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Full Notes
Nutrition and Longevity
- Nutrition and longevity are complex and interconnected topics
- People’s nutritional needs vary, and there’s no one-size-fits-all approach
- It’s important to be open to changing beliefs about nutrition as more data becomes available
Peter Atia’s Framework for Assessing Patients
- Overnourished or undernourished
- Under muscled or adequately muscled
- Metabolically healthy or unhealthy
- This framework helps determine if a person needs an energy deficit, energy surplus, and their protein intake needs
- The hardest phenotype to treat is overnutrition and under muscled, which is unfortunately common
Challenges in Nutrition Science
- Nutrition science is not inherently low quality, but it is a difficult problem to study
- The biology of aging and nutrition are both complicated and influenced by changing environments over time
- It’s important to recognize the limitations of nutrition science and not draw strong conclusions for everyone
- Achieving optimal nutritional intake and body composition can significantly contribute to overall health
Optimization and the 80/20 Principle - Tim Ferriss is known for applying the 80/20 principle to learning
- Can become 80% proficient in a language in a month
- Some people prefer to focus on perfection and the asymptote
- In nutrition, it’s better to focus on getting 80% right and put more effort into exercise
- More return on investment (ROI) in exercise than in optimizing nutrition
Caloric Restriction and Lifespan
- Research on caloric restriction and aging began almost 100 years ago
- First experiments published in the 1930s, likely started in the 1920s
- Early studies in rats showed significant increases in lifespan (40–50%) and health span
- Caloric restriction seemed to slow aging in laboratory animals
- Similar results found in fruit flies, sea elegans, and yeast
- Caloric restriction can slow aging in a wide range of organisms
- Some debate on whether caloric restriction extends lifespan in non-human primates
Rodent Studies and Cancer
- Laboratory mice tend to die from cancer, unlike humans who die from atherosclerosis
- Caloric restriction may primarily prevent cancer, leading to increased lifespan
- Mice still experience functional declines in organs and tissues with age
- Caloric restriction seems to delay or prevent these declines
- Functional measures (e.g., heart function, immune system) are more convincing than aging clocks
Aging Clocks and Epigenetic Changes
- Aging clocks refer to characteristic changes in the epigenome with age
- Epigenetic clocks can be used as a chronological measure (e.g., forensics, determining age of rescued dogs)
- The utility of aging clocks as a measure of biological aging is less clear and not yet convincing
Epigenetic Clocks and Biological Aging - Field in flux, with differing opinions on whether epigenetic clocks can predict biological aging
- Proof would involve predicting an individual’s biological age and future health outcomes
- Current studies show correlations between epigenetic profiles and mortality outcomes, but not definitive proof
Epigenetic Changes and Aging
- Epigenetic changes are one of several molecular processes contributing to aging
- Some believe changing the epigenome could change everything about aging, but there is no data to support this
- Reversing the epigenome is not the same as reversing aging
Yamanaka Factors and Reprogramming the Epigenome
- Yamanaka factors can reprogram the epigenome in cells, restoring them to a pluripotent state
- Recent experiments involve expressing these factors in animals, showing improvements in some tissues
- No experiment has successfully turned an old mouse into a young mouse, so claims of reversing aging are exaggerated
Understanding the Role of DNA and Epigenetic Changes
- Epigenetic changes affect gene expression, leading to certain genes being expressed or not expressed inappropriately as we age
- Loss of regulation contributes to loss of homeostasis, which is a key factor in aging
- DNA mutations and epigenetic changes both play a role in aging and the ability to maintain homeostasis
Factors Affecting Healing and Aging - Inflammation is a significant driver of loss of ability to recover as we age
- High levels of sterile inflammation impair stem cell function
- Senescent cells and factors may impair or promote wound healing
- Epigenetic changes may not drive all aspects of aging
- Fixing the epigenome may not fix all mutations or functional declines
- Unclear if epigenetic changes sit upstream of other hallmarks of aging
Partial Reprogramming and Aging
- Partial reprogramming aims to restore the epigenome to a more youthful state
- May restore gene expression and homeostatic mechanisms
- Evidence suggests it can improve function in some aged tissues and organs
- Challenges with partial reprogramming
- Potential side effects, such as pushing reprogramming too far or causing cancer
- FDA skepticism and need for solid data on safety and efficacy
- Long road to clinical implementation
Potential Niche Applications
- Some more feasible applications of reprogramming strategies
- Regenerating human cartilage for osteoarthritis treatment
- Specific targeted treatments, like David Sinclair’s work
- General caution against expecting major changes in lifespan and healthspan treatments in the next 20 years
- Many barriers and challenges to overcome in research and clinical trials
- Importance of maintaining a healthy lifestyle and not relying solely on future treatments
Rapamycin and Caloric Restriction
- Rapamycin and caloric restriction (CR) both show benefits in laboratory animals
- Preserve most functional measures of aging, including frailty and sarcopenia
- CR animals maintain muscle function proportionate to their body weight
- CR in humans
- Study: CR weight loss group experienced reduction in bone mineral density (BMD), exercise-driven weight loss group did not
- Unclear if CR is the right tool for longevity once optimal weight is achieved
- Optimal weight is still unknown
Caloric Restriction and Immune System
- Laboratory animals in specific pathogen-free environments
- CR animals respond better to pathogen challenges than ad libitum fed controls
- CR animals die more quickly when sepsis is induced
- Concerns about CR impairing immune function in humans
- CR with optimal nutrition (Cron) or adequate nutrition (Cran) can be controlled in animals, but not easily in humans
- Potential for nutrient deficiencies and increased risk of infectious diseases
Caloric Restriction and Sarcopenia
- CR animals do not lose muscle mass and function as expected
- Maintain muscle function proportionate to body weight
- In humans, losing 30% of body weight and 30% of strength may not be optimal
- Ideally, weight loss would be mostly adipose tissue with minimal loss of strength
Intermittent Fasting and Caloric Restriction
- Intermittent fasting studies sometimes claim to be isocaloric but are actually calorically restricted when normalized to body weight
- Mice lose weight on intermittent fasting, but normalization methods can be unclear
Caloric Restriction in Rhesus Monkeys
- Mice lose weight on intermittent fasting, but normalization methods can be unclear
- Two major studies on caloric restriction in rhesus monkeys: University of Wisconsin and National Institute on Aging (NIA) in Bethesda
- Results were conflicting, with Wisconsin study showing benefits of caloric restriction and NIA study showing no significant difference in lifespan
University of Wisconsin Study
- Rhesus monkeys fed a processed diet, high in sugar (28.5% sucrose)
- Calorically restricted (CR) animals were fed 25% less than control animals
- CR animals outlived control animals and had fewer age-related diseases (cancer, heart disease, metabolic disease)
National Institute on Aging (NIA) Study
- Rhesus monkeys fed a higher quality diet, low in sugar (3% sucrose)
- Animals came in at different ages, complicating the comparison
- No significant difference in lifespan between CR and control animals
- Some improvements in health span metrics were observed in CR animals
Reconciling the Findings
- Differences in diet and age of onset may have contributed to the conflicting results
- Wisconsin study may be more reflective of a typical American diet and situation
- Molecular signatures of caloric restriction in monkeys are similar to those in rodents, suggesting similar effects in humans
- Unclear whether the benefits observed in the Wisconsin study were due to weight loss alone or a combination of weight loss and reduced consumption of processed food
- Further research needed to determine the effects of caloric restriction on humans and the optimal diet for health and longevity
Comparing Human and Animal Diets and Metabolism - Humans have a unique capacity to store excess energy
- Higher energy expenditure due to brain development
- Greater energy storage necessary to tolerate low energy environments
- Animals in captivity may not gain much fat but can still become metabolically sick
- Metabolic sickness comes from fat spilling out into viscera, liver, and other areas
- Humans can tolerate a wide variety of diets for many years before significant consequences
- Resilience of our genome in terms of interaction with nutrition
- Ancestral diet may not be the optimal longevity diet for humans
- Evolution necessitated flexibility in nutrition
- Humans can survive in good health with diets that look nothing like one another
- Food quality and environment changing rapidly
- More processed foods, preservatives, and taste enhancements
- Need for humility around what is known and unknown in nutrition
Reviewing Nutritional Strategies and Aging
- Science paper published in 2021 critically reviewed caloric restriction and other dietary interventions
- Aimed to determine what is known and unknown about these diets and their effects on aging
- Many reviews in the literature are one-sided and opinion-based
- Proposed to examine whether there is evidence that these nutritional strategies impact the aging process in people
Dietary Interventions and Aging - Challenging area of literature with many questions and few answers
- Focus on mice to understand the effects of various dietary interventions on aging
- Popular dietary interventions:
- Caloric restriction
- Intermittent fasting
- Time-restricted feeding
- Fasting mimicking diets
- Ketogenic diets
- Protein restriction
Time-Restricted Feeding vs. Intermittent Fasting
- Time-restricted feeding: limiting the number of hours in a 24-hour period that an animal or person eats
- Intermittent fasting: a fast that occurs at a frequency of greater than once a day, typically 24 hours or more
Circadian Rhythms and Eating
- Connection between how much we eat and when we eat
- Recent studies in mice show that the lifespan benefit from caloric restriction is a combination of when the animals eat and how much they eat
- Most of the benefit comes from the calories, but a portion comes from the fact that mice eat all their food in a short window and are fasted the rest of the 24-hour period
- Mice go through rapid reductions in organ size and rapid hypertrophy when fasting and refeeding
Early Feeding vs. Late Feeding
- Studies have shown that there is a difference in the benefits of eating early in the day versus late in the day
- More research is needed to understand the exact effects and benefits of early versus late feeding in both mice and humans
Time Restricted Feeding in Humans - Mice may not be the best model for humans in this area
- Some studies suggest early feeding window is better for insulin sensitivity and nutrient arrival
- Eating right before bed may be suboptimal
- Different endpoints may yield different results (e.g. blood glucose levels, sleep quality, other biomarkers)
Intermittent Ketogenic Diets in Mice
- Only two studies on lifespan and health span in mice
- One study showed no effect on lifespan with lifelong ketogenic diet, but intermittent ketogenic diet increased lifespan by 15%
- Mice alternated between control diet and ketogenic diet
- Intermittent ketogenic diets can increase lifespan and health span in mice, but effects are not huge
Caloric Restriction in Mice
- Caloric restriction and protein restriction consistently give big effects on lifespan
- Most extreme study: 65% restriction resulted in 65% increase in lifespan
- Mice on caloric restriction are more active throughout life
- True caloric restriction in humans may have psychological consequences and social isolation
Caloric Restriction Later in Life
- Traditional thinking: caloric restriction only effective if started early in life
- More recent studies show benefits from caloric restriction starting at 20–22 months of age in mice
- Graded onset of caloric restriction may be key
- Consensus: starting caloric restriction late in life may not yield the same magnitude of benefits as starting early, but this could be wrong
Han Study (2019)
- Studied 800 female mice
- Mice on ad libitum diet for first 3 months, then split into 40% calorie restriction vs. ad lib until 24 months
- Each group further split into ad lib vs. continued calorie restriction
-
Results may provide insight into the effects of caloric restriction in humans
Late-Life Caloric Restriction and Lifespan - Study on mice with different caloric restriction (CR) and ad libitum (ad lib) feeding patterns
- Group 1: Ad lib until 3 months, then CR for the rest of their life
- Group 2: CR until 3 months, then ad lib for the rest of their life
- Group 3: Ad lib for their entire life
- Group 4: CR for their entire life
- Results:
- Group 1 (late-life CR) had a significant but smaller lifespan extension compared to Group 4 (lifelong CR)
- Group 2 (early-life CR, then ad lib) had a longer median life expectancy than Group 1 (late-life CR)
- The maximum lifespan difference between Group 1 and Group 2 was trivial
- Comparison to mTOR and Rapamycin:
- Rapamycin can be started well into middle age or even old age and still provide most of the benefits
- This is different from the smaller effect of late-life CR in mice
- The study raises questions about the underlying mechanisms of CR and its interaction with age and the developmental process
Rapamycin Bioavailability
- Rapamycin is not stable in gastric pH, which affects its bioavailability
- Encapsulated rapamycin (Errapa) was developed to prevent breakdown at gastric pH
- In humans, bioavailability may be lower in compounded rapamycin capsules compared to brand-name rapamycin tablets
- Physicians and patients should be aware of potential differences in bioavailability between different rapamycin formulations
Protein Restriction and Aging - Animal studies show lifespan extension through protein restriction
- Restricting all protein or specific amino acids (branch chains, tryptophan, methionine)
- Common mechanism: inhibition of mTOR
- Recommended Daily Allowance (RDA) for protein
- Developed for protein balance in 95% of sedentary population
- Minimum amount, not necessarily optimal
- Protein restriction in mice
- Inhibition of mTOR, reduction of IGF‑1
- FGF 21 (fibroblast growth factor 21) plays a role in lifespan extension
- Relationship between protein and total intake
- Mice on protein restriction can eat less, the same, or more
- Mice on amino acid restriction consume more calories but don’t gain weight and live longer
- Mechanisms of methionine restriction
- Inhibition of mTOR, effects on protein synthesis, sulfur amino acid biology, and epigenetic modifications
- Time course of mTOR activation
- Duration depends on factors like diet and activity
- Chronically elevated branch chain amino acids can have significant effects on downstream processes
- Hard to achieve persistent increases in mTOR from branch chain amino acid supplements
mTOR and Protein in Aging
- mTOR signaling affected by diet and protein intake
- Multiple paths to longevity, relationship between macronutrients and diet not fully understood
- In humans, relationship between protein and health during aging likely different than in mice
- Muscle mass and activity levels in humans over 75 decrease significantly, leading to health issues
- Dietary protein important for maintaining muscle mass and preventing sarcopenia
- Some studies suggest low protein beneficial for all-cause mortality up to age 65, then higher protein beneficial after 65
- Absolute reduction in mortality may be greater with a high protein strategy throughout life due to benefits later in life
Relative Effects of High Protein Diet on Mortality - High protein diet’s impact on mortality is debated
- Model suggests that the relative risk of mortality is lower with a high protein diet
- The crossover point where the benefits of a high protein diet outweigh the detriments is around age 50
IGF‑1 and Growth Hormone in Aging
- IGF‑1 (Insulin-like Growth Factor 1) is a hormone in the growth hormone pathway
- High growth hormone levels lead to high IGF‑1 levels and high mTOR
- Studies in mice show that mutations reducing growth hormone signaling extend lifespan
- However, the effects of IGF‑1 on human lifespan are not clear
Growth Hormone Therapy
- Growth hormone therapy is widely used, especially in sports
- Despite concerns about potential harm, there is no clear evidence of significant risks or benefits
- Some patients claim to feel better on growth hormone therapy
- More research is needed to determine the safety and efficacy of growth hormone therapy in humans
IGF‑1 and Cancer Risk - IGF‑1 is a growth factor that may be linked to cancer risk
- High growth hormone signaling and high IGF‑1 signaling may lead to a higher risk of developing cancer
- However, this relationship is complex and not fully understood
Epidemiological Studies
- Epidemiological studies on protein consumption and cancer risk are mixed
- Results may be influenced by factors such as obesity, metabolic disease, and lifestyle
- High protein in the context of high calories may be detrimental
Growth Hormone Signaling
- Low growth hormone signaling may reduce cancer risk
- Example: Laron dwarfs in Ecuador have low growth hormone signaling and a dramatically reduced risk of cancer
- However, this does not necessarily mean that high growth hormone signaling increases cancer risk
Interplay with Insulin
- Insulin levels may also play a role in cancer risk
- High insulin, high IGF‑1, low insulin, and low IGF‑1 are all different physiological states
- It is difficult to tease out the effects of insulin and IGF‑1 in broad population studies
Immune System and Cancer Detection
- The immune system plays a role in detecting and clearing early cancers
- As we age, the immune system’s ability to detect and clear cancers declines
- A healthy lifestyle may help maintain a more youthful immune system, potentially reducing overall cancer risk despite higher IGF‑1 levels
Takeaways
- Nutritional studies in laboratory animals have provided valuable insights into biological mechanisms and potential interventions for humans
- A healthy diet and lifestyle can go a long way in reducing cancer risk, even if the details of IGF‑1 and growth hormone signaling are not fully understood
Balanced Diet and Overthinking - Focus on eating good foods, not overeating, and being active
- Society and scientists sometimes overthink diet recommendations
- This can cause anxiety about specific diet details (e.g., protein intake, ketosis, fasting windows)
- Most benefits can be achieved without worrying about these details
- Importance of exercise and maintaining a balanced lifestyle
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