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((…)) to make ourselves masters and possessors of nature. This is not only to be desired for the invention of an infinite number of artifices, which would enable us to enjoy the fruits of the earth and all the conveniences found therein without any difficulty but principally also for the preservation of health ((…)) if it is possible to find some means that will commonly make men wiser and more skillful than they have hitherto been, I believe that it is in medicine that it must be sought. » René Descartes, philosopher, 1637.

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This month’s theme: Longevity and the Digestive System

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Introduction

The relationship between longevity and the digestive system is significant, as a healthy gut microbiota, balanced diet, and efficient digestion contribute to overall well-being and lifespan. A diverse gut microbiota supports immune function and reduces chronic inflammation, which is linked to many age-related diseases. Good digestive health prevents conditions like colorectal cancer and ensures efficient nutrient absorption. Additionally, the gut-brain axis shows that a healthy gut can improve mental health, further promoting longevity. Incorporating probiotics and prebiotics can enhance gut health by supporting beneficial bacteria. Thus, maintaining a healthy digestive system through diet, exercise, and stress management is crucial for a longer, healthier life.

Gut Microbiota

Diversity and Balance: A diverse and balanced gut microbiota is crucial for maintaining good health. Studies have shown that people with a wide variety of gut bacteria tend to have a healthier aging process and potentially longer lifespans.

Immune System Interaction: The gut microbiota plays a vital role in the immune system. A healthy gut can help prevent chronic inflammation, which is linked to many age-related diseases.

Research shows that alpha diversity, a measure of microbiota variety, increases with age among normal and successfully aging older adults. This rise in diversity seems to have a positive effect. Beta diversity, which reflects differences in microbial composition between individuals, significantly differs between older and younger adults, and even between the oldest-old and younger-old adults. Although the specific taxonomic composition and functional potential vary across studies, Akkermansia is consistently more abundant in older adults. At the same time, Faecalibacterium, Bacteroidaceae, and Lachnospiraceae are reduced, especially among the oldest-old. Compared to younger adults, older adults exhibit reduced pathways related to carbohydrate metabolism and amino acid synthesis. 

However, the oldest-old individuals show increased short-chain fatty acid production and enhanced pathways related to central metabolism, cellular respiration, and vitamin synthesis. Studies have shown that beta diversity significantly changes across different life stages, continuing to diverge even within older age groups. Oldest-old adults with high alpha diversity have greater temporal stability in their microbiota composition. Lower alpha diversity is associated with decreased cognition in aging and is a marker of metabolic and inflammatory diseases. These findings suggest that Akkermansia may support gut homeostasis and healthy aging by reducing inflammation and the risk of metabolic and cognitive disorders.

A fecal microbiota transplant (FMT), also referred to as a stool transplant, involves transferring fecal bacteria and other microbes from a healthy donor to another person. FMT is a proven treatment for Clostridioides difficile infection (CDI). For recurrent CDI, FMT is more effective than vancomycin alone and may enhance outcomes even after the initial infection.

Probiotics and Prebiotics

Probiotics are live microorganisms that provide health benefits when consumed, often found in fermented foods such as yogurt, kimchi, and sauerkraut. They support gut health by introducing beneficial bacteria to the microbiome and reducing the growth of harmful bacteria by occupying their space. Prebiotics are nutrients that promote the development of beneficial gut bacteria, thereby enhancing overall gut health. The primary prebiotics is microbiota-accessible carbohydrates (MACs), commonly known as dietary fiber. Found in fruits, vegetables, whole grains, legumes, and other plant materials, these complex carbohydrates resist digestion and absorption, allowing them to reach the colon intact and feed gut bacteria.

The gut microbiota influences cellular senescence and skin health through the gut-skin axis by secreting microbial metabolites. Metabolomics can help identify and quantify these metabolites involved in senescence. Novel anti-senescent therapeutics are useful. Probiotics and prebiotics may serve as effective alternatives, given their connection to the microbiome and healthy aging. However, the known effects are limited, and further research on gut composition during senescence is needed to develop immunomodulatory therapies.

Inflammation and Aging

An unhealthy gut can cause a « leaky gut, » leading to systemic inflammation and accelerated aging. 

The human body encounters potentially toxic and infectious substances daily in the gastrointestinal tract (GIT), which bears the greatest load of antigens. The GIT maintains intestinal integrity by permitting beneficial agents to pass while blocking harmful substances. Normally, a healthy intestinal barrier prevents toxic elements from entering the bloodstream. However, factors like stress, an unhealthy diet, excessive alcohol, antibiotics, and drug consumption can disrupt the intestinal microbiota and compromise the homeostasis of the intestinal barrier, leading to increased intestinal permeability. This condition, known as intestinal hyperpermeability, allows harmful agents to pass through the junctions of the intestinal epithelium into the bloodstream, affecting various organs and systems. 

Consequently, leaky gut syndrome and intestinal barrier dysfunction are linked to intestinal diseases such as inflammatory bowel disease and irritable bowel syndrome, as well as extra-intestinal diseases including heart disease, obesity, type 1 diabetes mellitus, and celiac disease. Given the relationship between intestinal permeability and numerous conditions, it is essential to develop effective strategies to prevent or reduce increased intestinal permeability. The impact of dietary nutrients on barrier function is crucial for designing new strategies for patients with leaky gut-related diseases associated with epithelial barrier dysfunction.

Aging of the Digestive System

Age-related changes in gut function have profound effects on the motility of the esophagus, stomach, and colon. Older adults are particularly vulnerable to conditions such as malnutrition, postprandial hypotension, dysphagia, constipation, and fecal incontinence. 

Reduced numbers of nerve cells in the myenteric plexus, crucial for digestive absorption, and degeneration of villi, which reduces the surface area of the small intestine, contribute to impaired nutrient absorption. Furthermore, aging impairs the intestinal immune system, including the mucosal layer of the gastrointestinal tract, leading to a higher incidence and severity of infections among older individuals. Defects in the structure and function of the mucosal defense system, a reduction in the capacity to produce protective immunity, and a rise in the frequency of inflammation and oxidative stress are all linked to aging.

Although it can affect people of all ages, gastroesophageal reflux disease, or GERD, is most frequent in older persons. Heartburn and associated symptoms of reflux disease (GERD) are brought on by stomach acid backing up into the esophagus. Reflux can be favored by eating the improper meals, such as fried and fast food, and by eating late at night. Heartburn can result from taking certain drugs, such as blood pressure medications, which are commonly taken by older persons. Gaining weight as you age increases your likelihood of developing GERD and heartburn.

Colorectal Cancer

Cancers concerning the digestive system are not the most current and well-known cancers. However, all cancers related to the digestive are responsible for about one-third of all cancer deaths​.

Mental Health

The gut-brain axis shows that a healthy gut can positively influence mental health, reducing depression and anxiety, which are linked to longevity. Disruptions in the gut-brain axis affect intestinal motility and secretion, contribute to visceral hypersensitivity, and lead to cellular alterations of the entero-endocrine and immune systems.

Gastrointestinal diseases, such as irritable bowel syndrome, frequently involve psychological comorbidities linked to changes in the gut microbiome. Furthermore, studies have shown that the makeup of the gut flora may have an impact on the brain development of fetuses and newborns. Not surprisingly, food has also been demonstrated to affect gut microbiota’s effect on cognitive performance.

Conclusion

Almost every day of our life, our body absorbs and transforms a big mass of substances, containing non-edible and often even toxic parts. In many aspects, our digestive system is the strongest part of our body. For example, intestinal Epithelial Cells are replaced approximately every 2 to 5 days which is essential for maintaining the integrity and function of the digestive barrier exposed to harsh digestive enzymes and varying pH levels​.

This part of the body can give some ideas to scientists about how to have a more resilient body and better stem cells.

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The good news of the month: Repair Biotechnologies developed the Cholesterol Degrading Platform, a safe approach to treating medical conditions that arise due to localized accumulations of excess cholesterol

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Repair Biotechnologies has developed LNP-mRNA gene therapy that has shown promising results in preclinical models of atherosclerosis. In the LDLR knockout mouse model, the therapy reduced aortic plaque volume by 17% after six weeks of treatment. Additionally, the APOE knockout mouse model, successfully removed plaque lipids and improved plaque stability. 

The therapy operates by eliminating toxic excess free cholesterol in the liver, restoring liver homeostasis, and generating systemic benefits throughout the body. The company is preparing for a series A funding round to pave the way for its first clinical trial in 2026, targeting the rare genetic condition of homozygous familial hypercholesterolemia. There is potential for fast-track approval, which could lead to off-label use for treating severe atherosclerosis in the broader population.

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For more information

• Heales, Longevity Escape Velocity Foundation, International Longevity Alliance, Longecity, and Lifespan.io 
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If immortality means perpetuating our own metabolisms, why not? This kind of immortality, whether bionic or technological, is conceivable. Jean-Michel Besnier, French philosopher (translation, source).

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This month’s theme: Our organs do not all age at the same rate

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Introduction

We begin to age, each of us differently, before our birth. For example, the epigenetic age of male babies is in average higher than that of female babies. When we die of diseases related to old age, some organs may be still relatively « young ».

Different organs in the human body can age at different rates. Aging is a complex process influenced by various factors, including genetics, lifestyle, environmental exposures, and overall health. Some organs may show signs of aging earlier or more prominently than others due to differences in their structure, function, and susceptibility to damage over time as well as specificities of our behavior and habits. 

The skin is often one of the first organs to show visible signs of aging, such as wrinkles and age spots, due to exposure to sunlight and other environmental factors. Similarly, the cardiovascular system may exhibit signs of aging through changes in blood vessel elasticity and function, leading to conditions like hypertension and atherosclerosis. The digestive system will slow down because of the weakening of the muscular contractions. The brain generally exhibits age-related changes such as a decrease in cognitive function and memory, but this varies widely among individuals and some centenarians can keep normal cognitive abilities due to the plasticity of the neural system.

Liver

The impact of aging on liver function remains a topic of limited understanding, with much of our clinical knowledge coming from transplantation surgery. While comparable outcomes have been observed in liver grafts from older donors, translating these findings to major liver resection poses challenges due to the substantial removal of liver mass.

Evidence suggests age-related alterations in liver processes, including post-transplantation deterioration of conventional liver function tests and regeneration issues, leading to poorer outcomes in older patients. Clinical studies often lack validated age cut-off values, making interpretation difficult.

Heart

As individuals age, they become increasingly susceptible to heart-related issues such as heart attacks, strokes, coronary heart disease, and heart failure. These conditions can significantly impact the quality of life for older adults and are major causes of disability. The aging process brings about changes in the heart and blood vessels. While the heart may not beat as rapidly during physical activity or stress as it did in younger years, the resting heart rate typically remains stable. However, one common age-related change is the increased stiffness of large arteries, known as arteriosclerosis or hardening of the arteries, leading to high blood pressure. 

High blood pressure, along with other risk factors like aging, heightens the risk of atherosclerosis—a condition where fatty deposits accumulate in artery walls, narrowing and hardening them. This restricts the flow of oxygen-rich blood to organs and tissues, potentially leading to heart disease. Plaque buildup in the coronary arteries can reduce blood flow to the heart muscle, causing heart damage and potentially heart failure over time. Regular blood pressure checks are essential for older individuals, even if they feel healthy, as arterial changes with age can predispose them to hypertension. Valves in the heart may become thicker and less flexible, impeding blood flow and causing fluid buildup. Additionally, heart chambers may enlarge, while the heart wall thickens, increasing the risk of atrial fibrillation—a common rhythm disorder among older individuals. 

Brain

As people age, changes occur in all parts of the body, including the brain: 

Certain areas of the brain responsible for learning and complex mental tasks may shrink. 

Communication between neurons in specific brain regions may become less efficient. 

Blood flow to the brain may diminish and inflammation, a response to injury or disease, may rise. These brain changes can affect mental function, even in healthy older individuals. 

For example, some may notice difficulties in complex memory tasks or learning, although they often perform equally well given extra time. This adjustment period is normal with aging. Evidence suggests that the brain retains the ability to adapt, enabling individuals to tackle new challenges as they age. The brain governs various cognitive functions such as memory, decision-making, and planning, crucial for daily tasks and independent living. 

Common cognitive changes with aging include: 

Older adults may take longer to find words or recall names. Challenges may arise in multitasking abilities. There may be mild decreases in attention span. However, aging can also bring positive cognitive changes. Older adults often exhibit larger vocabularies and deeper word meanings than younger counterparts, possibly due to accumulated life experiences and knowledge. Researchers are actively exploring how older adults apply this wisdom and its impact on brain function. Despite cognitive changes, older adults can still engage in various activities they’ve enjoyed throughout life. Research indicates they can:  acquire new skills, create new memories, and enhance language skills 

Lungs

Normal aging-related changes that affect the respiratory system encompass anatomical, physiological, and immunological shifts. Structural alterations include deformities in the chest wall and thoracic spine, reducing the compliance of the respiratory system and increasing the workload of breathing. The lung parenchyma experiences a loss of supportive structure, leading to the dilation of air spaces, often termed « senile emphysema. » 

With age, respiratory muscle strength declines, potentially hindering effective coughing, which is essential for clearing airways. Lung function typically matures by age 20–25, after which a progressive decline is observed. Alveolar dead space increases, affecting arterial oxygen levels without significantly impacting carbon dioxide elimination. Additionally, airway receptors undergo functional changes, becoming less responsive to drugs compared to younger individuals. Older adults may experience decreased sensation of dyspnea and a diminished ventilatory response to hypoxia and hypercapnia, rendering them more susceptible to ventilatory failure during periods of increased demand, such as in heart failure or pneumonia, potentially leading to poorer outcomes.

At least one lung is necessary for survival. While there is a documented case of a patient surviving for six days on life support after both lungs were removed until a lung transplant was performed, this is not a routine procedure and long-term survival without lungs is not possible. However, living with just one lung is feasible. Pneumonectomy, the surgical removal of an entire lung, is typically performed due to conditions like lung cancer or injury. Many individuals with one lung can achieve a normal life expectancy, although they may experience limitations with vigorous activities and may still have shortness of breath.

Kidney

Human aging is associated with molecular, structural, and functional changes in various organ systems, including the kidneys. As people age, their kidneys undergo progressive functional decline along with macroscopic and microscopic histological alterations, which are exacerbated by systemic comorbidities like hypertension and diabetes mellitus, as well as preexisting or underlying kidney diseases. Although aging itself does not cause kidney injury, the physiological changes associated with normal aging can impair the kidney’s reparative capacity, making older individuals more susceptible to acute kidney disease, chronic kidney disease, and other renal conditions

Cell senescence plays a crucial role in renal aging, involving numerous cellular signaling mechanisms. Many of these mechanisms could potentially be targeted for interventions aimed at slowing or even reversing kidney aging. The clinical characteristics of renal aging highlight recent advances in understanding the role of cell senescence in this process and explore potential interventional strategies and novel therapeutic targets. 

Life is incompatible with the complete loss of kidney function, though hemodialysis can serve as a substitute. However, unlike most other organs, our kidneys are overengineered, providing more capacity than necessary. In fact, a single kidney with just 75 percent of its functional capacity can sustain life effectively.

Thymus

The thymus is one of the useful organs, but not necessary for our survival. The size reduces with age and totally disappears for many people aged 60 or more.

Surgical removal of the thymus (thymectomy) is occasionally necessary for treating conditions like thymic tumors or myasthenia gravis. People can live without a thymus. However, studies have shown that removing the thymus in infants is linked to a higher risk of infections and autoimmune disorders. Adults who undergo this procedure typically experience fewer adverse effects.

You can also live without your pancreas, spleen, and gallbladder, as well as without organs such as your appendix, colon, and, for women, the uterus and ovaries. We can also live with only one lung or one kidney. However, living without these organs requires some lifestyle adjustments. It’s important to take any prescribed medications, monitor your blood sugar, and stay active.

Life of the organs after death

Organs have varying durations of viability after death, dictating the urgency of matching them with recipients. Here’s a breakdown: 

Heart: 4-6 hours 

Lungs: 4-6 hours Similar to heart transplants. 

Liver: 8-12 hours. 

Kidneys: 24-36 

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Conclusion

Aging is a fascinating process that slowly affects all parts of your body. To find a way to escape senescence, we will need either to find a way to stop senescence in each part of the body or, more probably, to find a global way and check if it is working for all body parts.

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The good news of the month: In Europe, we live longer than ever before.

In Europe, we live now longer than before the Covid-19 period. in 2023, life expectancy at birth in the EU was 81.5 years, up 0.9 years from 2022 and 0.2 years from the pre-pandemic level in 2019, data released by Eurostat on May 3.

This is a very positive evolution and the best progress in one year since many years. This means also that the negative consequences of the covid-19 are finally behind us.

In 15 out of 27 countries, life expectancy exceeded the EU average, with the highest expectancy recorded in Spain (84.0 years), Italy (83.8 years), and Malta (83.6 years). On the opposite side, the lowest life expectancy at birth is in Bulgaria (75.8 years), Latvia (75.9), and Romania (76.6).

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For more information

• Heales, Longevity Escape Velocity Foundation, International Longevity Alliance, Longecity, and Lifespan.io 
• Heales Monthly Science News
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The use of Artificial Generative Intelligence systems by healthcare professionals must become widespread; it would be unethical to do without the help of these tools.

Ethical principle of the French Academy of Medicine (translation). Generative AI systems in healthcare: challenges and prospects, 5 March 2024.

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This month’s theme: Organ-on-a-chip

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Introduction

Organ-on-a-chip (OOC) is a technology that involves the creation of microfluidic cell culture devices that simulate the activities, mechanics, and physiological responses of entire organs or organ systems. 

These chips typically contain small chambers lined with living cells that mimic the structure and function of specific organs, such as the heart, liver, lung, or kidney. The purpose of organ-on-a-chip technology is to provide a more accurate model of human physiology compared to traditional 2D cell cultures or animal testing. 

By recreating the microenvironment of an organ, including factors like fluid flow, mechanical forces, and cell-cell interactions, researchers can study disease mechanisms, test drug efficacy and toxicity, and even personalize medicine. Each chip can replicate certain functions of its corresponding organ, allowing researchers to study interactions between different organs and systems in the body, known as « body-on-a-chip » systems. This technology has the potential to accelerate drug discovery, toxicology testing, and personalized medicine by offering more reliable and relevant models for studying human biology and disease. Some aspects related to aging have been studied, but following interactions between organs on a long-term scheme and with senescence aspects is still to be done.

The difference between an organ on a chip and an organoid is that OOCs are microfluidic devices mimicking entire organs’ physiological responses, offering precise control over microenvironments for drug testing and disease modeling whereas the organoids are 3D cell clusters derived from stem cells, replicate specific organs’ structures and functions, serving as valuable tools for studying development, diseases, and personalized medicine, albeit with less control over microenvironments

Comparison of characteristics of 2D and 3D cell cultures

 

 

 

 

Types of Organ-on-a-chip

Lung

A study from 2021 shows that the lung-on-a-chip technology utilizes a biological, stretchable, and biodegradable membrane composed of collagen and elastin, simulating an array of miniature alveoli with dimensions akin to those found in vivo. This membrane undergoes biodegradation, and can be easily customized in terms of thickness, composition, and stiffness through a straightforward manufacturing process. The air-blood barrier is reconstructed using primary lung alveolar epithelial cells sourced from patients alongside primary lung endothelial cells. Notably, the membrane maintains typical alveolar epithelial cell markers and preserves barrier properties for up to three weeks.

Kidney

By utilizing kidney-on-a-chip technology, researchers can replicate physiological conditions found in human organs. Various kidney-on-a-chip models have been created to mimic the microenvironment of the kidney tubule, demonstrating improved accuracy in predicting drug nephrotoxicity compared to traditional methods. Using kidney-on-a-chip platforms, researchers can assess diverse drug-induced biological responses. In the future, the integration of kidney-on-a-chip into multi-organ systems is anticipated. Furthermore, kidney-on-a-chip holds promise for disease modeling and advancing the development of novel renal replacement therapies. 

Pancreas

The Pancreas-on-a-chip platform emulates the native functionality and cellular interactions of pancreatic cells more accurately than conventional human cell culture models. This chip facilitates the replication of fluid flow dynamics observed in vivo. Utilizing the Pancreas-on-a-chip has contributed to addressing a fundamental question in cystic fibrosis-related diabetes (CFRD): whether the loss of Cystic Fibrosis(CFTR) function in pancreatic duct epithelial cells (PDECs) is a primary factor in CFRD development. A study suggests that indeed, CFTR dysfunction in PDECs is a significant contributor to CFRD onset. 

Heart

Cardiovascular diseases (CVD) stand as the primary cause of mortality in numerous countries. However, the development of cardiovascular drugs faces significant hurdles: (a) Animal models for CVD often inadequately predict human responses; (b) Adverse effects vary between organisms; and (c) The process is lengthy and costly. Organs-on-a-chip technologies have been proposed to mimic the dynamic conditions of the cardiovascular system particularly, the heart and general vasculature. These systems pay particular attention to mimicking structural organization, shear stress, transmural pressure, mechanical stretching, and electrical stimulation.

A beating heart-on-a-chip has been engineered with highly functional micro-engineered cardiac tissues, enabling the prediction of hypertrophic changes in cardiac cells. This innovative device demonstrates the capacity to produce cardiac microtissues with enhanced mechanical and electrical coupling among neighboring cells. Furthermore, the model exhibits a positive chronotropic effect when exposed to isoprenaline, suggesting its potential utility in drug discovery and toxicity studies.

Companies involved in developing the technology

Several major companies are leading the development of organ-on-a-chip models across the globe. In Europe, we have Mimetas, headquartered in the Netherlands, which offers a wide range of organ-on-a-chip models including kidney, gut, tumors, and others. Elvesys, based in France, focuses on developing microfluidic systems. AlveoliX, located in Switzerland, specializes in human lung-on-a-chip models. TissUse, based in Germany, offers multi-organ-on-a-chip solutions. Lastly, BiomimX, headquartered in Italy, is renowned for its expertise in generating predictive models of human organs and pathologies for drug testing.

Emulate, one of the leading companies in the field, is based in the U.S. and specializes in creating advanced models such as lungs-on-chip, gut-on-chip, and blood-brain-barrier-on-chip systems. AxoSim, based in the U.S., is dedicated to creating specialized microfluidic chips for combating cancer. TaraBiosystems, another U.S.-based company, is known for its focus on heart-on-a-chip models. Nortis Bio, based in the U.S., specializes in kidney-on-a-chip models. BioIVT, also headquartered in the U.S., provides established models such as pancreatic islets and lung airway epithelium. 

Use of Organ on a chip in longevity studies

Organoids and microfluidic chip technology represent significant advances in molecular biology. Organoids, miniature models of organs generated from stem cells, effectively mimic the morphology and function of actual organs. On the other hand, organs-on-chips employ intricately carved tunnels on plastic or polymer surfaces to house cells, stimulating blood flow within the human body. These technologies have emerged as solutions to the challenges of drug development, which is often slow, costly, and prone to failure due to inadequate predictive tools. By combining organoids and organs-on-chips into « organoids-on-chips, » researchers can leverage the biological accuracy of organoids with the dynamic capabilities of microfluidic chips, enabling a more accurate study of disease traits and drug responses. For instance, integrating a functional vascular system into organoids enhances their complexity and physiological relevanceThe potential of organoids-on-chips extends beyond drug screening to applications in regenerative medicine and fundamental biological research. These technologies could revolutionize medical research and drug development practices, potentially replacing animal testing in toxicology studies and developing personalized therapies.

BIOFABICS, a Portuguese start-up funded by the European Union’s Horizon 2020 research and innovation program, is pioneering custom design tools for bio-fabrication, particularly in the emerging field of organ-on-chip (OOC) technology. The goal of the company is to leverage automated customization processes, allowing users to create large arrays of interconnected organ models. Currently, BIOFABICS is primarily engaged in pre-clinical research. 

In 2022, NASA, in collaboration with the National Institutes of Health (NIH), the Department of Health and Human Services Biomedical Advanced Research and Development Authority (BARDA), and the Food and Drug Administration (FDA), selected 8 research projects to enhance the longevity of 3D tissue chips to a minimum of 6 months. This multi-agency effort aimed to achieve tissue viability and physiological function extension through automated engineering capabilities, enabling real-time online readouts in complex human in vitro models, such as tissue chips or micro-physiological systems. The scientific objectives of this initiative included gaining deeper insights into disease models, facilitating drug development, optimizing clinical trial design, understanding chemical and environmental exposures and countermeasures, and investigating physiological changes induced by the spaceflight environment. Critical to the success of these endeavors is the in-depth characterization of tissue chips, particularly in distinguishing between acute and chronic exposures, marking a significant advancement in the evolution of these technologies.

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The good news of the month: Rejuvenating Aged Immunity by Depleting Myeloid-Biased Stem Cells

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Researchers of the University of Stanford (USA) found that depleting myeloid-biased hematopoietic stem cells (my-HSCs) in aged mice rejuvenated their immune systems, boosting lymphocyte progenitors, naive T cells, and B cells. This led to improved immune responses to viral infections, pointing to a potential approach to combat age-related immune decline and inflammation.

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For more information

• Heales, Longevity Escape Velocity Foundation, International Longevity Alliance, Longecity, and Lifespan.io 
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Imagine a rather educated mouse wondering whether it’s theoretically possible to live longer than the average life expectancy of two and a half years? Of course, it’s possible, » she’d say, « just look at the human species (…), mammals like us who live thirty to forty times longer! (translation) Au-delà de nos limites biologiques: Les secrets de la longévité. 2011. Miroslav Radman.

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This month’s theme. Different lifespans of animals: Very long, very short, in the real world and the labs

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Most people consider a lifespan of 80 years as something logical and good. If our normal lifespan was 20 years or 300 years, we would probably regard it as logical and good as well. Philosophers and religions would explain convincingly why shorter or longer lives would be bad. 

A normal lifespan for animals with senescence can vary in extreme ways, from a few days to a few centuries. There are even some specific animals that never age and can live for thousands of years and others who die before they are born. Concerning our close cousins mammals, the variation goes from two to two hundredth years. In this newsletter, we will approach animals with the longest life, and with the shortest lives and animals we study in the laboratories to understand their longevity.

Biologically immortality

Biological immortality means no irreversible senescence. This implies, among other things, that fertility is not decreasing with age. It has been said of quite a few animals. However, systematic observation for centuries is impossible and in most cases of affirmation of biological immortality, no lifespan of centuries is proved.

It can be noted, concerning life outside of the animal reign, that some plants, especially some trees, but also posidonia, and unicellular living beings seem biologically immortal.

Turritopsis nutricula

Turritopsis nutricula, commonly known as the « immortal jellyfish, » has captivated the scientific community due to its extraordinary ability to reverse its aging process and potentially achieve biological immortality. This unique jellyfish species, found in oceans worldwide, starts its life as a polyp, an underwater life form attached to the seabed. As it grows, Turritopsis nutricula gradually transforms into a jellyfish. In times of difficulty, it can regress to the polyp stage before transforming back into a jellyfish, capable of repeating this cycle indefinitely. This organism can reverse its mature cells back into their earliest form, essentially restarting its life cycle. Of course, the concept of biological immortality is complex but the remarkable rejuvenation ability of Turritopsis nutricula offers fascinating insights into the possibilities of life extension in the animal kingdom.

They are other animals (and plants) who do not show senescence. However, most of those animals (and of course plants) do not have a brain. Glass sponges, some corals, and maybe tubeworms can reach thousands of years. Hydra’s, planaria also do not seem to age, at least for the individual reproducing asexually. Lobsters also do not age. But they also do not stop growing and they will die at one moment because they become too big to survive. Tardigrades seem not to age when in cryptobiosis. Rougheye rockfishs and naked mole rats (see below) are also sometimes mentioned as biologically immortal but with no animal older than 100 known.

Very long life

The main characteristics of animals living very long are big size, low metabolism, and few predators. But not all those characteristics are necessary for very long-living animals. In general, vertebrates flying or living underground (for example olms in caves) tend to live longer.

Greenland shark

The Greenland shark, scientifically known as Somniosus microcephalus, is renowned as the longest-living vertebrate globally, with estimated lifespans of up to 512 years. Inhabiting the Arctic and North Atlantic waters, they don’t reach sexual maturity until they’re over a century old. These sharks owe their exceptional longevity to factors such as a slow metabolism and their cold-water habitat. This extended lifespan presents a unique opportunity for scientists to delve into the biological mechanisms behind their remarkable longevity, offering valuable insights into aging and adaptation in extreme environments.

Whales

The only mammals living longer than humans are whales. It is somehow logical for one of the biggest animals in the world, with no predator when adult. They probably can live more than 2 centuries.

Tortoises and sphenodons 

The extreme longevity of some tortoises, especially coming from the Galapagos is well-known and logical for animals of a big size, with no predators before humans came and a low metabolism. The oldest living turtle is 192 years old.

Less well-known are the Tuatara’s (sphenodons) who can live and lay eggs after more than one century.

Grey parrots

Parrots, known for their exceptional cognitive abilities and unusually lengthy lifespans, until 83 years, may correlate with these traits, according to a study led by Max Planck researchers. The study examined 217 parrot species, including well-known ones like the scarlet macaw and sulfur-crested cockatoo, which exhibit remarkably long lifespans of up to 30 years, typically observed in larger bird species. The researchers proposed a potential explanation for this longevity: a significant correlation between large relative brain size and extended lifespan. 

Albatrosses

A Laysan albatross named Wisdom is the oldest known wild bird (more than 70 years).  It is also the bird to have laid an egg at the oldest age: 68.

Bats

In contrast to various aging theories, bats, despite their elevated metabolic rate, exhibit remarkable longevity, living approximately three times longer than other mammals of comparable size. The mystery surrounding how bats achieve this extended lifespan has garnered significant attention, often drawing parallels to immortal fantasy figures like Dracula from Bram Stoker’s novel. Numerous ecological and physiological characteristics, including diminished mortality risks, delayed sexual maturation, and the ability to hibernate, have been associated with the prolonged lifespan observed in bats. Despite these insights, there remains a scarcity of information regarding the specific molecular mechanisms that contribute to the exceptional longevity observed in bats.

Eusocial insects and larvae.

Queens (this means reproductive females) and sometimes kings (reproductive males) of eusocial insects like bees, ants, and termites can live a much longer life than most insects. The record is 8 years for bees, for ants almost 30 years, and for termites, it is roughly 30 to 50 years. What is particularly interesting for those animals is that so-called workers or soldiers have often the same genes, but live lives tenths of times shorter. It would be interesting to know if some mechanisms allowing a much longer life for some insects can somehow be duplicated by mammals.

Some insects have a very long life as a larva. The longest normal larva period concerns periodical cicadas living 17 years as a larva (and then massively becoming adults to limit predation). Splendour beetles can be larvae during an even longer period. The longest recorded period is 51 years.

Very short lives

We wrote that animals with a very long life have usually a big size, a low metabolism, and few predators. Unsurprisingly, animals with a very short life are usually small, with a fast metabolism, and with many predators.

Some of those animals (C Elegans, drosophila, Nothobranchius, mice, and rats are studied in the laboratory and will be approached in the third part of this newsletter.

Many insects are considered to have a very short life but have a longer life during their larva phases. The famous mayflies who live only days, even hours or minutes as an adult and many species of butterflies who do not eat when they are adults have a nymphal of several months to several years,

The strange (non-)life of some mites.

The strangest shortest known lifespan is the life of males Acarophenax tribolii. Their lifespan is less than nothing because they die before they are born!   The mother Acarophenax produces young in a ratio of 15 females to one male. The male copulates with all its sisters during gestation and dies when still in the womb of the mother. The mother later literally explodes and dies, releasing her young daughters already pregnant. And the cycle starts again, they will grow and give birth by exploding.

Gastrotrich 

It is a very small worm-like animal found in freshwater areas everywhere in the world. The whole lifecycle can happen in 2 days, but it can also be longer than 40 days.

Chameleons

The terrestrial vertebrate with the shortest life is the Labord’s chameleon. He normally lives less than 6 months. It is an interesting animal because other chameleons, genetically probably not very different, can live up to 10 years. However, it must be said that apparently in favorable situations, some animals live longer.

Mammals. The shrew and the male antechinus.

The mammal having the shortest life for males and females is the common shrew. This very small carnivore animal will normally not live longer than one year. It is less than rats and mice that are abundantly suited for longevity, but far less easy to breed.

The male antechinus is a small marsupial that lives less than one year, dying during or just after the period of reproduction. This is sometimes called « suicidal reproduction ».

Roundworms 

 and their mammalian counterparts suggests that the roundworm will continue to be a valuable animal model for the study of aging. 

Fruit flies 

The Turquoise killifish is an extremely interesting freshwater fish for the study of aging. It is easy and not expensive to breed. It is so easy and nice that people keep it as a pet. It has also the shortest life of all vertebrates but one (Eviota sigillata, a sort of Gobi). The Kill fish has remarkable capacities for regeneration but will live for a maximum of twelve weeks. Hundreds of scientists around the world are studying the animal to try to understand and solve the fascinating questions of senescence. They do not study as much Eviota sigillata who live an even shorter life of a maximum of 59 days, because breeding this small saltwater fish is far more complicated. Another fish that must used for scientific studies is the Zebrafish, because of its capacity for regeneration. This animal can live up to 5 years in an aquarium. 

Animals in the laboratories

From widely used model organisms like fruit flies (Drosophila melanogaster) and nematode worms (Caenorhabditis elegans) to more complex mammals such as mice and rats, researchers explore various species to understand the genetic, physiological, and environmental factors influencing lifespan. Additionally, unconventional subjects like bats and parrots have recently captured scientific interest due to their exceptional longevity despite high metabolic rates. These animals serve as valuable models to investigate the intricate mechanisms that contribute to prolonged lifespans, shedding light on potential insights applicable to the broader spectrum of life, including humans.

Roundworms 

Caenorhabditis elegans is a roundworm with a 20-day lifespan, making it a good subject for research. More than 400 genes that extend lifespan in roundworms have been described. Among the genetic controls studied are a series of interacting proteins that act like insulin and control reproduction and longevity. Investigators have also looked at a mechanism controlled by a group of genes called clock genes. These regulate metabolism in the roundworm and affect lifespan. The roundworm genes that seem. to confer increased longevity do so by supporting resistance to external stresses, such as bacterial infections, high temperatures, radiation, and oxidative damage. The correlation between the existence of roundworm genes and their mammalian counterparts suggests that the roundworm will continue to be a valuable animal model for the study of aging. 

Fruit flies 

Drosophila melanogaster, or the fruit fly, is a favorite subject for studies on longevity. Researchers have identified one gene that they have named Methuselah, which can increase fruit fly life span by 35 percent. Molecular physiologist Xin-Yun Huang of Cornell University’s Weill Medical College in New York City has been conducting research to uncover what activates the Methuselah protein. Huang and his team found that another protein, the Sun protein, binds to Methuselah and alters fly longevity. Flies with a disabled copy of the Sun gene lived 50 percent longer than control flies. A number of studies on a fruit fly gene called Indy (for “I’m Not Dead Yet”) have been published. Because the fruit fly has genes such as Indy that produce proteins very much like human proteins, it makes an excellent animal model for aging research.

Nothobranchius furzeri

The Turquoise killifish is an extremely interesting freshwater fish for the study of aging. It is easy and not expensive to breed. It is so easy and nice that people keep it as a pet. It has also the shortest life of all vertebrates but one (Eviota sigillata, a sort of Gobi). The Kill fish has remarkable capacities for regeneration but will live for a maximum of twelve weeks. Hundreds of scientists around the world are studying the animal to try to understand and solve the fascinating questions of senescence. They do not study as much Eviota sigillata who live an even shorter life of a maximum of 59 days, because breeding this small saltwater fish is far more complicated. Another fish that must used for scientific studies is the Zebrafish, because of its capacity for regeneration. This animal can live up to 5 years in an aquarium. 

Muridae

Mice and rats are the favorite subjects of scientists interested in human aging. Because they are mammals, they are more closely related to us than yeast, flies, or worms, and their relatively small size and short life span make them easier to study than long-lived animals. Much of the excitement in recent aging research has come from discoveries that aging can be postponed in mice or rats by very low-calorie diets and by discoveries of mutant genes that can extend life span by as much as 50 percent. Through targeted genetic manipulation, researchers have already created genetic lines of mice that model Werner’s syndrome (premature aging), Alzheimer’s disease, other neurodegenerative conditions, atherosclerosis, diabetes, immune dysfunction, musculoskeletal disorders, oxidative stress, and many other medical conditions associated with aging. Other studies are using mice engineered to make them particularly vulnerable to DNA damage or damage to their mitochondria (energy-producing “organs” inside cells). The growing interest in mouse aging and genetics has been strongly stimulated by the sequencing of the mouse and human genomes and by the realization that most human genetic diseases can be modeled by changes in equivalent genes in these rodents.

Naked Mole Rats 

Those rodents already studied in a recent newsletter are living exceptionally long lives for a small mammal. They live in underground colonies and are relatively easy to observe in captivity. Contrary to all other well-studied vertebrates, they seem to show no senescence in the sense that their probability of dying does not seem to progress with age. However, they show other signs of aging. 

Dogs

The distant children of wolves have lived with us for so long that they acquired good and bad habits. They are so culturally and physically close to us that they are ideal to compare with us. And since we have millions of them of old age, it will be extremely easy to start experiments on longevity with animals of old age. It could even be in combination with treatments with their well-informed owners.

Nonhuman Primates

The discovery that fruit flies and roundworms carry genes that affect their longevity is exciting, particularly because many of those genes have human counterparts. However, the fact remains that the complexity of human physiology can’t be replicated in simpler organisms such as fruit flies and roundworms. But our DNA is very similar to that of nonhuman primates such as monkeys and apes. And it is nearly identical to that of chimpanzees. The National Institute on Aging (NIA) is sponsoring an extensive series of experiments into aging and longevity using primate models, including rhesus and squirrel monkeys. Rhesus monkeys are particularly useful because the rate of aging in rhesus monkeys is three times as fast as the rate in humans. It is important to say, in ethical terms, that the goal and result of the experiments is to allow a longer and healthier life for primates and consequently for humans. Primate studies are ongoing in neurobiology, skeletal deterioration, reproductive aging, and other age-related diseases such as heart disease and diabetes. Results from studies of caloric restriction and its impact on aging in primates are also available.

The good news of the month: LEVF experiments are progressing

The Longevity Escape Velocity Foundation is pursuing an experiment on 1,000 mice. After about 10 months, the results are already very promising, especially concerning the female mice with a big difference in mortality between mice with no treatment and mice with all treatments.

A second study is in the preparation mode, subject to. The interventions would be:  Deuterated Fatty (Arachidonic) Acids, Mouse Serum Albumin, Mesenchymal Stem Cells, and Partial Cellular Reprogramming

It is to be hoped that the LEVF will soon not be anymore the only working longevist organization working on a large number of old mice observed until their death with a promising treatment. Organizations like Hevolution, Google Calico, the Chan Zuckerberg Foundation, and Altos Labs should use a few million dollars among their billions to test their most promising ideas on our mammalian short-living far cousins.

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The primary difference between this current, pre-survival world, and the post-mortality world will be that our actions, and our future, have MORE [explicitly not less] meaning. The reckless abandon with which we sometimes live moments of our life, often to the detriment of ourselves and others, will no longer be universally justifiable with the calling excuse of “Oh, well. going to die someday anyway, might as well enjoy the moment”. 

Jed Lye, Molecular physiologist, 2021 Medium.com.

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This month’s theme: Is Ultra-processed food (UPF) causing accelerated aging?

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Introduction

Ultra-processed foods typically contain five or more ingredients, often incorporating additives and components uncommon in home cooking, such as preservatives, emulsifiers, sweeteners, and artificial colors and flavors. These products generally boast extended shelf life. Examples of ultra-processed foods include ice cream, ham, sausages, crisps, commercially produced bread, breakfast cereals, biscuits, carbonated beverages, fruit-flavored yogurts, instant soups, and certain alcoholic drinks like whiskey, gin, and rum.

Researchers frequently employ the NOVA classification, a four-part scale, to categorize foods based on their level of industrial processing. The classifications include unprocessed or minimally processed foods (encompassing items like vegetables and eggs), processed culinary ingredients (typically added to dishes and seldom consumed on their own, such as oils, butter, and sugar), processed foods (formed by combining elements from the first two categories, as seen in homemade bread), and ultra-processed foods (created using industrially modified raw ingredients and additives).

Harmful Effects 

British Heart Foundation in 2023 conducted two studies observing the effects of ultra-processed food. In the initial study, which observed 10,000 Australian women over a span of 15 years, it was discovered that individuals with the highest intake of ultra-processed foods (UPF) in their diet faced a 39 percent higher likelihood of developing high blood pressure compared to those with the lowest consumption. The second study, a comprehensive analysis encompassing 10 studies with a participant pool exceeding 325,000 men and women, revealed that individuals with the highest consumption of ultra-processed foods had a 24 percent increased risk of experiencing severe heart and circulatory events, including heart attacks, strokes, and angina.

A study, featured in the November 2022 issue of the American Journal of Preventive Medicine, indicated that these UPF items probably played a role in approximately 10% of deaths among individuals aged 30 to 69 in Brazil in 2019. Additional research, such as a study published in Neurology in July 2022, which revealed that a 10% rise in ultra-processed food consumption heightens the risk of dementia, has connected this category of food to significant health repercussions.

Direct Effect on Aging 

Consuming ultra-processed foods has been linked to the shortening of DNA telomeres, a factor associated with increased vulnerability of skin cells to aging. An Experimental Dermatology study conducted on lab mice revealed that those with shortened telomeres were more prone to slow wound healing, skin ulcers, premature hair greying, and hair loss. Dr. Bes-Rastrollo has highlighted that common contributors to telomere atrophy include oxidative stress and inflammation, both of which are associated with dehydration—factors often found in ultra-processed foods. Oxidative stress can disrupt the balance between free radicals and antioxidants in the body, potentially compromising the immune system and accelerating the aging process, manifesting in the appearance of older skin.

Another study shows that higher consumption of UPF (>3 servings/d) was associated with a higher risk of having shorter telomeres in an elderly Spanish population of the SUN Project (886 participants (645 men and 241 women) aged 57-91 y). Those participants with the highest UPF consumption had almost twice the odds of having short telomeres compared with those with the lowest consumption 

The primary conclusion from the study published in Springer in 2023  reveals a consistent trend: there is a rising odds of disease ratio associated with increasing consumption of processed and ultra-processed foods (UPFs) across quintiles, whereas an inverse pattern is observed for unprocessed or minimally processed foods. To put it in practical terms, the likelihood of nutritional frailty increases by nearly 50% with moderate daily consumption of processed foods and doubles for high versus very low consumption. 

Similarly, there is an escalating probability linked to higher UPF consumption. Their study suggests that individuals with nutritional frailty phenotypes tend to have a greater inclination toward consuming processed foods and UPFs compared to their counterparts. While these food choices contribute to food security by ensuring immediate availability, especially beneficial in cases of disability, they fall short in terms of nutritional quality. 

These items, primarily convenience foods or beverages, are composed mainly or entirely using food-derived substances and additives, often lacking natural, unaltered foodstuffs. Consequently, they are characterized as components of unhealthy dietary patterns associated with adverse health outcomes, including overall mortality, cardiovascular disease, metabolic syndrome, physical and cognitive decline, cancer, and other health issues.

Conclusion

Medical research progresses spectacularly. We constantly explore new ways to cure diseases and make lives healthier en longer. However, the maximal life expectancy has not risen anymore for decades. The oldest person ever, Jeanne Calment died 26 years ago when she was 122 years. The oldest person in the world now is « only » 116 years old. 

We all know that one of the biggest sources of medical care is the drugs that we swallow. We know how much the combination of drugs can be influential good or bad. But we tend to forget that we swallow many other substances as air and food. 

One global cause counterbalancing health progress could be all sorts of pollution we ingest. Air pollution is everywhere in the world, but happily globally decreasing in many aspects even if fine particles are deeply worrying. Food, especially ultraprocessed food could be also a major source of the decline. Actually, it could be the source of various damages: through preservatives, sugar, saturated fats… And because of « toxic cocktails » created from unknown combinations of products.  There is an urgent need to learn more about these substances, because of the risks they present. Beware, however, that the risks may be overestimated out of fear of the ‘artificial’. What’s more, some rarer processed products may be beneficial without us yet having detected them.

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The good news of the month: AI for longevity Research

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The fast developments of Artificial Intelligence are everywhere in the news. In the last weeks, world leaders met to adopt the Bletchley Declaration. The recent discussions about AI are about the risks, but also the hopes for more resilience and health.

It is clear that using AI primarily for goals related to medical research, longevity progress, and more resilience… is one of the ways to mitigate the risks of AI. Companies and organizations are active in this direction. See for example the Longevity GPT website.

In Europe, the combination of high-level AI Health companies and high-level data from the European Health Data Space (EHDS) opens large perspectives. If European public Health Institutions get involved, breakthroughs for longevity for all (and not only for a few) could be around the corner.

For more information

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Back in the 1900s, the pioneer immunologist Elie Metchnikoff, vice president of the Pasteur Institute in Paris, wrote, “Aging is a disease and it should be treated like any other.” His work helped to shape interest in aging as a manageable problem. (Source)

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This month’s theme:  Naked Mole Rats

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Introduction

Naked mole rats, often known as the « sand puppy” and scientifically known as Heterocephalus glaber (NMRs), hold the distinction of being the lengthiest-lived rodents in the animal kingdom, boasting an impressive maximum lifespan of 30 years. This longevity surpasses expectations based on their diminutive body size by a remarkable factor of five. These remarkably social, mouse-sized rodents are indigenous to the arid and semiarid regions of the Horn of Africa and parts of Kenya, particularly in Somali regions, where they naturally inhabit subterranean burrows. Due to their exceptional characteristics, they have become invaluable subjects for scientific investigations encompassing behavioral studies, neurological research, ecophysiological inquiries and especially geroscience!

Those strange looking (ugly) animals are also specific in other ways. As an adaptation to life in burrows, a stable underground environment that can be lacking respirable air, they are able to survive with less oxygen than other mammals. but they have difficulties changing their internal temperature. Naked mole rats together with the close  Damaraland mole-rat are considered the only mammals being « eusocial », living in groups with only a « queen mother ». 

Do they age ?

You can define aging in many ways. One of the ways of defining it is a degradation phenomenon, having for consequence that the probability to die augments with age.

For humans, this is called the Gompertz law, more precisely, the Gompertz–Makeham law of mortality. From age 30, the probability to die doubles each 8 years.  For many animals, there is a similar curve, but the rate of doubling is very different. For example, for mice, the probability to die doubles each 3 months.

We have reliable statistics for mortality of humans, rats, mice and some other mammals living with humans. But statistics are far less easy to establish for wild animals.

Concerning naked mole rats, a few colonies have been kept in captivity since decennia. The positive news is that there is no measurable growth of the rate of mortality. This was measured 5 years ago and again recently. Does this mean that those mammals are « biologically immortal »? We are far from sure at the moment.

First, the number of naked-mole rats proven to be still alive at an advanced age is until now low. The oldest animals are barely 30 years old and only one animal reached the age of 40. So, those statistics have to be confirmed.

It is true that a lifespan of forty years is almost 10 times longer than the maximal lifespan of rats and mice. However, this lifespan is not so much longer than the oldest long living rodents that are squirrels (23 years and 6 months). And there are even other small mammals who have a longer lifespan. A Brandt’s bat (Myotis brandtii) has been living in the wild for at least 41 years.

Also, it could be that the rate of mortality stops increasing until a certain age, but that the process of accumulation doesn’t stop, still inevitably leading to the death of old age after a « plateau ».The fact that the epigenetic age of naked-mole rats changes with age and the fact that very old individuals look older than younger ones are elements tending to confirm this hypothesis. Unfortunately for researchers hoping to find a recipe for longevity.

Transferring the genes of longevity

It is not sure that genetic differences between humans have a very big influence. What we found until know is only that many ((combination of)) genes have a moderate impact.

But it is certain that genetically close animals have very different maximal lifespans. So, the transfer of longevity genes is a possible solution.

This was recently tested on naked-mole rats to mice. The gene transferred improves the production of Hyaluronic acid, a substance with many positive aspects. The result of the first experiment is relatively good. Indeed « Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice,” The lifespan extension is between 4,4 and 16 % (for male mices) according to different estimates.

Conclusion: 

Will we have in a not so far future changes as spectacular as the changes in lifespan obtained many years ago with genetic changes in C Elegans worms with doubling of lifespan? We do not know, and the longevity field is complicated. But we should certainly try, with help from naked-mole-rats and also with help of A.I. to better understand, examine, compare, curate data and have clinical trials on rats and on humans.

The good news of the month: Dublin Longevity Declaration.

You are invited to sign this declaration. An increase in healthy lifespans, through much better treatment of age-related diseases would deliver extraordinary benefits, including savings of literally trillions of dollars per year in healthcare costs.  

Dozens of world-leading experts, hundreds of scientists and thousands of « ordinary » citizens declare that such an advance is now potentially within reach, by targeting the underlying processes of aging, and that efforts to achieve it should be immediately and greatly expanded.

For more information

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“First do no harm is a classical principle of medical ethics. Complement: Doing nothing is harming people.”

 The famous longevity scientist Brian Kennedy during the International Longevity Summit of Dublin, August 2023

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This month’s theme: Recent Longevity Conferences

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Introduction

During the past last weeks, many conferences have been organized concerning longevity. The Longevity+DeSci Summit in New York, August 10 and 11, the Longevity Summit in Dublin, August 17-20, the International Longevity Summit in Johannesburg August 23 and 24, the Aging Research & Drug Discovery meeting ARDD in Copenhagen, August 28 – September 1 and the Raadfest in California, September 5 – September 8.

Thousands of people assisted on the sites and online. Here, we will give short feedback about each conference and then general comments about what was discussed during the conferences.

One goal: longevity for all, many points of view

Hosts and sponsors are increasingly diverse in the longevity field. The increasing diversity of people within the field of longevity is useful and is also more gender equilibrated than in the past, especially among young scientists. Some offer grants and funds, others search for it. Some sell something, and most want to share their knowledge.

The longevity+Desci Summit NYC was organized by Lifespan.io, the biggest « activist » organization for longevity. One of the key aspects was the promotion of a decentralized way of medical research (Desci for « Decentralized science »). The goal of decentralized science (DeSci) is « to increase scientific funding, free knowledge from silos, and cut out profit-motivated intermediaries, such as publisher conglomerates that lock scientific data behind paywalls. »

The Longevity Summit in Dublin is the biggest conference of the Longevity Escape Velocity Foundation, the organization recently created by Aubrey de Grey. During 4 days, scientists, but also specialists of aging, representatives of longevity companies and organizations promoting medical progress met.

The International Longevity Summit in Johannesburg was a big conference, the first of its kind in the youngest continent. It was organized by Afro-Longevity and the Transdisciplinary Agora For Future Discussions (TAFFD).

The Aging Research & Drug Discovery meeting (ARDD) was organized in Copenhagen by a great scientist and host Scheibye-Knudsen. The conference lasted for 5 days, each day with speeches the whole day and even the evening. It is the best imaginable place for the confrontation of new ideas, discoveries, and hypotheses concerning the mysteries of aging.

The RAAD festival aims for a « Revolution Against Aging and Death. It is a place where scientists come, but also less « serious » people and where there is the biggest will and enthusiasm for radical longevity.

Main themes approached during the conferences

Biomarkers 

There were many significant discussions about « biomarkers of age. » They are molecular or physiological indicators used to assess an individual’s aging process. They provide valuable insights into a person’s overall health status and can be used to study the effects of aging on various aspects of biology, health, and longevity. During these conferences, numerous researchers presented their biomarkers, including glycan biomarkers, the nuclear envelope, and microbiota. These can be used to determine your biological age and are to find ways to slow it down. In the longevity field, there is a growing discourse surrounding all biomarkers and there has arguably been a certain trendiness surrounding them, possibly due to their commercial appeal to the public. 

Foods that promote a healthier, longer life 

Some talks revealed the potential of a healthy alimentation to promote a healthier and longer life. Natural senolytics foods have shown potential in reducing senescent cells, contributing to better aging. These include soy proteins, blueberries, resveratrol-rich grapes, omega-3-rich fish, apples, and broccoli. Moreover, passion fruit and krill oil were studied for their impact on preventing Alzheimer’s disease. These specific foods could provide protective properties that may help safeguard cognitive health and promote overall well-being as you age.

Physical activity 

Regular physical activity has been shown to have a significant positive impact on longevity. Studies on mice have revealed that exercising three times a week can increase their lifespan by restoring cyclin D1 function (an important regulator of cell cycle progression). The study suggests that inducing cyclin D1 may replicate the beneficial effects of exercise. Furthermore, genes like ACTN3 and R577X, commonly found in more athletic individuals, may play a role in promoting longevity. Exercise also triggers the release of Interleukin 6 (a molecule that plays a role in the immune system), which enhances glucose intake and promotes lipolysis, contributing to overall health. Additionally, regular physical activity can lead to positive epigenetic changes in gene expression, while splicing alterations associated with aging can be regulated through calorie restriction and exercise. Lastly, physical activity is associated with increased taurine levels, an amino acid which plays a role in slowing down cell aging. 

Drugs for longevity

Many drugs were presented. These included rapalogs called Next Generation Tornado, which inhibit a protein complex that tends to be dysregulated with age (TORC1). Claromer presented MXB-22,510, a potential substitute for the antimicrobial peptide LL-37, that shows promise in enhancing the immune system. Spermidine, through its role in enhancing CD8 functions and autophagy, may reduce the risk of memory loss and dementia in old age. Nicotinamide mononucleotide (NMN) has gained attention for its ability to increase NAD levels and prevent cellular senescence. Nintedanib is being explored as an anti-senescence drug. Quercetin and fisetin are being studied for their anti-inflammatory properties. These molecules represent exciting avenues in the pursuit of extending lifespan and promoting healthy aging. And last but not least 1500 mg of Metformin per day for those over 50 could have a positive impact on cancer, diabetes, and long COVID.

A few blind spots

It can be regretted that the global decrease in life expectancy (see our last newsletter) was practically never approached during the conferences.

In the same « not concrete enough » perspective, sadly most of the interventions concerning new therapies and how promising they are, are short of proving real progress of life expectancy in mice (and even less in humans). It is sometimes spectacularly disappointing that measures by biomarkers sustain strong affirmations of longevity, but not confirmed by measures of real longevity.

Luckily, there are exceptions, the biggest one being the experiment made with 1,000 old mice by the Longevity Escape Velocity Foundation.

Gene therapies, regulation of metabolic pathways and expression of genes.

The gene therapy received by Liz Parrish focuses its action on telomerase, which improves genomic stability, reduces senescence and may even prevent cancer, follistatin, which increases and improves muscle mass and reduces frailty, and klotho, an enzyme that optimises brain functions and eliminates the damage caused by oxidative stress

There have been many promising advancements in the field of rejuvenation. One of the most spectacular recent experiments approached during the conferences is the transfer of genes from naked mole rats to mice with a (moderate) life extension effect.

Also extremely promising is the research affirming that different chemical « cocktails » may restore a youthful genome-wide transcript profile and reverse transcriptomic age without compromising cellular identity. This should be far simpler than using the Yamanaka factors.

Conclusion: 

There were never so many and so interesting and diverse conferences in such a short time, never so much diversity of scientists, especially young individuals and women, and never so many sponsors and industrials actively working on longevity.

All this, more cooperation and the rapid rise of AI could announce golden times for human healthy longevity. This is in a relatively near future. 

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The good news of the month: The quest for rejuvenation without reprogramming progresses

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In 2012 Professor Shinya Yamanaka of Kyoto University won the 2012 Nobel Prize in Physiology or Medicine. He discovered that mature cells can be reprogrammed to induce pluripotent stem cells (iPSCs), which can differentiate into any type of cell by introducing 4 reprogramming factors (c-Myc, Klf4, Oct3/4, and Sox2).                                                                 

The scientists of the organization Clock.bio affirm that a cocktail of existing drugs may hold the key to restoring all the hallmarks of aging.

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“All my possessions for a moment of time.”

Attributed to Queen Elizabeth I on her deathbed, age 69, in 1603.

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This month’s theme: Decrease in life expectancy. After the Covid-19, (when) will the rebound come?

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Introduction

The average life expectancy has improved every year over the past 70 years, starting from the end of World War II. From around 1948, life expectancy surpassed the pre-war level. This means that concerning life expectancy (and also likely the average global wealth and happiness), each year was globally better than ever.

This seemed an unbreakable trend, even if life expectancy significantly decreased in some parts of the world. For example, the decrease in countries of the “European communist bloc” during the seventies of the last century and at the end of the 20th century in many African countries due to Aids didn’t interrupt the global trend.

But Covid-19 changed the situation dramatically, which many of us, especially longevists, still underestimate. 

Statistics

To fully understand the situation, these are the global data:

Between 2000 and 2019, life expectancy increased by more than 5 years.

In 2020 and 2021, we lost about one-third of this, returning to the situation around 2013. Patrick Heuveline in Population and Development Review wrote: After 69 years of uninterrupted increase from 1950 to 2019, the global life expectancy is estimated here to have declined by -0.92 years between 2019 and 2020 (for both sexes) and by another 0.72 years between 2020 and 2021.

The worst situation among the big industrialized countries is undoubtedly in the USA. This is the country with the highest budget in the world used for health (in absolute terms, per inhabitant, and in percentage of the GDP). This is the country with the most (reputed) scientists in the world. Still, life expectancy dropped to the level it was at the end of the 20th century (1996)!

We do not have much information concerning the evolution of 2022. However, we have relatively good data for European countries. We can say that the situation in this continent seems not to worsen anymore but also (still?) not going back to the pre-COVID situation. We know, for example, that life expectancy decreased in Denmark, was stable in Belgium, and was slightly improving in France.

To follow the evolution of the last months, the site Momo is monitoring  European MOnthly MOrtality activity, aiming to detect and measure excess deaths related to seasonal influenza, pandemics, and other public health threats. The last months seem back to (but not better than) the pre-COVID situation.

Primary Cause: COVID 

In 2020, the Centers for Disease Control and Prevention reported ten leading causes of death for adults aged 65 and above:

1. 1.  Heart disease: 556,665 
   2. Malignant neoplasms: 440,753 
   3. COVID-19: 282,836 
   4. Cerebrovascular: 137,392 
   5. Alzheimer’s disease: 132,741 
   6. Chronic lower respiratory disease: 128,712 
   7. Diabetes mellitus: 72,194
   8.  Unintentional injury: 62,796 
   9. Nephritis: 42,675 
   10. Influenza and pneumonia: 42,511

Of course, Covid-19 is new in this list compared to the former years. The number of victims is probably an underestimation.

Direct and Indirect medical consequences

Long Covid

Long COVID is of particular concern among older people (i.e., 65 years or older), who are at greater risk of persisting symptoms associated with COVID-19. In addition, this disease might trigger or exacerbate chronic conditions commonly in older people, such as cardiovascular diseases, respiratory diseases, neurodegenerative disorders, and functional decline. In addition, the disruptive effects of COVID-19 on older people should not be underestimated; lockdowns and other restrictions might have reduced the social interactions of older people, and they are also likely to have lost a spouse or loved one during the pandemic, which can contribute to mental and physical decline.

No rebound effect, at least until 2022

Logically, after the high death toll of COVID-19, there should be a “rebound effect” because « weak people » were « eliminated. » and « strong people » survived. Such an effect was not established, probably among other things, because of the negative consequences of the long covid.

Deficit of other medical interventions

Due to the COVID-19 crisis and all measures to prevent contamination, it has been challenging to have normal handling of many other diseases, especially in rich countries, and to keep the rhythm of vaccination, especially in poor countries. It is also probable that the trust concerning vaccination has been decreasing.

No rise in suicides in the older population

It was thought by many that the lockdown, restrictions and crisis would cause a surge in suicide. This was globally not the case as far as we know (statistics concerning suicides are not always reliable). 

Other possible causes of the decrease in life expectancy are food, (air) pollution, and other environmental aspects.

Sadly, Covid-19 is not the only reason, and we could have a reduction in longevity. There are at least three reasons to be pessimistic.

Firstly, obesity and too-processed food. Eating processed and refined foods can lead to weight gain and obesity because they are typically low in protein and high in fats and carbohydrates. This can cause people to overeat these foods to satisfy their body’s protein needs. During the last decades, on one side, the quality and quantity of food have been constantly improved, and very toxic substances are far less present. But new substances and « toxic cocktails » can gradually accumulate.

Secondly, Air pollution: Similarly to food, air pollution is at the same time less a problem and more a problem. It is less of a problem, especially in Europe and North America, because very heavy pollution, fast and lethal, is less present. For example, the Great Smog of London killed thousands of people in 1952, But it is more of a problem concerning long-term effects due to small particles, microplastics…

One of the most potentially worrying aspects of global health is the global decrease of the population of arthropods (insects and arachnids) in most parts of the world. This is very worrying because insects are supposed to be relatively resistant to many substances. Their number seems to decrease even in regions where natural spaces are improving. We do not know why this happened, but one of the causes is most probably the global rise of polluted substances.

Of course, this could affect humans in the future. Maybe the rise of some substances or « toxic cocktails » already impacts us without noticing, except through weak signals like allergies.

Last but potentially not least, global warming is increasingly killing people. There is no negative global impact yet because, at the moment, there are more people dying of situations related to (too) cold situations than (too) warm situations. However, this could dramatically change when global warming will provoke higher and longer heat waves. 

Conclusion: What could longevists do?

Covid-19 was not only a bad news concerning the struggle against senescence. Covid-19 was more related to aging than most communicable or non-communicable diseases. This disease pushed States, international organizations, and health authorities to invest more in prevention, research, and economic measures than for any other disease. 

“We civilizations now know that we are mortal” wrote Paul Valery in 1919, at the end of the World War I. About one century later, we know that even fast scientific and medical progress can coexist with decreased health (and wealth). 

To inverse this, we should be better organized, less bureaucratic, and more transparent, use fewer patents and IP, and really share more knowledge in an open-source vision.

We also need to think about resilience and health more systematically. We need data that is more reliable and really accessible for scientists, with more clinical trials. The results, bad, good, and even non-significant, must be available to open avenues (if positive), to close doors (if negative or neutral), and to be further analyzed and curated thanks to the Artificial Intelligence of today and tomorrow.

It could be that the decrease in wealth is temporary, where the accumulation of knowledge doesn’t stop. The negative snowball effect could stop. However, this is not sure. We could be generous to the citizens to rise again collectively as fast as possible. This is also generosity to our future senescent self.

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The good news of the month: The mortality rate of naked mole rats does not increase with age

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Most small mammals have a short life span. Naked mole rats are among the exceptions. The oldest known naked-mole rat is almost 40 years old, living ten times longer than the oldest mouse or rat.

But there is more positive news. These rodents have been followed for many years; until now, they do not seem to age. More precisely, even if there are some signs that they get old, the known statistics establish that their probability of dying doesn’t increase at all with age. This was already announced in 2018 and was firmly confirmed with data from the same group of animals a few days ago.

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For more information

• Heales, Longevity Escape Velocity Foundation, International Longevity Alliance, Longecity and Lifespan.io 
• Heales Monthly Science News
• Heales YouTube channel
• Source of the image 
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