Mois : octobre 2024

The Longevity Science Foundation (LSF), a nonprofit organization dedicated to funding research aimed at extending the healthy human lifespan, is proud to announce a grant award to researchers at the University of Oxford’s Department of Physiology, Anatomy, and Genetics, within the Medical Sciences Division, for the study “Metabolic Mechanisms of Ageing in the Heart – Novel Dietary Interventions for Enhancing Healthspan.” The research is led by Pawel Swietach, Professor of Physiology, and co-supervised by Richard Siow, Visiting Professor in the same Department at Oxford and Director of Ageing Research at King’s College London (ARK). The Foundation’s grant, which forms a critical part of the study’s overall budget, is being provided over a three-year period, beginning in 2024.

The research undertaken by Prof. Swietach’s team focuses on improving cardiac function to extend the human healthspan by studying the chemical modifications to molecules that regulate the heart. Since the heart’s ability to regenerate is limited, damage accumulates over time: sadly, about one in three deaths are related to heart disease. This study explores how metabolism, particularly changes in methylation related to diet, influences heart aging. By using genetically-altered experimental models, the team investigates how elevated methionine accelerates age-related heart dysfunction. They are testing whether diet changes can reverse these effects and studying its impact on cardiac function, metabolism, and methylation patterns to identify potential therapies. The LSF is funding critical aspects of the study which will advance the understanding of heart aging. The funding also provides training opportunities for students and fellows, fostering the next generation of leaders in aging and longevity research. As the LSF plays a crucial role in the success of this research project, we look forward to ongoing collaboration in developing a center of excellence in longevity research at the University of Oxford, as well as fostering additional partnerships at this global leading institution.

“We eagerly anticipate the outcomes of the research Pawel Swietach’s team will make to the scientific field,” said Joshua C. Herring, the President & CEO of LSF. “We are proud to have the Department of Physiology, Anatomy and Genetics at the University of Oxford as partners, and we look forward to the mutual impact we will create. As the Foundation seeks and sources substantial additional capital through donations, we plan to continue reverberating through the community via our granting to the best research teams available”

Pawel Swietach, Professor of Physiology and principal investigator says: “We are excited that we can implement an element of longevity research into our portfolio, thanks to support from the LSF. The research we plan is ambitious, innovative and important, but expensive to run. Every contribution to this effort makes a massive difference to us, and we hope it brings tangible benefits to the wider community.”

“This groundbreaking research will contribute to a better understanding of metabolic changes in the heart during aging and the mechanisms by which dietary interventions can prevent heart disease. We are grateful to the Longevity Science Foundation for enabling this groundbreaking research at the University of Oxford and look forward to contributing to the development of novel interventions to enhance healthy longevity,” said Dr. Richard Siow.

​​Press Contact

Lev Dvornik

press@longevity.foundation

About the Longevity Science Foundation

The Longevity Science Foundation (LSF) is a nonprofit organization advancing human longevity by funding research and development of medical technologies to extend the healthy human lifespan. The long-term mission of the Longevity Science Foundation is to help make longevity-focused care accessible to everyone, no matter their background, by bringing cutting-edge science on aging out of the laboratory and into the mainstream. To learn more, visit www.longevity.foundation.

About the Department of Physiology, Anatomy and Genetics, University of Oxford

The Department is home to internationally-renowned teams of scientists addressing major questions in biomedicine, the answers to which will have a profound effect on modern biology, working to provide outstanding opportunities for graduate students and postdoctoral workers to gain a research training of the very highest quality, which will enable them to become the leaders of tomorrow and to communicate and employ their research in the wider world. The University of Oxford has been ranked number one in the world by the Times Higher Education (THE) World University Rankings for nine consecutive years, from 2017 to 2025, and the Anatomy and Physiology at Oxford has been ranked #1 in the QS World University Rankings by subject from 2020 to 2024. To learn more, visit https://www.dpag.ox.ac.uk/

A new study links damage caused by digestive enzymes escaping from the gut to several hallmarks of aging. The researchers dubbed this effect “autodigestion.” [1]

Don’t eat yourself up!

To live, we must eat, which involves breaking down compounds that we ourselves consist of, such as fat and proteins. Evolution has developed ingenious ways to prevent our bodies from consuming themselves. Digestive enzymes are produced by the pancreas and are only activated in the gut. However, once activated, they hardly differentiate between ingested food and the body’s own biomolecules, and they happily chomp on both.

What prevents them from harming us is the protective mucosal barrier in the gut. Unfortunately, like any bodily system, this one gets dysregulated with age [2]. In a new study, scientists from the University of California San Diego investigated this process in depth and ended up proposing what they call “a previously unexplored mechanism of aging due to autodigestion.”

The rogue enzymes

In young rats, the researchers found low levels of the protein-breaking enzyme trypsin, although the tiny folds (villi) of the small intestine and the lungs contained more of this molecule. However, trypsin levels were much higher in old animals.

“High densities are on sections of the intestine, liver, and lung, organs that are in the pathway of digestive enzymes leaking from the small intestine,” the paper says. Elevated levels of other digestive enzymes (elastase, lipase, and amylase) were also detected throughout the body.

These findings suggest that pancreatic enzymes find their way out of the intestine and into vital organs. In further experiments, the researchers focused on trypsin. They report that a two-week treatment with an oral trypsin inhibitor resulted in a significant reduction in trypsin accumulation in internal organs and the skin.

Moreover, the treatment alleviated some of the damage ostensibly caused by trypsin. This includes collagen degradation and fragmentation, which is a significant aspect of aging. The researchers call the extensive cleavage of collagen in organs “a key finding” of their study.

Digestive proteases are also suspected of cleaving various receptors on cellular membranes, causing further damage. This includes insulin receptors, which participate in insulin signaling and must work properly to prevent metabolic problems.

The researchers found that the density of the receptors’ extracellular domains was decreased in aged mice, which coincided with an increase in plasma glucose levels. Trypsin inhibition partially rescued receptor density and lowered blood glucose. The researchers hypothesize that cleavage of insulin receptors by rogue trypsin might be linked to increased diabetes prevalence in old age.

Inhibiting trypsin partially restored the integrity of the mucosal barrier, which is under constant attack by digestive enzymes, even in young organisms. The treatment attenuated the accumulation of not just trypsin but also another digestive enzyme, amylase, in the intestinal wall.

Relevant to aging

“This research brings to light that whereas life is only possible with digestion (of the food we eat), there is a price to pay in the form of autodigestion (of one’s own tissue) due to pancreatic digestive enzymes,” said Geert Schmid-Schönbein of the University of California San Diego, the corresponding author on the study, to Lifespan.io. “Autodigestion is consistent with end-of-life multi-organ failure.”

The study has numerous potential implications. For instance, the non-specificity of trypsin can partially explain the heterogeneity of the loss of function in various cells (i.e., trypsin cleaves various receptors, causing cells to stop working properly).

The researchers also suggest that this enzyme leakage might be a cause of the pervasive age-related inflammation known as inflammaging. Inflammation is a sign of tissue repair, which might be a reaction to tissue damage caused by digestive enzymes.

Thus, digestive enzymes’ leakage might directly impact at least two hallmarks of aging: inflammation and extracellular matrix degradation. While no inflammation markers were investigated in this study, others have found that enteral blockades of digestive proteases attenuate even severe acute inflammation [3].

We are what, when, and how much we eat

The levels of digestive enzymes in the gut can be affected by the amount and type of food as well as by meal frequency. This might be particularly relevant for older people whose mucosal barriers are already thinned out.

The researchers hypothesize that this effect might explain some of the benefits of caloric restriction and time-restricted eating. “Prolonging the periods between meals may enhance the reconstitution of the microvilli and the epithelial/mucin barrier and thereby minimize autodigestion,” the paper says.

“We only have general ideas at the moment, no specific data,” said Schmid-Schönbein, “but the amount of food we eat is likely to influence the damage to the intestine: exacerbate it with more food consumption versus alleviate it with less food consumption.”

With regard to food types, Schmid-Schönbein mentioned a high-fat diet: “It leads to excessive generation of free fatty acids by pancreatic lipase. Free fatty acids can damage the intestinal epithelium and break the mucosal barrier.”

Alcohol consumption is probably not a good idea either. “Ethyl alcohol,” Schmid-Schönbein said, “can dissolve lipid membranes and thus also damage the mucosal barrier.”

The researchers admit that inhibiting digestive enzymes is a balancing act that “needs to be nuanced to block autodigestion but not digestion.” Asked whether long-term trypsin inhibition or other similar treatments are plausible in humans, Schmid-Schönbein said, “Yes, to some degree, and we are working on that.”

Literature

[1] DeLano, F. A., & Schmid-Schönbein, G. W. (2024). Aging by autodigestion. PloS one, 19(10), e0312149.

[2] Sovran, B., Hugenholtz, F., Elderman, M., Van Beek, A. A., Graversen, K., Huijskes, M., … & Wells, J. M. (2019). Age-associated impairment of the mucus barrier function is associated with profound changes in microbiota and immunity. Scientific reports, 9(1), 1437.

[3] DeLano, F. A., Hoyt, D. B., & Schmid-Schönbein, G. W. (2013). Pancreatic digestive enzyme blockade in the intestine increases survival after experimental shock. Science translational medicine, 5(169), 169ra11-169ra11.

It might take a second renaissance bringing polymaths across science to solve aging and enhance human mental capacity to groundbreaking heights. This week’s Longevity, Computing, and Cognition Research Hackathon at MIT tackles this initiative. From 10/25 to 10/27, Ekkolápto, Augmentation Lab, and Meditation Artifacts will unite interdisciplinary minds to explore how emerging computational paradigms can address the age-old inscrutability of aging and consciousness.

Building on MIT’s reputation as the global epicenter of innovation, this hackathon features special guest speakers:

Michael Lustgarten PhD (Conquer Aging or Die Trying!)
David Barzilai MD PhD (AgingDoc)
Nick Norwitz PhD (Lean Mass Hyper Responders + Lipid Energy Model)
Gil Blander PhD (InsideTracker)
Kennedy Schaal (Rejuve.bio)
Curt Jaimungal (Theories of Everything)

Details:

Win Prizes: Winners can walk away with free Apple Watches, AirPods, a Meta Quest VR Headset, a ticket to the 2024 Biomarkers of Aging Conference, and more!
Networking: Participants and spectators will connect with leading researchers, industry professionals, and peers passionate about advancing longevity, cognitive augmentation, and computing.

Key Themes:

Could the physics and computational properties of aging—such as information loss—inspire new ways of enhancing the human brain and building AI? Participants will delve into cutting-edge fields such as reservoir computing, optical computing, and biocomputing to develop solutions that could revolutionize our understanding of aging, consciousness, and the future of human-machine interfaces.
Longevity Breakthroughs: solve aging through new biological paradigms (e.g., calorie restriction, senolytics, fasting, exercise, Free Radicals, How Life Works, Antagonistic Pleiotropy, Information Theory of Aging, etc.)
Unconventional Computing: build innovations in computing methods (e.g., quantum computing, biological computing, chemputation, neuromorphic computing, planetary or mortal computation, etc.)
Cognitive Breakthroughs: advance our understanding of cognition (e.g., Levin’s TAME, Friston’s FEP, The Book of Minds, memory sports, plant cognition, lucid dreaming, meditation, cessation, psychedelics, QRI’s Neural Annealing, Patterns in Nature, etc.).

Registration and Additional Information

Registration for the Longevity, Computing, and Cognitive Research Hackathon is now open. For more up-to-date details on registration, schedule, and speakers, please visit the official event website. If interested in speaking in-person or remotely, or in sponsoring this event, please contact us here!

About Ekkolápto: A research community of polymaths rigorously trying to understand and improve reality, building new foundations in cognition and aging through our polyMath conferences and cognitiveHackathons. Follow Ekkolápto on Instagram and X (Twitter).

About Augmentation Lab: A hacker collective dedicated to developing practices, systems, and technologies that augment our minds and bodies. We work trans disciplines and deeply integrate ethics into human engineering, building systems that encourage flourishing and protect people from malicious behavioral hijacking. Follow Augmentation Lab on Instagram and X (Twitter).

About Meditation Artifacts: Through his research, founder Luca Del Deo focuses on the cognitive and phenomenological science of meditation in American populations to innovate multicultural services for meditation learning. Find Luca on LinkedIn.

Special Thanks to James Hale from Lifespan.io and our friends Dr. Will Hahn, Misha Klopukh, and Michael Ostroff at the innovative Rubin Gruber Sandbox in Florida Atlantic University.