#222 ‒ How nutrition impacts longevity | Matt Kaeberlein, Ph.D
Dr. Matt Kaeberlein discusses nutrition's role in aging, delving into calorie restriction, epigenetic changes, and protein's complex relationship with mTOR. He emphasizes the uncertainty in human nutritional science and the importance of exercise over dietary optimization for longevity.
Deep Dive Analysis
19 Topic Outline
Challenges in Nutrition and Aging Research
Evolving Convictions on Nutrition and Health
Caloric Restriction for Lifespan in Animal Models
Utility and Limitations of Epigenetic Clocks
Epigenetic Reprogramming: Potential and Exaggeration
First Applications of Anti-Aging Therapies
Impact of Caloric Restriction on Immune System and Muscle
Insights from Rhesus Macaque Caloric Restriction Studies
Evolutionary Perspective of the Human Diet
Review of Anti-Aging Diets: Fact vs. Fiction
Time-Restricted Feeding and Circadian Rhythms in Mice
Nutritional Interventions and Lifespan in Mice
Caloric Restriction Started Later in Life
Rapamycin's Lifespan Extension in Older Mice
Protein Intake and Aging: Rodent Studies
Protein Intake, mTOR, and Muscle Mass
Low vs. High Protein Diets and Mortality
IGF-1 Signaling and Growth Hormone on Lifespan
Parting Thoughts on Nutrition's Contribution to Longevity
7 Key Concepts
Epigenetic Clocks
These measure characteristic changes in the epigenome (epigenetic marks) that occur with age across various organisms. While useful as a chronological measure (e.g., in forensics), their ability to definitively measure biological aging or predict future health outcomes at an individual level is still unproven.
Yamanaka Factors
These are specific reprogramming factors (typically four) that can wipe clean epigenetic changes in cells, restoring them to a pluripotent state. In the context of aging, partial reprogramming using these factors aims to restore the epigenome to a youthful state without reverting cells entirely to pluripotency, which would be dangerous in a complex organism.
Partial Reprogramming
This is the process of using Yamanaka factors to reset the epigenome of cells or tissues to a more youthful state, but not all the way back to a pluripotent stem cell state. The goal is to restore youthful gene expression and homeostatic mechanisms, potentially improving function in aged tissues without the risks of full reprogramming.
Caloric Restriction (CR)
A dietary regimen involving a significant reduction in overall caloric intake (e.g., 20-65%) while maintaining adequate nutrition. In laboratory animals, CR consistently increases lifespan and healthspan, often by delaying age-related diseases like cancer and metabolic syndrome.
mTOR Pathway
The mechanistic Target of Rapamycin (mTOR) pathway is a central regulator of cell growth, proliferation, and metabolism. It is activated by nutrients, particularly amino acids like leucine, and its inhibition by drugs like rapamycin or by caloric/protein restriction is associated with beneficial effects on aging and healthspan in animal models.
FGF21 (Fibroblast Growth Factor 21)
A protein secreted in response to low-protein diets. It influences liver metabolism, inhibits mTOR, and reduces IGF-1 levels. Overexpression of FGF21 has been shown to extend lifespan in mice, suggesting it plays a role in the longevity benefits observed with protein restriction.
IGF-1 (Insulin-like Growth Factor 1)
A hormone in the growth hormone pathway that promotes growth in many tissues. In simple organisms and mice, reduced IGF-1 signaling (often due to mutations in the growth hormone pathway) is associated with increased lifespan, though its role in human aging and the impact of dietary protein on it is complex and debated.
12 Questions Answered
The first experiments on caloric restriction and its effects on aging in mammals were published in the early to mid-1930s, meaning the research began almost a hundred years ago.
Typical laboratory mice, when allowed to live out their natural lives, will have a very high tumor burden, and most likely 80% would die from cancer, which is different from humans where cardiovascular disease is a leading cause.
While epigenetic clocks can measure chronological age, their ability to predict an individual's future health outcomes or definitively measure biological aging is not yet proven, and there is no data to support that reversing the epigenome reverses all aspects of aging.
While partial epigenetic reprogramming in mice has shown some impressive improvements in function in specific aged tissues (e.g., optic nerve), nobody has ever taken an old mouse and turned it into a young mouse, and the idea of reversing aging is currently an exaggeration.
Significant caloric restriction in humans can have real psychological consequences, including constant hunger and social isolation. If not carefully managed with optimal nutrition, it could also lead to immune deficits and other health problems.
The two major rhesus macaque studies (Wisconsin and NIA) had conflicting results, likely due to differences in diet composition (Wisconsin's diet was more processed, NIA's was higher quality) and age of CR onset. The Wisconsin study showed lifespan extension and reduced age-related diseases, while the NIA study showed healthspan benefits but no lifespan extension.
The vast majority of studies on intermittent fasting and time-restricted feeding in mice are actually flavors of caloric restriction, meaning the experimental group consumed fewer calories than the control group, even if not explicitly designed as such.
More recent mouse studies, particularly with a graded onset of caloric restriction, have shown lifespan benefits even when started at 20-22 months of age (mouse equivalent of 60-65 human years), though the magnitude of benefit may be less than starting early.
Unlike caloric restriction, rapamycin treatment in mice, even when started well into middle age (20 months, equivalent to 60-65 human years), can produce robust lifespan extension, almost as significant as starting early in life.
The RDA for protein is 0.8 grams per kilogram of body weight, developed to ensure protein balance for 95% of sedentary individuals. This is considered a minimum amount to prevent muscle loss, not necessarily the optimal amount for muscle protein synthesis or longevity, especially for active individuals or older adults.
Epidemiological studies suggest a complex relationship: low protein intake may be associated with lower all-cause mortality before age 65, but this trend reverses after age 65, where higher protein intake appears beneficial for reducing all-cause mortality.
While mouse studies with genetically reduced GH/IGF-1 signaling show increased lifespan and reduced cancer risk, human data on GH therapy or naturally high IGF-1 levels are more ambiguous. It's not clear that there are significant detriments to GH therapy, and the impact of IGF-1 levels on mortality can be U-shaped or flat depending on the context and population.
18 Actionable Insights
1. Prioritize Exercise Over Nutrition
Focus your mental energy and time on exercise for a much higher return on investment (ROI) compared to incrementally optimizing nutrition. Getting most of the nutritional benefits is sufficient, while exercise offers greater gains for additional effort.
2. Achieve Basic Fitness Baseline
Before debating the fine points of nutrition, ensure you have a foundational level of physical fitness, such as being able to deadlift twice your body weight and perform 15 pull-ups. This emphasizes the importance of fundamental strength and activity.
3. Aim for “Good Enough” Nutrition
You don’t need to optimize every single nutritional detail; getting close to optimal total caloric intake and maintaining a healthy body composition provides most of the benefits for health. Prioritize broad healthy eating over minute optimization.
4. Choose Whole, Recognizable Foods
Prioritize foods that your great-grandmother would recognize, typically found on the perimeter of a grocery store, as they carry inherently less risk than processed items with many ingredients. This emphasizes a focus on natural, unprocessed food choices.
5. Hedge Against Future Cures
Do not rely solely on future scientific breakthroughs to reverse aging; instead, adopt a risk management approach by actively caring for your health now. Treat your life as your most important asset and hedge against uncertainty.
6. Manage Expectations for Cures
Do not expect major changes in treatments to improve lifespan and healthspan within the next 20 years, as the scientific and regulatory path is long and complex. This encourages focusing on current, proven health strategies.
7. Increase Protein Over 50
If you are over 50 and exercising, aim for a dietary protein intake higher than the Recommended Daily Allowance (RDA) for beneficial health outcomes. This helps maintain muscle mass and function as you age.
8. Optimize Protein for Muscle
To optimize muscle protein synthesis, aim to consume approximately one gram of protein per pound of body weight, spread into four servings of about 0.25 grams per pound each. This helps ensure amino acids are utilized efficiently for muscle growth rather than oxidized.
9. Pair Protein with Resistance Training
To maximize muscle mass and strength, combine adequate protein intake with hypertrophy (resistance) training. Protein alone makes some difference, but the synergy with training is far greater.
10. RDA Is Minimum Protein
Understand that the Recommended Daily Allowance (RDA) for protein represents a minimum to prevent muscle wasting in sedentary individuals, not an optimal amount for active people or those seeking to build muscle.
11. Assess Your Metabolic Health
Evaluate your health by asking: are you overnourished or undernourished, under-muscled or adequately muscled, and metabolically healthy or not? This framework helps determine individual nutritional and exercise needs.
12. Aim for 15 MET-Hours Exercise
To capture a significant portion (30-50%) of the full health benefits of exercise, aim for at least 15 MET-hours per week, which could be achieved through activities like three hours of brisk walking or slow jogging.
13. Be Open to Changing Beliefs
It is crucial to be willing to change your beliefs about nutrition and other health aspects as new scientific data emerges. This promotes adaptability and evidence-based decision-making.
14. Recognize Study Limitations
Be careful about assuming causation from correlation, especially in backward-looking epidemiological studies or when extrapolating animal study results to humans, due to changing environments and biological complexities.
15. Verify Rapamycin Bioavailability
If taking rapamycin, be aware that compounded versions in capsules may have significantly lower bioavailability than brand-name serolimus (Rapamune) pills due to gastric pH instability. Consult your physician and pharmacist.
16. Caution with Extreme CR
Be realistic about the psychological consequences (e.g., constant hunger, social isolation) and potential immune deficits associated with extreme caloric restriction in humans. Ensure optimal micronutrient intake if pursuing CR.
17. Avoid High Protein with Sedentary
If you are overweight, obese, or diabetic and sedentary, a high-calorie diet combined with high protein intake could be problematic. Ensure your protein intake is balanced with your activity level and metabolic health.
18. IGF-1 Not Always Informative
Be cautious about over-interpreting total IGF-1 levels as a definitive biomarker for aging or health, especially in individuals over 50, as its signaling activity is complex and influenced by many factors.
7 Key Quotes
This idea that reversing the epigenome is reversing aging is at best an exaggeration, at worst an outright lie. I mean, it's just not true.
Matt Kaeberlein
My advice would be don't expect major changes in treatments to improve lifespan and healthspan in the next 20 years.
Matt Kaeberlein
If you can be somewhere close to optimal nutritional intake, just say total calories, regardless of composition, body composition is somewhere close to where it should be. That's a big chunk of what you need to give yourself the best chance of being healthy going forward. You don't have to optimize every single thing.
Matt Kaeberlein
There should be a rule that says, if you can't deadlift twice your body weight and do 15 pull-ups, you shouldn't be allowed to pontificate endlessly about the finer points of nutrition.
Peter Attia
I think the enthusiasm has just gotten so far ahead of where the science is.
Matt Kaeberlein
If your great grandmother didn't recognize what you're eating, it doesn't mean it's not good... Eating a carrot is inherently less risky than eating a protein bar with 14 ingredients in it. That's just a fact.
Peter Attia
The impact of a change in mortality late in life is going to usually swamp the impact, certainly swamp the same impact on mortality early in life.
Peter Attia