The Optispan Podcast with Matt Kaeberlein

In this episode, Matt and Nick react to investigative journalist and author Scott Carney's video describing what he calls "David Sinclair's longevity lie" in the context of David's longevity-focused entrepreneurial ventures. Matt shares his professional history with David, including his early interactions with David in Leonard Guarente's lab at the Massachusetts Institute of Technology (MIT) and scientific differences that emerged after Matt and colleagues were unable to reproduce a key result from David's work pertaining to resveratrol. Their discussion touches on some of David's scientific claims about age reversal, the role of institutions such as Harvard University in regulating scientific integrity, the potential for future interventions in healthspan and longevity, and the importance of separating personal feelings from scientific evaluation.

David, currently a professor in Harvard Medical School's Department of Genetics at the Paul F. Glenn Center for Biology of Aging Research, is a prominent aging researcher whose lab focuses on age-related epigenetic change, cellular reprograming, longevity drug discovery, mitochondrial fitness, reproductive aging, neurodegenerative disease,, and the human secretome. He has received awards including the National Institutes of Health Nathan Shock Award, the Merck Prize, and the Australian Medical Research Medal, and was elected to TIME's 2014 “100 Most Influential People in the World" list. David conducted postdoctoral research at MIT and obtained a PhD in Molecular Genetics at the University of New South Wales.

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 SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms

Matt and colleagues coauthored this paper in 1999 demonstrating that the SIR2 gene regulates yeast lifespan. Upregulating SIR2 extended yeast lifespan by about 30 percent.

Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan

This paper really kicked off David's sirtuin story. The paper's authors, which included David, developed an assay—a test or an analysis done to figure out the amount or presence of a specific substance or component in a sample—to identify drugs to activate the SIR2 gene and/or sirtuins, a family of proteins that help regulate important processes like metabolism, DNA repair, and stress response in the body. They found that resveratrol and several other compounds activated sirtuins and made yeast live longer.

Substrate-specific Activation of Sirtuins by Resveratrol

Matt and colleagues examined the effects of resveratrol on yeast SIR2 and found that the resveratrol-induced activation of yeast SIR2 was entirely dependent upon the presence of a particular fluorescent group. Without that group, resveratrol no longer had a significant effect on yeast SIR2 activity.

Mechanism of Human SIRT1 Activation by Resveratrol

This paper independently reproduced the findings of Matt and colleagues that resveratrol did not, in fact, affect sirtuin activation. Researchers tested the effects of resveratrol on three enzymes—yeast SIR2, human SIRT1, and human SIRT2—using the same assay that the authors of the original yeast life-extension-by-resveratrol paper developed and presented. They found that resveratrol activated only one of the enzymes, SIRT1. Crucially, it seemed that removing a particular fluorescent group removed the effect of resveratrol on SIRT1, suggesting that the finding was an artifact. The rather mild title of both this paper and Matt's may have contributed to the resveratrol story's persistence in the public consciousness for many years after these findings should have called the molecule's effectiveness as a lifespan extension tool into question.

A randomized, controlled clinical trial demonstrates improved owner‑assessed cognitive function in senior dogs receiving a senolytic and NAD+ precursor combination

This study describes the results of a clinical trial that Animal Biosciences, a company that David founded, funded. The clinical trial examined the effects of a therapeutic consisting of an NAD+ precursor and senolytic on dogs with mild to moderate cognitive impairment and reported a significant difference in cognitive impairment as measured by the owner-reported Canine Cognitive Dysfunction Rating (CCDR) scale. In a press release, David made claims about the findings of this study that Matt criticized as dishonest.

Coach, bodybuilder, and powerlifter Greg Doucette published a video on his Youtube channel discussing what he sees as the shortcomings of DEXA scans and why DEXA scans are not, in fact, the gold standard of body composition measurement. He bases his views on personal experience as well as his interpretation of a 2019 study that examined how closely DEXA and MRI measurements correlate.

In this episode, Matt reacts to Greg's video and presents his own opinion about the validity of DEXA scan measurements. Together with Nick, he discusses what DEXA scans do and don't measure, potential sources of inaccuracy in DEXA scans, honest interpretations of scientific literature, and more.

A DEXA (dual-energy X-ray absorptiometry) scan is an advanced imaging procedure for measuring bone density and composition. DEXA scans utilize two different energy levels of low-dose X-ray beams—one absorbed mostly by soft tissue, and the other absorbed mainly by bone—to differentiate between bone, fat, and lean tissue. In so doing, they provide noninvasive and detailed information about bone health, risk of osteoporosis or fractures, and body composition. While medical practitioners typically perform DEXA scans on the lower spine and hips, they can also perform DEXA scans on the whole body for the purposes of early detection and intervention.

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!

Changes in DXA-derived lean mass and MRI-derived cross-sectional area of the thigh are modestly associated

This is the paper upon which Greg bases his argument that DEXA scans are not necessarily useful tools for body composition measurement (though he does also state his opinion that studies are wrong half the time). This study examines the correlation between magnetic resonance imaging (MRI) and DEXA scans measurements of lean mass, and argues that while the cross-sectional correlation between the measurements is strong, the correlation of percent change over time is modest and thus DEXA scans may not be able to detect lean mass changes over time to a degree of accuracy necessary for use in clinical trials.

What Is a DEXA Scan and How Can It Help You?

This is an introduction to DEXA scans that covers the history of DEXA scans, how DEXA scans work, what happens during a DEXA scan, and how DEXA scans compare to imaging techniques such as CT scans, magnetic resonance imaging (MRI) scans, and x-rays.

Unexpected DEXA Scan Results? Here are Some Potential Causes:

You may have gotten your DEXA scan results back and balked at what you saw. This list addresses some possible reasons for DEXA scan surprises.

Abdominal fat analyzed by DEXA scan reflects visceral body fat and improves the phenotype description and the assessment of metabolic risk in mice

This study found a high correlation between visceral fat content measured by DEXA scans and the actual excised visceral fat content of mice, suggesting that DEXA scans are accurate tools for noninvasive fat distribution measurement.

DEXA FAQ

This list of FAQs covers many questions people have about DEXA scans, including how much radiation exposure we receive from DEXA scans, height and weight limits, the safety of DEXA scans for pregnant wome, and more.

In June 2024, the Aspen Ideas Festival held a three-day health-focused event in which speakers discussed new breakthroughs, policy developments, and possible futures in healthcare. "You Can Live Longer!" was a panel discussion during the festival that consisted of Altos Labs founder and chief scientist Rick Klausner, Cradle CEO and cofounder and venture capitalist Laura Deming, BioAge Labs CEO and cofounder Kristen Fortney, and NPR News Food and Health Correspondent Allison Aubrey discussing developments in the longevity field.

In this episode, Matt and Nick react to the panel discussion and discuss the potential of epigenetic reprogramming for improving organ transplants and reversing organ aging, the limitations of current techniques, the relevance of aging models in disease research, 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!

You Can Live Longer!

The panel discussion that Matt and Nick discuss in this episode took place at the 2024 Aspen Ideas Festival, a gathering of thinkers from different fields in an immersive event exploring new ideas and innovations. The three speakers, each of them leaders in different niches of the longevity space, discuss a wide range of topics, including new drugs in the pipeline that target healthy aging, the manipulability of the cellular aging process, and the functional significance of biological age clocks. They also discuss talent entering the longevity field and difficulties convincing investors to pay attention to aging in years past.

Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors

In 2006, Kazutoshi Takahashi and Shinya Yamanaka published this paper reporting four key transcription factors—Oct3/4, Sox2, c-Myc, and Klf4—whose overexpression induced mouse fibroblasts to return to their pluripotent, or immature, state. We now refer to these four factors as "Yamanaka factors". Transplanting the pluripotent cells that arose from Yamanaka factor introduction gave rise to certain adverse effects such as tumors.

Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors

This paper, which Takahashi and Yamanaka coauthored along with several collaborators, demonstrated that the four Yamanaka factors described in the previous paper also worked to induce a pluripotent cell state in adult human dermal fibroblasts. The Yamanaka-factor-induced pluripotent cells shared many features with human embryonic stem cells. The authors acknowledged the increased risk of tumor formation as a result of Yamanaka factor reprogramming.

Altos Co-founder and Chief Scientist Rick Klausner teases Yamanaka factors success at Aspen Ideas Health Conference

This article covering the Aspen Ideas Festival panel speculates that Altos Labs, a Jeff Bezos-backed company whose founder and chief scientist is panelist Rick Klausner, has achieved positive results with a "reprogramming cocktail" based on the Yamanaka factors.

When are mice considered old?

Mice are some of the most common animal models researchers use for studying human aging. This short article provides a helpful comparison of mouse and human life phases and aging, and shows that the correlation between mouse and human aging is not linear. It proposes an age at which "old mice" best correlate with "old humans", an important metric to consider in studies of mouse aging aimed at eventual translation to human aging.

Entrepreneur and competitive bodybuilder Mike Israetel recently released a video discussing Bryan Johnson's anti-aging protocol. Towards the end of the video, he gives us his take on the "big rocks" that account for the bulk of our longevity.

In this episode, Matt reacts in real time to his first watch of this end portion of Mike's video. Together with Nick, he goes over Mike's suggestions about diet, drugs, body composition, and supplements and provides some additional context and nuance to each recommendation where he sees fit.

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!

Renaissance Periodization

Mike Israetel's company, Renaissance Periodization, offers diet and exercise consultations and coaching as well as a hypertrophy app aimed at helping people get bigger muscles. This is the company's Youtube channel. The channel publishes videos featuring diet, exercise, and mindset tips, critiques of workout programs, and more.

Big mice die young: early life body weight predicts longevity in genetically heterogeneous mice

This study found that mice with a smaller body size outlived those with a larger body size. This association was present in both male and female mice and was stronger for weights taken earlier rather than later in life, suggesting that low body weight at earlier ages is particularly advantageous for mouse longevity. The authors hypothesize that body weight is likely a surrogate measure of biological changes that influence weight as well as later life outcomes.

Is height related to longevity?

Good news for short people: according to this study, rates of diet-related chronic disease are lower in people of shorter height, especially after middle age. Shorter people also tend to live longer. Data from centenarians—people who reach 100 years of age—bear this finding out: the study reported that Japanese centenarians were around 10 centimeters shorter than 75 year-olds, and that Hungarian centenarians had an average height of 154cm (about five feet one inch).

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

Matt and George Sutphin discussed this preprint in a recent episode. The preprint 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.

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.

Last month, entrepreneur and venture capitalist Bryan Johnson released a Youtube video detailing his trip to Prospera, Honduras to receive follistatin gene therapy from the Minicircle Gene Therapy clinic. Bryan describes Minicircle's gene therapy as "a pioneering technology with the potential to improve muscle and strength, slow the speed of aging, and many more benefits".

In this episode, Matt reacts in real time to his first watch of Bryan's video and responds to Nick's questions about various topics that come up along the way. He provides a primer on gene therapy and its potential as a longevity intervention, discusses the clinical evidence for follistatin's effects on humans and model organisms, and goes through several things one might want to consider when deciding whether to partake in a new therapy. He also gives his honest take on "offshore medicine"—medicine performed in countries that lack the regulatory oversight of the United States Food and Drug Administration—and discusses potential mechanisms for safely offering experimental therapies in the United States.

Follistatin is a glycoprotein that functions as a potent inhibitor of several members of the TGF-beta superfamily, particularly activin and myostatin. It is involved in various physiological processes, including muscle growth and development, reproduction, and inflammation. By binding to these proteins, follistatin prevents them from interacting with their receptors, thereby regulating their activity.
Minicircle Gene Therapy https://minicircle.io

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!

Minicircle Gene Therapy

Here's Minicircle's website if you'd like to check out the company's claims, follistatin primer, and more for yourself. The website includes the company's answer to "will this turn me into a superhuman?".

What is Gene Therapy?

This is a quick primer on gene therapy that the United States Food & Drug Administration has released. It covers potential mechanisms for manipulating gene expression in humans as well as some of the products currently available to do so.

Plasmid delivery of follistatin gene therapy safely improves body composition and lowers extrinsic epigenetic age in sex- and age-diverse adult human subjects

This paper, sponsored by Minicircle Gene Therapy, presents the results of a clinical trial demonstrating the efficacy of follistatin gene therapy on body composition and extrinsic epigenetic age in humans. Mean lean mass increased by 1.96 lbs, with a maximum increase of 12.15 lbs, and mean body fat reduction was 0.87 percent. The study reported mild trends in inflammatory markers, glucose metabolism, and cholesterol, none of which were significant. Participants did not experience severe adverse effects related to the therapy.

New intranasal and injectable gene therapy for healthy life extension

Matt mentions this paper in the podcast as a piece of research that has received some criticism for several reasons, among them a small sample size of mice in each treatment group. This study tested the efficacy and safety of a viral vector for delivering telomerase reverse transcriptase and follistatin gene therapy, and found lifespan extension effects for both therapies of 41.4 percent and 32.5 percent respectively. The paper also describes other observed effects of one or both gene therapies, including telomere length increases in some tissues, improvements in hair loss and texture, weight loss prevention, improved motor coordination, and preserved mitochondrial integrity.

Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice

A senolytic is an agent that selectively clears senescent cells. This paper describes vaccination as a potential delivery agent for a senolytic, enabling delivery to specific sites and the avoidance of off-target effects. The researchers suggest that a vaccination targeted at glycoprotein nonmetastatic melanoma protein B (GPNMB), a protein that is enriched in senescent cells, increases mouse lifespan and improves various aging-associated phenotypes such as atherogenesis.