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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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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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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

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

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This month’s theme: Longevity and the Digestive System

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Introduction

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

Gut Microbiota

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

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

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

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

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

Probiotics and Prebiotics

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

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

Inflammation and Aging

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

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

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

Aging of the Digestive System

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

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

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

Colorectal Cancer

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

Mental Health

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

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

Conclusion

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

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

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

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

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

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For more information

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If immortality means perpetuating our own metabolisms, why not? This kind of immortality, whether bionic or technological, is conceivable. Jean-Michel Besnier, French philosopher (translation, source).

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

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Introduction

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

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

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

Liver

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

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

Heart

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

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

Brain

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

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

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

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

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

Common cognitive changes with aging include: 

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

Lungs

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

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

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

Kidney

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

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

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

Thymus

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

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

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

Life of the organs after death

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

Heart: 4-6 hours 

Lungs: 4-6 hours Similar to heart transplants. 

Liver: 8-12 hours. 

Kidneys: 24-36 

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Conclusion

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

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

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

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

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

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For more information

• Heales, Longevity Escape Velocity Foundation, International Longevity Alliance, Longecity, and Lifespan.io 
• Heales Monthly Science News
• Heales YouTube channel
• Contact us

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The use of Artificial Generative Intelligence systems by healthcare professionals must become widespread; it would be unethical to do without the help of these tools.

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

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This month’s theme: Organ-on-a-chip

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Introduction

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

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

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

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

Comparison of characteristics of 2D and 3D cell cultures

 

 

 

 

Types of Organ-on-a-chip

Lung

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

Kidney

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

Pancreas

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

Heart

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

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

Companies involved in developing the technology

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

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

Use of Organ on a chip in longevity studies

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

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

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

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

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

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For more information

• Heales, Longevity Escape Velocity Foundation, International Longevity Alliance, Longecity, and Lifespan.io 
• Heales Monthly Science News
• Heales YouTube channel
• Contact us