#204 - Centenarians, metformin, and longevity | Nir Barzilai, M.D.
Dr. Nir Barzilai, Director of the Institute for Aging Research at Albert Einstein College of Medicine, discusses insights from centenarian studies, longevity genes, and the TAME trial investigating metformin's potential to delay age-related diseases and extend healthspan.
Deep Dive Analysis
20 Topic Outline
Centenarians: Genetics vs. Environment in Extreme Longevity
Challenges in Twin Studies for Longevity Research
Hypotheses on Centenarian Longevity: Perfect Genome vs. Protective Genes
Discovery of Longevity Genes: CETP and APOC3
Growth Hormone, IGF-1, and Antagonistic Pleiotropy
Insights from Growth Hormone Receptor Deletions
The Role of Exogenous Growth Hormone in Longevity
Longevity Genotypes: APOE2, Lp(a), and TSHR
Polygenic Risk Scores and Resiliency to Disease
Future of Centenarian Research: The 10,000 Centenarian Study
Centenarian Healthspan: Delayed Disease Onset and Compressed Morbidity
Defining and Measuring Healthspan
Psychological Adaptation and Lessons from Centenarians
Metformin: History, Mechanism, and Safety Profile
The TAME Trial: Targeting Aging with Metformin
Metformin in Animal Models and Dosage Considerations
Biomarkers of Aging: Proteomics and Epigenetic Clocks
Impact of Metformin on Exercise and Muscle Health
Efficacy of NAD Precursors as Geroprotective Agents
Future of FDA-Approved Anti-Aging Therapies
5 Key Concepts
Antagonistic Pleiotropy Hypothesis of Age
This hypothesis suggests that certain genes or biological pathways that are beneficial for growth and reproduction in early life can become detrimental later in life, contributing to aging and age-related diseases. An example discussed is IGF-1, which is protective when young but associated with increased disease risk when old.
Contraction of Morbidity
This refers to the phenomenon observed in centenarians where they experience a significantly shorter period of illness and disability at the end of their lives compared to the general population. They develop age-related diseases much later and die more quickly once they become sick.
Geroscience
Geroscience is a field of research that posits aging itself is the primary driver of age-related diseases, rather than individual diseases occurring in isolation. The goal is to intervene in the aging process to prevent or delay the onset of multiple diseases simultaneously.
Polygenic Risk Scores
This approach involves looking at numerous genetic variants across an individual's genome and integrating them to assess the overall genetic risk for a disease or a trait like longevity. It moves beyond single gene analysis to a more comprehensive genetic prediction.
Omics (Proteomics, Metabolomics, Genomics)
Omics refers to the study of large sets of biological molecules (e.g., proteins in proteomics, metabolites in metabolomics, genes in genomics) to understand biological systems on a global scale. These fields generate 'big data' that require computational analysis to identify biomarkers and understand mechanisms.
12 Questions Answered
Yes, genes play a significant role, especially when comparing lifespans beyond 80 years; centenarians often have protective genetic variants that contribute to their exceptional longevity.
No, scientific studies show that many centenarians engage in behaviors typically considered unhealthy, such as smoking or being overweight, suggesting their longevity is not primarily due to lifestyle choices.
No, centenarians typically carry multiple genetic variants known to increase disease risk, indicating they possess protective genes that counteract these risks rather than simply lacking 'bad' genes.
High IGF-1 levels are protective in young people but are associated with increased age-related diseases and mortality in individuals over 60, demonstrating an antagonistic pleiotropy where what's good when young turns detrimental when old.
These individuals are highly sensitive to growth hormone during puberty, leading to increased height, but their IGF-1 levels remain low after puberty, a phenotype associated with longevity.
Centenarians and their offspring often exhibit higher TSH levels (e.g., 5-8 mIU/L) with normal thyroid hormones, suggesting a physiological state of slightly lower metabolism that may be protective and contribute to longevity.
Yes, centenarians typically experience a 'contraction of morbidity,' meaning they develop age-related diseases 20-30 years later than average and are sick for a much shorter period at the end of their lives, leading to a better quality of life for longer.
Metformin is a drug derived from the French lilac, initially used to treat conditions like flu and malaria. Its ability to lower glucose was observed, leading to its primary use for type 2 diabetes since the 1950s/60s.
The TAME (Targeting Aging with Metformin) trial is a study investigating whether metformin can delay the onset of multiple age-related diseases (cardiovascular disease, cancer, cognitive decline) and mortality in non-diabetic individuals aged 65-79, aiming for an FDA indication for aging.
Potential reasons include suboptimal dosing in the animal models, where very high doses were toxic and very low doses showed minimal effect, suggesting that the precise dosage is critical for observing longevity benefits.
Metformin can blunt the increase in cardiorespiratory fitness and muscle hypertrophy induced by exercise, likely by inhibiting mTOR, but it may also make the muscle biologically 'healthier' by affecting inflammation and autophagy.
The biological mechanism for NAD precursors is not well understood, and while some animal studies show benefits, human data is inconclusive and inconsistent, making their efficacy as geroprotective agents uncertain.
10 Actionable Insights
1. Prioritize Ultra-Primary Prevention
Focus on preventing chronic diseases long before they manifest, as secondary prevention (after a disease onset) is not true prevention. This is considered the most important lesson from centenarians for extending healthspan and lifespan.
2. Embrace Exercise and Nutrition
For most individuals, the fundamental path to longevity involves consistent exercise and thoughtful nutrition, regardless of genetic predispositions.
3. Discuss Metformin with Doctor
To explore metformin as a potential geroprotective agent, share relevant scientific papers (e.g., Nir Barzilai’s 2016 and 2020 Cell Metabolism papers) with your doctor to initiate a discussion about its suitability for you.
4. Take Metformin with Food
To minimize potential gastrointestinal side effects, take metformin in small doses with food, ideally after the first bite when your stomach is already full.
5. Metformin for Active Individuals
If you are biologically young or highly active, consider that metformin might not be beneficial for you, as it could potentially blunt some of the positive adaptations from exercise.
6. Consider Metformin After 50
Based on studies showing significant effects, metformin may be beneficial for individuals starting around age 50, although the TAME study is recruiting people aged 65-79.
7. Senolytics After 70-80
Avoid taking senolytics before the age of 70 or 80, as their benefits are likely targeted towards older populations.
8. Cautious TSH Treatment in Elderly
If an elderly person has an incidental finding of TSH between 5 and 8 with normal thyroid hormones, it may be a physiological adaptation, and immediate treatment is not always necessary.
9. Question Biological Age Clocks
Do not rely on biological age clocks for individual guidance or therapeutic decisions, as they are easily manipulated, not mechanistic, and lack sufficient validation for guiding interventions.
10. Caution with NAD Precursors
Exercise caution when considering NAD precursors (NR, NMN) due to a lack of clear biological understanding of their mechanism, inconsistent animal study results, and concerns about preparation stability and efficacy.
7 Key Quotes
The things that are good for you when you're young can turn against you when you're old.
Nir Barzilai
The most common thing that centenarian tells me, the thing that underlined their age is when the children of their friends were long gone.
Nir Barzilai
The lesson from centenarians is that there are longevity genes that could be translated into drugs.
Nir Barzilai
If there are any side effects to metformin, they happen usually in the first week of use.
Nir Barzilai
Absolutely. Remember, all I want with TAIL is an FDA indication for aging. That's all I want.
Nir Barzilai
We're not built with one genotype at a time. We're built with numerous genotypes.
Nir Barzilai
I think you shouldn't get senolytics before you're 70 or 80 years old.
Nir Barzilai