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Faced with the changes longer lives will bring, humans will not miss the Reaper and construct one to solve their problems. Just as with our larger cities, we don’t remix the (clean) water (with sewage water) to bring back cholera. Why die? Kurzgesagt (studio d’animation allemand).

This month’s theme: Stem Cells and Aging

Stem cells are special cells in the body that have the unique ability to develop into many different types of cells, such as muscle, nerve, or blood cells. Unlike most cells, stem cells can divide and make copies of themselves over long periods. This makes them essential for growth, development, and repair in the body. There are different types of stem cells, including embryonic stem cells, which can turn into any cell type, and adult stem cells, which are more limited but still help maintain and repair specific tissues. Scientists can also create induced pluripotent stem cells by reprogramming adult cells to act like embryonic stem cells.

How does aging affect the stem cells?

Aging significantly impairs the function and regenerative capacity of stem cells, which are vital for maintaining tissue homeostasis throughout life. One of the primary effects of aging is stem cell exhaustion, characterized by a decline in the number of active stem cells and their ability to self-renew and differentiate. Over time, stem cells accumulate DNA damage due to environmental stressors and diminished repair mechanisms, while telomere shortening limits their replicative potential, pushing them toward senescence or apoptosis (programmed death cell). Simultaneously, epigenetic alterations, such as changes in DNA methylation and histone modifications, disrupt gene regulation. Aging also affects the stem cell niche, the specialized microenvironment that provides signals for their maintenance. These signals weaken or shift toward pro-inflammatory cues, further compromising stem cell activity. 

In addition, aged stem cells exhibit mitochondrial dysfunction and a shift in cellular metabolism, resulting in increased reactive oxygen species (ROS) and oxidative stress, which further damage cellular components. Functionally, these changes lead to reduced tissue regeneration, impaired immune responses, and increased risk of degenerative diseases and cancers. For example, aging hematopoietic stem cells tend to produce more myeloid cells and fewer lymphoid cells, weakening adaptive immunity and promoting clonal hematopoiesis.

The Hayflick limit refers to the finite number of times a normal somatic cell can divide before entering senescence, typically due to progressive telomere shortening. While this limit applies strictly to most somatic cells, stem cells present a more nuanced case. Adult stem cells, such as hematopoietic or mesenchymal stem cells, do exhibit a form of the Hayflick limit but can divide more extensively than typical somatic cells. This is largely because they express higher levels of telomerase, the enzyme responsible for maintaining telomere length. However, this telomerase activity is not unlimited, and over time, these adult stem cells also experience telomere attrition and eventually enter senescence. In contrast, embryonic stem cells and induced pluripotent stem cells (iPSCs) possess high levels of telomerase. They can maintain their telomere length indefinitely, allowing them to divide without a limit under optimal conditions. This distinction underlies their unique regenerative potential and highlights the fundamental difference in aging and replicative capacity between various cell types.

Stem Cell Therapies

Stem cell therapy is a medical treatment that uses stem cells to repair, regenerate, or replace damaged or aging tissues. It works by either directly injecting stem cells into affected areas or using them to stimulate the body’s natural healing processes. As we age, our natural stem cell supply decreases and becomes less effective, which contributes to slower healing, tissue damage, and chronic diseases. By introducing healthy, functional stem cells, therapies aim to rejuvenate tissues, improve organ function, and possibly delay the effects of aging. Research is ongoing in areas like improving skin elasticity, reducing joint pain, boosting immune function, and even enhancing cognitive health in older adults. These therapies are often marketed by private anti-aging clinics as established treatments. However, they are still largely experimental and require further evidence to demonstrate their long-term safety and efficacy…

Among the most promising types are mesenchymal stem cells (MSCs), known for their potent anti-inflammatory, immunomodulatory, and regenerative effects. Clinical studies suggest that MSCs can enhance cognitive function, reduce systemic inflammation, and improve tissue repair in aging-related conditions, including neurodegenerative diseases and frailty. 

Another powerful avenue is the use of induced pluripotent stem cells (iPSCs), which are adult cells reprogrammed to an embryonic-like state. These can be differentiated into virtually any cell type, such as insulin-producing pancreatic cells or natural killer (NK) immune cells. iPSC-derived NK cells are particularly relevant in older adults due to their lower risk of graft-versus-host disease and utility in targeting age-related malignancies. 

Meanwhile, neural stem cells (NSCs) are gaining traction for their ability to restore brain function in models of traumatic brain injury and neurodegeneration, offering potential therapies for Alzheimer’s and other forms of cognitive decline. Furthermore, stem cell-derived hepatocytes and β-cells are being explored for treating metabolic dysfunction-associated steatotic liver disease (MASLD) and diabetes, which are prevalent in the elderly. These cells can be used both as therapeutic agents and as disease models for drug discovery. As the field advances, challenges such as cell delivery, immune compatibility, tumorigenicity, and long-term safety become key areas of focus. 

Current Clinical Trials

One of the leading clinical studies exploring the use of stem cell therapy in aging involves mesenchymal stem cells (MSCs) for treating age-related frailty, a condition characterized by decreased strength, endurance, and physiological function. The CRATUS study (NCT02065245), a Phase 2 randomized clinical trial, evaluated intravenous allogeneic MSCs in older adults diagnosed with frailty. The results were compelling: patients treated with MSCs exhibited significant improvements in physical performance, walking speed, and inflammatory biomarkers, including a notable reduction in tumor necrosis factor-alpha (TNF-α), a key driver of chronic inflammation in aging. Importantly, the treatment was well-tolerated with no serious adverse events reported, supporting its safety profile.

Another clinical study in stem cell therapy targeting aging is a Phase I clinical trial evaluating the safety and efficacy of autologous adipose-derived mesenchymal stem cell (AD-MSC) transplantation in patients with aging-related low-grade inflammation, a condition also known as inflammaging. Conducted by Nguyen et al. (2024), this open-label, single-group trial involved 12 patients who received two intravenous infusions of 100 million AD-MSCs. These individuals exhibited high levels of pro-inflammatory cytokines and were also diagnosed with two of the following metabolic conditions: diabetes, dyslipidemia, or obesity. TheAD-MSC therapy may offer a safe and effective intervention to reduce chronic inflammation associated with aging and potentially mitigate the onset or progression of age-related diseases

Biotech companies are working on stem cell therapy

Aspen Neuroscience, based in San Diego, focuses on developing personalized stem cell therapies for neurodegenerative diseases, particularly Parkinson’s disease. Its lead therapy, ANPD001, uses autologous induced pluripotent stem cells (iPSCs) to replace dopamine-producing neurons lost in Parkinson’s. The company received FDA IND clearance in 2023 to begin Phase 1/2a trials. 

BlueRock Therapeutics, a Cambridge-based company owned by Bayer, is also working on iPSC-based regenerative medicines, with a focus on Parkinson’s disease. Their lead program, Bemdaneprocel (BRT-DA01), involves implanting iPSC-derived dopamine neurons into the brain. 

Cellino, another Cambridge-based company, aims to revolutionize personalized medicine with a scalable, automated biomanufacturing platform using iPSCs. The company leverages advanced technologies like label-free imaging and AI to streamline the production of patient-specific therapies for diseases like Parkinson’s, diabetes, and heart disease

The rise in chronic and degenerative diseases, like heart disease, neurodegenerative conditions, and cancer, is pushing the demand for stem cell therapies that can help repair and regenerate damaged tissues. The field still faces challenges, including high treatment costs, regulatory hurdles, and ethical concerns. Here, as elsewhere, the lack of large-scale research programs and clinical trials with public funding and sharing of results is hindering rapid progress.

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The good news of the month- Eli Lilly’s Orforglipron: A Potential Breakthrough in GLP-1 Therapy

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The Glucagon-like peptide (GLP-1) is an intestinal hormone that could slow down different aspects of senescence. Eli Lilly’s new GLP-1 medication, Orforglipron, is making headlines as an oral, once-daily pill currently in late-stage clinical trials. Early data from a Phase 3 study show promising results, with the drug significantly lowering levels of glycated hemoglobin and promoting weight loss in adults with type 2 diabetes.

Unlike existing GLP-1 treatments like Ozempic and Mounjaro, which require injections, orforglipron is a small molecule GLP-1 receptor agonist that offers the convenience of oral delivery. This could dramatically expand access and appeal to a broader population.

Lilly is seeking regulatory approval for both type 2 diabetes and obesity treatment, and if approved, Orforglipron could mark a major shift in how GLP-1 therapies are used.

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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
• Image
• Contact us

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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.

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

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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.

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

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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:

• The WHO aims to enable citizens “to enjoy a state of complete physical, mental and social well-being, and not merely the absence of disease or infirmity.”
  One of the consequences of the decision to leave will be to strengthen China’s weight in this organization.
  The USA is the country with both the highest per capita health expenditure and the lowest life expectancy among countries with a high standard of living.
• The blocking of numerous health-related expenditures. So, a month after Donald Trump took office as the 47th President of the United States, almost all grant review meetings remain suspended at the National Institutes of Health (NIH), preventing the world’s largest public funder of biomedical research from spending much of its $47 billion annual budget.
  

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Find out more:

• See in particular: heales.org, sens.org, longevityalliance.org and longecity.org.
• Image source. 

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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.

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This month’s theme: Blood Brain Barrier and Aging

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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.

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

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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.

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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
• Image
• Contact us

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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.

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This month’s theme: Muscular system and longevity

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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.

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

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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.

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For more information

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• Heales Monthly Science News
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• Source of the image: Leonardo Da Vinci
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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.

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This month’s theme: Planaria

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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.

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

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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.

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

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

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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:

• Gapminder
• Our World in Data
• Worldometer
• Statista
• Macrotrends
• Eurostat
• Human Mortality Database 

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.

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

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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.

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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 graphs: Life expectancy at birth in some big countries (Wikipedia) and Life expectancy in Africa as of 2023 (Unicef)
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