The Optispan Podcast with Matt Kaeberlein

Matt recently exchanged a lively correspondence about biological age with Harold Katcher, cofounder of a stealth biotechnology company and inventor of E5. E5 is a compound consisting of the purified exosome fraction of blood from young piglets—in other words, young pig blood. Katcher recently co-published a paper suggesting that injecting this young pig blood into rats made rats younger on several biological aging measures, including inflammatory markers and epigenetic aging signatures. Indeed, Katcher has injected E5 into his own right hand and presented differences in the appearance of his right and left hands on social media.

Putting pig blood into other animals (and into ourselves!) to reverse biological age might seem like a crazy thing to do. But this idea actually stems from a methodology with a decades-long history called heterochronic parabiosis, an area of research that explores the effects of joining the circulatory systems of different-aged organisms. In this experimental technique, researchers surgically connect two animals, typically mice, of disparate ages so that they share a common bloodstream. This union leads the older and younger individuals to exchange not just blood cells but also signaling molecules, growth factors, and other circulating factors. Remarkably, when an older animal is paired with a younger counterpart, it often experiences improvements in various aspects of health and tissue function, while the younger partner may exhibit corresponding signs of accelerated aging. The mechanisms underlying these effects are complex, multifaceted, and very much still under investigation.

In this episode, Matt takes a magnifying glass to E5: what we know about the compound, how it affects lifespan, and how its impact on lifespan stacks up with that of other longevity inventions such as caloric restriction and rapamycin. He discusses whether Harold's recent paper truly proves a reversal of biological age and where his findings fit into the larger body of literature in the field. He also gives us a window into the methodology of heterochronic parabiosis, what the primary data about life expectancy gains through this intervention show, and whether heterochronic parabiosis-inspired interventions such as E5 are realistic approaches to human lifespan extension.

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!

Reversal of biological age in multiple rat organs by young porcine plasma fraction

This paper details the experiment featured in this podcast episode as well as the creation of epigenetic clocks for rat tissues. Scientists examined the effect of a plasma fraction from young adult pigs on these epigenetic clocks, and found that the treatment reduced epigenetic age, as measured by the clocks, by up to 30 percent across several rat organs. E5 also improved other parameters such as inflammatory markers and grip strength. The paper did not present lifespan data for the treated rats.


The Retardation of Aging in Mice by Dietary Restriction: Longevity, Cancer, Immunity and Lifetime Energy Intake

This decades-old paper presents results showing a significant lifespan extension in mice undergoing caloric restriction, an intervention that Matt describes as "arguably the gold standard" for rodent lifespan extension. The longest-lived mice in this paper averaged 53 months of life (average mouse lifespan is 12 to 18 months). It would have been interesting to do an apples-to-apples comparison of E5's effects on mouse lifespan to that of the caloric restriction this paper describes.

Studies that shed new light on aging

In this 2013 paper, Katcher describes his disagreement with the "wear and tear" or "accumulated damage" model of aging, which suggests that the primary driver of aging is a gradual accumulation of damage to cells and tissues over time that eventually leads to declines in their function and the onset of age-related diseases. He proposes paying greater attention to rejuvenation of aged cells, possibly via heterochronic plasma exchange, on the thesis that it is actually factors in the blood that regulate aging, and that young plasma carries factors that enable cellular youthfulness.

Harold Katcher's rejuvenated hand self-experiment

Katcher applied a topical version of E5 to his own right hand in 2022. This post from The Longevity Newsletter presents a side-by-side photographic comparison of his right (E5) and left (no E5) hands. According to Katcher, E5 thickened the skin and improved the color of as well as erased scars and wrinkles from his right hand.

Heterochronic parabiosis: historical perspective and methodological considerations for studies of aging and longevity

This review covers the history of heterochronic parabiosis, from the earliest documented instances of experimentation with animal grafting to 21st-century studies of regeneration. It also presents the methodology, technical challenges, and limitations of heterochronic parabiosis, such as mortality risk and parabiotic disease.

We typically think of prescription drugs as targeted treatments designed to address the underlying mechanisms and biochemical pathways associated with specific diseases or conditions. For example, healthcare providers commonly prescribe statins that lower cholesterol levels and reduce cardiovascular disease risk by inhibiting the enzyme involved in cholesterol synthesis. Similarly, doctors might prescribe antibiotics to target bacterial infections by disrupting the bacteria's growth or killing them outright.

But prescription drugs may have multiple uses or indications beyond their original intended purpose. A recent preprint from the biotech startup EPITERNA describes a study exploring the link between prescription drugs and human lifespan. Researchers analyzed more than 40 years of prescription drug data from over 500,000 patients in the UK Biobank to examine how commonly prescribed medications affect mortality risk. Many drugs have negative consequences for lifespan for reasons that include drug resistance, drug dependency, and side effects such as organ damage and immunosuppression—but a number of drugs actually appear to be beneficial for longevity. In this episode, Matt goes over the study's top-performing drugs for lifespan, and discusses how we might interpret and extend these intriguing findings about common prescription medications.

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!

Association between prescription drugs and all-cause mortality risk in the UK population

This is the EPITERNA preprint Matt discusses in the podcast. The preprint describes the results of analyzing prescription medication and mortality data from over half a million patients recorded in the UK Biobank, a biomedical database and research resource of health-related data from participants aged between 40 and 69 years old in the United Kingdom, for a period of over 40 years. After comparing the mortality of patients taking the top 406 prescribed drugs to that of controls not taking a given drug, they found a number of prescription medications correlated with longer lifespans.

Effect of Aspirin on All-Cause Mortality in the Healthy Elderly

Aspirin, also known as acetylsalicylic acid, is one of the most widely used medications globally, renowned for its pain-relieving, anti-inflammatory, and blood-thinning properties. Its accessibility, affordability, and proven efficacy in pain relief contribute to its frequent use. This study found that healthy older adults taking daily aspirin had a higher risk of death than those taking placebo drugs, and that most deaths were cancer-related.

Geroscience-guided repurposing of FDA-approved drugs to target aging: A proposed process and prioritization

This article makes the case for a greater focus on repurposing existing drugs to target the biology of aging and age-related disease. The authors, who trawled the literature for FDA-approved drugs or drug classes that have a potential lifespan-extending effect in rodents, present a framework for assessing whether a given therapeutic might demonstrate geroprotective effects in a clinical trial.

The Mortality Toll of Estrogen Avoidance: An Analysis of Excess Deaths Among Hysterectomized Women Aged 50 to 59 Years

In the preprint Matt discusses in this podcast episode, six prescription medications containing estrogen had a positive impact on mortality risk. That is a striking result, and one worth further exploration. This paper examined the mortality toll of estrogen avoidance among middle-aged women who had undergone hysterectomies, and found that nearly 20,000 hysterectomized women had experienced premature death after the publication of findings that led to an aversion to hormone replacement therapy.

Canagliflozin extends life span in genetically heterogeneous male but not female mice

Matt mentions this study in the podcast as one showing that canagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor aimed at treating type 2 diabetes, was one of the more potent mouse lifespan-extending drugs to emerge from the Interventions Testing Program. Canagliflozin extended male mouse lifespan by 14 percent, and the age for 90th percentile survival by nine percent. The study found no lifespan extension effects in female mice.

At the Optispan Podcast, we aim to help you become your own detective of research in the geroscience field and beyond. Critical thinking is our compass. We want to help you dig into every aspect of a study: are the methods they used solid? Was the sample size big enough? Did they crunch the numbers right? What's the most reasonable interpretation of the data? Might a conflict of interest skew the results?

In Part II of a two-part series about a recent study of how a supplement called "Leap Years" affects canine cognitive function, Matt takes a magnifying glass to a bioRxiv preprint describing the clinical trial's methodology and findings. Beginning with a sentence-by-sentence dissection of the study's abstract, he describes various things he finds unusual or questionable about the way researchers ran and publicized the clinical trial: exclusion of certain data, a lack of disclosure around the supplement's ingredients, the use of an assessment tool that was not validated for its intended purpose, and more. He discusses conclusions we can actually draw from the study based on the information the researchers have supplied, and whether or not he would give the supplement to his own dog.

This episode is Part II of a two-part series. In part I, Matt talks about the press release announcing the drug's potential ability to reverse age-related decline and improve cognitive function in dogs, as well as the importance of interrogating bold advertising claims rather than taking them at face value.

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!

LeapYears

You can get more information about and purchase the LeapYears product here. Animal Biosciences, the company selling the product, describes LeapYears as "the only dual action dog supplement system that targets aging at the source – the cellular level." The website provides several resources about dog aging, cellular senescence, NAD boosters, and its clinical trial results.

A Randomized, Controlled Clinical Trial Demonstrates Improved Cognitive Function in Senior Dogs Supplemented with a Senolytic and NAD+ Precursor Combination

This is the preprint upon which the LeapYears product is based. Preprints are drafts of full papers that have not yet undergone peer review, a process of ensuring the credibility, validity, and reliability of published research by subjecting it to rigorous evaluation by independent experts. Preprint results can be exciting, valid, and spark interesting discussions, but should be interpreted with caution. This preprint provides some insight into the nuances of the clinical trial that led to the product's eventual introduction to the pet market.

NAD+ homeostasis in human health and disease

Nicotinamide adenine dinucleotide (NAD), an essential cofactor present in all living cells that modulates several metabolic pathways, became more prominent in the scientific literature in the last two decades when it was highlighted as a crucial component of sirtuin function. In this review, the authors discuss current knowledge of NAD's role in various human diseases as well as current therapeutic strategies that target NAD.

Age-Dependent Decline of NAD+—Universal Truth or Confounded Consensus?

This article questions the consensus view that NAD levels decline with age by examining NAD changes in various species, including yeast, worms, rats, mice, monkeys, and humans. They find that the evidence for age-dependent NAD declines is limited, in part due to a relative paucity of studies assessing how NAD levels change with age, and in part due to the many discrepancies in the literature about this topic, even down to the level of individual tissues. They note that human studies of age-related NAD changes are particularly limited and inconclusive, and call for larger-scale studies of and greater nuance in discussing the relationship between NAD levels and age.

A common signature of cellular senescence; does it exist?

At its core, cellular senescence represents a state of irreversible growth arrest in cells. Pinpointing a universal definition of senescence is challenging, however, because senescence manifests differently across cell types and contexts and encompasses a spectrum of phenotypic changes beyond just growth arrest, including alterations in gene expression, metabolic activity, and the secretion of pro-inflammatory factors. Subsets of senescent cells may exhibit distinct properties and functions. This review examines the question of whether there exists a common signature of cellular senescence.

Don't just swallow information whole—question it, test it, poke and prod it to see if it holds up under scrutiny.

One of our core goals at the Optispan Podcast is to help you become your own detective of research in the geroscience field and beyond. Critical thinking is our compass. We want to help you dig into every aspect of a study: are the methods they used solid? Was the sample size big enough? Did they crunch the numbers right? What's the most reasonable interpretation of the data? Might a conflict of interest skew the results?

In this episode, Matt puts the spotlight on a recent finding that made a splash in the longevity community: a combination senolytic/NAD booster product that researchers suggested had the potential to reverse age-related decline in dogs. Matt goes over what the product might contain (spoiler: we're not sure), what we do and don't know about it, and his personal feelings about whether it should actually be on the market for pet owners to purchase.

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!

Leap Years

You can get more information about and purchase the LeapYears product here. Animal Biosciences, the company selling the product, describes LeapYears as "the only dual action dog supplement system that targets aging at the source – the cellular level." The website provides several resources about dog aging, cellular senescence, NAD boosters, and its clinical trial results.

A Randomized, Controlled Clinical Trial Demonstrates Improved Cognitive Function in Senior Dogs Supplemented with a Senolytic and NAD+ Precursor Combination

This is the preprint upon which the LeapYears product is based. Preprints are drafts of full papers that have not yet undergone peer review—a process of ensuring the credibility, validity, and reliability of published research by subjecting it to rigorous evaluation by independent experts. Preprint results can be exciting, valid, and spark interesting discussions, but should be interpreted with caution. This preprint provides some insight into the nuances of the clinical trial that led to the product's eventual introduction to the pet market.

CORRECTING and REPLACING Animal Biosciences Announces New Canine Clinical Research Evaluating Reversal of Age-Related Signs in Dogs

The press release covering the LeapYears drug, originally published in Feburary 2024, makes several claims that Matt interrogates in this episode. In response to pushback on one of the claims, the Animal Biosciences team made a correction to a quote by founder and Harvard genetics professor David A. Sinclair about the supplement's ability to reverse dog aging.

Can Your Dog Live Longer With a Pill?

This article breaks down how the clinical trial tested the LeapYears formulation for its effects on older dogs. It discusses the statistical significance of the clinical trial's findings, and offers a perspective on how to interpret statistically significant data points among a basket of other statistically insignificant outcomes. It also discusses external confounders that could have influenced the clinical trial results.

While scientific papers are generally considered trustworthy sources of information, it's important to approach them with a critical mindset and to avoid blindly accepting their claims. The peer-review process, which helps ensure high research quality, is not foolproof. Errors or biases can slip through the cracks. In reading a paper, we should independently evaluate the evidence, scrutinize the methodology, and reflect on alternative interpretations of the data. Considering the influence of funding sources, conflicts of interest, and the potential for selective reporting can also help in maintaining a healthy skepticism about new information.

In this episode of Longevity This Week, Matt takes us through a recently-published paper about the effects of senolytic CAR T cell therapy on the aging process in mice to help us figure out whether the paper's claims hold water. He also analyzes a BBC article describing the findings. Popular press adaptations of the scientific literature often serve as a useful bridge between the complex world of research and the general public, but can be misleading in their attempts to make science accessible. They might, for example, inadvertently distort or oversimplify findings, exaggerate the significance of results, or selectively report research while ignoring contradictory or inconclusive evidence from other sources. We hope this episode will encourage viewers to approach science communication with a discerning eye, and to stay vigilant, curious, and open-minded in learning about the latest discoveries and developments.

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!

Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction

This is the paper Matt discusses in the podcast. It suggests that injections of chimeric antigen receptor (CAR) T cells with senoloytic, or senescent cell-eliminating, properties improves symptoms associated with physiological aging in mice.

Breakthrough anti-ageing cell discovery could help you stay younger for longer

This BBC article covered the paper describing the senolytic CAR T cell finding. Matt discusses the accuracy of its coverage in the podcast episode.

Naturally occurring p16Ink4a-positive cells shorten healthy lifespan

Senescent cells are cells that have entered a state of irreversible growth arrest, meaning they have stopped dividing and replicating. While senescence can serve a beneficial role in wound healing and preventing cancer, accumulated senescent cells can promote chronic inflammation and tissue dysfunction, and may contribute to the development of age-related conditions. This study found that clearing senescent cells from mice increased lifespan and delayed various age-associated pathologies, including cataracts and glomerulosclerosis.

Senolytic CAR T cells reverse senescence-associated pathologies

The lab that published the paper Matt discusses in this episode released this paper in 2020. This paper test the idea that CAR T cells can target a protein induced during cellular senescence, and in so doing improve pathology associated with liver fibrosis and lengthen the lifepsan of mice with lung adenocarcinoma.

Longevity This Week is a series of episodes discussing new findings or articles relevant to geroscience, longevity, and healthspan that may have popped up in the news.

This week we're featuring Richard Morgan, a 93-year-old rowing champion whom the Washington Post recently described as being "as fit as a 40-year-old". We talk about Richard's diet, exercise routine, and other aspects of his lifestyle that may have led to his enviable state in older age. We also discuss a recent Wall Street Journal article about how Americans are spending more of their lives in poor health, and about how "sickspan"—the amount of time we spend sick near the end of our lives—might change in years to come.

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!

Physiological characteristics of a 92-yr-old four-time world champion rower

This is the study on which the article in The Washington Post that Matt references in this episode is based. The study measured the oxygen uptake, carbon dioxide production, ventilation, and heart rate of 92-year-old Irishman Richard Morgan at rest and while using an ergometer, and found that Richard’s oxygen uptake kinetics were similar to those of healthy young adults. It also outlines his training and nutritional habits, which include an “extremely consistent diet”, 40 minutes per day of rowing, and two to three days per week of resistance training. Richard only began rowing at 73 and was not involved in any structured exercise regime prior to that.

Americans are sick for more of their lives

This article, which Matt discusses in the podcast, describes the decline in time that Americans spend in good health towards the end of their lives. In 1990, Americans spent 85.8% of their lives in good health. In 2021, that number went down to 83.6%. This change is in part due to medical advances that prevent us from dying of certain diseases, so we live for a longer time, but continue to suffer from many of the functional declines and diseases that accompany old age. The article discusses how the growing gap between healthy life and death has significant implications for healthcare, the economy, and the wellbeing of patients and their caregivers.

How healthy is the healthspan concept?

In 2018, Matt published this article exploring the concept of healthspan and the lack of clarity in the usage of the term. He notes that while a common definition of healthspan is “the period of life spent in good health, free from the chronic diseases and disabilities of aging”, there are many issues with this definition—for example, are all diseases equal in heralding the end of healthspan? If you are simply frail and get sick more often, has your healthspan ended? He discusses the implications of imprecise definitions of healthspan for interpreting new findings in the geroscience field.

Life-long spontaneous exercise does not prolong lifespan but improves health span in mice

According to this study, spontaenous exercise does not impact how long mice live, but delays their age-associated decline as measured in strength, endurance and motor coordination. They propose mechanisms by which exercise may prolong healthy cognitive and skeletal muscle function such as increases in neurotropic factors, or proteins crucial roles in the development, survival, and function of neurons, and the formation of new mitochondria within cells.