completed a postdoc with Brian Kennedy at the Buck Institute for Research on Aging, a PhD in Biochemistry and Molecular Biology with Cynthia Kenyon at the University of California, San Francisco, and a B.S. in Mechanical Engineering as well as a B.S. in Biology from the University of Texas at Austin.

In this episode, Matt and Mark chat about aminoacyl-tRNA synthetases, a group of enzymes that play an essential role in protein synthesis. They discuss the promise and risks of tRNA synthetase inhibitors to treat diseases of aging and extend life- and healthspan (spoiler: don't take tRNA synthetase inhibitors yet). They also talk about why Mark's lab has held off on doing mouse experiments thus far, the challenges of proving causality in longevity experiments, interventions about which Mark is optimistic (or not), and more.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

McCormick lab
If you're an aspiring undergraduate researcher, PhD student, postdoc, collaborator, research sponsor, or even just someone who wants to know more about what Mark and his team get up to, here's where you can go to learn all about Mark's lab at the University of New Mexico. Many who know Mark can attest to the care and effort he puts into mentoring the next generation of scientists. On this page, you will also find a comprehensive list of Mark's lab publications from which you can learn more about some of the topics he discusses in this podcast (and more).

Induction of proteasomal activity in mammalian cells by lifespan-extending tRNA synthetase inhibitors
Mark coauthored this paper discussing a potential mechanism of action of tRNA synthetase inhibitors to increase lifespan. The researchers demonstrate that tRNA inhibitors may upregulate pathways that promote protein turnover, specifically proteasomal degradation and autophagy, a process of breaking down damaged proteins and other cellular components. Protein turnover is essential for maintaining cellular function and homeostasis, and disruptions in protein turnover can contribute to various diseases via the accumulation of damaged or misfolded proteins or the excessive degradation of functional proteins.

Cytosolic and mitochondrial tRNA synthetase inhibitors increase lifespan in a GCN4/atf-4-dependent manner
This paper, which Mark also coauthored, demonstrates lifespan extensions in both yeast and worms as a result of tRNA synthetase inhibitors. The study hypothesizes that these inhibitors act in yeast by upregulating the translation of General Control Nonderepressible 4 (Gcn4), a crucial yeast transcription factor that regulates the expression of genes required for amino acid biosynthesis and stress adaptation. Meanwhile, tRNA synthetase inhibitors act in worms in an Activating Transcription Factor 4 (ATF4)-dependent manner. ATF4 is a mammalian transcription factor that plays a key role in the cellular response to various forms of stress.

Roles of tRNA metabolism in aging and lifespan
This review provides an overview of how tRNA metabolism, including tRNA transcription, tRNA molecules, tRNA modifications, tRNA aminoacylation (where tRNA-synthetase comes in), and tRNA derivatives, influences aging and lifespan.

Acarbose improves health and lifespan in aging HET3 mice
Matt and Mark discuss the merits of acarbose, an antidiabetic drug that slows carbohydrate digestion and absorption, as a potential longevity intervention in this podcast episode. This study is one of several reporting lifespan increases in mice receiving acarbose, with some sex differences. The field doesn't yet have a lot of data about the effects of acarbose on human longevity.

George Sutphin is back! So many of you enjoyed Matt's interview with him back in March 2024 about 3HAA and NAD+ that we decided to bring him on the podcast once again to chat about the potential effects of oral NMN supplementation.

You may have heard of over-the-counter supplements aimed at boosting nicotinamide adenine dinucleotide (NAD+) levels. Underlying these supplements is the hypothesis that levels of NAD+, a central coenzyme found in all living cells and involved in innumerable biochemical reactions that include DNA repair, glycolysis, and stress responses, decrease with age. The decrease, according to supplement manufacturers, may be associated with aging and age-related disease and thus restoring NAD+ levels via supplementation is likely to increase health- and/or lifespan.

In this episode, Matt and George examine a recent finding that oral supplementation of NAD+ boosters increases molecular signatures that indicate kidney damage. They discuss the NAD+ signaling pathway, models for how NAD+ might drive kidney damage, how they would expand upon the study for further research, and more.

University of Arizona Assistant Professor of Molecular and Cellular Biology George Sutphin runs a lab that investigates genetic determinants of longevity, the effects of kynurenine-based interventions on lifespan, and environmental regulators of the aging process. George, who was an aerospace engineer before he discovered the promise of geroscience, completed his PhD at the University of Washington and worked as a postdoctoral associate at the Jackson Laboratory prior to his current faculty position. He currently serves as Chairperson of the American Aging Association.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!


Metabolite accumulation from oral NMN supplementation drives aging-specific kidney inflammation

This is the preprint Matt and George discuss in the episode. The authors found that, contrary to their expectations that NAD+ boosters would help ameliorate kidney aging in mice, an NAD+ booster actually led to increased levels of potential kidney damage markers. These results do not conclusively demonstrate a negative effect of NAD+ boosters on kidney health, but there's smoke there, as Matt says, and the finding is worth further investigation.

NAD precursors cycle between host tissues and the gut microbiome

The gut microbiome seems to play a role in many biological processes, including NAD+ biosynthesis and metabolism. This paper suggests that the gut microbiome breaks down NAD+ intermediates such as nicotinamide riboside and nicotinamide mononucleotide into nicotinic acid, which you may know by its generic name niacin. Cells then generate NAD+ from nicotinic acid.

SS-31 and NMN: Two paths to improve metabolism and function in aged hearts

The NMN-kidney inflammation paper that Matt and George discuss in this episode has roots in this piece of research, which shares several authors with the later paper. Researchers administered two mitochondria-targeting drugs, including the NAD+ precursor NMN, to mice and found that treating mice with a combination of both drugs restored various aspects of mitochondrial and heart health.

Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women

How might NAD+ precursors such as NMN affect people? This study reported that overweight or obese prediabetic women who had undergone menopause showed improved muscle insulin sensitivity and insulin signaling with NMN supplementation. They also experienced higher levels of downstream muscle NMN metabolites, or nicotinamide byproducts.

Kynurenine pathway, NAD+ synthesis, and mitochondrial function: Targeting tryptophan metabolism to promote longevity and healthspan

This paper, which George co-authored, provides a useful review of the kynurenine pathway, a major metabolic pathway for the degradation of the amino acid tryptophan that ends in the production of either kynurenic acid or NAD+. He reviews the potential roles of NAD+ and kynurenine metabolism in aging and the potential of interventions targeting components of these pathways.

No single discipline or approach holds the key to making big strides in the longevity field. Human aging is incredibly complex, and we're going to need multiple shots on goal in our pursuit of human life- and healthspan extension. At the Optispan Podcast, we're always excited to learn about the various angles researchers and founders are taking to advance our understanding of longevity and get impactful therapeutics that will transform human health into the clinic.

In this episode, Ora Biomedical CEO and cofounder Mitchell Lee gives us the lowdown on doing high-throughput drug discovery using a combination of worms, robotics, AI, and the general public. Matt and Mitchell talk about the company's ambitious goal to create the world's largest and most rigorous database of longevity interventions, and how a new robotics and AI data analysis platform is helping the company get there. They discuss the state of drug discovery in the longevity field, whether we can really believe any data we get from worms, the intervention that killed all their worms in one day, and more.

Prior to cofounding Ora Biomedical, Mitchell spent his career focused on scientific research and mentorship, mentoring nearly 50 trainee researchers of all levels during his graduate and postdoctoral research periods. He was the founding Chair of the American Aging Association (AGE) trainee chapter, which offers early-career financial, career development, and networking benefits, and has served on the AGE Executive Committee and Board of Directors. Mitchell received a B.S. in biology, a B.A. in philosophy, and an M.S. in biology from Western Washington University. He completed his PhD in Experimental Pathology at the University of Washington School of Medicine, during which time he received a Howard Hughes Medical Institute (HHMI) Gilliam Fellowship for Advanced Study.

Matt is a cofounder and Chair of the Board of Directors of Ora Biomedical.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

WormBot: A high-throughput system for studying aging in C. elegans

This animation explains the mechanics of the WormBot-AI platform in a clear and accessible way.

The million-molecule challenge: a moonshot project to rapidly advance longevity intervention discovery

In this article, Mitchell, Matt, and their colleagues propose the Million Molecule Challenge, a plan to screen one million interventions in C. elegans, a nematode worm, for their effects on longevity. They describe their reasoning for using C. elegans as a model organism as well as the WormBot-AI robotics platform they have developed to facilitate this high-throughput screening. They also present a proof-of-principle screen of 1,266 compounds that they completed in one month using their WormBot-AI technology.

The Million Molecule Challenge for Life Extension - Matt Kaeberlein at Longevity Summit Dublin

Matt spoke at the Longevity Summit Dublin 2023, a gathering of researchers, founders, and other leaders in the longevity field, about moving longevity science into clinical practice, how close we are to "solving aging", and what we need to make an impact in the field. About halfway through the talk, he talks about the Million Molecule Challenge: why C. elegans are a reasonable model organism with which to study aging, how much of the intervention space we have explored, and why we need a Million Molecule Challenge at all. He also presents a time-lapse video of the WormBot-AI technology, an AI and robotics platform for studying the effect of interventions on C. elegans, in action.

Using C. elegans for aging research

This short article reviews the history of using C. elegans in geroscience research. It also discusses several reasons that C. elegans is a suitable model organism for studying aging, such as cost, short lifespans, and evolutionary conserved lifespan pathways; as well as the disadvantages of using C. elegans in geroscience research, including a lack of complexity in the organism and limits to biochemistry due to the worms' small size.

Rise of the WormBots: it’s time to scale up longevity R&D

Longevity.technology profiled Ora Biomedical and interviewed Mitchell about the company's development strategy, scale of operations, and plans for the future. Mitchell describes his aim to get from longevity biotech 1.0 to longevity biotech 2.0: "discovering the next generation, most efficacious interventions".

We talk a lot about the science of longevity and healthspan on the Optispan podcast—how DEXA scans work, what an optimal rapamycin dose might look like, how the intersection of optogenetics and mitochondria are helping us understand biological aging, what supplements one might consider taking and why.

But the longevity field runs on way more than just science. It takes a village—a community of researchers, engineers, entrepreneurs, investors, regulators, and beyond who believe in the value of tackling the biology of aging as a crucial strategy for extending healthy lifespan—to create tangible results that benefit as many people as possible. At Optispan, we're eager to support and interact with the many levers that keep this machine going. One of these is the Alliance for Longevity Initiatives (A4LI), a nonprofit organization focused on catalyzing social and political action that will benefit the longevity field.

In this episode, Matt chats with A4LI founder, president, and CEO Dylan Livingston about forming a bipartisan longevity science caucus, redirecting funding towards geroscience research, and engaging with policymakers to help them understand the importance of transitioning towards a proactive healthcare model. Dylan, who founded A4LI in 2021, served as a field organizer for President Joe Biden's 2020 presidential campaign. He also worked as a community organizer for Organizing Corps 2020, where he registered hundreds of Democratic voters in Pennsylvania for the 2020 presidential compaign. Dylan graduated from Haverford College with a B.S. in physics and a minor in economics.

Matt joined the A4LI Board of Directors in 2024.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Longevity Gets Political at an Unprecedented DC Event

Lifespan.io, a nonprofit organization that aims to help accelerate discovery in the aging field through journalism, crowdfunding, and community building, profiled a two-day congressional briefing on longevity science held at Washington, D.C.'s Mayflower Hotel in April 2024. The event included presentations from Matt and other longevity biotech startup founders such as Kristen Fortney (BioAge) and Joe Betts-Lacroix (Retro Biosciences). Attendees also heard from former Speaker of the House Newt Gingrich, Republican Congressman Gus Bilirakis, and Democratic Congressman Paul Tonko.

A Policymaker’s Guide the Longevity Therapeutics Industry

This guide serves as a primer on the ever-evolving longevity space for policymakers. It describes the dominance of aging as a risk factor in chronic diseases such as cancer and diabetes, the thesis behind the geroscience approach, and recent academic and industry initiatives in longevity medicine. It also addresses several arguments for and against tackling age-related diseases and lifespan—think overpopulation, economic disparity, and the "unnaturalness" of longer lifespans—and ends with concrete steps that policymakers can take to help advance the field.

The Advanced Approval Pathway for Longevity Medicines

This document proposes a special approval track for longevity medicines to accelerate the development process for drugs that tackle the biological aging process. It includes standards for designating a therapeutic as a longevity medicine and solutions for overcoming status quo barriers such as a priority review voucher system and patent term extensions.

How can ARPA-H be a transformative agency to advance the development of biotechnology that targets human aging?

The Advanced Research Projects Agency for Health (ARPA-H) is a National Institutes of Health (NIH) entity that aims to accelerate the development of transformative solutions to our greatest health challenges. The agency provides funding to support high-impact, high-risk, high-reward research in the private and public sectors under the leadership of a Program Manager who champions a core idea and uses their subject matter expertise to see the idea to fruition. This post provides several examples of how ARPA-H might support the longevity field.

Make Your Voice Heard: Contact Your Representative on Behalf of Longevity Science

A4LI has prepared a letter template for you to use in the event that you want to request that your congressperson provides support to longevity initiatives. You are welcome to customize the letter as you see fit, and may email A4LI at info@a4li.org if you need any assistance, such as contact information for your congressional office, to send the letter.

Optogenetics is a cutting-edge field at the intersection of optics and genetics. This technique introduces microbial opsins, light-sensitive proteins naturally found in certain microorganisms such as algae and bacteria, into specific organelles, cells, or tissues to make them sensitive to light and thus precisely manipulable. Optogenetics has served as a powerful tool in neuroscience research, enabling scientists to dissect complex neural circuits and understand how they give rise to behavior, cognition, and disease; and is expanding its reach to other fields such as endocrinology, vision restoration, and muscle physiology.

In this episode, researcher Brandon Berry chats with Matt about the development and application of optogenetic tools to manipulate mitochondrial function in cells. He shares his experiences with engineering optogenetic proteins for mitochondrial targeting, the challenges involved in controlling mitochondrial charge, and the potential of optogenetics to manipulate mitochondrial membrane potential. He also discusses the complexities of mitochondrial dysfunction, the relationship between mitochondrial dysfunction and aging, and the role of mitochondrial membrane potential in longevity interventions, including caloric restriction.

Brandon, who is currently working on a stealth project, was a former postdoctoral research associate in Matt's lab at the University of Washington, where he did a lot of his work on developing tools for mitochondrial control. He received a PhD in Physiology from the University of Rochester.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Why Are Cells Powered by Proton Gradients?

This article discusses biochemist Peter Mitchell's model of proton gradients' role in cellular respiration. Proton gradients power the synthesis of adenosine triphosphate (ATP, an energy-providing nucleotide), providing a crucial mechanism for cellular metabolism. The article also explores how reliance on proton gradients might have constrained the evolution of complexity until the advent of eukaryotic cells, which harnessed mitochondria to control these gradients and may have facilitated the leap to multicellular life forms. Mitchell's proposition, though initially controversial, ultimately earned him a Nobel Prize and reshaped our understanding of cellular energy production.

Optogenetic control of mitochondrial metabolism and Ca2+ signaling by mitochondria-targeted opsins

This article describes an optogenetic approach that enables precise control of mitochondrial membrane potential through light-dependent activation of channelrhodopsins—light-sensitive proteins—targeted to the inner mitochondrial membrane. The method offers insights into cellular processes without the drawbacks of conventional pharmacological interventions.

Optogenetic control of mitochondrial protonmotive force to impact cellular stress resistance

Brandon is the lead author on this paper describing the engineering of an optogenetic technique for increasing the proton gradient, or protonmotive force, in worm mitochondria. "Charging up" mitochondria in this way has several beneficial effects for mitochondria, including increased resistance to toxins, better ATP synthesis, and hypoxia resistance.

Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan

In the podcast, Brandon discusses lifespan experiments he conducted to assess the impact of optogenetic mitochondrial manipulation on longevity. This study presents his finding that optogenetically controlling mitochondria slows aging and improves measures of healthspan in worms.

Extending lifespan by rejuvenating mitochondrial membrane potential - Dr Brandon Berry

Brandon chats with Eleanor Sheekey of The Sheekey Science Show about his mtON tool and its effects on worm lifespan. He provides an introduction to mitochondria ("the best organelles ever") and its role in cells, discusses the potential role of mitochondria in aging and age-related biological processes such as cellular senescence, offers some advice for aspiring academics, and more.

Senescent cells, cells that cease to divide and proliferate while remaining metabolically active, are a complex and intriguing aspect of biological aging. They serve as both a protective mechanism against cancer, preventing damaged cells from uncontrollable replication, as well as a contributor to tissue dysfunction and age-related pathologies such as cardiovascular disease, neurodegenerative disorders, and diabetes. The precise mechanisms that underlie senescence and its contributions to the aging process remain areas of ongoing investigation and debate.

In this episode, Matt chats with Sapere Bio co-founder and CEO Natalia Mitin about measuring cellular senescence, using those measurements in the clinic, and the complex and heterogeneous role of cellular senescence in aging and disease. They also discuss Natalia's personal experiences using rapamycin off-label to improve energy levels and immune function, the importance of monitoring biomarkers when using off-label medications, and Natalia's thoughts on "rapamycin for all".

Prior to co-founding Sapere Bio, Natalia served as an assistant professor at the University of North Carolina at Chapel Hill's Department of Pharmacology. She spent over two decades developing assays for use in cancer research. She holds a B.S. in chemical engineering from the Mendeleev Institute for Chemical Technology and a PhD in biochemistry and molecular biology from Bowling Green State University.

Optispan uses the SapereX test in its healthspan optimization program.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders

This seminal paper demonstrated a potential causal link between cellular senescence and various aging phenotypes. Removing senescent cells exhibiting the kinase inhibitor and senescence biomarker p16 delayed the onset of age-related phenotypes in mouse skeletal muscle, adipose, and eye tissues.

Naturally occurring p16 Ink4a-positive cells shorten healthy lifespan

This paper, which shares several authors with the previous one, showed that clearing senescent cells impeded tumor and cataract formation as well as age-related deterioration of organs and tissues including kidney, heart, and fat in mice. It also extended lifespan in mice from two different genetic backgrounds that were eating different diets.

Senolytics improve physical function and increase lifespan in old age

If you want to prematurely age a mouse, give it a senescent cell transplant. Transplanting senescent cells into young mice led to physical dysfunction, the spread of cellular senescence to host tissues, and reduced survival in mice. Selective elimination of senescent cells via senolytic therapy alleviated these negative effects and increased survival after treatment by 36%.

Expression of p16(INK4a) in peripheral blood T-cells is a biomarker of human aging

This study found an association between the kinase inhibitor and senescence biomarker p16 and human chronological age. It also found a more rapid increase in p16 expression with older age in those who smoked compared with those who didn't smoke, a finding consistent with other evidence for tobacco smoke's age-accelerating effects; as well as a relationship between the expression of p16 and interleukin-6 (IL-6), a cytokine that plays an important role in cell signalling and can serve as a biomarker of inflammation.

A quantitative model for age-dependent expression of the p16INK4a tumor suppressor

This paper presents results from computational modeling of p16+ cellular senescence dynamics in healthy people. The model revealed how the p16 accumulation rate changes with chronological age and lifestyle factors such as smoking and exercise habits.

University of Arizona Assistant Professor of Molecular and Cellular Biology George Sutphin runs a lab that investigates genetic determinants of longevity, the effects of kynurenine-based interventions on lifespan, and environmental regulators of the aging process. George, who was an aerospace engineer before he discovered the promise of geroscience, completed his PhD at the University of Washington and worked as a postdoctoral associate at the Jackson Laboratory prior to his current faculty position. He currently serves as Chairperson of the American Aging Association.

We sat down with George to talk about his research, including the effects of caffeine on lifespan and, more recently, his discovery of a new metabolite with the ability to greatly extend lifespan when given late in life. We also discuss George's thoughts on biological age clocks, his own healthspan optimization protocol, and much more.

The probiotic George mentions taking in this podcast episode is Garden of Life Probiotics Ultimate Care.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Caffeine extends life span, improves healthspan, and delays age-associated pathology in Caenorhabditis elegans

This paper began as a side project during George’s PhD work at the University of Washington. It showed that caffeine extended life- and healthspan in nematode worms, and also had positive effects on pathologies such as paralysis in a worm model of polyglutamine disease. The paper attracted a lot of interest, perhaps because it seemed to justify people’s coffee-drinking habits. No conclusive evidence about caffeine’s effects on human lifespan currently exists.

Lifespan extension in Caenorhabditis elegans by complete removal of food

What is the optimal amount of food to give worms so that they’ll live longer? According to this study, which also came out of George’s PhD at the University of Washington, the answer is no food at all. This paper found that completely taking away worms’ food in adulthood increased lifespan by up to 50%. While a starvation protocol like this one is unlikely to work in humans, these findings add an interesting set of data points to evolving research into how diet affects longevity in humans.

Dietary restriction by bacterial deprivation increases life span in wild-derived nematodes

This study was a follow up to the previous paper and investigates the effects of dietary restriction on the lifespan of wild worm populations collected from various locations worldwide. The results indicate that bacterial food deprivation extends lifespan across multiple wild C. elegans (a worm species) populations. Additionally, the longevity-enhancing effects of bacterial food deprivation are conserved in a related worm species, C. remanei. The study highlights the potential impact of genetic and environmental factors on worm lifespan variation and suggests that food-deprivation-induced lifespan extension may be a characteristic of wild-derived nematode populations.

Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity

This paper came out of George’s time at the Jackson Laboratory. The researchers conducted an RNA interference (RNAi) longevity screen on 82 genes in C. Elegans, chosen based on their orthology to human genes that show age-related changes in expression. Their results revealed a significant enrichment in genes where knockdown increased lifespan compared to previously published longevity screens, with 46 genes being newly identified as impacting lifespan. Knockdown of these genes, which included genes that encoded the enzyme kynureninase, a tetraspanin, and a voltage-gated calcium channel subunit, increased healthspan with no effects on reproduction. The kynureninase gene knockdown specifically delayed pathology in worm models of Alzheimer's and Huntington's diseases.

The Emerging Role of 3-Hydroxyanthranilic Acid on C. elegans Aging Immune Function

3-hydroxyanthranilic acid (3-HAA) is a metabolite within the kynurenine pathway, a metabolic pathway involved in the breakdown of the amino acid tryptophan. The kynurenine pathway plays a crucial role in various physiological processes, including immune response regulation, neurotransmitter synthesis, and inflammation modulation. This paper showed that the 3HAA appeared to slow age-associated immune function decline in addition to helping mice fend off pathogenic challenges. 3HAA is not sufficiently well-understood to be a candidate for supplementation in humans.

Optispan CEO Matt Kaeberlein chats with Prime Health Associates Physician Kevin White about making the transition from research to building a company, moving towards preventative medicine in the 21st century, incorporating new discoveries into medical practice, and more.

Optispan CEO Matt Kaeberlein chats with Prime Health Associates Physician Kevin White about improving bloodwork results, monitoring glucose readings, taking supplements, and more.

Matt and guest Jonathan An, Assistant Professor of Oral Health Sciences at the University of Washington School of Dentistry, discuss oral health and its relationship to aging, including published studies involving rapamycin effects on oral health. This is a 3-part episode.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Aging and Oral Health with Dr. Jonathan An!

Our guest, Assistant Professor of Oral Health Sciences and Faculty in the Healthy Aging and Longevity Institute at the University of Washington School of Dentistry Jonathan An, recently appeared on Lets Get Oral, a podcast that explores oral health from multiple angles—think the oral microbiome, taste, bad breath. In this episode, Jonathan talks about how our teeth change as we get older, the potential impact of medications on oral health, why he supports taking a more systemic approach to dental care, and more.

Oral health in geroscience: animal models and the aging oral cavity

Animal models are indispensable tools for studying the biology of aging. They provide insight into underlying mechanisms of aging, enable scientists to test interventions that promote healthy aging, and advance our understanding of age-related diseases. While animal models have their limitations, their use in research allows for controlled experimentation and the generation of valuable data that can ultimately benefit human healthspan and longevity. Jonathan and our host Matt Kaeberlein co-authored this journal article about which animal models are best suited for studying the intersection of aging and oral disease. They discuss rodents, the current premier preclinical models for geroscience research, as well as dogs and nonhuman primates such as the southern pig-tailed macaque.

Rapamycin rejuvenates oral health in aging mice

In 2020, Jonathan and Matt demonstrated that rapamycin treatment rejuvenated the aged oral cavity of older mice. The treatment reversed "clinically defining features of periodontal disease", including periodontal bone loss, periodontal inflammation, and pathogenic oral microbiome changes. This paper lends support to the idea that interventions that target mechanisms of biological aging may delay multiple age-related declines. Further work should investigate whether the rejuvenating effects of rapamycin persist after the treatment period as well as whether rapamycin improves other oral health declines that commonly occur with age, such as salivary function.

Oral health for healthy aging

This article calls for an end to the siloing of oral health from general health care. The authors note that the global prevalence of oral disease is higher than it should be, given the preventable nature of most oral diseases, and that this prevalence is likely to worsen with population aging. They make suggestions for concrete policy action and mindset shifts towards addressing the burden of oral disease care, including shifting dental care models away from curative and interventionist models and towards more preventative upstream action.

Aging and Dental Health

This is a short primer from the American Dental Association about the clinical and oral health context of older adults. By one estimate, 68 percent of adults aged 65 years and older have periodontis. The primer covers comorbid conditions; the potential impact of common medications for age-related conditions on oral health; and cognitive, physical, and sensory limitations affecting dental care and home oral care.

Matt and guest Jonathan An, Assistant Professor of Oral Health Sciences at the University of Washington School of Dentistry, discuss oral health and its relationship to aging, including published studies involving rapamycin effects on oral health. This is a 3-part episode.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Aging and Oral Health with Dr. Jonathan An!

Our guest, Assistant Professor of Oral Health Sciences and Faculty in the Healthy Aging and Longevity Institute at the University of Washington School of Dentistry Jonathan An, recently appeared on Lets Get Oral, a podcast that explores oral health from multiple angles—think the oral microbiome, taste, bad breath. In this episode, Jonathan talks about how our teeth change as we get older, the potential impact of medications on oral health, why he supports taking a more systemic approach to dental care, and more.

Oral health in geroscience: animal models and the aging oral cavity

Animal models are indispensable tools for studying the biology of aging. They provide insight into underlying mechanisms of aging, enable scientists to test interventions that promote healthy aging, and advance our understanding of age-related diseases. While animal models have their limitations, their use in research allows for controlled experimentation and the generation of valuable data that can ultimately benefit human healthspan and longevity. Jonathan and our host Matt Kaeberlein co-authored this journal article about which animal models are best suited for studying the intersection of aging and oral disease. They discuss rodents, the current premier preclinical models for geroscience research, as well as dogs and nonhuman primates such as the southern pig-tailed macaque.

Rapamycin rejuvenates oral health in aging mice

In 2020, Jonathan and Matt demonstrated that rapamycin treatment rejuvenated the aged oral cavity of older mice. The treatment reversed "clinically defining features of periodontal disease", including periodontal bone loss, periodontal inflammation, and pathogenic oral microbiome changes. This paper lends support to the idea that interventions that target mechanisms of biological aging may delay multiple age-related declines. Further work should investigate whether the rejuvenating effects of rapamycin persist after the treatment period as well as whether rapamycin improves other oral health declines that commonly occur with age, such as salivary function.

Oral health for healthy aging

This article calls for an end to the siloing of oral health from general health care. The authors note that the global prevalence of oral disease is higher than it should be, given the preventable nature of most oral diseases, and that this prevalence is likely to worsen with population aging. They make suggestions for concrete policy action and mindset shifts towards addressing the burden of oral disease care, including shifting dental care models away from curative and interventionist models and towards more preventative upstream action.

Aging and Dental Health

This is a short primer from the American Dental Association about the clinical and oral health context of older adults. By one estimate, 68 percent of adults aged 65 years and older have periodontis. The primer covers comorbid conditions; the potential impact of common medications for age-related conditions on oral health; and cognitive, physical, and sensory limitations affecting dental care and home oral care.

Matt and guest Jonathan An, Assistant Professor of Oral Health Sciences at the University of Washington School of Dentistry, discuss oral health and its relationship to aging, including published studies involving rapamycin effects on oral health. This is a 3-part episode.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Aging and Oral Health with Dr. Jonathan An!

Jonathan recently appeared on Lets Get Oral, a podcast that explores oral health from multiple angles—think the oral microbiome, taste, bad breath. In this episode, Jonathan talks about how our teeth change as we get older, the potential impact of medications on oral health, why he supports taking a more systemic approach to dental care, and more.

Oral health in geroscience: animal models and the aging oral cavity

Animal models are indispensable tools for studying the biology of aging. They provide insight into underlying mechanisms of aging, enable scientists to test interventions that promote healthy aging, and advance our understanding of age-related diseases. While animal models have their limitations, their use in research allows for controlled experimentation and the generation of valuable data that can ultimately benefit human healthspan and longevity. Jonathan and our host Matt Kaeberlein co-authored this journal article about which animal models are best suited for studying the intersection of aging and oral disease. They discuss rodents, the current premier preclinical models for geroscience research, as well as dogs and nonhuman primates such as the southern pig-tailed macaque.

Rapamycin rejuvenates oral health in aging mice

In 2020, Jonathan and Matt demonstrated that rapamycin treatment rejuvenated the aged oral cavity of older mice. The treatment reversed "clinically defining features of periodontal disease", including periodontal bone loss, periodontal inflammation, and pathogenic oral microbiome changes. This paper lends support to the idea that interventions that target mechanisms of biological aging may delay multiple age-related declines. Further work should investigate whether the rejuvenating effects of rapamycin persist after the treatment period as well as whether rapamycin improves other oral health declines that commonly occur with age, such as salivary function.

Oral health for healthy aging

This article calls for an end to the siloing of oral health from general health care. The authors note that the global prevalence of oral disease is higher than it should be, given the preventable nature of most oral diseases, and that this prevalence is likely to worsen with population aging. They make suggestions for concrete policy action and mindset shifts towards addressing the burden of oral disease care, including shifting dental care models away from curative and interventionist models and towards more preventative upstream action.

Aging and Dental Health

This is a short primer from the American Dental Association about the clinical and oral health context of older adults. By one estimate, 68 percent of adults aged 65 years and older have periodontis. The primer covers comorbid conditions; the potential impact of common medications for age-related conditions on oral health; and cognitive, physical, and sensory limitations affecting dental care and home oral care.