Matt Kaeberlein: How Nutrition Impacts Longevity

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

1. Overnourished or undernourished
2. Under muscled or adequately muscled
3. Metabolically healthy or unhealthy 
4. This framework helps determine if a person needs an energy deficit, energy surplus, and their protein intake needs 
5. 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
• 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