This is the artificial intelligence voice of Peter Attia narrating this pod slice summary of the Drive Podcast.

The Drive Podcast features Peter Attia, the host, in conversation with Richard Miller. They discuss a variety of research and interventions aimed at slowing the aging process and, correspondingly, extending overall lifespan within the context of the Interventions Testing Program (ITP).

The ITP, supported by the National Aging Institute, is operational for over 20 years now. The ITP is run by three different research laboratories, including Richard Miller’s lab at the University of Michigan. This program seeks out potential drugs capable of extending the lifespan of mice, with the broader aim of finding such drugs for human use. Every year, fellow researchers worldwide propose potential drugs which the ITP evaluates based on their potential benefits and risks to the mice. Subsequently, the committee selects five to six drugs for testing. Ever since its initiation, the ITP has had four published significant hits, a couple of smaller significant influences, and a few more under pressing cross-checking.

The budget allocated to these labs is roughly a million dollars per year from the National Institute on Aging (NIA). However, despite the seemingly large budget, only a fraction goes towards widespread global aging biology, with a significant portion going towards Alzheimer’s disease research.

The podcast also delves into the choice of mouse models in aging research. Specifically, the significance of the UM-HET3 mice, a genetically heterogeneous model, over the common inbred mouse model (C57BL/6 or B6). The standard B6 mice don’t offer a vast genetic pool for experimenting as they are all genetically identical due to inbreeding over generations, whereas the UM-HET3 mice, despite having the same set of grandparents, are genetically diversified. Their DNA samples have led to essential discoveries about the varying impact of genes on lifespan across genders and ages, providing valuable insights into human genetics and aging proceses.

While the ITP hasn’t yet discovered an “anti-aging” drug to universally slow the aging process in people, the sophisticated complexity of its research may lay a foundation for significant breakthroughs in the future. The ITP’s methodology allows more accurate drug testing and insights into genetics that might eventually guide the development of effective age-slowing therapies for humans.

Peter Attia and Richard Miller continue their discussion on The Drive Podcast, focusing on the details of their research process within the Interventions Testing Program (ITP) and the peculiarities they came across. They use three different sites for their experiments, and they’ve noted some unexpected consistencies. While female mouse survival curves are often the same across the three sites, male mice at the Michigan site live about 5-10% longer than those at the other two. Similarly, both male and female mice at the Michigan site are about 10% lighter than those at the other locations.

When it comes to selecting a candidate molecule for testing, the board chooses based on enough biological plausibility. The primary outcomes they measure are proportional hazard (or risk of death over the whole lifespan, closely related to median lifespan), and some measure of maximum lifespan. For maximum lifespan, they use a test statistic calculated when 90% of mice in both the control and treated populations are dead. Then they look at the fraction of survivors in each group, which informs them if the tested drug increases the chance of being alive when the mice are much older.

The methodology in conducting experiments is rigorous. Each year, three hundred control mice are used for both genders, with fifty males and fifty females for each drug to be tested, spread across the three sites. They oversample controls to maximize statistical power as they compare controls to multiple drugs. At each site, they keep the same number of mice to maintain consistency.

The experiments throughout the years have shown variability in lifespan for controls, with male mice at Michigan consistently outliving their counterparts at other sites. The reasons for this are not definitively known, but it does not prevent comparison of results for male mice as they stratify by the site.

In terms of dosing and drug administration, significant effort is placed into ensuring the drugs are incorporated into the mice’s food correctly in the right dose and then absorbed effectively. Prior to use in a lifespan experiment, the drug’s presence in the mice’s system is confirmed through an eight-week pilot. This way, they manage to ascertain that the drug shows up in the liver and plasma.

Endeavoring to support open and collaborative science, the ITP’s rigorous approach strengthens the accuracy and validity of their findings, optimizing their potential to contribute to human anti-aging efforts.

The success of the Interventions Testing Program (ITP) in extending the lifespan of mice is closely related to the rigorous methodology utilized in drug administration. For instance, whenever a novel drug is introduced, a careful study is conducted to ensure its presence in the mice system. A detailed examination is carried out on blood concentrations, which may signal potential challenges. For instance, they found that the blood concentrations of the drugs Rapamycin and Kagan are three times higher in female mice than in males. Although they have not conclusively established why, it certainly raises questions about the differential impact of certain drugs based on gender. It seems probable that the blood concentrations in female mice may have reached toxic levels, which hints at adjusting the dosages for females or timing its administration differently.

Importantly, all candidate drugs must be administered in the mice’s food, as intravenous or intramuscular administration is not feasible given the vast number of mice involved. That said, the ITP does not monitor individual food consumption, which leaves room for variability in drug consumption. However, this is beyond control unless individual caging, which poses severe issues, is implemented.

The experiments have yielded intriguing findings. For instance, they have demonstrated that the drug Rapamycin, when started late, can still significantly extend the lifespan of old mice. This was surprising since it was hypothesized that for a drug to slow aging, it should ideally start when the mice are young. Similar effects were found with drugs like 17 alpha estradiol, acarbose, and canagliflozin, proving that it was not an isolated phenomenon with Rapamycin.

In total, the ITP has run about 100 drugs through their protocol over the past two decades with significant successes in some of them like Rapamycin, 17 alpha estradiol, and Canagliflozin. Each of the drugs showed substantial lifespan extensions, underscoring that the potential for anti-aging interventions may be higher than anticipated. As the discussion continues, the hosts underscore the need for a finer understanding of the sex-specific differences in drug absorption, conjugation, and excretion, primarily as it affects human healthcare.

The podcast transcript delves deeper into the crux of the Interventions Testing Program (ITP) approach and its findings. The guest, Richard Miller, admits that there was a hurdle in formulating Rapamycin initially, and there were debates within the ITP team on whether to continue with the study, given that mice were now in their geriatric phase. However, the team took a calculated risk and proceeded. The outcome was unexpectedly significant, supporting the theory that starting Rapamycin treatment in older mice can still extend their lifespan considerably.

The patterns they found in Rapamycin treatment were also evident in middle-aged mice treated with Acarbose, Canagliflozin, and 17 Alpha Estradiol, suggesting this phenomenon is not exclusive to Rapamycin. Laboratory tests, like grip strength and longevity on a rotating rod, proved that even if drugs were started during middle age, there was a marked improvement in these specifications.

Research priorities for the ITP now include diving into cognition, with promising discussions underway with neurobiologist Katherine Kerosi. The focus lies not only on extending lifespans but also measuring and improving health quality indicators. These secondary measures of health are only investigated once a drug proves successful in extending lifespan. Depending on each site’s strengths and interests, various health aspects, like visual acuity, strength, body temperature regulation, and glucose homeostasis, can be examined.

The ITP process involves Stage 1 and Stage 2 testing. In the Stage 1 study, only lifespan and body weight at four ages are measured due to cost and standardization difficulties. In Stage 2, however, tests vary based on each location’s interests, strengths, and weaknesses. For example, Jackson Labs incorporated numerous tests such as visual acuity, hearing acuity, strength, and body temperature regulation. The Texas team specialized in glucose control, while Miller’s lab focused on pathology, narrowing down on specific organs and tissues affected by the drugs.

When they move to a tissue-level investigation, cross-collaboration with other labs equipped to analyze specific tissues becomes essential. This spotlight on tissues also highlights epigenetic changes in treated versus untreated mice—an area that’s piqued interest among researchers like Steve Horvath and Vadim Gladyshev. However, they are cautious about connecting these changes to any aging process as they believe it’s still early days.

Through the podcast discussion, Richard introduces the concept of Aging rate indicators contrasting with traditional biomarkers. Aging rate indicators function as the ‘speedometer’ of aging, showing the rate of aging rather than the distance covered (age). Currently, the ITP has identified 13 aging rate indicators that show consistent changes in different varieties of slow-aging mice. A deeper understanding of these aging rate indicators may be instrumental in idiosyncratically inspecting the rate of aging, providing another tool in the arsenal against aging.

Taking a step back to Bio101, we begin to understand how we turn DNA into mRNA into tRNA and protein. The process is beautifully complex, and it starts with the DNA, which is located in the cell’s nucleus. Here lies the blueprint for everything the body does. The DNA is comprised of four distinct bases: Adenine (A), Thymine (T), Cytosine (C), and Guanine (G). The information in DNA is stored as a code made up of these four chemical bases.

The first part is called transcription, and it occurs inside the nucleus. An enzyme called RNA polymerase attaches itself to one strand of the DNA and starts to assemble a chain of nucleotides to produce a mRNA molecule. The RNA bases pair with their complementary partners on the DNA strand (C with G and A with T in DNA, but U replaces T in RNA), therefore transcribing the genetic information from the DNA onto the new RNA molecule. This mRNA molecule, a mirror image of a portion of the DNA strand, then leaves the nucleus and moves into the cytoplasm.

The second part, called translation, starts when this mRNA molecule arrives at the ribosomes, the protein-making structures located in the cytoplasm. Here, every three bases, known as a codon, correspond to a specific amino acid or indicate start or stop. Transfer RNA (tRNA) molecules with attached amino acids recognize and bind to these codons, lining up the amino acids in the correct sequence for the new protein. This way, the genetic code from the original DNA strand is translated into a chain of amino acids, resulting in a newly synthesized protein.

Now, it’s interesting to note that studies have shown that the correlation between the RNA and the protein outcomes is about 30%. In simpler terms, it means that only 30% of the changes seen at the protein level can be attributed to alterations at the RNA transcription level. This indicates that other factors influence protein levels, highlighting the importance of researching not only genetic information at the RNA level but also at the protein level. These factors include processes like differential RNA translation or alternate protein degradation pathways.

The guest, Richard Miller, emphasized the growing interest in proteomic data collection because proteins are the real doers of the cell. While RNA-level studies give valuable information on genetic transcription, they might miss out on around 70% of what is controlling protein levels—proteins, which are integral to the cell’s activities and functions. This revelation is beginning to wake up the scientific community, ushering in new streams of investigation focusing on protein-level dynamics.

So, in understanding DNA, RNA, and protein synthesis, we’re also uncovering the complexities of cellular function. The process is more intricate than a straightforward linear pathway, pointing to a wealth of unexplored potential in the biological sciences.

In this segment, we delve deeper into the DNA translation process and the role of proteomic data collection. Richard Miller emphasized the significance of proteomic data, as proteins are the key players in cellular function. He noted that while RNA-level research is essential, it only contributes to about 30% of the changes seen at the protein level. This suggests there are other factors at work that drive protein levels, such as differential RNA translation or alternate protein degradation pathways.

Also, the point was made that different cells in the body have varying RNA specifications, despite having the same DNA. This explains why the liver, eye, and muscle produce different types of proteins, a process controlled at the epigenome level by turning genes on and off.

Expanding on the concept of transcription, another point is made on how proteins are synthesized. When the mRNA molecule arrives at the ribosomes, it carries a genetic code in sets of three bases, known as codons, each corresponding to an amino acid. Transfer RNA (tRNA) molecules with attached amino acids recognize and bind to these codons, leading to the production of a newly synthesized protein.

Miller points out that many in the scientific community once thought that the correlation between mRNA and protein outcomes is a straightforward linear process. However, studies have shown this is not the case, as only 30% of changes at the protein level can be attributed to changes at the RNA transcription level. Other factors, such as selective RNA translation, selective RNA sequestration, and selective protein degradation, among others, play significant roles.

Wrapping up this summary, Miller urges the scientific community to pay more attention to studies at the protein level and explore protein dynamics further. He posits that a better understanding of DNA, RNA, and protein synthesis will lead to the discovery of a wealth of unexplored potential in the biological sciences, especially in the context of aging and anti-aging drugs.

Miller also mentions an “Aging speedometer”—a tool to measure the aging rate of humans by looking for consistent differences in known genetic mutations, effects of caloric restriction, and responses to drugs. It could potentially be utilized for finding significant anti-aging measures. Ultimately, the goal is to examine the effects of these factors on humans — specifically changes in aging rate indicators when certain drugs are introduced. This could further advance aging research.

In this conversation, Richard Miller and Peter Attia dive into the intricacies of various anti-aging drugs and their impacts on different age-sensitive properties, discussing their potential in both advancing human lifespan and healthspan. As a case study, they examine 17 alpha estradiol. According to Miller, this is a stereoisomer of the dominant form of estrogen (17 beta estradiol), but unlike its counterpart, it does not bind effectively to the typical estrogen receptors.

This characteristic sparked the curiosity of James Nelson who hypothesized that estrogens are beneficial (potentially explaining why females have a longer lifespan) and that 17 alpha estradiol could provide the health benefits of estrogen without having the feminizing effects. Although much of this initial supposition proved incorrect, the proposal was enough to spark the pursuit of empirical studies through the Interventions Testing Program (ITP).

The ITP found that 17 alpha estradiol was indeed beneficial, although the reasons remain unclear. The precise mechanisms of action and target receptors of the compound are as yet undetermined, and it is suggested that the impacts may be due, not to interaction with traditional estrogen receptors, but other receptors or factors.

Miller and Attia likewise discuss a drug called “Acarbose”, which has been shown to positively impact mice’s grip strength and blood glucose control, adding to a growing list of substances that hold promise for both extending lifespan and improving healthspan. In evaluating these drugs, Miller stresses the importance of researching not just cancer, which is the primary cause of death in 80% of the mice treated, but also other factors that are not related to cancer.

This dialogue emphasizes that understanding the mechanisms at play in these anti-aging substances is a difficult but critical task, as is getting better at detecting ‘biomarkers of health’ as opposed to simply biomarkers of life extension. In this sense, findings that point towards maintaining youthful cognitive and physical functioning in mice, for example, could hold substantial value. In the pursuit of these goals, potentially ground-breaking work is being done by researchers such as a young scholar at Stanford named Hamilton O, who is concentrating on deconvoluting plasma signals.

As a closing point, the conversation observes the ethical considerations involved in the production of ‘anti-aging’ drugs, pointing out that there is indeed a difference between a drug that could extend one’s lifespan and one that improves one’s healthspan. The implications of these distinctions remain to be carefully explored and understood.

Following a look into the anti-aging potential of 17 Alpha estradiol, Peter Attia and Richard Miller move on to discuss a few other notable substances, including a specific estriol (16 Hydroxy estriol), which, surprisingly, has been found to harm female mice while benefiting male ones.
Richard Miller also talks about the Interventions Testing Program’s track record with well-known substances like Resveratrol, Metformin, and Nicotinamide Riboside, each of which was once touted to have anti-aging benefits. In conducting tests with mice, however, the ITP did not find that these substances extended the lifespan of mice. This doesn’t necessarily mean that they wouldn’t work in humans, but the evidence in their favor is arguably weak or even, as Miller suggests in the case of Resveratrol, heavily overhyped.
Discussing these popular supplements, Miller mentions how a failure in mice isn’t necessarily indicative of failure in humans. Despite the “failures,” the case for such substances may still be open, although determining the effective dose and possible side effects will be more complex. Potentially, these substances, especially Nicotinamide Riboside, could still prove effective when used with other substances or administered with a particular enzyme. Meanwhile, for metformin, despite being safe for human consumption, it didn’t lead to lifespan prolongation in mice. As for resveratrol, despite plenty of hype, it failed to extend lifespan in normal mice.
With no definitive conclusions across the board, there is a pressing need for rigorous human trials in this area. Such studies could provide a more accurate understanding of these drugs’ potential health benefits in humans while acknowledging that the effects of these substances could differ significantly between mice and humans.

In his discussion with Peter Attia, Richard Miller brings up the potential anti-aging benefits of over-the-counter drugs like Meclizine and Astaxanthin, both of which were found to increase the lifespan of male mice by about 10%. Both of these drugs were studied using the Interventions Testing Program (ITP), the rigorous testing protocol followed by Miller’s lab. While Miller admits that more research is essential to understand exactly how these drugs interact with the body and whether their anti-aging benefits will translate to humans, he believes that the initial results are promising.

Meclizine, well-known as an over-the-counter treatment for seasickness, was studied after it was found to inhibit mTOR, a protein linked to aging. Even though mTOR inhibition’s specific role in Meclizine’s potential lifespan-extending effect has yet to be confirmed, the drug’s effect on lifespan was significant. Miller’s lab is currently preparing to test Meclizine at higher concentrations to see if its lifespan-extending benefits can be enhanced.

Astaxanthin, a compound found in various seafood, was also found to have significant lifespan-extending effects in male mice. Despite having potentially broad health benefit claims, more research is required to find which specific mechanisms Astaxanthin interacts with to increase lifespan.

Interestingly, Miller’s lab found that neither of these over-the-counter drugs extended ‘maximum lifespan,’ (the age at which the longest-lived 10% of a group of organisms remain alive). However, further exploration with different doses may yet yield different results.

Miller’s lab also tested Fisetin, a plant flavonoid purported to have senolytic properties (i.e., it supposedly helps remove aging or damage-accumulating senescent cells in the body). Contrary to expectations, Fisetin did not impact the lifespan of male or female mice. Furthermore, it didn’t appear to remove senescent cells.

Miller expresses some skepticism about the concept of ‘senescence cells’ contributing to aging. He explains that “senescence” is not a one-size-fits-all term; there are different types of cellular stress responses that could presumably fall under the umbrella of “senescence,” all with different markers and effects, hence the need to be specific when discussing these cell types.

Expanding on this, Miller suggests that assuming ‘senescent cells’ cause aging and that removing these cells can reverse it is an oversimplification since there is a diverse range of ‘senescent cell’ types and functions. To further knowledge and make significant inroads in anti-aging research, Miller advocates examining these nuanced distinctions rather than resorting to overly broad classifications.

In the discussion around senescent cells, Miller brings to focus a study where beta-galactosidase positive cells, a commonly used marker for senescence, were examined in skin samples from individuals of varying ages. Emphasizing that even among the oldest age groups, the number of actual senescent cells was minimal, he proposes that the concept of senescent cells contributing to aging has been overly emphasized.

The Interventions Testing Program (ITP) also studied Fisetin, a plant flavonoid reportedly holding senolytic properties, implying it could help remove senescent cells. However, it neither impacted the lifespan of the mice nor seemed to remove senescent cells. The outcome led Miller to reiterate the viewpoint that assuming the removal of senescent cells can reverse aging is oversimplified thinking, given the array of cell types and functions classified as ‘senescent.’

Peter and Miller delve into the idea of an anti-senescent drug, a chemotherapy-type, and its potential inclusion in the ITP. Though certain details couldn’t be disclosed, they agreed that a rundown of upcoming studies is essential. These would include studies of ‘Meclizine,’ ‘Astaxanthin,’ and ‘177 Alpha Estrad’ as well as evaluations of aging indicators and plasma biomarkers that may aid in assessing human interventions.

Adding to the list, Miller emphasizes the need to investigate whether these drugs slow cognitive failure. It builds on the growing recognition that understanding health span is as crucial, if not more so, than lifespan. The addition of neurocognitive assessment to the other tools bundled into the program is viewed as an exciting development. This comprehensive approach not only stimulates other labs to extend the work but also encourages collaborations and innovative ideas.

Peter also explores the benefits of potentially doubling the program’s capacity through further funding. He posits that philanthropists may be interested in significantly impacting the throughput of molecules, biomarkers, and insights. As such, the conversation anticipates the growth and increased diversity of anti-aging research in the coming years.