The following article will discuss some longevity markers from primates as clues to how metformin increases lifespan and by how much. The article goes further to discuss the rate of ageing of different organ systems. Monkeys are used as test subjects because they age more than 3 times slower yet have similar and translatable results to humans.

What Is Metformin and Why Is It Important?

Metformin is a medication derived from the French lilac plant, first synthesized in the 1920s. It was approved by the U.S. Food and Drug Administration (FDA) in 1994 as a treatment for type 2 diabetes. Metformin works by lowering blood sugar levels, improving insulin sensitivity, and reducing glucose production in the liver.

Why It Matters: Beyond its primary use, metformin has been observed to have various beneficial effects on the body, including weight management and cardiovascular protection. These observations have led scientists to investigate its potential anti-aging properties.

The Groundbreaking Study: A Closer Look

A recent study published in the prestigious journal Signal Transduction and Targeted Therapy,  has provided compelling evidence that metformin may have geroprotective effects—that is, it might protect against the biological processes that lead to aging.

Study Overview:

• Subjects: Healthy male cynomolgus monkeys (a type of non-human primate) aged between 13 and 16 years, which is roughly equivalent to 40-50 human years.
• Duration: 3.3 years, approximating about 10 human years.
• Groups:
  • Metformin Group: Monkeys received a daily dose of metformin at 20 mg per kilogram of body weight.
  • Control Group: Monkeys did not receive metformin.
  • Additional Groups: Younger monkeys aged 3-5 years and middle-aged monkeys aged 10-12 years for baseline comparisons.
• Methods: Researchers used advanced techniques to analyze changes in DNA methylation, gene expression (transcriptome), protein levels (proteome), and metabolism (metabolome) across 79 different tissues and organs.

How Was the Study Conducted?

Dosage and Administration:

• Metformin Dosage: Each monkey in the treatment group received 20 mg of metformin per kilogram of body weight daily.
• Administration: The medication was given orally, mixed with their regular food to ensure consistent intake.

Data Collection Methods:

• DNA Methylation Analysis: This examines chemical modifications to DNA that affect gene expression without changing the DNA sequence.
• RNA Sequencing (RNA-seq): A technique to study the transcriptome, revealing which genes are active and how active they are.
• Proteomics and Metabolomics: These fields study the entire set of proteins and metabolites in the cells, providing a comprehensive picture of cellular function.

Statistical Analysis:

• Researchers developed an Elastic Net regression model to integrate data from multiple sources and calculate “aging rescue scores.” This model helps determine how much metformin treatment “rescued” or reversed aging markers compared to the control group.

Key Findings Explained

1. Slowing Down the Biological Clock

• Protein Age Reduction: Metformin treatment decreased the calculated “protein age” by an average of 6.41 years compared to the control group.
  What This Means: Proteins are essential for virtually every cellular function. A younger protein profile suggests healthier cellular activity.

2. DNA Methylation Age Reversal

• Frontal Lobe: Age reduced by 6.1 years.
• Lung: Age reduced by 5.11 years.
• Kidney Cortex: Age reduced by 4.9 years.
• Liver: Age reduced by 3.95 years.
• Skin: Age reduced by 2.65 years.
  What This Means: DNA methylation patterns change as we age, affecting gene expression. Reversing these changes suggests a slowing or reversal of the aging process at the genetic level.

3. Improved Brain Health

• Neural Cells Showed Significant Age Reduction:
  • Microglia (immune cells in the brain): Age reduced by 6.86 years.
  • Oligodendrocytes (cells that insulate nerve fibers): Age reduced by 6.79 years.
  • Astrocytes (support cells in the brain): Age reduced by 6.08 years.
  • Neurons (nerve cells): Age reduced by approximately 5.5 years.
• What This Means: Brain aging was significantly slowed, which could have implications for neurodegenerative diseases like Alzheimer’s.

4. Reduction in Aging Markers

• Decrease in p21 Positive Cells: p21 is a protein associated with cell aging and senescence (when cells stop dividing). Metformin reduced the number of these cells in key organs.
  Interpretation: Fewer aging cells mean healthier tissues and organs.
• Attenuation of Inflammation and Oxidative Stress: Metformin inhibited pathways that lead to inflammation and the production of harmful reactive oxygen species (ROS).
  Why It Matters: Chronic inflammation and oxidative stress are major contributors to aging and age-related diseases.

5. Reactivation of Youthful Pathways

• Lipid Metabolism Improvement: Enhanced processing of fats can lead to better energy use and reduced fat accumulation.
• Wnt Signaling Activation: This pathway is crucial for cell growth and regeneration.
• DNA Repair Mechanisms: Improved DNA repair leads to healthier cells and prevention of mutations.

Understanding the Biostatistics

Elastic Net Regression Model:

• What Is It? A statistical method that combines the properties of two other methods (Lasso and Ridge regression) to handle complex data.
• Why Use It? To integrate vast amounts of data from different sources (DNA, RNA, proteins, metabolites) and identify patterns that simpler models might miss.
• Aging Rescue Scores: This model calculated how much metformin “rescued” or reversed aging markers, quantifying the effect in years.

Layperson’s Interpretation: Think of the model as a sophisticated tool that helps scientists estimate how much younger the cells and tissues became due to metformin, similar to measuring how many years a clock was turned back.

Why Are These Results Significant?

Potential Impact on Age-Related Diseases:

• Alzheimer’s Disease: By reducing tau protein levels and amyloid-beta accumulation—both hallmarks of Alzheimer’s—metformin could delay or prevent the onset of this debilitating disease.
  Stat Fact: Alzheimer’s affects about 15% of people over 65. Delaying its onset could improve millions of lives.
• Cardiovascular Health: Reduced inflammation and improved lipid metabolism can lower the risk of heart disease.

Affordable and Accessible Treatment:

• Metformin is inexpensive and widely available, making it a practical candidate for widespread use in anti-aging therapy.

Safety Profile:

• Decades of use have established metformin as a safe medication with manageable side effects, primarily gastrointestinal issues that often subside over time.

How Does Metformin Work Against Aging?

Activating the Nrf2 Pathway:

• Nrf2 (Nuclear factor erythroid-derived 2-like 2): A protein that regulates the expression of antioxidant proteins.
• Under Stress: Normally, Nrf2 is inactive, but under oxidative stress, it moves to the nucleus of the cell and turns on protective genes.
• Metformin’s Role: Helps release Nrf2, enhancing the cell’s ability to combat oxidative stress.
  Simplified Explanation: Metformin boosts the cell’s natural defense system, helping it fight off damage that leads to aging.

Epigenetic Changes:

• H3K9me3 Restoration: This is a chemical modification of DNA-associated proteins (histones) that influences gene expression.
• Why It’s Important: Loss of H3K9me3 is linked to accelerated aging. Metformin helps restore these levels, promoting healthy gene function.

Real-World Implications

Ongoing Human Trials:

• TAME Trial (Targeting Aging with Metformin): A large-scale study involving over 3,000 participants aged 65-79 is investigating metformin’s effects on aging.
• Expected Outcomes: Researchers hope to confirm metformin’s ability to delay age-related diseases like cancer, heart disease, and cognitive decline.

Gender Considerations:

• Importance of Including Women: Since women have higher rates of certain age-related diseases, future studies need to assess metformin’s effects across genders.

What Does This Mean for You?

While it’s too early to start taking metformin solely for anti-aging purposes, these findings are encouraging. They suggest that a well-understood and widely available medication could one day be used to extend healthy lifespan.

Important Notes:

• Consult Your Doctor: Never start or change a medication regimen without professional medical advice.
• Lifestyle Still Matters: Diet, exercise, and other lifestyle factors remain crucial for healthy aging.

Conclusion

The possibility that a common diabetes medication like metformin could slow down aging is both exciting and hopeful. By understanding and harnessing its mechanisms, we may be on the brink of a new era in medicine—one where aging is no longer an inevitable decline but a manageable aspect of life.

As research progresses, we’ll keep you updated on the latest findings. Stay tuned to our blog for more insights into how science is shaping the future of health and longevity. 

Disclaimer: This article is for informational purposes only and does not substitute professional medical advice. Always consult a qualified healthcare provider for guidance tailored to your health situation.

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