#171 - Steve Austad, Ph.D.: The landscape of longevity science: making sense of caloric restriction, biomarkers of aging, and possible geroprotective molecules
Peter Atiyah discusses aging with Steve Austad, a distinguished biology professor and aging research director. They explore caloric restriction, sex differences in longevity, and promising geroprotective molecules like rapamycin and metformin.
Deep Dive Analysis
16 Topic Outline
Steve Austad's Unconventional Background and Childhood
Adventures as a New York City Cab Driver
Accidental Career as a Lion Tamer
Transition to Studying Animal Behavior and Longevity
Challenges and Limitations of Laboratory Animal Research
History and Impact of Caloric Restriction in Animals
Differences Between Rats and Mice in Longevity Research
Comparing Caloric Restriction Studies in Rhesus Macaques
Impact of Diet Composition and Sucrose in Monkey Studies
Caloric Restriction in Wild vs. Laboratory Mice
Human Studies on Caloric Restriction and Adherence
Alternative Dietary Protocols and Intermittent Fasting
Biological Explanations for Sex Differences in Human Lifespan
The Importance of Longevity Biomarkers
Promising Molecules for Geroprotection: Rapamycin and Metformin
The 150-Year Human Lifespan Bet
5 Key Concepts
Laboratory Evolution
This refers to the process by which laboratory animals, like mice, have been inadvertently selected and bred over hundreds of generations for traits such as faster growth, rapid reproduction, and larger litter sizes. This intense selection makes them genetically identical and significantly different from their wild counterparts, creating what Steve Austad calls 'mouse-like objects'.
Genetically Heterogeneous Mice
These are laboratory mice, such as those used in the Intervention Testing Program (ITP), where each individual mouse is genetically unique, but the overall population can be reliably recreated. This model is considered a significant improvement over inbred strains for more robust and generalizable research outcomes.
Testosterone Dementia
A humorous term coined by Steve Austad to describe the period, typically during adolescence, when men often engage in extremely risky, impulsive, and unintelligent behaviors. These actions can lead to dangerous situations and are attributed to the influence of testosterone.
X-Chromosome Inactivation Bias
In women, one of the two X chromosomes is typically inactivated in each cell, usually in a random manner. However, as women age, there can be a bias where one X chromosome is inactivated more frequently than the other, potentially leading to differential gene expression over time.
Mitochondrial-Nuclear Genome Incompatibility
This hypothesis suggests that the male nuclear genome might be less compatible with the mitochondrial genome, which is passed down exclusively through females. This potential incompatibility could contribute to the observed sex differences in lifespan, as male mitochondria are at an evolutionary 'dead end'.
8 Questions Answered
Laboratory mice are typically twice as big as wild mice, reach sexual maturity twice as fast, have much larger litters, and possess bizarre mutations. They are also genetically identical and homozygous at every locus due to hundreds of generations of inbreeding, making them fundamentally different from their wild counterparts.
In the 1930s, Clive McKay, a nutritionist, serendipitously discovered that restricting the diet of rats, particularly females, led to them staying healthier and living substantially longer. This was a landmark discovery in aging research, though McKay himself did not fully appreciate its long-term significance.
The Wisconsin study used ad libitum-fed control animals that became obese and were fed a purified diet high in sucrose (28.5%), while the NIA study maintained control animals at a healthy body weight with a natural ingredient diet low in sucrose (3%). These differences in baseline health and diet composition led to varying outcomes regarding lifespan extension.
It is unlikely, and possibly detrimental. In the wild, restricted animals would need to forage longer, increasing their exposure to predators and potential toxins. Additionally, caloric restriction can slow wound healing and increase susceptibility to pathogens, which are significant risks in natural environments.
Human studies indicate that while even modest caloric restriction (around 10-12%) can improve cardiovascular risk factors, blood pressure, insulin, and glucose, it is very difficult for most people to sustain. Extreme restriction can also lead to negative effects like low bone mineral density and reduced muscle mass.
The exact reason is unknown, but several hypotheses exist, including women's redundant X chromosome potentially compensating for defective genes, or a possible incompatibility between the male nuclear genome and the maternally inherited mitochondrial genome. Women also exhibit better survival rates across all ages and conditions.
Previous large-scale efforts, such as a $100 million NIA initiative in the 1990s, yielded little, possibly due to the lack of appropriate scientific tools at the time. Current challenges involve the computational complexity of analyzing vast proteomic and metabolomic data, and ensuring biomarkers are clinically meaningful over long timescales.
Based on mouse data, rapamycin appears to have the most potential for geroprotection. However, when considering human data, metformin shows more compelling evidence of benefit, though both have qualifications and combination therapies (e.g., rapamycin plus metformin) might ultimately be most effective.
11 Actionable Insights
1. Improve Health at Any Age
It’s never too late to significantly improve your health; even if you’re 50 and have a history of poor diet and no exercise, you can still achieve substantial health benefits. This challenges the notion that past habits dictate future health outcomes.
2. Focus on Diet Quality Over Quantity
The quality of your diet, specifically reducing harmful components like sucrose, may be as important or more important than caloric restriction for health benefits. The worse the diet, the more beneficial caloric restriction becomes, while a healthy diet reduces the impact of further restriction.
3. Short-Term Fasting Boosts Resilience
Engaging in short-term fasts (e.g., 2-3 days of water-only fasting, as seen in mouse studies) can significantly improve the body’s ability to recover from severe injury or stress. This suggests that transient periods of fasting can induce robust protective benefits.
4. Consider Episodic Rapalog Dosing
For potential immune boosting and longevity benefits, consider episodic dosing of rapalogs (like everolimus at 5mg or 20mg once a week). Lower doses have shown effectiveness in enhancing vaccine response in older adults with fewer side effects.
5. Metformin for Broad Health Benefits
Metformin, an extremely safe drug taken by millions, shows compelling data from human studies (beyond mouse data) for a wide range of benefits including reduced risk of dementia, cancer, and heart disease, making it a promising candidate for geroprotection.
6. Combine Geroprotective Interventions
Combining different geroprotective molecules or strategies, such as rapamycin and metformin, may offer synergistic and more helpful health benefits than single interventions alone.
7. Avoid Extreme Constant Caloric Restriction
While some caloric restriction can be beneficial, constant and extreme caloric restriction (like that practiced by ‘cronies’) is not the answer for most people. It can lead to negative side effects such as low bone mineral density, negligible sex hormones, and loss of muscle mass.
8. Exercise to Maintain Muscle Mass
If practicing caloric restriction, it is crucial to exercise more to counteract the tendency to lose muscle mass. Individuals on restrictive diets often struggle to maintain adequate muscle.
9. Accumulate Diverse Life Experiences
Actively seek out and accumulate a wide range of life experiences and adventures. This approach can broaden your perspective and provide unique insights, as demonstrated by Steve Austad’s varied career path.
10. Skepticism of Single Mouse Studies
When evaluating scientific claims, especially in longevity, maintain skepticism towards findings based solely on a single mouse study. These findings may not be generalizable or replicable in humans due to genetic and environmental differences.
11. Caution with Epigenetic Age Clocks
Be cautious about relying on current epigenetic age clocks as definitive clinical biomarkers. They are highly sensitive to short-term changes and easily manipulated, making their long-term clinical utility questionable.
5 Key Quotes
I always thought it was going to happen because we would develop something or some things that would fundamentally change the rate of aging. And we haven't developed that yet.
Steve Austad
I always say that humans are the worst animal to study that you could imagine, because they don't do what you tell them to do, you know, and they'll lie about what they do.
Steve Austad
I think Alzheimer's disease is going to turn out to have an autoimmune component because that's the kind of thing that women seem to be more prone to than men is some of the autoimmune diseases.
Steve Austad
I think the worse the diet, the more beneficial the caloric restriction. The better the diet, the less of an impact caloric restriction has.
Peter Attia
I think of this as looking at the world through one eye. We have one comparison with humans now. It's mice. And just like you don't have much perspective when you close one eye, I don't think you have much perspective when you have one comparison.
Steve Austad