Podcast Summary
Dr. Richard Miller's Research on Aging in Mice: Dr. Richard Miller, a renowned aging researcher, leads the NIA-funded interventions testing programs for longevity in mice, discovering positive and negative findings for various molecules like SGLT2 inhibitors and nicotinamide riboside.
Dr. Richard Miller, a professor of pathology at the University of Michigan and the director of Michigan's Paul F. Glenn Center for Aging Research, has made significant contributions to the field of aging research. He has received numerous awards for his work and serves on various editorial and advisory positions for organizations like the American Federation for Aging Research and the National Institutes of Aging. Dr. Miller's research primarily focuses on the basic biology of aging in mice, and he is known for his work on the NIA-funded interventions testing programs (ITPs), which represent the gold standard for testing molecules for longevity. The ITPs are conducted in three labs, including Dr. Miller's, and the results have shown interesting findings for various molecules, some positive and some negative. Recently, there have been exciting findings regarding an SGLT2 inhibitor and nicotinamide riboside, which are topics of discussion in Dr. Miller's conversation on the Drive podcast. Dr. Miller's personal interest in science and aging began at a young age, leading him to pursue an MD and PhD at Yale in the 1970s and eventually a postdoc at Memorial Sloan Kettering.
The relationship between the Hayflick limit and telomeres in aging: The discovery of the Hayflick limit, initially linked to aging, was later found to be due to telomere shortening. However, the relationship between the two is still not fully understood and requires further research. Importantly, having the right mentor and research environment is crucial for scientific growth and success.
The discovery of the Hayflick limit, which is the number of times normal human cells can divide in culture before they stop, was initially thought to be related to aging. However, it was later found that the limitation of growth was actually due to the shortening of telomeres. Unfortunately, many researchers bought into the idea that the Hayflick limit and telomeres were linked to aging, leading to a generation of scientists focusing on these areas as the primary causes of aging. Recently, a study in Israel suggested that hyperbaric oxygen could lengthen telomeres, further reinforcing this belief. However, it's important to note that the relationship between the Hayflick limit, telomeres, and aging is still not fully understood and requires further research. Another key takeaway from the conversation is the importance of finding the right mentor and research environment. The speaker shared their experience of leaving a postdoc position due to a difficult mentor-mentee relationship and how it led them to change their research focus. This highlights the significance of having a supportive and productive research environment to thrive in and make meaningful contributions to the field.
The telomere theory and its limitations: While telomere shortening is linked to aging and disease, it's not a definitive solution or biomarker for aging. Focus on multiple interventions and their effects on various aspects of aging, rather than relying solely on telomere length.
While the telomere theory, which suggests that shortening telomeres leads to aging and disease, is an important area of research, it should not be considered a definitive solution or biomarker for aging. The idea that manipulating telomeres directly can extend life or cure aging is a common misconception. Instead, research on aging should focus on various interventions and their effects on multiple aspects of aging, rather than relying solely on telomere length as a marker. The discussion also touched upon the importance of studying aging in different species and the role of telomeres in cancer biology. The move from BU to Michigan was prompted by Patsy's job offer there, and the idea for the Interventions Testing Program (ITP) came from a group of researchers commissioned by the National Institute on Aging to discuss potential ways to test interventions directly on various organisms.
The Evolution of Anti-Aging Research: Recognizing the potential of anti-aging research despite its evolving nature, as shown by promising signs like caloric restriction and daft mutants in sea elegans.
Discussions around anti-aging medicine were not taken seriously 18 years ago, but the development of strategies to extend life was worth pursuing. The notion of aging being a single process was not widely accepted among researchers, making the idea of interrupting it seem futile. However, with the understanding that aging is a unitary process, the possibility of slowing it down becomes permissible. At the time, there were promising signs such as caloric restriction and the discovery of daft mutants in sea elegans, which provided hope for extending life. The article emphasizes the importance of recognizing the potential of anti-aging research, even if it was still an evolving process.
Discovering genes that extend lifespan in C. elegans challenged the belief that aging was too complex to be influenced by a single gene.: The discovery of genes like DAF16 and DAF2 in C. elegans showed that aging could be influenced by specific genetic interventions, paving the way for further research into malleable aging processes.
The discovery of genes like DAF16 and DAF2 in C. elegans, which were shown to extend the lifespan of the worm, challenged the prevailing belief that aging was too complex to be influenced by a single gene. This discovery, which was met with skepticism at the time, paved the way for further research into the possibility that aging could be influenced by specific genetic interventions. The debate around this idea was heated, with some scientists arguing that it was impossible for a single gene to extend lifespan in any species. However, the discovery of the Ames dwarf mutation in mice, which also extended lifespan, helped to shift the consensus towards the idea that aging was indeed malleable. Today, the question is no longer whether aging can be influenced by genetic interventions, but rather what specific processes can be targeted to slow aging. The discovery of DAF16 and DAF2 was a crucial proof of principle that aging is not a fixed process, but rather one that can be influenced by specific biological processes.
Effectively framing research questions: The Interventions Testing Program (ITP) is a rigorous scientific framework designed to test single drug interventions for their ability to extend lifespan reliably and reproducibly by having enough statistical power, running tests in parallel, and using genetically heterogeneous mice.
Asking the right question is crucial in scientific research. Dr. Richard Miller emphasizes the importance of framing questions effectively to make progress in understanding complex issues, such as the aging process. He also highlights the significance of the Interventions Testing Program (ITP), a rigorous scientific framework designed to test single drug interventions for their ability to extend lifespan in a reliable and reproducible manner. The ITP's key principles include having enough statistical power to detect small effects, running tests in parallel at multiple sites, and using genetically heterogeneous mice to account for genetic variations. By employing these principles, the ITP aims to provide reliable and believable answers to the fundamental question of whether a drug can extend lifespan.
Using genetically diverse sites and mice increases research power and reproducibility: Using genetically diverse sites and heterogeneous mice in research enhances findings' reliability and applicability to humans, but remains underutilized.
Conducting research using three genetically diverse sites not only increases the power of the results but also ensures reproducibility. This approach allows researchers to avoid potential methodology issues and increases the likelihood of discovering drugs that work across different genetic backgrounds. Additionally, using genetically heterogeneous mice, each with unique genetic makeup while sharing half of their genes, provides a more accurate representation of the human population and ensures reproducibility over time. Despite the advantages, the use of genetically heterogeneous mice in research is not widely adopted, with less than 10% of research in mice utilizing this method. The National Institute on Aging (NIA) once had a colony of genetically heterogeneous mice but discontinued it due to lack of demand, as most researchers preferred using the more commonly used inbred black six mice. However, there is a growing recognition of the importance and benefits of using genetically heterogeneous mice, and the NIA is starting to receive more requests for them.
ITP: Testing drugs for aging research: The ITP selects drugs for aging research based on human safety, potential benefits, and previous human use.
The ITP, or Interventions Testing Program, allows anyone to suggest potential molecules for aging research. During the early stages of the ITP, four suggestions were accepted, including aspirin and NDGA. Aspirin initially showed promising results, but when tested at higher doses, it did not extend longevity. The decision to use a low dose was based on the sponsor's suggestion, but later, it was speculated that a higher dose might have been more effective. The budgetary commitment for the ITP is significant, and resources must be allocated carefully. Clinical data in humans plays a crucial role in the decision to include a drug in the program. For instance, metformin, which is FDA-approved for diabetes, is a promising drug for aging research due to its previous human use and proven safety. The ITP prioritizes testing drugs that have potential health benefits for humans, as testing in humans for aging is slow and expensive.
Exploring drugs' potential impact on aging and disease in mice: Studying drugs with promising mechanisms of action in mice, even if their effects may not directly translate to humans, can provide valuable insights into aging and disease processes.
While the effectiveness of certain drugs in preventing diseases or extending lifespan in mice may not directly translate to humans, it's still worth studying these drugs due to their potential mechanisms of action. For instance, aspirin, which is known to be a strong anti-inflammatory, was tested in mice not to prevent heart attacks but due to its potential impact on inflammation and aging in both species. Another example is rapamycin, which was reformulated and tested on older mice, and its strong effects on extending lifespan in both males and females are still being studied for potential human applications. These findings demonstrate the importance of continuing research on drugs with promising mechanisms of action, even if their effects may not be immediately clear in humans.
Extending lifespan with drugs like rapamycin in older animals: Contrary to belief, certain drugs can significantly extend the lifespan of older animals, improving median survival but not necessarily extending old age.
Giving certain drugs like rapamycin to older animals, even if started late in life, can still extend their lifespan significantly. This goes against the traditional belief that aging processes become irreversible with age. The difference between increasing median survival (the age at which half have died) and maximum survival (the longest living individual) is important to understand when interpreting survival statistics. While extending median survival is beneficial for public health, it doesn't necessarily affect how much longer one lives in old age. Authentic anti-aging interventions should ideally extend the lifespan of the oldest individuals in the treated group compared to the control group. In the case of rapamycin, both males and females showed considerable extensions in their lifespan, with females experiencing a more pronounced effect due to higher blood levels in females when given the same dose.
Rapamycin extends lifespan by 9% for males and 14% for females when started young.: Rapamycin adds approximately 25% more life once midlife is reached, but calculating exact years or months may not be as informative as focusing on change in median lifespan. Late-started drugs like Acarbose and 17 alpha estradiol also have benefits, especially for muscle strength and glucose tolerance.
The drug rapamycin extends the lifespan of mice by 9% for males and 14% for females when started at a young age. This translates to approximately 25% more life once midlife is reached. However, calculating the exact number of additional years or months of life after administering the drug may not be as informative as focusing on the change in the overall median lifespan. An exception to this is when a drug is started very late in life, as in the case of rapamycin, where statistics on how many animals reach the 90th percentile become more informative. Other drugs like Acarbose and 17 alpha estradiol, when started late in life, also show beneficial effects, although not as effective as when started in youth. Recent studies have shown that even late-started 17 alpha estradiol has highly beneficial effects on muscle strength, glucose tolerance, and muscle structure.
Effects of rapamycin on mTOR complex one and two: Rapamycin inhibits mTOR complex one for potential longevity benefits but destabilizes complex two, which may cause negative consequences. Human data suggest intermittent dosing may inhibit complex one without complex two for benefits, but research is ongoing.
The effects of rapamycin on mTOR complex one and two are more complex than previously thought. While rapamycin inhibits complex one, leading to potential longevity benefits, it also destabilizes complex two, which may cause negative consequences. Recent human data using intermittent dosing strategies suggest that inhibiting complex one without inhibiting complex two may be beneficial. However, the intricacies of the kinetics and cell type differences require further research. Additionally, the findings from mutant mice suggest that the elevation of mTOR complex two could be beneficial, adding another layer of complexity to the understanding of rapamycin's effects. Ultimately, the interactions between mTOR complex one and two, and their specific targets, will be crucial in developing a more sophisticated understanding of rapamycin and other drugs' effects on aging.
Considering sex and individual differences in animal drug studies: When studying drug effects on mice, it's crucial to account for sex differences and individual variations in blood levels to avoid misinterpretations.
When studying the effects of drugs on mice, it's important to consider variables such as sex and individual differences, as well as the actual blood levels of the drugs in the mice. For example, a study on rapamycin found that female mice had higher and longer-lasting blood levels than male mice, which complicates comparisons between the two sexes. Regarding the drug A-Caribose, it was originally proposed by David Allison and Daniel Smith as a caloric restriction-like intervention due to its ability to block the absorption of glucose in the gut. However, the researchers were unsure if the mice would consume fewer calories overall or just have lower glucose levels despite consuming the same amount. This highlights the importance of carefully considering the potential mechanisms and outcomes when designing and interpreting animal studies.
Acarbose may reduce peak glucose levels after meals in mice: Acarbose, a diabetes drug, may reduce peak glucose spikes after meals in mice, extending their lifespan, and warrants further human clinical trials.
Acarbose, an FDA-approved drug used for diabetes treatment, may work by reducing the peak glucose levels after meals in mice, rather than overall glucose reduction. This theory is supported by the drug Conagliflozin, which also blocks peak glucose and extends lifespan in mice and humans. The mice did not show signs of GI distress during the study, but weight loss or lack of weight gain was inconsistent among studies. Acarbose's long safety history and its use in hundreds of thousands of people make it a strong candidate for human clinical trials. Despite efforts to test it on dogs, no studies have been reported yet.
Misinterpretation of resveratrol study results: Research findings should be evaluated in context and with consideration of limitations to avoid misinterpretations.
The widely publicized study on resveratrol and its anti-aging benefits in mice, published by David Sinclair's lab at Harvard, was not a demonstration of a drug that slowed aging or extended maximum lifespan. The mice in the study were on a highly toxic diet, and the reported increase in median lifespan was only significant in those mice. The misinterpretation led to the National Institute on Aging ordering studies on resveratrol, but the results showed no effect on longevity when given to mice on a normal diet. This serves as an example of the importance of considering the context and limitations of research findings.
The Significance of Resveratrol in Anti-Aging Debate: Despite ongoing research, there's no conclusive evidence that Resveratrol or Sirtuin activators slow the aging process or provide health benefits.
The hype surrounding Resveratrol as a youth elixir or anti-aging supplement may have been premature based on current scientific evidence. The debate surrounding the significance of Sirtuins and Resveratrol in the aging process has been ongoing, with conflicting results. Some studies suggest that Resveratrol may have a positive effect, while others indicate minimal or no impact. The reaction to these findings has varied, with some companies continuing to profit from the sale of Resveratrol-related products, while others have moved on to researching alternative compounds. The ITP (Interventions Testing Program) is an ongoing effort to evaluate various compounds and mixtures for potential health benefits, including green tea extract, which was also discussed in the conversation. The evaluation process involves a rigorous scientific review by a committee of experts. Despite the ongoing research, there is currently no conclusive evidence that Resveratrol or Sirtuin activators slow the aging process or provide health benefits.
Not all promising compounds extend lifespan in animals: Green tea extract and methylene blue failed to extend lifespan in animal studies, while 17 alpha estradiol showed remarkable effects in male mice, but more research is needed to understand its sex-specific efficacy and potential use in females.
Not all compounds, even those with promising initial results, prove to be effective in extending lifespan. For instance, green tea extract and methylene blue, despite initial hype, did not show significant benefits in animal studies. On a more intriguing note, 17 alpha estradiol, a compound synthesized to mimic estrogen but with a different bond orientation, showed remarkable effects on male mouse longevity, surpassing that of females. However, the reasons behind its sex-specific efficacy remain unclear, and further research is needed to determine if it can be made to work in females as well. Additionally, the estrogen receptor researcher, Jim Simkins, had an interesting theory that giving estrogen to males could make them live as long as females without the feminizing side effects. This theory, while intriguing, has yet to be fully understood or proven.
Under-investigated areas in the study of aging drugs in male mice: The role of 17 alfesterol dial and hydrogen sulfide in aging is unclear, and the SGLT2 inhibitor extends male mouse lifespan but not females, highlighting the complexity of aging and the need for further research.
Despite impressive findings on the effects of certain drugs on aging in male mice, there are still many under-investigated areas and unknowns in the field. For instance, the role and potential of 17 alfesterol dial is unclear, and its investigation as an investigational new drug has not been pursued extensively. Another example is the ongoing research on hydrogen sulfide and its potential impact on aging, which is still in the early stages and has yet to yield definitive results. Additionally, the SGLT2 inhibitor, which extends the lifespan of male mice by up to 14%, has no effect on females, but the reason for this difference is unknown. These findings underscore the complexity of the aging process and the need for continued research to uncover new insights and potential interventions.
Link between high glucose levels and cancer risk in mice, with hematopoietic cancers being the leading cause for both genders: High glucose levels increase cancer risk in male mice, particularly hematopoietic cancers, but the reasons behind the gender difference are unclear.
High glucose levels are linked to a higher risk of various types of cancers in male mice, with hematopoietic cancers being the leading cause of death for both males and females. However, the reasons behind this gender difference are not yet clear. The discussion also touched upon the possibility that glucose excursions could impact cancer risk or immune defenses, or even modify some fundamental element of the aging process in the hypothalamus. While the exact mechanism is unknown, it's important to note that SGLT2 inhibitors, such as canagliflozin, may not work in the same way in mice as they do in humans, and their effects on cancer are still being explored. The failure of Metformin as a standalone treatment in mice is another intriguing finding, and its reasons, such as the study design or potential limitations, were not extensively discussed in the conversation.
Metformin's effectiveness in extending lifespan in humans is uncertain: Observational studies hint at metformin's potential benefits for non-diabetics, but more trials are needed to confirm its efficacy and safety
While metformin has shown promising results in extending lifespan in some studies in mice, its failure in others and the discrepancies in study results highlight the complexity of translating animal research to humans. The drug's effectiveness in humans, particularly for non-diabetics, is still an open question. An observational study suggesting that non-diabetic people not taking metformin have a higher mortality risk than diabetic users on the drug provides intriguing evidence, but further randomized clinical trials are needed to definitively answer whether metformin is beneficial for non-diabetics. The challenges in conducting such trials include their high cost, ambitious timelines, and the need to meet rigorous FDA criteria.
Nicotinamide Riboside and its Role in Aging: Recent study did not find definitive evidence for Nicotinamide Riboside (NR) extending lifespan or consistently raising NAD levels in various tissues, but further research is ongoing to determine potential health benefits.
Nicotinamide Riboside (NR), a precursor to NAD (Nicotinamide Adenine Dinucleotide), has received significant attention for its potential role in aging and age-related diseases. NAD is a crucial molecule involved in intermediary metabolism and is believed to influence the aging process. NR is orally bioavailable and more stable than other proposed methods for increasing NAD levels. However, a recent study conducted by the Interventional Testing Program (ITP) using mice did not find a lifespan extension or consistent major changes in NAD levels in various tissues. The study used a dose suggested by the company providing the NR, and further research is needed to determine if other health outcomes were improved. The dose used in the study is not clear, but humans typically take several grams of NR daily. Despite the lack of definitive evidence for lifespan extension, some companies have marketed NR as a way to boost NAD levels and improve health. However, it's important to note that these claims are not FDA-approved and should be approached with caution.
Discovering drugs that extend healthy lifespan in mice: Research shows certain drugs can significantly extend healthy lifespan in mice, with effects ten times greater than a cancer cure. These drugs can be effective even when started in middle age, and sex-specific effects are an emerging area of research.
Researchers have found that administering certain drugs in the food can significantly extend healthy lifespan in mice, with effects ten times greater than a cancer cure. This discovery challenges the conventional thinking in medical research and underscores the importance of focusing on finding drugs that slow aging. Another surprising finding is that some of these drugs are effective even when started in middle age, challenging the assumption that they must be administered in youth. Lastly, the sex-specific effects of these drugs have also emerged as an important area of research, as some drugs show significant effects in both males and females, while others are sex-specific. These findings open up new avenues for understanding the aging process and discovering new drugs that can work in old age and in both sexes.
Animal models for aging research: Choosing the right one: Researchers should consider specific research questions and trade-offs between duration and human similarity when selecting animal models for aging research. Focus on interventions that address multiple age-related changes for overall healthspan improvement.
The choice of animal models for aging research depends on the specific research questions and the trade-off between duration and closeness to humans. While mice are often used due to their similarities to humans and the availability of resources, other animals like primates and worms also have unique characteristics that make them valuable for certain types of research. Additionally, aging research should focus not only on specific diseases or causes of death, but also on slowing the aging process as a whole. For instance, rapamycin, an anti-aging drug, has been shown to slow a wide range of age-associated changes in mice, including in organs not typically associated with aging, such as tendons and kidneys. Therefore, the focus should be on finding interventions that can address multiple age-related changes and improve overall healthspan.
Exploring the Reversibility of Aging in Late Middle Age: Research on mice suggests that some aspects of aging may be reversible or preventable, even in late middle age, challenging the notion that interventions must start at a younger age.
While the connection between aging and diseases is plausible, the idea that aging processes and related diseases can be slowed down or even reversed, even in late middle age, is a developing area of research. Anti-aging medications have shown success in postponing diseases and aging processes in mice, challenging the notion that interventions must start at a younger age. A study by Mike Garrett, John Herrera, and Charlene Day showed that even old mice experienced improvements in muscle strength, rotor rod ability, and glucose tolerance when treated with 17-alpha-estradiol. These findings suggest that some aspects of aging may be reversible or preventable, even in late middle age. However, more research is needed to confirm these findings and understand their implications for humans. Additionally, while the idea of flying pigs may seem far-fetched, the ability to approach complex problems with a grounded, reality-based perspective is a valuable trait in scientific research.
Significant extension of human lifespan and health span: Experts discuss potential 10-15% extension in human lifespan and health span through scientific means, emphasizing importance of thorough research and ethical considerations.
A potential 10-15% extension in human lifespan and health span through scientific means is considered a significant achievement, according to the guests on the podcast. They also emphasized the importance of thorough research and ethical considerations when discussing the possibility of extending human life beyond that. The guests shared their enthusiasm for the scientific progress being made and their belief in the potential benefits of such discoveries. Additionally, they encouraged listeners to engage in the podcast community through a membership program, which offers exclusive content and discounts on recommended products. It's important to note that the podcast's content is for informational purposes only and should not be considered medical advice. Conflicts of interest are also disclosed on the podcast's website.
