All posts by didiercoeurnelle

The death of death Nr 191. March 2025. Tardigrades


The wish to escape the human condition, I suspect, also underlies the hope to extend man’s lifespan far beyond the hundred-year limit. Hannah Arendt, philosopher. The Human Condition, 1958 (source).


This month’s theme: Tardigrades


 What are tardigrades?

Tardigrades, also known as water bears, are microscopic invertebrates measuring between 0.1 and 1 mm in length and have 8 legs. Discovered in 1773, they inhabit a wide range of environments, including oceans, freshwater bodies, and terrestrial ecosystems such as mosses, lichens, and soil. 1380 species of living tardigrades have been recognized worldwide. Despite their small size, tardigrades play important ecological roles in nutrient cycling and microbial regulation within their habitats. 

Tardigrades are best known for their extraordinary survival abilities: They have survived several mass extinctions, flown into orbit, and landed on the Moon. They can survive for 20 months at -200°C, in immense pressures, the vacuum of space, and toxic substances. Some species (in the genus Paramacrobiotus, for instance) are 1000 times more resistant to UV and X-ray radiation than humans and can even survive without oxygen for several days. Their unique physiological adaptations make them a subject of interest in scientific research, particularly in astrobiology, genetics, and environmental studies. 

How do they survive everything? 

Tardigrades owe their extreme resilience to several biological adaptations. One of their main survival strategies is cryptobiosis, a state in which they almost completely shut down their metabolism in response to extreme environmental conditions. In this state, tardigrades lose 99% of their body water and curl into a desiccated form called a tun, allowing them to survive extreme dehydration (anhydrobiosis), freezing temperatures (cryobiosis), high salinity (osmobiosis), and lack of oxygen (anoxybiosis). For instance, in a 2016 study, Japanese researchers were able to recover and reproduce an Antarctic tardigrade retrieved from a moss sample frozen for over 30 years.

A key factor in their survival is the production of bioprotective proteins known as Tardigrade-Specific Intrinsically Disordered Proteins (TDPs). These proteins replace water inside their cells and form a protective gel-like structure that prevents damage to sensitive biological molecules, such as DNA and proteins. When conditions become favorable again, tardigrades can rehydrate and return to normal activity within hours.

Tardigrades also possess highly efficient DNA repair mechanisms that help them survive high levels of radiation, which would typically cause lethal mutations in other organisms. In addition, some species produce pigments that act as a shield against harmful ultraviolet radiation.

These remarkable adaptations make tardigrades one of the most resilient life forms on Earth. Their ability to survive in space has attracted significant scientific interest, especially in the fields of astrobiology and biotechnology, where researchers study their unique survival mechanisms for potential applications in medicine, food preservation, and space exploration.

Application for science and longevity

The Tardigrade Damage Suppressor Protein (Dsup) has been identified as a key factor in the tardigrade’s ability to protect its DNA from damage caused by stressors such as radiation and dehydration. Research has shown that when Dsup is introduced into human cells, it helps regulate genes involved in DNA repair and transcription. A study found that the expression of Dsup increased antioxidant levels and restored key parameters altered by UV exposure, such as pollen tube length, position of the male germ unit, and expression of stress proteins (tubulin, HSP70). These results suggest that Dsup could enhance pollen resistance to UV-B and improve plant tolerance to solar radiation. This protein could play a vital role in protecting human DNA against environmental damage and may have therapeutic applications in cancer treatment, where DNA repair mechanisms are crucial for the efficacy of therapies. Chemotherapy and radiotherapy often induce DNA damage in healthy cells, which limits their success and causes harmful side effects. By applying tardigrade-derived proteins or genes to human cells, researchers could potentially enhance the cells’ ability to repair DNA, making them more resilient to the damaging effects of cancer therapies. This could help increase the effectiveness of treatments while minimizing harm to healthy tissues.

Cryopreservation, the process of preserving cells, tissues, or organs at low temperatures, is another area where tardigrade research has applications. Tardigrades are capable of surviving extreme desiccation (drying out), a process that is similar to cryopreservation. By studying the genes responsible for their stress resistance, researchers are working on improving cryopreservation techniques for human cells, tissues, and organs, which could revolutionize organ transplantation and the preservation of genetic material.

As extremophile organisms, tardigrades can survive in space. In 1964, it was first suggested that tardigrades could serve as model organisms for space research due to their extraordinary resistance to radiation. Over the years, studies on their cryptobiosis revealed even greater resilience, particularly in space conditions. Several space missions, such as FOTON-M3 in 2007 and the Endeavour mission in 2011, explored how tardigrades survived space stressors like microgravity and radiation. The final space research involving tardigrades was the Phobos Life Project, which aimed to test the survival of organisms during an interplanetary flight, supporting the panspermia theory. Unfortunately, the mission failed when the spacecraft crashed in 2012.
Furthermore, this organism has shown remarkable resilience to sustained extreme pressures, enduring up to 74,000 atmospheres—equivalent to a descent of 180 km toward Earth’s core. This surpasses the pressure needed to form diamonds. Despite such intense conditions, the structure and integrity of their cells remain unchanged.

The ability of tardigrades to enter cryptobiosis makes them well-suited for surviving long cosmic journeys and opens the possibility of exploring whether they could survive and thrive on other planets.

Another potential use of tardigrades as a model could be to investigate how they age when they enter cryptobiosis. The “sleeping beauty” hypothesis suggests that tardigrades may not age during this dry state, even if it has not been fully explored. Recently, this hypothesis has been tested by subjecting a group of tardigrades to alternating periods of freezing at -30°C and feeding at 20°C. The results showed that the frozen tardigrades lived twice as long as the control group. This study represents the first experimental evidence that tardigrades reduced ageing during cryobiosis. 

Tardigrades are not the only ones to practice cryptobiosis

Like tardigrades, some bdelloid rotifers can enter cryptobiosis to survive extreme conditions, including prolonged freezing. A study published in 2021 revealed that a bdelloid rotifer from the genus Adineta, extracted from Siberian permafrost and radiocarbon-dated to approximately 24,000 years BP, was successfully revived. Genetic analysis confirmed its classification and demonstrated that it could resume reproduction by parthenogenesis in a laboratory setting. This discovery represents the longest documented case of survival in a frozen state for a multicellular organism, highlighting cryptobiosis as a remarkable biological strategy that enables certain life forms to withstand extreme environments and remain dormant for thousands of years.


The good news of the month: We understand more about the life of supercentenarians.


Maria Branyas Morera died in 2024 at the age of 117 years. She agreed to be examined to study her exceptional health during her lifetime. A study published as a preprint in February shows that she had almost a « child’s gut microbiome ». Her genes protected her from cardiovascular, neurodegenerative, and metabolic diseases. 

The lead author of the article, Manel Esteller, says that the record-breaking supercentenarian suggests that, under certain conditions, aging and disease can be decoupled. This is, of course, sadly, for a limited time and for a small group of people. But our knowledge progress to make this possible for more people for longer.


For more information

The death of death Nr 190. February 2025. The impact of nanoparticles on our bodies.


Why desire the radical extension of life? Because everything valuable requires time. Time to write, to read, to create and refine work that leads us to deep meaning. Time to learn multiple languages, to peel back the endless layers of our identity, to reinvent the best version of ourselves. Time to love and be loved. Time to raise children, nurture grandchildren, and play with great-grandchildren — all part of the gradual unfolding of love. Yana D’Cortona, medical student, January 9, 2025.


Theme of the month: The impact of nanoparticles on our bodies.


The number of nanoparticles created directly or indirectly by humans is increasing overall, even if there are improvements in certain areas. Invisible to the naked eye (1-100 nanometers), these particles are omnipresent in our environment and infiltrate our bodies by various routes, including breathing, ingestion, or skin exposure. Their minute size enables them to pass through the respiratory tract, the digestive system, and other routes to cross biological barriers (air-blood, blood-brain, placental) and reach the brain, where they can potentially interact with our cells. These interactions, still poorly understood, raise an essential question: how do these tiny particles influence our health?

In general, it can, unfortunately, be said that many nanoparticles accelerate ageing or increase the likelihood of cancer. To date, fortunately, the benefits of medical progress continue to outweigh the effects of pollution, but disastrous medium- and long-term effects of nanomaterials (possibly combined in « toxic cocktails ») cannot be ruled out. 

How do nanoparticles enter our bodies?

Among the ways in which nanoparticles can be absorbed, we will study two main routes here:

  1. Respiration: Inhalation of airborne nanoparticles. They can reach the lungs and brain.
  2. Ingestion :
    Through food: Ingestion of particles contained in food and impact on the digestive system.
    By hydration: Consumption of water-containing nanoparticles promotes their absorption by vital organs.

Nanoparticles in the air: Inhalation and respiratory risks

Airborne nanoparticles come from industrial pollution, exhaust fumes, forest fires, and certain domestic activities. When inhaled, they can reach the lungs and enter the bloodstream.

These include: nanoparticles (Np) of titanium dioxide (TiO₂) used in paints and cosmetics (sunscreens) which, when generated in large quantities, can cause lung inflammation. The International Agency for Research on Cancer (IARC) has declared TiO2 NPs to be « possibly carcinogenic when inhaled », and highlighted the need to better understand their potential adverse effects via different routes of exposure in humans. Studies have shown that they can cross the placental barrier and reach fetal organs (liver, brain) in mice, causing developmental disorders and neuronal damage.

Nanoparticles resulting from the combustion of fossil fuels, notably soot and carbon black, are ubiquitous in our environment. The toxicity of soot particles stems from their physico-chemical characteristics. Soot particles penetrate deep into the respiratory tract, and are difficult to eliminate from the pulmonary alveoli. These fine particles penetrate deep into the respiratory tract, increasing the risk of asthma and cardiovascular disease. In 2013, IARC classified soot as a definite carcinogen (Group 1) in chimney sweepers, due to its association with skin and lung cancers.

Nanoparticles of heavy metals such as lead, mercury, and cadmium, present in industrial emissions, can also be found in the air. Heavy metals cannot be degraded or attacked by bacteria. The U.S. Environmental Protection Agency (USEPA) has classified mercury, cadmium, and lead as among the most toxic pollutants. Exposure to these heavy metals can cause neurotoxic effects, disrupting the nervous system.
Lead, for example, is recognized for its effectsmarked neurotoxic , affecting neurological development and neuronal transmission. Mercury, for its part, can cause serious neurological disorders such as Minamata disease. Oral exposure to high doses of cadmium can cause severe gastrointestinal irritation and significant effects on the kidneys. Chronic inhalation exposure has been associated with lung effects, including emphysema, and kidney damage. It can also cause bone damage.


A case study shows the impact of atmospheric nanoparticles on mortality in Canada: A study conducted between 2001 and 2016 in Canada revealed that prolonged exposure to atmospheric nanoparticles is associated with a significant increase in the risk of non-accidental mortality (+7.3%) and, more specifically, respiratory mortality (+17.4%). In Montreal and Toronto, this pollution is estimated to cause around 1,100 additional deaths per year. These results underline the urgent need to integrate nanoparticles into air quality regulation policies in order to limit their harmful effects on public health.

Nanoparticles in the food chain.

Heavy metals such as mercury (Hg), cadmium (Cd), lead (Pb), arsenic (As), and chromium (Cr) are present in the environment, due to industrial, agricultural, or urban activities. These activities lead to their incorporation into soils, water, and sediments, affecting living organisms including humans. At each trophic level, the concentration of metals increases. For example, a fish contaminated with mercury will be eaten by a predator, which will accumulate even more mercury in its body. This phenomenon is known as biomagnification.

Main food sources :

  • Fish and seafood: Contamination by mercury, particularly methylmercury, which is neurotoxic. A recent study (2024) revealed that one in ten cans of tuna (a predatory species) exceeds the permitted mercury limit in Europe, exposing consumers to health risks.
  • Vegetables and cereals: Absorption of heavy metals via polluted soils.
    In a study carried out in Canada in 2021, arsenic was detected in high concentrations (up to 2.20 ppm) in vegetable powders (92% of samples concerned). Leafy vegetables, such as kale, also showed higher levels of contamination than other vegetables, due to their high absorption capacity for soil particles.
  • Meat and dairy products: Accumulation through ingestion of contaminated livestock feed.

Zinc oxide (ZnO) and copper oxide (CuO) nanoparticles used in agriculture are involved in the disruption of intestinal microbiota. By eating contaminated food, we absorb these particles, which can accumulate in our vital organs (liver, kidneys, brain), causing chronic poisoning, digestive disorders, and metabolic diseases.

Nanoparticles in water: Drinks and their impact on the body

Nanoparticles found in water come from industrial waste, microplastics, and chemicals. Nanoplastics (PE, PP, PET): present in tap and bottled water, now known to affect the hormonal system (Campanale et al., 2020). Silver nanoparticles (AgNPs): used for their antibacterial properties in certain filters and food packaging, can affect the intestinal microbiota. Heavy metal nanoparticles (lead, mercury, arsenic, cadmium): present in drinking water and certain contaminated water sources, can accumulate in our bodies and lead to neurological and renal risks (Khan et al., 2019).

Genotoxic effect of certain

Nanoparticles (NPs) of copper, zinc, silver, and quantum dots are attracting particular attention because of their potential genotoxic effects, mainly linked to the generation of reactive oxygen species (ROS), responsible for DNA damage. ZnNPs, commonly found in sunscreens and cosmetics, can release Zn²⁺ ions, inducing oxidative stress that alters DNA. In vitro studies have confirmed their genotoxicity, revealing DNA damage. Similarly, quantum dots, often composed of heavy metals such as cadmium (Cd) or selenium (Se), can release toxic ions capable of generating oxidative stress and causing genetic damage.
Although nanoparticles may represent a health risk, they offer innovative solutions for combating cellular aging by targeting its key mechanisms.

Nanoparticle applications in medicine: Nanotechnology.

Nanoparticles have also been studied for their positive impact on health. They can repair DNA damage by delivering repair enzymes, as shown by gold nanoparticles that reduce age-related mutations. They also act against oxidative stress with antioxidant nanoparticles, such as those based on cerium dioxide (CeO₂), which protect cells from free radicals. In addition, nanoparticles can eliminate senescent cells by carrying senolytic drugs, such as quercetin, thus reducing inflammation and tissue damage. Finally, they help protect telomeres by delivering agents such as telomerase, extending cell lifespan. These applications position nanoparticles as promising tools for slowing or reversing cellular aging.

Conclusions and outlook:

Nanoparticles, because of their small size and ability to penetrate deep into our bodies, present both health risks and opportunities for therapeutic innovation. Their omnipresence in the environment and their presence in air, water, and the food chain underscore the importance of studying and understanding their long-term effects.

In this field, as in others, it is urgent and vital to :

  • Make available data on nanoparticle densities in the human body and their known impact, whether negative or (unfortunately more rarely) positive.
  • Reference any knowledge of negative (or, unfortunately, more rarely) positive « cocktail effects ».
  • Whenever possible, for new or increasingly used nanoparticles, organize longevity tests comparing the lifespan of mice (or other animals) with and without the substances concerned.
  • Require companies developing nanomaterials to share data on the health effects of substances, particularly those for which they hold patents.

Alongside the study of nanoparticles, it is also crucial to examine the impact of microplastics, a category of plastic particles that are larger in size (< 5 mm), but still of concern due to their ubiquitous presence in our environment. Although their direct impact on human health is even less documented than that of nanoparticles, microplastics raise concerns due to their ability to transport toxic substances and accumulate in specific areas of the body, such as the digestive system and, even more seriously, the brain. This subject will be explored in greater detail in a future newsletter.


The bad news of the month: the United States and Health.


Among the tsunami of initiatives, President Trump’s new US administration has made decisions that have, at least in the short term effects generally considered negative for the health of Americans de of the world’s population:

These include:

Withdrawal from the World Health Organization. Along with Liechtenstein, the USA will thus be the only United Nations member state not to be a member of the WHO. It should be remembered that:

 

Find out more:



Heales monthly newsletter. The death of death N°189. January 2025.Blood Brain Barrier and Aging.


The truth is, of course, that death should no more be considered an acceptable part of life than smallpox or polio, both of which we have managed to bring under control without denouncing ourselves as pretentious. Alan Harrington, The Immortalist. Source.


This month’s theme: Blood Brain Barrier and Aging


What is the Blood-Brain Barrier (BBB)?

The BBB is a highly selective barrier formed by endothelial cells of brain capillaries, supported by pericytes, astrocytes, and the extracellular matrix. It regulates the exchange of substances between the bloodstream and the brain, protecting the brain from toxins, pathogens, and inflammatory molecules, while allowing essential nutrients and gases to pass through.

BBB and Longevity

As we age, the BBB tends to become more permeable, leading to:

  • Increased neuroinflammation: Leakiness of the BBB allows peripheral immune cells and inflammatory molecules to enter the brain, contributing to chronic neuroinflammation.
  • Accumulation of toxins: Impaired BBB function leads to reduced clearance of neurotoxic substances like amyloid-beta, implicated in neurodegenerative diseases such as Alzheimer’s.
  • Reduced nutrient transport: Nutrient and oxygen transport efficiency declines, affecting neuronal function and energy metabolism.
  • Oxidative stress: Aging-related oxidative damage further compromises BBB integrity, exacerbating cognitive decline.

The aging process significantly impacts the blood-brain barrier (BBB), leading to functional decline that contributes to neurodegenerative diseases and cognitive impairment. Age-associated endothelial cell senescence disrupts tight junctions and increases BBB permeability, allowing harmful substances to infiltrate the brain and compromise its integrity. Senescent brain endothelial cells (BECs) also exhibit phenotypic alterations, including impaired tight junction regulation, exacerbating BBB dysfunction during aging.

Moreover, BBB decline varies by brain region and demographic factors, with studies showing a steeper decline in males than females in parietal and temporal areas as early as the 60s, likely due to sex-based protective mechanisms. Structural changes in BBB components, such as astrocytes and pericytes, further compromise its homeostasis, linking these alterations to neurodegenerative disease pathways. Increased BBB permeability due to vascular risk factors such as hypertension also directly correlates with white matter injury and cognitive decline, underscoring the importance of vascular health in mitigating these effects.

Maintaining BBB integrity is critical for cognitive health and overall longevity:

  • Cognitive Reserve: Intact BBB function supports neural health, reducing the risk of age-related cognitive decline and dementia, major determinants of quality of life in older age. 
  • Neurovascular Coupling: Healthy BBB function supports optimal neurovascular coupling, which is essential for brain plasticity and repair mechanisms. 
  • Systemic Aging Impact: BBB dysfunction can lead to systemic inflammatory signaling, accelerating aging processes across other organ systems.

Several strategies show promise in maintaining BBB integrity and promoting longevity:

Exercise promotes vascular health, reduces inflammation, and enhances BBB integrity. Aerobic exercise has been shown to increase the expression of tight junction proteins and reduce oxidative stress in animal studies. The Mediterranean Diet is rich in antioxidants, omega-3 fatty acids, and polyphenols and this diet reduces oxidative stress and inflammation, protecting the BBB. Modest caloric restriction can reduce age-related BBB permeability by lowering systemic inflammation. Omega-3 Fatty Acids found in fish oil, enhance BBB integrity by reducing inflammation and promoting endothelial cell function. Found in berries, green tea, and dark chocolate, flavonoids protect against BBB dysfunction through their antioxidant properties. Vitamin E and C neutralize free radicals, protecting BBB endothelial cells from oxidative damage.

The brain-gut axis and the blood-brain barrier (BBB) 

These are intricately linked systems that play crucial roles in maintaining both neurological and gastrointestinal health. The brain-gut axis is a bidirectional communication network involving the central nervous system, the enteric nervous system, the gut microbiota, and the immune and endocrine systems. This axis enables the brain and gut to influence each other through neural, hormonal, immune, and microbial pathways. The BBB, on the other hand, serves as a protective barrier that regulates the transport of substances between the bloodstream and the brain. This ensures that the central nervous system is shielded from toxins, pathogens, and fluctuations in blood chemistry while maintaining nutrient and signaling molecule access.

Disruptions in the brain-gut-BBB connection have significant implications for health and disease. Conditions such as neurodegenerative diseases (e.g., Alzheimer’s and Parkinson’s), mental health disorders (e.g., depression and anxiety), and autoimmune diseases (e.g., multiple sclerosis) are increasingly linked to dysfunction. Similarly, gut dysbiosis can exacerbate these conditions by altering neurotransmitter production, immune responses, and metabolic signaling.

Emerging Therapeutics

The BBB is formed of specific cells. To protect the barrier from aging or even rejuvenate it, specific treatments that can be envisaged are treatments involving those cells.

Senolytics: A recent study investigated non-invasive biomarkers and their responses to a senolytic therapy combining dasatinib and quercetin (D + Q) in PS19 mice, a widely used tauopathy model. This study found D + Q treatment promoted a shift in microglial phenotype from a disease-associated state to a homeostatic state, reducing senescence-like features. Additionally, D + Q-treated PS19 mice showed improved cognitive performance in a tracing fear conditioning test, indicating enhanced cue-associated memory

mTOR Inhibitors: The results from a recent study identify mTOR activity as a key driver of BBB breakdown in Alzheimer’s disease (AD) and potentially in vascular cognitive impairment. They also suggest that rapamycin and related compounds (rapalogs) could serve as therapeutic agents for restoring BBB integrity in these conditions. This study highlights the mammalian/mechanistic target of rapamycin as a critical regulator of BBB breakdown in models of Alzheimer’s disease and vascular cognitive impairment. It underscores the potential of mTOR-targeting drugs to restore BBB integrity and mitigate disease progression.

Pituitary adenylate cyclase-activating polypeptide (PACAP): is a natural molecule with protective and growth-supporting effects on brain cells. Since PACAP and its receptor, PAC1, are found in brain regions affected by Alzheimer’s disease (AD), this study explores whether PACAP could be a helpful treatment for Alzheimer’s disease. A study tested PACAP in a mouse model of AD by giving it to the mice daily through their noses for an extended period. This treatment encouraged a healthier way of processing the amyloid precursor protein (APP), which reduced the production of harmful amyloid-beta (Aβ) proteins. It also increased the levels of brain-derived neurotrophic factor (BDNF), which supports brain health, and Bcl-2, a protein that prevents cell death.

Other Barriers of the Human Body

1. Physical Barriers

These act as the first line of defense to block the entry of harmful substances or organisms.

  • Skin: A tough outer layer (stratum corneum) prevents the entry of pathogens and minimizes water loss. It acts as a mechanical shield.
  • Mucous Membranes: Line body cavities (e.g., respiratory, digestive, and urogenital tracts). Produce mucus to trap microbes and particles.
  • Tight Junctions: Found between epithelial cells in tissues like the gut and blood-brain barrier, preventing the passage of harmful substances.

2. Chemical Barriers

These involve substances produced by the body to neutralize or destroy pathogens.

  • pH Levels: The acidic environment of the stomach (gastric acid, pH ~1.5–3.5) kills ingested pathogens. Skin and vaginal pH (slightly acidic) deter microbial growth.
  • Enzymes: Lysozymes in saliva, tears, and mucus break down bacterial cell walls. Digestive enzymes (e.g., pepsin in the stomach) degrade microbial proteins.
  • Antimicrobial Peptides: Defensins and cathelicidins disrupt microbial membranes and inhibit pathogen growth.
  • Sweat and Sebum: Contain antimicrobial compounds and create an inhospitable environment for bacteria.

3. Biological Barriers

These involve living organisms or systems within the body that protect against pathogens.

  • Microbiota (Flora): Commensal bacteria in the gut, skin, and other areas outcompete pathogens for resources and space. Produce substances (e.g., lactic acid) that inhibit harmful microbes.
  • Immune Cells: Phagocytes (e.g., macrophages, neutrophils) engulf and destroy pathogens. Natural Killer (NK) cells target infected or abnormal cells.

4. Specialized Barriers

Certain structures serve as advanced protective mechanisms.

  • Placental Barrier: Protects the fetus by regulating the exchange of nutrients, gases, and waste while preventing the passage of harmful substances.
  • Corneal Barrier: Protects the eye, comprising a multi-layered structure (epithelium, stroma, and endothelium).

All those barriers, like the BBB, lose their efficiency when we age. This happens at different rhythms. The more we understand what is happening, the better our chances of finding new therapies. And in 2025, we still have much to discover concerning the diversity of the evolutions.


The good news of the month. Open discussion about (hereditary) genome editing.


An important article about gene therapy was written in Nature: We need to talk about human genome editing. « In a few decades, gene-editing technologies could reduce the likelihood of common human diseases. Societies must use this time to prepare for their arrival. Scientists know about tens of thousands of DNA variants that are associated with human diseases. On their own, the vast majority of these variants have small effects. But taken together, the result can be substantial. « 

This point of view is opening the discussion about possible gene therapies for future generations. The diseases that we could cure are diseases that injure and kill mostly when people age since the mortality of young people is low, especially in rich countries.


For more information

Heales monthly newsletter. The death of death N°188. December 2024. Eroom’s Law and Moore’s Law


“It’s less that there are strong arguments why death is good,” he argues, “but what I call palliative philosophy: death is inevitable, we want convincing reasons as to why that’s good, so we create them. In fact, we spend vast amounts globally on healthcare and medical research.” It makes up 10% of global economic activity. “Modern medicine is really the practice of trying to keep death at bay. But we haven’t yet acknowledged or agreed – as a society – that the end goal of medical research is actually to eliminate disease completely. Dr Ariel Zeleznikow-Johnston, neuroscientist, The Guardian, December 1st, 2024.


This month’s theme:  Eroom’s Law and Moore’s Law


What is Moore’s law (conjecture)? Is it still holding?

Moore’s law was formulated by Gordon Moore, co-founder of Intel, in 1965. He posits that the number of transistors on a microchip doubles approximately every two years, leading to a corresponding increase in computing power and a decrease in relative cost. This exponential growth has been a fundamental driver of the rapid advancement in electronic and computing technologies over the past several decades. The consistent doubling of transistors has created smaller, more powerful, and cost-effective computing devices, spurring innovation and productivity across multiple sectors. However, maintaining the pace predicted by Moore’s Law has become increasingly challenging due to physical and economic limitations. 

Moore’s Law is not a law. It is an observation and became a rule for the industry. It has influenced strategic planning and research and development efforts within the technology industry, shaping the direction and focus of innovation.  Despite the challenges in maintaining its pace, Moore’s Law remains a cornerstone of technological progress. Its impact on the evolution of computing and electronics continues to be profound, ensuring that the principles of rapid improvement and cost reduction remain integral to the industry’s advancement. The end of the law has been announced in the past and is still announced. The general concept of exponential growth of technological capacities is also popular in other fields. Some longevists used it to announce « exponential » progress in longevity. For example, Ray Kurzwzeil announced In the Age of Spiritual Machines (1999), Kurzweil predicted that the life expectancy would reach about 100 in 2019.  Sadly, until now, the trend has not been the same for longevity. And for the pace of healthcare therapies, we see a disappointing evolution.

Eroom’s Law

Eroom’s Law, named by ironically reversing the name « Moore, » is a concept in pharmaceutical research and development (R&D) that highlights the increasing inefficiency and costliness of drug (and therapies) discovery over time. Unlike Moore’s Law, which observes the exponential improvement in computing power, Eroom’s Law points to a trend where the number of new drugs approved per billion dollars spent on R&D has halved approximately every nine years since the 1950s. It is now estimated that the total cost of the creation of a new drug reaches an astronomical amount of 2 billion dollars.

Eroom’s Law was described by Jack W. Scannell and colleagues in a 2012 paper in Science. They documented the declining productivity in drug R&D despite technological advancements and increased investments. They noted that while the investment in R&D has grown exponentially, the output in terms of new drug approvals has not kept pace, leading to a paradoxical decline in productivity. What is causing this?

  1. The « Better than the Beatles » Problem refers to the increasing difficulty of surpassing the therapeutic effectiveness of existing drugs. As more effective treatments are developed, new drugs must demonstrate significant improvements over these high benchmarks, discovering truly novel and superior treatments more challenging. It is also said that « low-hanging fruits are plugged first ». 
  2. Regulatory requirements have become more stringent over time, aiming to ensure drug safety and efficacy. While this improves patient safety, it also increases the time, cost, and complexity of bringing a new drug to market. The demand for extensive clinical trials and post-market surveillance contributes to higher R&D costs. Pharmaceutical companies often increase R&D budgets in response to declining productivity. However, this can lead to diminishing returns. There has also been a shift towards high-throughput screening and other brute-force methods in drug discovery. This focus on quantity over quality can dilute efforts and resources. 
  3. « Regulatory Ratchet ». Over time, regulations tend to become more stringent. Each safety issue or scandal leads to new regulations, which accumulate and increase the burden on R&D processes. There is a radical disproportion between the wide attention to negative consequences of the testing of new therapies and the limited attention to lost lives because of the slowness of medical research. One of the reasons is that a victim of a clinical trial is generally a healthy person and always a person benefiting from higher attention. And a victim of a medical mistake is a well-defined person while the victims of non-discoveries will remain unknown.
  4. The growth of bureaucracy, for-profit industry, and legal complexity. Time dedicated to research in the research sector is diminishing constantly. When you follow the information about longevity research, you will see more claims of new patents than claims of new therapies, more announcements of the creation of start-ups than announcements of new drugs, more demands for new funding than offers for new posts of researchers… Maybe the most disastrous situation is the multiplication of litigations and lawyers opportunities. The goal is seldom to save lives, but almost always to prove that somebody has to pay somebody else for a medical reason and, of course, to pay the lawyers (and the ever-growing services related) who “demonstrated” the situation.

Eroom’s law has significant implications for longevity research. The declining productivity may deter public and private investment in innovative therapy research. 

How to accelerate the finding (and approval) of new therapies? Will AI Beat The Eroom’s Law?

Addressing Eroom’s Law requires multifaceted strategies: 

  • Streamlining regulatory processes and adopting adaptive regulatory frameworks can help balance safety with innovation. 
  • Leveraging advanced technologies like artificial intelligence, machine learning, and big data can enhance predictive accuracy and streamline drug discovery. 
  • Partnerships between academia, industry, and regulatory bodies to facilitate knowledge sharing and reduce duplication of efforts must be encouraged. This includes:
  1. The publication of « negative » results
  2. Less bureaucracy
  3. Fewer patents and more open results
  4. More researchers, and fewer lawyers

One key question is -of course- how fast medical AI will accelerate research for healthy longevity. It depends on how much AI will be a priority for human longevity. In the domain of artificial intelligence (and increasingly artificial general intelligence), we live in times, that are fascinating, but that can be dangerous. Safe AI and medical longevity research are not directly related. However, making healthy resilience a common goal for the development of AI is a part of proactive work towards a better and more secure world.


The interesting news of the month: Startling nominations announced in the new US administration


You may not like the newly elected president of the USA. However, concerning health, his presidency could bring interesting evolutions. The announced Secretary of Health Robert Kennedy is a very controversial person having positions that do not conform to recognized scientific views. But the chosen No. 2, future Deputy Secretary of Health will be Jim O’Neill. He is a long-time longevist and was CEO of the longevity organization SENS Research Foundation. 

Even more important is the announced nomination of Elon Musk and Vivek Ramaswamy. for a radical simplification of administrations through a new Department of Government Efficiency (DOGE). FDA included. Musk and Ramaswamy have radical views in many domains, including concerning scientific research. It remains to be seen if the general trend will be a destructive or a regenerative one.


For more information

Heales monthly newsletter. The death of death N°187. November 2024. Fluid System and Aging


Jean-Charles Samuelian-Werve, 38, co-founder and CEO (of neoinsurance startup Alan), says without batting an eyelid that he “wants to revolutionize healthcare, so that everyone can live better, up to the age of 100”. Le Soir 4 november 2024


This month’s theme: Fluid System and Aging


Our body is first made of water, but the body water percentage decreases with age. Water is, of course, present in the fluids composing the body. The human fluid system, encompassing blood, lymph, and other bodily fluids, is crucial in maintaining homeostasis and overall health. As we age, several changes occur in these systems that will impact our health and well-being. Here’s an overview of how the passing of time affects the human fluid system: 

Blood Hemostasis and Coagulation 

Increased Clotting Risk: Aging is associated with changes in the blood coagulation system, leading to an increased risk of thrombosis. This is due to higher levels of clotting factors and decreased natural anticoagulants. A study shows that cardiovascular risk factors can have different implications in the oldest old than in young adults. For example, high total cholesterol levels are linked to increased longevity because they are associated with lower mortality from cancer and infection.

Delayed Healing: Wound healing becomes slower in older adults due to impaired hemostasis and reduced cellular response. The incidence of chronic wounds increases with age, significantly affecting the quality of life in older adults. However, the underlying biology of chronic wounds and the effects of age-related changes on wound healing are poorly understood. Most research has relied on in vitro methods and various animal models, but the findings often need to be translated better into human healing conditions. One of the reasons for this situation is that older adults are usually excluded from randomized clinical trials, leading to a need for more data.

Circulation 

Arterial Stiffness: Arteries become stiffer with age, increasing blood pressure and the risk of cardiovascular diseases. As we get older, our large arteries undergo several consistent changes. The inside of the arteries becomes wider, the walls become thicker, and the arteries become less elastic. This happens because the constant pulsing of blood through these arteries over many years wears out and damages the elastic fibers in the artery walls. Additionally, older arteries tend to accumulate more calcium and the inner lining of the arteries (endothelium) doesn’t work as well. These changes cause blood to travel faster through the arteries, leading to higher systolic blood pressure (the top number in a blood pressure reading) and a greater difference between systolic and diastolic pressure (pulse pressure). 

The heart’s ability to pump blood efficiently decreases with age, leading to reduced cardiac output and circulation. Other health problems like high blood pressure, metabolic syndrome, and diabetes worsen these age-related changes in the arteries. Aging arteries increase the risk of cardiovascular diseases such as atherosclerosis (hardening of the arteries), coronary artery disease, stroke, and heart failure. Managing high blood pressure and other risk factors can help slow down or reduce these changes in the arteries, improving overall heart health. 

Lymphatic System 

Impaired immune response decreased lymphocyte production: One of the most notable signs of an aging immune system is a significant decrease in the number of naïve lymphocytes (white blood cells) in the blood. This decline occurs continuously as age advances, mainly due to reduced thymic output after puberty and inadequate peripheral maintenance. Lymphatic flow can slow down, reducing the efficiency of toxin and waste removal from tissues. Aging is an independent risk factor for the occurrence of some lymphatic-associated diseases. Lymphatic senescence, an important contributor to organ deterioration and failure, is associated with alterations in lymphatic structure and function, inflammatory and immune responses, as well as effects of chronic ultraviolet light exposure and oxidative stress. 

Other Bodily Fluids 

Interstitial Fluid Edema: Aging can lead to fluid retention and edema, especially in the lower extremities, due to reduced mobility and changes in blood and lymphatic vessel function. Edema, characterized by fluid trapped in the body’s tissues causing swelling, is common in the elderly and can significantly impact their quality of life. It often affects the arms, legs, hands, and feet, and can be caused by factors like physical inactivity, high salt intake, prolonged sitting, certain medications, and underlying health conditions such as heart, liver, or kidney disease. Recognizing symptoms like swelling, puffiness, aching joints, and decreased urine production is crucial. Edema can lead to serious complications if left untreated, including infections and blood clots. Proper management involves addressing the underlying causes, dietary adjustments, promoting physical activity, and possibly medical treatments like diuretics.

Cerebrospinal Fluid (CSF) Dynamics: The production and flow of cerebrospinal fluid changes with age, potentially affecting brain function and contributing to conditions like hydrocephalus. Studies have shown that aging increases the levels of many proteins in cerebrospinal fluid (CSF). As we age, the turnover of CSF slows down, which causes protein levels to rise due to concentration effects rather than specific diseases. 

Possible new therapies and treatments

For thousands of years, bloodletting was thought to be a way to cure many if not most diseases. For decades, we also used the circulatory system to inject drugs and products into the body.

Recent advancements in understanding defects in the human fluid system, including lymphatic and vascular issues, have led to several promising therapies. Therapies promoting angiogenesis and lymphangiogenesis, like those targeting vascular endothelial growth factor (VEGF), help improve fluid drainage. Advanced diuretics and nanotechnology-based drug delivery systems enhance treatment efficacy and reduce side effects.  Regenerative medicine, including tissue engineering and biomaterials, aims to restore fluid system function. Pharmacological chaperones and minimally invasive surgeries, such as lymphaticovenular anastomosis (LVA), provide additional solutions. 

Maybe the most promising research concerns the glymphatic drainage of cerebrospinal fluid that could slow down Alzheimer’s disease.

Together, these therapies hold promise for better managing fluid system disorders. Since fluids are everywhere in our bodies, new therapies could improve the whole patient’s quality of life and health.


The good news of the month: The progress of the European Health Data Space and a Declaration for sharing health data


The European Union is creating a “European Health Data Space” (EHDS) where scientists will be able to use health data for research. This work is extremely useful, but sadly extremely slow. And only really available data saves lives! In Brussels, the participants of the Eurosymposium on Healthy Ageing adopted a Declaration of Sharing Health Data and using AI for Healthy Longevity insisting on accelerating progress.


For more information

Heales monthly newsletter. The death of death N°186. October 2024.  Maximal Lifespan of mammals. Decades of stagnation.


Alongside Francis Bacon and Gottfried Leibniz, Benjamin Franklin was one of the few people in the pre-modern era to seriously consider extending lifespans. It is likely no coincidence that these three are among the most brilliant and versatile minds in history.  Liz Parish, CEO of Bioviva. May 2024.


This month’s theme: Maximal Lifespan of mammals. Decades of stagnation.


A sad introduction

We see the extraordinarily small (1 million times smaller than the naked eye).

We see the extraordinarily distant (hundreds of times farther than the naked eye).

We move extraordinarily fast (hundreds of times faster than on foot).

We harness extraordinary amounts of energy (hundreds of times more than human energy).

We have instant access to more knowledge today than anything written until the 20ᵉ century.

But we do not live much longer than 2,000 years ago.

Give 100 million dollars and old mice aged 18 months to the 100 best longevity scientists. Give them the liberty to test anything they know to favor longevity. Come back 30 months later. All mice will be dead.

Find the 100 healthiest male centenarians in the world. Give them the best treatments available today, and the best doctors in the world. Come back 20 years later. There will be no survivors.

In other words, the maximal lifespan of mammals is a limit that we cannot yet change with our actual scientific knowledge. There is a glass ceiling of longevity, very probably for each species of mammal, certainly for mice, rats, dogs, cats, horses, and humans.

This is the inconvenient truth about the research of longevity today. We know more about the biology than ever. We can save more children from diseases and affections than ever before. There are more sexagenarians, septuagenarians, octogenarians, nonagenarians, and even centenarians than ever. But for supercentenarians, people living 110 years and more, there is no progress and even maybe some regression.

What is the maximal lifespan of mice, and rats?

The maximal lifespan of mice and rats is about 4 years. For decades, scientists have tested promising treatments to extend the lifespan of mice. Hundreds of therapies have been tested, but no one is making a really big difference.

In 2003, the Methuselah Mouse Prize (Mprize) was created to increase scientific and public interest in longevity research. One of the two prizes is for the scientists who broke the world record for the oldest-ever mouse. This price attributed in 2003 was for a dwarf mouse almost aged 5 years (precisely 4 years, 11 months, and three weeks): No mice lived longer since then.

We could hope that the progress of research is at least stimulating scientists to make more experiments of longevity. But this is not the case, many experiments concerning mice and rats are done on old animals, but once the therapy is tested during a certain period, animals are sacrificed.

The reasons given by researchers for this are:

  • To see the results of a therapy, an autopsy is often necessary, making it impossible to keep all animals alive.
  • If scientists had to wait for animals to die a natural death, the publication of results would be delayed
  • Due to strict protection laws concerning animal ethics, it can be complicated to keep very old mice. The law requires the animal to not have prolonged suffering. They have to be euthanized if they suffer too much, even if the suffering is only due to ageing.
  • Once good physiological results are known, scientists tend to consider that it proves that longevity will be better (even if this is only a positive signal, not proof)

So, this has for consequence that many experiments to improve longevity are done quite surprisingly without measuring longevity. 

What is the maximal lifespan of other non-human mammals?

Concerning other mammals, some animals may appear to live longer than before, but globally there is no significant increase even if the registration of pets and probably their number increases. The oldest dog ever died at the age of 29 years in 1939. The oldest cat died in 2005, aged 38. The oldest horse died aged 62 in 1822. Of course, reliable information for this is less available than for mice and humans. What is sure is that even pet owners and zoos who sometimes invest enormous amounts of money to keep animals alive do not succeed in breaking records with a considerable difference from records.

They are organizations trying to test therapies on dogs and cats. Unfortunately, not many experiments have been done yet, and none have been successful until now.

The measure of the maximal longevity of naked mole rats, a rodent living a very long life, seems to be increasing. One specimen lived already 39 years! But this is not thanks to a specific therapy. This is because the lifespan of animals has been registered long enough only relatively recently.

What is the maximal lifespan of women and men?

The oldest woman ever was very probably Jeanne Calment. She died when she was 122 years old in 1997. The oldest woman today is « only » 116 years (in October 2024). This means that Jeanne Calment’s record will at least last for more than 30 years. We could almost say that there has been no progression since 2 millennia. Indeed, Terentia, the widow of Cicero, died aged 103 years in Italy when Augustus was emperor. Today, attaining 103 years is still something very rare.

The oldest man ever was, very probably Jiroemon Kimura. He died in 2013, aged 116 years. The oldest man today is « only » 112 years old. This means that the age attained by Jiroemon will stand for at least 15 years.

So, sadly, those who speak of exponential progress for longevity are wrong concerning maximal lifespan. There is no progression. Even worse, logically, since the number of centenarians is increasing, the number of supercentenarians should also be increasing, even if there is no progress in medical science for people attaining this age. Indeed, if you have one supercentenarian for 1000 centenarians and the number of centenarians doubles in 30 years, you should have two times more supercentenarians. 

No increase in maximal lifespan, why?

First, it could be that the number of supercentenarians was overestimated in the past. In countries where the registration of births is poor, there are more mistakes. For example, it can happen that one child dies when young and the parents give the same first name to another child later without registering the second birth. It can also happen that people or their families overestimate the age to receive some benefit (pension) of for social prestige. In the past, there were many claims of people attaining age far behind 120 years and even far behind 200 years. Nowadays, those claims are rarer and almost disappear in countries that have a good registration of births.

A far darker possible explanation is pollution, especially air or water pollution that can go everywhere from polluted cities and industrial areas to Antarctica. The exposition of small amounts of combined pollution (“toxic cocktails”) during decades could progressively accelerate senescence. But why would this be so much more for supercentenarians than for older people?

Another possible explanation is given by scientists who speak about old age as something having not one main cause, but many causes. The causes could be the initially listed 9 hallmarks of ageing described in a seminal article from Carlos López-Otín, Maria Blasco et al. (recently increased). It can also be the 7 causes of aging determined by Aubrey de Grey and the Strategies for Engineered Negligible Senescence. We could say that the maximal lifespan for each cause is a maximum of 120 years. So, human longevity may have reached its upper limit if we do not have therapies stopping all causes of death together.

How to break the glass ceiling?

It will very probably not be easy. We need radical progress. This means:

  • The use of artificial intelligence must concentrate on everything concerning the resilience of humans behind our actual biological limitations. This is important for healthy longevity. This is also important as one of the ways to mitigate risks concerning AI. The more we use it to save ourselves, the less we use it for other goals. Important remark: mitigating the risks this way is only a small part of the question concerning AI risks, but it is not the theme of this newsletter.
  • Testing new therapies as fast as 
  • Testing new therapies as fast as possible with old and even very old well-informed volunteers.
  • Better ethical committees and less blocking bureaucracy. For those who respect the right to health, today the main cause of suffering and death is more and more diseases related to high age. We have to do better for the common good. 
  • Public organizations, especially international organizations like the World Health Organization must invest far more for longevity.
  • We have to make society understand that « Aging is inevitable, but senescence isn’t ». We have difficulties fighting against aging because of psychological reasons. We accept death and do not try to defeat it because we have no choice. But we have less chance to have any choice if we do not try. A proverb says: They didn’t know it was (supposed to be) impossible, so they did it! 

The good news and the bad news of the month: Experiment on mice demonstrating an effect of combination on therapies, but not enough money to pursue.


The experiment on 1000 mice organized by the Longevity Escape Velocity Foundation has almost ended. The partial public results show that the combination of 4 therapies gives good results but with differences between males and females.

There will be phase 2 of the experiment with 4 new therapies and a better treatment thanks to the lessons of the first experiment. Sadly, there is not enough money yet. Didier Coeurnelle, co-chair of the board of Heales is matching until 200 000 € of gifts to start the experiment, but more is needed. Why are the billionaires and public organizations not supporting this? There are many reasons, and you can be a part of the solution.


For more information

Donations from Didier Coeurnelle enable next phase of Robust Mouse Rejuvenation research program

Longevity Escape Velocity Foundation (LEVF) today welcomes two very generous donations from long-time supporter of longevity research and activism, Didier Coeurnelle.

The first donation is 200,000 euros (approximately 220,000 US dollars). The second donation, of up to another 200,000 euros, is dependent on LEVF receiving matching gifts from other donors from 1st October until the end of the month (October 31st).

These donations enable a key set of pre-study pilots ahead of the next phase of LEVF’s groundbreaking investigations into the effects of combining different damage-repair interventions for middle-aged mice.

RMR1, the first phase of this Robust Mouse Rejuvenation project, has been running since February 2023, and is now nearing completion. Mice in this project have received combinations of up to four different treatments.

Caitlin Lewis, Director of Project Pipeline & Strategy at LEVF, commented: “These donations come at exactly the right time, as we are ready to commence pre-study pilot trials ahead of RMR2. RMR2, which will involve mice receiving combinations of up to six different life-extension treatments, takes into account significant findings from RMR1. These experiments have the potential to achieve record-breaking extension of both healthspan and lifespan of middle-aged mice, and to catapult longevity intervention combinations into the mainstream and into the clinic.”

Didier Coeurnelle commented: “The RMR investigations are poised to transform public understanding of the possibilities of treatments to extend healthspan and lifespan, not only in mice, but in humans. These investigations particularly deserve financial support, from anyone who shares my conviction that treating aging is a profoundly urgent humanitarian task. October 1st is the start of Longevity Month, in which longevity advocates around the world place a special focus on the need for faster progress. I hope my own donations can inspire others to consider how they, too, can best help to accelerate the defeat of aging.”

Aubrey de Grey, President and CSO of LEVF, replied: “This is a wonderfully generous donation from Didier. Via his previous financial support and his tireless advocacy for more than 15 years, Didier has long been a bold champion of the quest to reverse aging. This is by far the largest donation he has made, and affirms our joint belief that now is the time to greatly expand research to target the underlying processes of aging. Anyone else who wishes to make a donation to support RMR or any of the other activities undertaken by LEVF can do so via the donation page on our website, https://www.levf.org/donate.”

About LEVF: Longevity Escape Velocity Foundation is a 501(c)(3) tax-exempt California nonprofit public benefit corporation (EIN 93-2716970). It exists to conduct and inspire research to proactively identify and address the most challenging obstacles on the path to the widespread availability of comprehensively effective treatments to cure and prevent human age-related disease. See https://www.levf.org/.

About RMR: The Robust Mouse Rejuvenation research program is a sequence of large mouse lifespan studies, each involving the administration of various subsets of at least four interventions that have, individually, shown promise in others’ hands in extending mean and maximum mouse lifespan and healthspan. The research focuses on interventions that have shown efficacy when begun only after the mice have reached half their typical life expectancy, and mostly on those that specifically repair some category of accumulating, eventually pathogenic, molecular or cellular damage. See the results of the first phase https://www.levf.org/projects/robust-mouse-rejuvenation-study-1.

About Didier Coeurnelle: Didier Coeurnelle is co-chair of HEALES, the Healthy Life Extension Society, an organization that promotes and supports anti-aging research by raising awareness about technological and medical developments in the field of biogerontology. See https://heales.org/. Didier is also a member of the board of the International Longevity Alliance, https://longevityalliance.org/, and is the author of the highly regarded newsletter “La Mort de Mort” which is published each month in French, English, Spanish, and Dutch, https://heales.org/category/deathofdeath/monthly-newsletter/. He has published two books (in French) about longevity and transhumanism, is a Belgian citizen, and works in Brussels as a senior civil servant.

Heales monthly newsletter. The death of death N°185. September 2024. Muscular system and longevity


And if we manage to lengthen life – even if that’s not the case today – there are so many men and women to love and so many books to read, that three centuries isn’t very long at all. Luc Ferry Philosopher. Interview on Europe 1, April 2016.


This month’s theme: Muscular system and longevity


The aging of the muscular system in humans, also known as sarcopenia, involves a complex interplay of physiological changes that lead to the gradual loss of muscle mass, strength, and function. 

Individual muscle fibers, especially type II (fast-twitch) fibers, shrink and reduce in number with age. Type II fibers are responsible for quick and powerful movements, so their loss contributes to decreased strength and speed. Overall muscle mass 

declines with age due to the loss of muscle fibers and the reduction in the size of remaining fibers. This process is influenced by hormonal changes, decreased physical activity, and altered protein metabolism. The neuromuscular junction (NMJ), where nerve cells connect with muscle fibers, also deteriorates with age. This degeneration leads to impaired communication between the nervous system and muscles, resulting in reduced muscle function and strength. We also see mitochondrial dysfunction, the energy-producing organelles in cells, become less efficient with age. This dysfunction leads to reduced energy availability for muscle contraction and increased production of reactive oxygen species (ROS), which can damage cellular components. 

Aging affects the balance between muscle protein synthesis and degradation. Levels of anabolic hormones such as growth hormone, testosterone, and insulin-like growth factor 1 (IGF-1) decrease with age. These hormones play crucial roles in muscle maintenance and repair. Chronic low-grade inflammation, often referred to as « inflammaging, » is associated with aging. Pro-inflammatory cytokines can promote muscle catabolism and interfere with muscle repair and regeneration processes. Satellite cells are muscle stem cells that play a key role in muscle repair and regeneration. Their number and function also decline with age, impairing the muscle’s ability to recover from injury and maintain muscle mass. 

Aging is often accompanied by a decrease in physical activity levels, which accelerates muscle loss. Regular exercise, particularly resistance training, can mitigate some of the effects of aging on the muscular system by promoting muscle protein synthesis and improving neuromuscular function.

Sarcopenia

It is defined as the age-related, involuntary loss of skeletal muscle mass and strength. Starting as early as the 4th decade of life, evidence suggests that both skeletal muscle mass and strength decline in a linear fashion, with up to 50% of muscle mass being lost by the 8th decade of life. Since muscle mass accounts for up to 60% of body mass, pathological changes to this metabolically active tissue can have significant consequences for older adults. The strength and functional declines associated with sarcopenia can lead to severe outcomes, including loss of function, disability, and frailty. Additionally, sarcopenia is linked to both acute and chronic disease states, increased insulin resistance, fatigue, falls, and ultimately mortality. Among chronic diseases, sarcopenia is particularly associated with rheumatologic conditions, especially rheumatoid arthritis (RA) in women.

Overall declines in the size and number of skeletal muscle fibers characterize the physiological and morphological changes in skeletal muscle with advancing age. Additionally, there is a significant infiltration of fibrous and adipose tissue into the skeletal muscle. Satellite cells, which are skeletal muscle precursor cells residing in a quiescent state associated with myofibrils, also undergo important age-related changes. These satellite cells are activated to initiate skeletal muscle repair and regeneration in response to the stress of heavy muscle use, such as weight-bearing activities, or traumatic events, such as injury. 

Molecular Mechanisms of Muscle Aging

In older individuals, the balance between protein synthesis and breakdown may be disrupted, leading to increased muscle catabolism and a reduction in skeletal muscle mass. These changes are characteristic of old age and frailty. Frailty has been reported to exacerbate aging-related disruptions in protein metabolism. A lack of dietary protein is a potential factor contributing to decreased muscle protein synthesis in the elderly. The dietary protein intake of old people is often below the recommended daily allowance for both men and women. 

Gender Differences in Muscle Aging

Higher rates of muscle mass loss during aging have been reported in males compared to females and a higher prevalence of sarcopenia has been observed in males compared to females. Some studies have identified sex-specific markers for sarcopenia. One electron microscopy study measured mitochondrial content and found that intermyofibrillar mitochondrial size primarily decreased in older females, not in older males. Moreover, in the FITAAL study, it was found that intramuscular (acetyl) carnitine levels decreased with age in females but not in males. These findings suggest that during aging, females experience more changes in mitochondrial content and function compared to males. Additionally, the composition of the plasma proteome is known to change with aging, and interestingly, a large human study found that these age-associated changes were highly sex-specific.

Therapies

A study investigated the long-term effects of muscle hypertrophy, achieved through the overexpression of human follistatin (a myostatin antagonist), on neuromuscular integrity in C57BL/6J mice aged 24 to 27 months. Follistatin was delivered via self-complementary adeno-associated virus, resulting in significant improvements in muscle weight and torque production. The treatment enhanced neuromuscular junction innervation and transmission, although it did not affect age-related motor unit losses. These findings show that follistatin-induced muscle hypertrophy not only boosts muscle weight and torque but also mitigates age-related neuromuscular junction degeneration in mice.

The team of George Church along with Liz Parish from Bioviva Science demonstrated that using CMV as a gene therapy vector allows for monthly inhaled or intraperitoneal treatment for aging-related decline. In a murine model, exogenous telomerase reverse transcriptase (TERT) or follistatin (FST) genes were delivered safely and effectively. This treatment significantly improved aging biomarkers and increased mouse lifespan by up to 41% without raising cancer risk, offering a promising approach to address the global rise in aging-related diseases. As seen in other studies, FST-treated mice showed increased body mass, correlating with muscle mass gains. FST enhances mitochondrial biogenesis, energy metabolism, cellular respiration, and thermogenesis, promoting the browning of white adipose tissue. This regimen required monthly administration to maintain continuous effects, which could be beneficial for episodic treatment needs, reducing long-term adverse reaction risks.


The good news of the month: Government-funded research aims to Replace Aging Brain with Lab-Grown Tissue


Jean Hébert (A genetics and neuroscience professor at the Albert Einstein School of Medicine in The Bronx), recently hired by the US Advanced Projects Agency for Health (ARPA-H), spearheads a groundbreaking anti-aging approach by replacing parts of the human brain with cloned tissues. His research focuses on progressively replacing brain parts with young, lab-grown tissues, allowing the brain to adapt and maintain its functions. 

This could preserve memories and key identity facets, leading to significant advancements in anti-aging treatments. His innovative work, if successful, could lead to breakthroughs in reversing brain aging and enhancing human longevity.


For more information

Heales monthly newsletter. The death of death N° 184. August 2024. Planaria


In my ideal world….maybe 50% of 7.8 billion people would have online access to education and information and would collectively work (each contributing in their own way like mining or gamers or up to researchers and decision-makers and with a limitless supply of money) to address aging or the degeneration known as aging that leads to all chronic diseases….that’s not the world we live in. Martin O’Dea in 2021, CEO Longevity Summit Dublin.


This month’s theme: Planaria


Introduction

When stem cells divide for healing wounds, reproduction, or growth, they typically show signs of aging. This aging process results in stem cells losing their ability to divide, thus becoming less capable of replacing exhausted specialized cells in our tissues. A clear example of this effect is seen in human aging skin. However, planarian worms and their stem cells somehow bypass this aging process, allowing their cells to continue dividing indefinitely. One key factor in cellular aging is related to telomere length. For normal growth and function, cells in our bodies must continually divide to replace worn-out or damaged cells. Planarian worms maintain the ends of their chromosomes in adult stem cells, theoretically granting them immortality.

Planaria are capable of profound feats of regeneration fueled by a population of adult stem cells called neoblasts. These cells are capable of indefinite self-renewal that has underpinned the evolution of animals that reproduce only by fission, having disposed of the germline, and must therefore be somatically immortal and avoid the aging process. How they do this is only now starting to be understood. A study suggests that the evidence so far supports the hypothesis that the lack of aging is an emergent property of both being highly regenerative and the evolution of highly effective mechanisms for ensuring genome stability in the neoblast stem cell population

Planaria. Common genes with humans, how many?

Planaria and humans share a surprising amount of genetic material despite their differences. Approximately 80% of the genes in planaria have homologs in the human genome. This significant overlap includes genes involved in fundamental biological processes, such as those related to stem cell function and regeneration. This genetic similarity makes Planaria an important model organism for studying biological processes relevant to humans​.

Scientists hope that understanding how these cells activate and differentiate could one day lead to methods for regenerating human tissues. One gene, called piwi in planaria and hiwi in humans, is expressed in both species’ stem cells and is likely involved in regeneration. In planaria, piwi plays a crucial role in producing new, functional stem cells. In humans, the hiwi gene is expressed in reproductive cells and some stem cells, such as those responsible for generating new blood cells. There is hope that studying this gene could be useful to trigger human stem cells into regenerative action.

Almost Immortal Planaria

Many people first encounter planaria, tiny flatworms with remarkable regenerative abilities, during biology class when they cut one up. Planaria, found in freshwater, marine environments, and on plants worldwide, can be sliced into hundreds of pieces, each growing into a completely new flatworm. This extraordinary ability allows planaria to reproduce asexually, effectively cloning themselves. Scientists have discovered that planaria are filled with cells akin to stem cells, which are always ready to transform into any specific type of cell needed for tissue regeneration. This capability closely mirrors that of embryonic stem cells in humans and other vertebrates, making planaria fascinating subjects for scientific study. Their simple bodies and limited tissue types make them relatively easy to research. Remarkably, the stem cell-like cells in planaria are distributed throughout their bodies in large numbers, which contributes to their incredible regenerative powers. 

Planarian regeneration is notable for its dramatic extent, rapid speed, and the underlying mechanisms that enable it. Not only can each piece of a cut-up planarian regenerate into a new flatworm, but this process occurs quickly, taking just a week or two for each fragment to become a miniature version of the original worm. 

During regeneration, planaria perform an impressive feat: for instance, a tail regenerating a head might lack the ability to eat, or a head without a gut can’t digest food. Planaria solve this by consuming themselves—cells in the tail self-destruct to provide the energy needed for regeneration. As the head regrows, the tail shrinks to a size proportionate to the new head. Once the planarian is fully regenerated, it resumes feeding and returns to normal size. Understanding how planaria achieve this proportion adjustment during regeneration is one of the many mysteries scientists are eager to solve. When a planarian loses a part of its body, a regeneration blastema—a cluster of embryonic-like cells—forms at the wound site. These cells, rich in stem cells, can develop into various cell types needed to replace the lost body part. 

Planarians do age, from the loss of fertility to a reduction in muscle mass and mobility. However, when elder planarians regenerate tissues, the newly formed parts show no signs of aging. It’s as if they completely turn back the clock. Understanding and « copying » what they do could lead to ways of slowing or even reversing age-related conditions in humans.

Michael Levin Study

The study of this American developmental and synthetic biologist provides a comprehensive model connecting bioelectric signals with molecular feedback loops during early anterior-posterior (AP) axis establishment in planaria. 

Bioelectric signals influence early polarity decisions in regeneration, and manipulating these signals can lead to significant anatomical outcomes, such as the formation of double-headed planaria. In other words, as strange as it seems, at least in some circumstances, bioelectric signals can create a morphology that would not exist in a « normal » environment. 

Understanding the interplay between bioelectric signals and molecular pathways could lead to improved control over regeneration and morphogenesis. Given that many ion transporter modulators are already clinically approved, this research holds promise for applications in regenerative medicine. 

This study underscores the importance of bioelectric signals in regeneration, a field of science largely unexplored. It is one of the many avenues for regeneration and rejuvenation of human beings. We need more scientists and more investment in all research, who could one day make possible longer and healthier lives for billions of people.


The good news of the month: An antibody extends life span in mice by 25%


The mice received a therapy against IL-11, a pro-inflammatory cytokine. This cytokine has a negative effect on the lifespan of mice and also on humans.

The scientists from London who published in Nature explain that the mice that received the antibody looked more active, and leaner, with better coat, vision and hearing, and better walking ability.


For more information

Heales Monthly Newsletter. The death of death N°183. July 2024. Recent positive evolutions of life expectancy in the world


Death makes me very angry. Premature death makes me angrier still. Larry Ellison, founder of Oracle (source)


This month’s theme: Recent positive evolutions of life expectancy in the world


Introduction

From 1946 until 2019, at the World level, it could be said that each year was the best time ever to be alive, at least concerning the duration of it. This almost secular trend was broken in 2020, 2021, and maybe 2022. The Covid period it marked the first time since the Second World War with a global decrease in life expectancy. A previous letter exposed the situation known one year ago.

Since 2022, the situation considerably improved especially in Europe and in the USA. We can reasonably think that today is again the best time ever to be alive. However, we have to wait for more data to be sure …. and to hope for the future.

About data concerning life expectancy

What is life expectancy? It is the average period that a person may expect to live. There are various ways to calculate it. Period life expectancy at birth is life expectancy since birth calculated for a given year (or sometimes another period). It is based on the probability of death of each person during this year. So, it uses mortality rates from a single year and assumes that those rates apply throughout the remainder of a person’s life. This means that when there is a high mortality during a given year, the calculated life expectancy will decrease strongly. This means also that any positive or negative future changes to mortality rates are not taken into account.

Life expectancy approached in this letter is measured for countries and by sex. Data concerning life expectancy in good health, life expectancy for various groups, levels of income … are interesting, but not available worldwide and generally less reliable.

We could think that life expectancy is something very easy to measure. The date of birth and the date of death of a person is basic information known precisely to almost everyone. However, there are problems, namely:

  • Especially in countries with poor administrative organization, births, and deaths can be not registered; Since in general, a high life expectancy is seen as positive, there can be a trend to exaggerate longevity, especially for very old people. 
  • People migrating can influence: what if a person is born in one country and dies in another, what about foreigners dying, will they be considered for life expectancy in their country of nationality or residence… ?
  • And the biggest difficulty: the slow transmission of data.

Official data are slow to be available. In 2024, available real-life expectancy data still often predates the Covid-times. More recent data are often contradictory. Data you find online for 2022 and 2023 are often actually prospects. For example, data for Kyrgyzstan and Bhutan. This is in a way fascinating and depressing. Not only do we not yet know how to stop aging, we don’t even know how to calculate it globally. 

In most countries, an official institution gives information about life expectancy. But to compare at the world level, we have to rely on data coming from international institutions, especially the World Health Organization. The Wikipedia page on life expectancy gives data from 2023 from the United Nations, from 2022 for the World Bank Group and the OECD, and from 2019 for the World Health Organization.

Other good sources are:

Those sources are mostly based on official data, often from the UN.

World analysis of life expectancy by the WHO

The rise in life expectancy was temporarily halted during 2020 and 2021 due to the impact of the COVID-19 pandemic. At the height of the pandemic, global life expectancy at birth fell to 70.9 years, down from 72.6 in 2019. However, since 2022, life expectancy has returned to levels observed before the emergence of COVID-19 in nearly all countries and regions. This recovery marks a return to the positive trend in longevity seen over the past decades.

Globally, life expectancy at birth reached 73.3 years in 2024, an increase of 8.4 years since 1995. Further reductions in mortality are projected to result in an average longevity of around 77.4 years globally by 2054. According to the WHO projections, more than half of all deaths worldwide will occur at age 80 or higher by the late 2050s, compared to 17 percent in 1995. 

European situation

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, according to 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 COVID-19 are finally behind us.

The highest expectancy was 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). In France and Belgium, life expectancy is respectively of 82,7 and 82,3 years.

For Europe, very recent statistics are available. Mortality levels observed by EuroMOMO have been lower than expected throughout spring 2024. So, the positive situation seems to continue.

The situation in North America

US life expectancy began to stagnate specifically in 2012, before declining from 2015 onwards. The impact of COVID-19 in the US was worse than in Europe. This meant that life expectancy in 2021 dropped to the level it was 20 years before, reaching its lowest point since 1996.

Happily, the situation has radically improved in the last few years. In 2022, by gaining 1.1 years between 2021 and 2022, life expectancy at birth reached 77.5 years.  In 2023, life expectancy is reported as 79.74 years for both sexes, 82.23 years for women, and 77.27 years for men. The current outlook is much better than at the end of the COVID-19 period, especially for women.

In 2023, the Mexican national statistical agency INEGI reported that the total life expectancy in Mexico was 75.3 years, surpassing the pre-COVID 2019 level by 0.5 years. INEGI forecasts that in 2024, life expectancy in Mexico will continue to rise, predicting it to reach 75.5 years. Detailed life expectancy data for each Mexican state can be found on this Wikipedia page.

In 2022, for the third consecutive year, life expectancy in Canada had declined, marking a historic and concerning trend with a more significant decline among females.

The year 2020 marked a breaking point in Canada’s increasing life expectancy. However, Quebec rebounded quickly, reaching 83 years in 2021, surpassing pre-pandemic levels. Elsewhere in Canada, the decline persisted according to the latest data.

Asia

It is strangely difficult to have precise information about life expectancy in the two largest countries of the world. 

In India, the life expectancy for both sexes in 2023 is 72.03 years, with females at 73.65 years and males at 70.52 years. This is supposed to be more than in 2019, but these data are not without questions.

In China, according to data released by the National Health Commission, life expectancy at birth increased from 77.9 years in 2020 to 78.2 years in 2021. By 2023, for some information, life expectancy for both sexes reached 78.79 years, with females at 81.52 years and males at 76.18 years. However, the COVID situation has a negative peak later than in the other countries and the number of deaths in 2023 was rising 6,6 %.

In Japan, life expectancy has been declining in 2021 and 2022 but is probably rising again.

Hong Kong residents no longer hold the record for the world’s longest life expectancies, having ceded this position to Japan as COVID and overall stress impact local lifespans. In 2022, the average life expectancy for women in Hong Kong was 86.8 years, while their Japanese counterparts were expected to live until 87.1 years, according to the latest statistics released by Hong Kong’s government. Data for 2023 and 2024 has not yet been published.

African analysis of life expectancy by the WHO

Before the pandemic, the African region saw substantial gains in life expectancy, with an increase of 11.2 years since 2000. 

Life expectancy has been rising again since 2022. As of 2023, the African countries with the highest life expectancies are Algeria, Tunisia, and Cape Verde, each with 77 years, followed closely by Mauritius at 76 years.

In contrast, the countries with the lowest life expectancies in Africa are the Central African Republic and Lesotho, both at 55 years, and Nigeria and Chad, both at 54 years. These disparities highlight the ongoing challenges and varying progress in healthcare across the continent.


The good news of the month: Age-reversal trial with old human volunteers


The company Mitrix Bio plans to begin the first age-reversal trial in human volunteers later this year. The study is first aimed at helping astronauts withstand the high-radiation, microgravity conditions of space, which lead to muscle loss and other complications of premature aging. The company will transplant young, bioreactor-grown mitochondria into a group of volunteers in their 70s and 80s to see if the technique reverses aging.

It is positive that Space Research may help for longevity and that with an experiment made with aged well-informed volunteers.


For more information