#222 ‒ How nutrition impacts longevity | Matt Kaeberlein, Ph.D
Sep 12, 2022
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Dr. Matt Kaeberlein, a globally recognized expert on aging from the University of Washington, discusses how nutrition affects longevity. He explores the nuances of calorie restriction and its surprising impacts on lifespan and healthspan. The conversation dives into the effects of dietary protein, mTOR pathways, and the complex roles of IGF-1 and growth hormone. Kaeberlein also examines the potential of epigenetic reprogramming to combat aging and emphasizes the importance of balanced nutrition alongside exercise for optimal health.
Caloric restriction (CR) can have complex effects on immune function in animals and may not fully translate to humans.
CR in laboratory animals preserves most functional measures of aging, including sarcopenia, despite initial concerns.
Implementing optimal CR in humans requires consideration of body weight, composition changes, and individual needs.
Translating the effects of CR in laboratory animals to humans is challenging due to genetic variations and environmental complexity.
Protein restriction has been shown to extend lifespan in mice, highlighting its role in regulating aging.
The ketogenic diet and intermittent fasting have shown potential benefits for lifespan extension in animals.
Deep dives
Caloric restriction and immune function
The effect of caloric restriction (CR) on immune function in laboratory animals is complex. Studies have shown mixed results, with some indicating improved response to pathogen challenges and others showing a deficit in immune function, particularly in cases of sepsis. It is important to note that laboratory animals are maintained in controlled environments, which may not fully reflect the real-world challenges faced by humans. Additionally, the implementation of optimal CR with adequate nutrition in humans is challenging, and variations in nutrient intake may have implications for immune health.
CR and functional measures of aging
In laboratory animals, caloric restriction (CR) has been found to preserve most functional measures of aging, including frailty and sarcopenia. Despite initial expectations that CR and the inhibition of mTOR (the mammalian target of rapamycin) could accelerate sarcopenia due to their impact on muscle synthesis, experimental observations have not shown significant muscle loss or decline in muscle function. However, it should be noted that these studies often normalize muscle function to body weight, and the weight loss associated with CR may confound the interpretation of these findings.
Considerations for CR in humans
When considering the implications of caloric restriction (CR) in humans, it is important to account for factors such as body weight and body composition changes. Studies in humans have shown that weight loss driven by CR can lead to reductions in bone mineral density, highlighting the need for a nuanced approach. Furthermore, implementing optimal CR with adequate nutrition poses challenges in real-world settings. Variations in nutrient intake and potential deficiencies may have consequences for overall health and immune function. It is essential to consider individual needs and consult with healthcare professionals when considering CR as a longevity strategy.
CR and the complexity of aging
The interplay between caloric restriction (CR) and aging is a complex topic. While studies in laboratory animals have demonstrated increased lifespan and potential health benefits with CR, translating these findings to humans is challenging. The environmental complexity and genetic variations that humans face differ from controlled laboratory settings. Additionally, the effects of CR on specific aspects of aging, such as DNA mutation and cellular function, require further investigation. It is important to have realistic expectations about the pace of progress and potential limitations in the field of aging and caloric restriction.
Protein restriction: Extending lifespan in mice
Studies on mice have shown that protein restriction can extend lifespan. Various experiments have been conducted, restricting protein intake to different levels. It has been observed that reducing protein intake leads to significant lifespan extension in mice. These findings suggest that protein restriction plays a role in regulating the aging process.
Effects of caloric restriction in mice
Caloric restriction, or CR, has been extensively studied in mice. It has been found that mice subjected to caloric restriction experience significant benefits in terms of lifespan and age-related diseases. The magnitude of these effects is influenced by factors such as the extent of caloric restriction and the age at which it is initiated. While early onset of caloric restriction tends to yield greater benefits, studies have also shown that late onset of caloric restriction can still have some positive impacts on lifespan and health span.
Intermittent fasting and its impact on aging in mice
Intermittent fasting, characterized by limited eating windows or alternate day fasting, has been investigated for its effects on aging in mice. Research suggests that intermittent fasting can lead to lifespan extension, improved health span, and reduced age-related diseases in mice. The timing and frequency of fasting periods may influence the magnitude of these effects. However, further research is needed to fully understand the mechanistic processes behind intermittent fasting and its potential benefits for human aging.
Ketogenic diet and its influence on lifespan in mice
Studies have shown that a ketogenic diet, low in carbohydrates and high in fat, can impact lifespan in mice. Mice subjected to a ketogenic diet have exhibited lifespan extension, as well as potential improvements in health span and age-related diseases. The specific mechanisms underlying these effects of the ketogenic diet on aging are not yet fully understood and require further investigation.
The Impact of Protein Restriction on mTOR and Lifespan
Protein restriction, particularly in branched chain amino acids, has been shown to potentially extend lifespan and improve health span in mice. The common mechanism underlying this benefit is the inhibition of mTOR, a protein that is activated by protein intake. By reducing protein intake, mTOR is turned down, which is believed to have positive effects on aging and health. Another protein called FGF21, secreted in response to low protein intake, also plays a role in the lifespan extension seen in protein-restricted mice. However, the effects of protein restriction can vary depending on the specific amino acids restricted and the composition of the diet. Some studies have shown that restricting certain amino acids like methionine or tryptophan can actually lead to increased food intake without weight gain and improved longevity. The exact mechanisms behind these effects are still being studied, with potential factors
including methylation, protein synthesis, and sulfur amino acid biology.
Protein Intake, mTOR Activation, and Caloric Restriction
The relationship between protein intake, mTOR activation, and caloric restriction is complex. While protein is known to activate mTOR, which can have positive effects on muscle growth and protein synthesis, the context and timing of protein intake can influence mTOR activation. For example, consuming a protein-rich meal can transiently activate mTOR, but the duration and magnitude of activation can vary depending on factors such as the composition of the meal, timing of consumption, and activity level. Studies on animals and humans suggest that slightly elevated levels of branched chain amino acids can have significant downstream effects on mTOR signaling and other processes. However, long-term persistent effects on mTOR from protein supplementation alone are unlikely. The window for muscle protein synthesis after a workout is believed to be sufficient in most cases, and delivering an adequate source of protein during that timeframe is key for muscle growth.
Protein Intake, Age, and Health Outcomes in Humans
The impact of protein intake on health outcomes in humans is still a topic of debate. Epidemiological studies have shown mixed results, with some suggesting that low protein intake is beneficial for longevity up to a certain age, while others indicate that higher protein intake is associated with lower all-cause mortality in older adults. The effects of protein intake may also depend on various factors such as body weight, metabolic health, and physical activity levels. It's important to consider the overall diet and lifestyle when evaluating the relationship between protein intake and health span. Generally, eating a balanced and nutritious diet, being physically active, and avoiding overeating appear to be more important for overall health and longevity than obsessing over specific protein intake levels.
Dr. Matt Kaeberlein is a globally recognized expert on the biology of aging and recurring on The Drive. In this episode, Matt explains his research findings on nutrition as it relates to aging and longevity, including the results from his recent review article in Science. From there, he and Peter dive deep into the literature on calorie restriction (CR), explaining the nuance, benefits for lifespan and healthspan, and potential downsides of CR. He discusses the epigenetic changes that occur with age and potential benefits and downsides of epigenetic reprogramming, often viewed as a panacea for reversing aging. Matt also explains the impact of dietary protein on aging, including the interesting dichotomy around how protein, a critical macronutrient, and rapamycin, a geroprotective molecule, have opposite effects on mTOR. Additionally, he talks about low-protein vs. high-protein diets and their effects on muscle mass and mortality, as well as the impact of IGF-1 signaling and growth hormone on lifespan.
We discuss:
Challenges with understanding the effects of nutrition and studying interventions for aging [3:30];
How Peter’s and Matt’s convictions on nutrition and thoughts optimal health have evolved [8:15];
Calorie restriction for improving lifespan in animal models [16:15];
Utility of epigenetic clocks and possibility of epigenetic reprogramming [22:00];
Mutations and changes to the epigenome with aging [31:45];
Epigenetic reprogramming: potential benefits and downsides and whether it can work in every organ/tissue [35:15];
First potential applications of anti-aging therapies and tips for aging well [43:00];
Impact of calorie restriction on the immune system, muscle mass, and strength [47:00];
Insights from famous calorie restriction studies in rhesus macaques [55:00];
An evolutionary perspective of the human diet [1:03:45];
Antiaging diets: Separating fact from fiction—Matt’s 2021 review in Science [1:12:30];
Mouse models of time-restricted feeding in the context of calorie restriction [1:19:30];
Nutritional interventions that consistently impact lifespan in mice, and concerns around efficacy in humans [1:27:00];
Differing impact of calorie restriction when started later in life [1:31:00];
Lifespan extension with rapamycin in older mice [1:37:15];
Relationship between protein intake and aging, and mouse studies showing protein restriction can extend lifespan [1:43:30];
Impact of protein intake on mTOR, and why inhibition of mTOR doesn’t cause muscle loss [1:50:45];
Low-protein vs. high-protein diets and their effects on muscle mass, mortality, and more [1:55:30];
The impact of IGF-1 signaling and growth hormone on lifespan [2:06:30];
Parting thoughts on the contribution of nutrition to healthspan and lifespan [2:19:45];
