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In this episode, Dr. Gil Blander welcomes Dr. Haim Cohen to Longevity by Design to explore his revolutionary approach to understanding aging. Haim's team analyzed acetylation sites across 107 mammalian species, creating its most extensive comparative study. This computational approach revealed specific post-translational modifications that evolved exclusively in long-lived animals.
The research identifies critical pathways where evolution engineered longevity solutions. These acetylation changes affect DNA repair, cell cycle regulation, and mitochondrial function. Unlike traditional aging research focusing on single pathways like mTOR or caloric restriction, Haim's unbiased screening simultaneously reveals multiple longevity targets. Evolution provided a natural laboratory for testing anti-aging modifications over millions of years.
The findings offer exciting therapeutic possibilities for human longevity. Haim's team is now creating transgenic mice to test whether mimicking these evolutionary changes can extend lifespan in the lab. This research suggests humans could potentially "accelerate evolution" by implementing modifications that nature has already proven effective in whales, elephants, and other long-lived species.
💡 Name: Dr. Haim Cohen
💡 What they do: Professor of Molecular Genetics focused on the biology of aging
💡 Institution(s): Bar-Ilan University (Israel); Founder & Director, Minerva Israel-Germany Center forBiological Mechanisms of Aging; Founder & Director, Sagol Center for Human Health and Longevity
💡 Noteworthy: Global leader in aging research; author of 75+ peer-reviewed papers, including work showing SIRT6 over-expression can extend mouse lifespan by ~30 percent
💡 Where to find them: Bar-Ilan University faculty page
Episode highlights:
[00:00:00] Introduction
[00:01:00] Dr. Haim Cohen background and SIRT6 research update
[00:05:50] Gender-specific effects in aging research
[00:07:40] Introduction to the groundbreaking Nature paper on acetylation
[00:08:30] What is acetylation and why study it
[00:11:40] Study design across 107 mammalian species
[00:15:00] Using evolution as a research laboratory
[00:19:00] Key findings and statistical approach
[00:28:00] Validating specific proteins - CBS and hydrogen sulfide
[00:31:30] Mitochondrial acetylation and metabolism
[00:34:10] DNA repair pathways and the Peto Paradox
[00:35:00] Cancer prevention mechanisms in large animals
[00:38:30] P53 tumor suppressor conservation
[00:40:50] Cat family longevity anomaly
[00:42:10] Therapeutic implications and drug development
[00:45:00] Targeting proteins versus modifications
[00:47:40] Study limitations and future validation
[00:49:20] Comparing effects to existing longevity interventions
[00:51:00] Implications for human longevity
[00:55:00] Dr. Cohen's top tip for longevity
Evolution Functions as Nature's Longevity Laboratory
Evolution has already conducted millions of years of anti-aging experiments across mammalian species. By analyzing acetylation sites in 107 different mammals, researchers can identify which molecular modifications correlate with extended lifespans. This approach eliminates the need for decades of laboratory testing since nature has already proven which changes work. Long-lived species like whales and elephants carry genetic modifications that short-lived animals lack, providing a roadmap for potential human longevity interventions. This evolutionary perspective transforms aging research from guesswork into evidence-based discovery
Post-Translational Modifications Control Aging at the Molecular Level
Acetylation acts like a molecular switch that can turn protein functions on or off with minimal changes. Adding or removing small chemical groups weighing just 42 daltons can completely alter how proteins behave, affecting everything from DNA repair to metabolism. These modifications are more subtle than significant genetic changes, allowing organisms to fine-tune their responses to environmental challenges. Unlike permanent genetic mutations, post-translational modifications offer reversible ways to optimize cellular function, making them ideal targets for therapeutic intervention.
Multiple Pathways Must Work Together for Maximum Longevity
Single-pathway approaches like targeting mTOR or practicing caloric restriction only address part of the aging puzzle. Successful longevity requires coordinated changes across DNA repair systems, cell cycle regulation, mitochondrial function, and inflammation control. The research reveals that long-lived animals have simultaneously evolved modifications in hundreds of different sites. This suggests that future anti-aging therapies will need combination approaches rather than silver bullet solutions. The challenge lies in determining the optimal mix of modifications for maximum effect.
Cancer Prevention May Drive Evolutionary Longevity Advantages
Larger animals face a mathematical paradox: they have millions more cells and live longer, yet don't develop cancer at higher rates than smaller animals. Evolution solved this through enhanced DNA repair and cell cycle control mechanisms. Many longevity-associated acetylation sites occur on proteins involved in cancer suppression, suggesting that anti-cancer adaptations enable longer lifespans. This connection explains why elephants have multiple copies of the p53 tumor suppressor gene and why larger animals generally live longer despite having more opportunities for cancer development.
SIRT6 Research Update and Gender-Specific Effects
Haim updates his ongoing SIRT6 research, revealing tissue-specific effects and unexplained gender differences. His lab has moved beyond whole-body SIRT6 overexpression to focus on individual tissues, discovering similar longevity effects when SIRT6 is overexpressed locally. The research shows how SIRT6 maintains energy balance in the hypothalamus, allowing older animals to maintain young-like activity levels. The most puzzling aspect remains stark gender differences observed across multiple aging pathways.
"It's extremely gender specific. That's, and I wish that I knew why it's gender-specific. That is the biggest question. I think of aging in many ways. In many pathways in aging, you see gender specific effects."
The Computational Evolution Laboratory Concept
Haim explains using evolution as a natural laboratory for longevity research. Rather than spending decades testing individual modifications, his team realized evolution has already conducted these experiments over millions of years. The approach uses amino acid similarities between lysine, glutamine, and arginine to identify which sites evolved to mimic acetylation states. This allows researchers to survey massive datasets and identify longevity-associated changes across different evolutionary branches.
"During evolution, some acetylation sites evolved. If you have a lysine that is acetylated, it looks like glutamine. If it's deacetylated, it looks like arginine. So we need to survey evolution, which sites were converted either to glutamine or arginine, and it happened only in long-lived animals."
Mitochondrial Acetylation and Metabolic Regulation
The discussion reveals unique properties of mitochondrial acetylation that distinguish it from other cellular locations. Unlike other parts of the cell, where specific enzymes tightly regulate acetylation, mitochondrial acetylation levels depend more on metabolic activity and diet. This creates a direct connection between energy metabolism and protein function. The acetylation state reflects the cell's metabolic condition, including fat-burning efficiency and overall energy production.
"In mitochondria, the circulation is unique. Why? It's unique because any other location in the cell where acetylation is tightly regulated. You have enzymes that add the acetylation and enzymes that remove the acetylation. In the mitochondria, the regulation is different, meaning that the level of acetylation depends on the activity of the mitochondria."
Therapeutic Applications and Future Directions
Haim outlines therapeutic strategies emerging from his research, including accelerating human evolution by implementing modifications found in longer-lived species. His team is creating databases of acetylation sites that evolved in long-lived animals but haven't appeared in humans yet. The research explores targeting proteins rather than modifications directly, since activating proteins through drugs may be easier than manipulating specific acetylation sites. This approach could repurpose existing medications for longevity applications.
"What we're doing now is searching for specific post-translational modifications that happen in long-lived animals during evolution, but haven't happened yet in humans. We have already found a bunch of them, which means that all we need to do now is take these sites and be faster than evolution."
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