Imagine a rather educated mouse asking himself if it is theoretically possible to live more than two and a half years his average life expectancy? Of course, it is possible, she would say, look at the human species (…), mammals like us that live thirty to forty times longer! Beyond our biological limits: The secrets of longevity. 2011. Miroslav Radman.

Theme of the month: If humans didn’t die of old age, would we regret it?

Introduction
Let’s imagine a world not so different from ours. However, humans and most animals would not experience aging.

In this world, would we wish senescence, that is, the progressive degradation until death, on ourselves and our children?

Let’s imagine, for example, a biological environment a little more « Lamarckian » than the one we live in. In epigenetic evolutions, acquired characteristics would be more transmissible. An older animal would have, as here, advantages in terms of experience. Moreover, the descendants would benefit from an increased transmission of acquired characteristics. In this case, natural selection would have less « need » for senescence, since the evolution of species could occur because of changes during the life of individuals. Let us imagine that the probability of dying of natural causes is therefore relatively stable, from one year to the next, once the adult age is reached. Let’s imagine a planet with no aging death (and also no aging degradation) for most living species.

For the rest, the « laws of nature » would apply: selection of the most adapted, evolution of preys, predators and parasites, competition and cooperation between animals, plants, bacteria, fungi… Animals would live longer, without aging, but would still die from all other causes. Biological immortality is not the same as immortality.

A world without aging would not be paradisaical but…
Obviously, it is impossible to imagine all the consequences. Let’s focus on humans. Theoretically, some could live for thousands of years. But this would be extremely rare before the development of civilizations because epidemics, predation, violence would strike all individuals.

But once civilizations appeared, the environment would be radically different. The accumulation of knowledge would be faster, philosophers, scientists, leaders could be influential for centuries. Religions would exist, but they would logically be more peaceful, less focused on the afterlife, more concerned with bodies and souls here than with the afterlife.

Soon enough, in the more prosperous regions, birth control would expand. Soon enough, science and medicine could focus more on preventable causes of death. Indeed, the positive stakes of disease control would be higher, there would be more years of life to gain.

As for these humans, the capacities would not decrease with age, the mechanisms of nostalgia, of withdrawal to the past, would be less. Indeed, nostalgia is often the regret of youth following the loss of energy, health, taste, other senses… Nostalgia following the loss of loved ones would also diminish. 

In our contemporary world, philosophy is sometimes defined as « learning to die » (and to die quickly). Where death would no longer be inevitable, at least on the scale of centuries, philosophy would be more about learning to live, learning to respect others and oneself. In a more stable world, the need for an environmental balance is more obvious.

Advancing age would be, as in our world, synonymous with wisdom. It would be a wisdom with less bitterness and regret of the past and therefore more openness to the future.

In this place where death is no longer inevitable and is becoming rare thanks to technological and medical progress, it is possible to imagine that any death inflicted, any murder, would not only be unacceptable, it would become unimaginable. Just as today killing a child is almost unimaginable, because he has « his whole life ahead of him », whereas in the past infanticide was often tolerated and sometimes totally accepted, especially because many children died in infancy.

In a world without age-related degradation, would we invent aging?
Some philosophers, some religious leaders might want the older ones to disappear. Some might say that it is necessary to renew the population, to have children without the risk of overpopulation.

Would the representatives of this current of thought want to kill the most advanced people in age? And if so, create a system where death is slow, insidious, progressive, painful, ineluctable… rather than, for example, creating compulsory euthanasia for some?

This seems unlikely in a world of less violence. Already today, even the most bloodthirsty regimes no longer (almost?) officially practice torture as a means of pressure. So inflicting aging and then death …

What if the glass was half full?
Let’s finally imagine an environment where humans are not amortal, but live twice as long once they are adults. The prime of life would be at 100 years and Jeanne Calment would have lived 245 years.

No one would likely propose ending life after 80 or 90. It is the situation well beyond that which would be « normal » and would appear to almost everyone as desirable… until the situation changes.

Just as no one today proposes to end life at age 50, when that was the « normal » maximum lifespan for most of human history.

Conclusion
If aging did not exist, we would not have to invent it. All other things being equal, we probably wouldn’t consider it, even for our worst enemy. We would not wish for years and sometimes decades of unbearable degradation ending in death.

Moreover, if we lived in a world without aging, not only human life, but also the lives of sentient beings (capable of suffering) would be far more precious. Even the most disrespectful of individuals, raised in this universe, would have difficulty imagining inflicting the torments of an endless torture called aging. Just as today, even a violent recidivist thief would probably not think of burning the feet of an elderly person to make him confess where his money is, and then murdering him, a common practice in France and elsewhere until the early 19ᵉ century.

Aging is now inevitable. We have already managed to humanize it considerably. We are also managing to slow it down a bit. Tomorrow we may be able to stop it. In all likelihood, we will not regret it any more than we regret the eradication of the plague and cholera.

Good news of the month

• Japanese scientists develop a vaccine to eliminate cells responsible for aging. The team, including Toru Minamino, a professor at Juntendo University, confirmed that mice given the vaccine had a decrease in the number of zombie cells, known medically as senescent cells. The team identified a protein found in senescent cells in humans and mice and created a peptide vaccine based on an amino acid that constitutes the protein. This news has received significant media coverage. It is part of the many hopes for senolytic products. However, the experiment concerns only mice. Moreover, the maximum life expectancy was verified on « progeroid » mice (with a much shorter life span), but not on « normal » mice.
• The first clinical trial of a nasal vaccine for Alzheimer’s disease began in Boston. The vaccine, formulated from an immune-boosting substance (Protollin), is intended to prevent and slow the progression of Alzheimer’s disease, the disease associated with aging for which medical research has been slowest… A Phase 1 trial involves 16 participants, aged 60 to 85, all with early-stage Alzheimer’s disease but in good general health. They will receive two doses of the vaccine. The research team will measure the effect of nasal Protollin on the immune response, particularly its effect on white blood cells, by examining cell surface markers, genetic profiles and functional tests.

For more information:

• See: heales.org, sens.org, longevityalliance.org and longecity.org.
• Source of the image
  

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John Harris, former editor of the Journal of Medical Ethics, argues that as long as life is worth living, according to the individual, we have a powerful moral imperative to save life and therefore to develop and offer life-prolonging therapies to those who want them (Source). 

Theme of the month: Recent developments in gene therapies for longevity

Introduction 

The average lifespan of both animals and humans varies according to many factors. For animals,  diet, predation, disease and  climatic conditions play the most important roles. In humans, lifestyle, disease and social conditions are the determining factors.

But when it comes to the maximum lifespan of animals, like that of humans, the most important element is the genetic heritage. 

We still know very little about the genetic differences that favour or hinder longevity in humans. Studies of genetic characteristics related to longevity have been conducted, including studies of supercentenarians.  Although genes such as the klotho gene are sometimes cited, no single gene or group of genes appears to have a very strong positive influence.

A human being who lives in a perfect environment with adequate health care and an exemplary lifestyle would never live past the age of 122. It should be noted that the oldest person in the world has been a woman for almost 40 years, which can be explained by the genetic difference between men and women. 

Place a mouse in a mouse paradise. No matter what happens, it won’t live past five years. Place a Galapagos tortoise in a chelonian paradise and it will live at most two centuries.

Very similar animals can have very different maximum life spans. For example, the Labord’s chameleon of Madagascar is the terrestrial vertebrate with the shortest life span. It lives only 4 or 5 months. While its distant cousin from the same big island, Parson’s Chameleon, can live for about ten years.

In other words, we know that few genetic modifications can allow considerable changes in lifespan.

This is one of the reasons why gene therapies are among the most promising therapies for longevity.

What is gene therapy? 

Gene therapy is one of the preferred ways to treat genetic diseases, but also certain cancers. It consists of inserting into the patient’s cells a normal version of a gene that does not work and causes the disease. 

The functional gene then allows the patient to produce again the protein whose deficiency was the source of the disease.

However, three conditions must be met: 

• Knowing the gene responsible for the disease, i.e. the function of that gene, so that the cell can be « repaired ».
• Allowing the gene to reach and enter the cell with the help of a « vector », most often a virus that has been rendered harmless to the patient.
• And associate the gene with a « promoter », a small DNA sequence that allows it to function once inside the cell.

It is also possible to transform the genetic heritage of subsequent generations. It is conceivable that one day our children could live longer and healthier lives as a result of genetic modification. This raises innumerable ethical questions, some of which have been addressed by the birth of two (or perhaps three) genetically modified babies in China. These issues will not be discussed here.

The gene therapy revolution

In 2000, for the first time in the world, gene therapy demonstrated its effectiveness with bubble babies, children with severe immune deficiency who returned to normal life with the treatment. However, the therapies were slowed down and then virtually halted for more than a decade following the deaths of two patients, including Jesse Gelsinger. However, during this interruption countless lives could have been saved.

Between 2015 and 2020, gene therapy has experienced a considerable boom. Several clinical trials have been conducted to treat certain blood, skin and neuromuscular diseases. Some of these trials have been sufficiently successful to lead to market authorization in the United States and Europe. 

In 2017, a team of European doctors managed to replace 80% of a little boy’s epidermis (suffering from epidermolysis bullosa) with gene therapy.

By 2019, about ten gene therapy treatments for rare blood, vision, muscle and certain cancers had received marketing approval in the United States or Europe.

In the same year, the first gene therapy drug (Zolgensma) capable of saving the lives of babies with diseases such as spinal muscular atrophy was put on the US market. 

Other treatments for Pompe disease, adenosine deaminase deficiency, beta-thalassemia, acute lymphoblastic leukemia, diffuse large B-cell lymphoma, and Leber’s amaurosis have been developed.

However, treatments are still usually aimed at uncommon diseases, generally linked to an « error » in a single gene.

Gene therapy and longevity: Can it delay or reverse age-related diseases including neurodegenerative diseases?

In 2019, a study by George Church and his teams showed favorable results of a therapy acting simultaneously on three genes in mice with various age-related symptoms.

In the same year, an experiment on a gene for telomeres was carried out by researchers from the Chinese Academy of Sciences on mice in 2019. This resulted in a longer life expectancy.

In 2020, mRNA vaccines were used to induce immunity against COVID-19. This method is similar to gene therapy. However, the changes concern the RNA and not the DNA. 

In October 2021, BioViva, a biotechnology startup led by E. Parrish, demonstrated that by administering gene therapy to six patients with dementia that a reversal of dementia symptoms such as cognitive impairment could be observed. 

The American Elizabeth Parrish is also the first known case of self-testing of a gene therapy targeting ageing processes. The treatment consists of injections of adenovirus, which could extend leukocyte telomeres and thus strengthen muscle mass.

Conclusion

A massive sharing of knowledge, including statistics, about genetic endowments is developing. Investments for a longer healthy life seem to accelerate and improve. The European Union is proposing legislative tools for « altruistic » databases. 

Billions of sequencings (total or partial) have been performed on animals, plants and humans. The pooling of these data and their analysis, in particular by means of tools based on artificial intelligence, is continuing. Thanks to genetic modification technologies such as CRISPR, it should be possible to break through the « glass ceiling » of the maximum lifespan for mice and then for humans in the near future.

The good news of the month

The European Longevity Initiative was launched by a non-governmental organization with members in some 20 EU countries.

Its proposal was the most supported of the Conference on the Future of Europe and is still one of the most supported.

The main promoter of the idea is the Hungarian scientist Attila Csordas, who said:  » The only real solution (for many, many diseases) is to start treating the root causes of biological aging (…). We have experimental strategies to slow down the rate of accelerated aging and reduce morbidity and mortality in late life. To achieve this in the European Union, we would like to propose effective legal, budgetary, regulatory and institutional commitments to enable science-intensive healthy longevity research and technologies, large-scale geroprotective clinical trials focused on ageing and equitable access to these technologies to increase healthy life expectancy in the European Union.”  

The European Health Data Space is at the centre of many projects aimed at better exchange of health data for medical and research purposes. An international conference on 19 November on « Innovations in Consumer Longevity Data » is one example. 

For more information:

• See: heales.org, sens.org, longevityalliance.org and longecity.org.
• Source of the image

We have long since (…) touched Mars, the Moon, harnessed nuclear power, artificially reproduced DNA, and now have the biochemical means to control births; why should death itself, « the last enemy », be considered sacred and beyond conquest? Alan Harrington, novelist, 1977 (The immortalist). 

Theme of the month: The Terror Management Theory 

Introduction

Terror Management Theory (TMT) was developed in the 1980s by Jeff Greenberg, Tom Pyszczynski and Sheldon Solomon. 

According to these authors, all human beings are confronted with two realities.

On the one hand, humans, like all animals, have an instinct to protect themselves and to try to survive. On the other hand, they have a higher level of self-awareness that allows them to understand, unlike other animals, that they are alive and that they will eventually die.

It undeniably involves the frustration of the desire to stay alive. This is both frightening and motivating, and represents a central and unique psychological conflict in human beings.

But this theory, already discussed in a letter The Death of Death from May 2010, also teaches us that man, in order to face the fear of death, has developed defense mechanisms. Knowing that we are not going to survive as individuals, we identify ourselves with the collective, our survival goals become collective goals. In a global vision, we could say that all forms of art, culture, tradition, long-term collective construction participate in this mechanism. It is a matter of valuing the culture of belonging that allows us to strengthen our self-esteem in the conviction that as individuals we contribute to building this sense.

Unfortunately, this mechanism also has negative aspects. By reinforcing group values, it encourages the rejection of those who are different. Here, as in other areas, fear is a bad counsellor, a counsellor of withdrawal not into oneself, but into one’s group.

How has Covid-19 influenced our reaction to death?

The coronavirus pandemic has reminded us how vulnerable we are, especially as we age. A fact we put out of our minds when times are less threatening.

Across the world, we have seen solidarity, but also withdrawal: some have mobilized to help others (e.g. making protective gear for caregivers or organizing fundraisers), others have stockpiled cans and toilet paper.

Some recent studies show that the perception of threat (Covid-19) is related to government decisions such as lockdowns (if the government orders lockdowns, the disease must be very serious) and to the number of reported cases. The increase in the number of cases in some countries would be correlated with the increase in conservatism and authoritarianism.

Only humans are affected

As already written, awareness of inevitability of the death is unique to humans. It is possible that some animals are aware of the death of their fellow creatures and the risk to themselves. Moreover, this awareness does not even concern all humans. Young children usually live a life that seems limitless to them with joy and without boredom.

Could it be human nature to learn how to die…

Neither the sun nor death can be looked at steadily, wrote La Rochefoucauld. To philosophize is to learn to die, as Socrates and Montaigne have said. No conscious adult human being is indifferent to the inevitability of his end. Faced with the passing of time, we feel, as on the edge of a precipice, fear, but also fascination. No civilization deals with the death of our fellow human beings without a specific approach.

Or could it be the nature of man to always struggle to overcome death?

Almost all civilizations, almost all religions, explain that death is not the end of the journey.  From an agnostic perspective, the main reason for beliefs in the afterlife is of course to deal with the fear of dying.  The search for immortality is found in beliefs, practices and rituals. Sometimes these are affirmations, incantations.  Sometimes they are methods that could be called « pre-scientific », instructions for avoiding death or for making death only a temporary phenomenon. 

For the Taoists, it was a matter of learning to live according to very ascetic methods. In ancient Egypt and Christianity as it was taught until recently, it was a matter of preserving the body, by embalming or burial to allow for the return, the reincarnation (return to the flesh). The Catholic Church refused cremation until recently.

An unconscious mechanism 

This is a fundamental aspect of managing terror. Our defences are constituted by what Ernest Becker called « The Denial of Death« . Faced with what is both unbearable and inevitable, we develop unconscious processes. If these processes were conscious, they would lose much of their effectiveness.

What about tomorrow, in a world where amortality becomes conceivable?

Living without unbearable fear is, of course, a desirable mechanism. But it can also be an obstacle to the struggle for healthy longevity, when unconscious mechanisms lead us not to fight against, or even to « love » death (from old age).

Collective ideals are the result of feelings of belonging to groups that were initially opposed to each other. Today, they allow us to behave in an increasingly global community to live in a more peaceful, more united and more sustainable way, especially in the fight against global warming. In the same way, tomorrow, a better « management of the fear of death » could allow us to make better progress towards a much longer healthy life, even one day without time limits.

Good news of the month

• Although this is a fragile development, mortality from the Covid-19 epidemic is slowing down. While the number of people affected continues to rise, the number of deaths both in Belgium and worldwide is decreasing, showing the increasing effectiveness of preventive vaccines and therapeutic treatments.
• Among the most promising treatments for the coronavirus, molnupiravir is providing renewed hope: the tablet is believed to halve the risk of hospitalization or death in Covid-19.

For more information:

• See in particular: heales.org, sens.org, longevityalliance.org and longecity.org.
• Source of the image

« But there is every reason to believe that adding Triphala and these probiotics to the diet is a guarantee of longevity and health. »

Satya Prakash (Biomedicine and Cellular Therapy Research Laboratory, Department of Biomedical Engineering, McGill University, Canada) (note: this is only about moderate improvements in healthy life span with better nutrition). 

Theme of the month: Microbiome and healthy longevity

Introduction 

Our body is made up of complex, fascinating, interdependent and changing systems.

All of them vary throughout the ages of life and, unfortunately, gradually deteriorate. 

The digestive system is the one that most directly confronts the outside world, the most changing, hostile and dangerous environment.

Every year, nearly a ton of food and drink, but also kilos of medicines, non-nutritive substances and millions of billions of bacteria, viruses and parasites pass through it and sometimes settle in it. As humans are omnivores, the diversity is particularly great. This is one of the reasons why research approaches to longevity are also diverse.

The importance of the gut microbiota

Our body is home to many different bacterial species. These communities of microorganisms, called « microbiota« , take up residence in different parts of our body: the mouth, the skin, the vagina… But above all the intestine! This organ, which is about 8 meters long, is home to up to 100,000 billion bacteria, mainly located in the small intestine and the colon. Scientists estimate that nearly 90% of fecal matter is made up of bacteria!

These bacteria, associated with other microorganisms such as viruses and yeasts, form the intestinal flora, now renamed « gut microbiota » by the scientific community.

In utero, the fetal digestive tract remains a sterile environment. During birth, breastfeeding and dietary diversification, the intestinal microbiota of an individual builds up over the years, until it contains nearly 1,000 different bacterial species in a healthy adult. A bacterial world that weighs nearly 2 kilos.

The 200 million neurons of the digestive tract

The same neurons as those in our brain line our digestive tract, some people call it a « second brain« ! 

The primary function of the enteric nervous system is to ensure the motor function of the intestine. The nerve cells are also responsible for transmitting information from our intestine to our brain. In addition, like the brain, the neurons of the intestine are able to produce hormones and neurotransmitters. 

Our emotions are also lodged in our intestines. Being « scared to death » or « having a knot in your stomach », « digesting information » are expressions that illustrate realities.

Links between Alzheimer’s disease and the microbiome have been established by studies. On the other hand, it does not seem that the neurons of the « second brain » suffer from a specific Alzheimer’s or neurodegenerative disease, even if the nervous control degrades with age (one of the causes of incontinence in the elderly).  

Could the microbiota and the gut be the key to improving longevity?

Recently, variations in the gut microbiota have been associated with age-related phenotypes and probiotics have shown promise in managing the progression of chronic disease. 

In a scientific paper published in Nature in May 2018, researchers highlight a longevity extension in Drosophila. By adding a combination of probiotics and a plant-based supplement to the diet of Drosophila flies, scientists at McGill University were able to extend their lifespan by 60% and protect them from chronic diseases usually associated with aging.

In this study, novel probiotic and symbiotic formulations were shown, in combination, to extend longevity in male Drosophila melanogaster through gut-brain communication mechanisms with implications for chronic disease management.

Longevity in mice

Researchers discover the potential of microbes to slow brain aging

Research from the APC Microbiome Ireland (APC) SFI Research Centre at University College Cork (UCC) published in Nature Aging presents a new approach to slowing aspects of age-related brain and cognitive deterioration via gut microbes. This research opens up potentially new therapeutic avenues in the form of microbial interventions to slow brain aging and associated cognitive problems.

There is a growing appreciation of the importance of microbes in the gut to all aspects of physiology and medicine. In a very recent study in mice, the authors show that by transplanting microbes from young animals into older animals, they could rejuvenate aspects of brain and immune function.

The researchers explained in the journal Nature Aging, « The gut microbiota is increasingly recognized as an important regulator of host immunity and brain health. The aging process leads to dramatic alterations in microbiota, which are linked to poorer health and frailty in older populations. Transplantation of microbiota from young donors reversed age-associated differences in peripheral and brain immunity, as well as the hippocampal metabolome and aging transcriptome of recipient mice. »

Longevity in humans

A recent study by the Institute for Systems Biology (ISB) shows that depending on the type of intestinal microbiota (the composition of the microbial flora that permanently inhabits our intestines), we age in better or worse health. This would therefore have an impact on longevity.

The microbiota changes after age 50

The researchers analyzed the gut microbiota and health status of more than 9,000 people aged 18 to 101, with a particular focus on the 78+ age group. In the latter group, they found that the microbiota changes in composition as we age and becomes more and more « unique » but that the different microbiota of healthy people all perform similar metabolic functions.

Our bacteria produce anti-aging substances

In correlation, higher concentrations of certain metabolites produced by the microbes in the intestines were measured in the subjects’ blood. Thus, it seems that changes in intestinal flora in healthy aging are linked to the production of certain metabolites whose effect on longevity is known, such as indole for example.

It is known that certain types of intestinal bacteria convert tryptophan (an essential amino acid) into indole, which passes into the bloodstream. It has been shown that indole prolongs life in mice and reduces intestinal inflammatory processes.

Another microbial metabolite, phenylacetyl glutamine, is found in large quantities in the blood of centenarians.

To conclude, it is noted that the microbial flora, continuing to evolve at an advanced age, would make it possible to better preserve health and to improve longevity, it is in relation to the common production of certain metabolites (like the 2 examples quoted previously). These modifications would be done especially after the fifty years.

Changes in microbiota with age

While the composition of our microbiota remains relatively stable during adulthood, changes in diet, even medication (antibiotics, anti-acids, …), the slowing down of gastrointestinal transit and digestion … lead to an imbalance of the digestive flora as we age

The diversity of bacterial species tends to decrease with age. Among other things, there is an increase in enterobacteriaceae and germs that can then become pathogenic by their number, such as streptococci, staphylococci, etc. These develop more easily in an inflammatory environment, and will themselves maintain a localized inflammation, as well as a too great permeability of the intestinal mucous membrane.

It has been observed in people over 105 years old, an increased presence of certain bacterial families (akkermansia, bifidobacteria and christensenellaceae). This suggests that this presence appears to favor the control of inflammation and a better maintenance of immunity, in spite of repeated stress and the constant work of defense of a whole life, against foreign microbial elements.

For example, bifidobacteria represent nearly 90% of the bacteria of breast-fed infants, and only 5% at the end of life. Their contribution seems beneficial in several ways in the elderly, according to studies.

It would be possible to define a person’s age by studying the composition of their microbiota 

Longevity researcher Alex Zhavoronkov and his colleagues from artificial intelligence startup InSilico Medicine analyzed the DNA of the gut microbiota of healthy people from different countries. A total of 1165 people between the ages of 20 and 90 were enrolled in the study and more than 3600 stool samples were collected to study the gut microbiota data and enable the tool to be trained.  The machine was able to give the age of the individuals with a margin of error of only 4 years!

Moreover, of the 95 bacterial species studied, 39 of them could predict age. The researchers were also able to show that certain species of bacteria were more abundant as we aged, such as Eubacterium hallii, which is associated with a healthy balance of intestinal metabolism; and others, on the contrary, were in smaller quantities, such as Bacteroides vulgatus, which is correlated with ulcerative colitis.

What about tomorrow?

So far, very different diets (without excess) and microbiota lead to relatively similar maximum lifespans. A Japanese and a French person have a very different diet, but a similar longevity.

However, further research, particularly the analysis of genetic data from the countless organisms that populate our digestive organs, opens up significant prospects for longevity. Among the leads, those influencing the nervous system are among the most important. 

September News

Aubrey de Grey, the world’s best known biogerontologist, helped the SENS organization raise $28 million. Immediately afterwards, on the basis of harassment charges, he was expelled from SENS, among others. However, at the time of writing, none of the thousands of women and men, minors or adults, who have been in public or private contact with him for decades have, to our knowledge, taken legal action. Whatever the

media’s temptation and the pressure to condemn without procedure, and while respecting the rights and opinions of everyone, including the alleged victims, we will stick to fundamental human rights: Everyone accused of a criminal act is presumed innocent until proven guilty in a public trial in which he or she has been given all the guarantees necessary for his or her defense.

American billionaire and philanthropist Yuri Milner has announced the creation of Altos Labs, a company that aims to make radical advances in human longevity with funding in the hundreds of millions of dollars. Jeff Bezos is also widely quoted as a co-founder. Renowned scientists specializing in aging research have been recruited or associated, including epigenetic clock specialist Steve Horvath, Nobel laureate Shinya Yamanaka and Spanish rejuvenation researchers Juan Carlos Izpisúa Belmonte and Manuel Serrano. 

 For more information:

• See the following sites: heales.org, sens.org, longevityalliance.org and longecity.org.
• Source of the image. 

« And so, if for millennia the task of common men and daydreaming philosophers alike had been to ask, “What happens if we die?”. Today we’re tasked with a goal far more challenging: that of examining what happens if we live. […] What if, for the first time in history, we’re building a civilization that relies not on death, but on the deployment of ethical technologies, for its enhancement? » Raiany Romanni, bioethics researcher, Harvard Medical School. Source.

Theme of the month: Longevity and Altruism  

Introduction

The importance of wanting the good of others, for the sake of others (and not for any religious reason or moral obligation) is a concept that is far more important today than it was yesterday. The word altruism itself is less than two centuries old. It was created by Auguste Comte, as an antonym of the word egoism, in 1850. In this letter, we will not address philosophical questions about the deep reasons for altruism. What is important in this letter is that conscious solidarity is one of the reasons for the enormous social progress and longevity. Thus, never in the history of humanity have we been more concerned about others, starting with the elderly and therefore the weakest, than during the current Covid epidemic.

Altruism in animals

Altruism does not only refer to the conscious mobilization of humans for others. In biology, altruism refers to the behavior of an individual that increases the selective value of another individual while decreasing its own abilities. Altruistic behaviors in biology appear most obviously in kinship relationships, such as kin selection. They can also be observed in larger social groups, such as in social insects.

They allow an individual to increase the transmission success of his or her genes by helping related individuals who share those same genes.

Obligate altruism is the permanent loss of direct  fitness (reproductive) (with the potential for indirect gain). For example, worker bees may forage for food for the colony (individual cost, but collective gain).

Optional altruism is a temporary loss of direct capacity (with a potential indirect gain from personal reproduction). For example, a Florida scrub jay may help at the nest, then gain parental territory.

Examples:

• Wolves and wild dogs provide meat to pack members not present at the kill. 
• Mongooses support old, sick or injured animals.
• Meerkats often have a guard to warn of predator attacks while others are feeding.
• Male baboons threaten predators and cover the rear while the herd retreats.
• Bonobos have been observed helping other injured or disabled bonobos.
• Vampire bats usually regurgitate blood to share with unlucky or sick roosting companions who have been unable to find a meal, often forming a « buddy system. »
• Lemurs of all ages and both sexes will care for infants that are not related to them.
• Dolphins support sick or injured animals, swimming under them for hours and pushing them to the surface so they can breathe.
• In many bird species, a breeding pair receives support in raising their young from other « helper » birds, including help in feeding their chicks. Some will even go so far as to protect the young of an unrelated bird from predators.

Being altruistic may be good for your health!

What if helping others was not just an altruistic gesture? A study published in 2006 in Evolution and Human Behavior suggests that helping children, grandchildren, or more distant relatives may give a boost to longevity.

Scientists at the University of Basel in Switzerland studied 500 people aged 73 to 103. They found that those who cared for their grandchildren lived longer than those who did not: half of the caregivers were still alive 10 years after the study began, while half of the less devoted grandparents died within five years.

In the absence of grandchildren, direct assistance to children, such as housework, has the same effect on longevity. Prosocial behavior by grandparents towards children and grandchildren appears to set an example of altruism for future generations and inscribe this model in their nervous and hormonal systems.

Be careful, however, it is also possible that the differences can be explained by the fact that only healthy grandparents can take care of their grandchildren, because people in poor health have fewer children and therefore fewer grandchildren, less contact, fewer activities…

According to American researchers, the feeling of well-being acts on our genes and boosts our immune system. But happiness is differentiated into two different types and only altruism seems to be able to influence the human epigenome.

 The immune system of altruistic people is found to be more developed than that of people experiencing hedonic well-being (i.e., cultivating one’s own emotions in order to feel happy), researchers reveal in their study published by the scientific journal Proceedings of the National Academy of Sciences (Pnas). 

Specifically, after taking blood samples from 80 healthy volunteers, the researchers observed that the human genome seems to respond to a positive psychological state. In case of altruism, inflammatory genes decrease and antiviral genes increase, in order to protect the body.

Effective Altruism

The phrase « It’s the thought that counts » sounds nice, but it is actually morally untenable. Our altruistic actions must be measured by their effectiveness. Effective altruists advocate that we should estimate the « cost-benefit » of our actions to others. For example, providing food worth a certain amount of money may be less altruistic than investing the same amount in better agricultural production by farmers.

In the health field, funding care and medication to reduce the effects of age-related diseases is a useful act, but less so than funding research to end these diseases.

Of course, the outcome of these investments is not certain and the benefit is longer term. Most often, effective altruists invest in projects that are relatively easy to measure and therefore not in wide-ranging efforts such as research. Yet, the benefits of wide-ranging advances are considerable. One euro for care in a nursing home will benefit a few people. One euro for a therapy for a healthy life can benefit all.

The duty of altruism

Helping your fellow man in certain circumstances is a duty for most philosophical and religious currents. It is also a legal obligation whenever a person is in danger in some countries such as France or Germany. This is called the duty to rescue.

 There have been cases where people have been prosecuted for this type of crime because they did not act correctly in view of scientific progress. If the demand and social pressure became strong enough, we could likewise consider it a crime not to invest in research for healthy longevity. The State, at least, could be legally, even constitutionally, ordered to make these investments (in the same way that it is today ordered to guarantee the health of its citizens).

 Note that the fact that the outcome of the assistance is uncertain does not absolve the duty. A person who refuses to help an injured person cannot justify himself by saying that he would probably have died anyway. Therefore, the fact that the outcome of the search is uncertain does not mean that there is no duty.

 In France and Belgium, case law generally considers that only the effect requiring immediate action should be considered. But this could change.

Long-term altruism

Many citizens, especially environmentalists, rightly insist on concern for future generations. In fact, it is also about current generations, because climate change and pollution will already have impacts in our lifetime. They even have some today. But the concern, the altruism for the future, is also to offer a healthier and much longer life to the children who will be born tomorrow.

Finally, we could say that there is even a form of altruism towards this other person who is oneself in the long term. Many of our behaviors are a choice between short-term interest (« bad » eating, smoking, distraction…) and long-term interest (exercise, study…). The choice to work for a longer and healthier life is in my opinion an altruism for one’s future self.

Good news of the month. Potentialities of gene therapies.

It is the genetic heritage that determines quite precisely the maximum lifespan of a human, any other mammal and most animals. The potential of gene therapies for longevity is expanding and becoming clearer. Renowned scientist George Church gave an interview on this topic for the organization Lifespan.io.

For more information

See: 

• heales.org, sens.org, longevityalliance.org and longecity.org.
• Image source

Scientist Shin Kubota expresses his vision in the New York Times: « Turritopsis application for human beings is the most wonderful dream of mankind,” he told me the first time I called him. “Once we determine how the jellyfish rejuvenates itself, we should achieve very great things. My opinion is that we will evolve and become immortal ourselves.”. » (November 28, 2012)

Theme of the month : Longevity records of living organisms

How to understand the longest lifespan? And why? 

The maximum lifespan of living things is extremely variable depending on the species. Overall, for animals, the maximum lifespan is longer with one or more of the following favorable factors:

• Predators are rare 
• The metabolism is slow 
• Size is large

The differences in lifespan can be enormous between species that are biologically quite close. This is one of the reasons to consider gene therapy or other medical treatment to dramatically increase the maximum lifespan of humans.

This letter includes known cases of extreme longevity. Obviously, in these cases of very long lifespans, only indirect and sometimes questionable measures are possible.

The naked mole rat and the bat, exceptional longevity and no cancer! (35-40 years)

The longevity of naked mole rats is especially surprising when compared to other captive rodents of similar size. Naked mole rats are not expected to live more than six years. However, the oldest naked mole rat known in the laboratory is… 35 years old! And, among some of its fellow rats that are over 30 years old, some females are still fertile.

Researchers have discovered why naked mole rats are cancer-free. It is thanks to hyaluronic acid, a molecule that is thought to prevent the formation of tumors in the body. According to researchers Vera Gorbunova and Andrei Seluanov, who published their results in the journal Nature, the molecular weight of hyaluronic acid in the naked mole rat is five times greater than in mice.

The tiny Brand’s bat, at seven grams, lives for almost forty years. It is the same for the great mouse (Myotis myotis), which is five times heavier. An international team undertook a longitudinal study over eight years. Their results, published in the journal Nature Ecology & Evolution, open up promising avenues for research on aging.

Longest-lived insect: the termite queen (50 years)

Insects are normally thought of as living less than a year as adults. However, termite queens, protected from predators, can reach 50 years.

Birds: The albatross can live up to 80 years

Albatrosses are the largest seabirds in the world: the howler albatross reaches a wingspan of 3.50 meters! Their longevity is also remarkable, as they can live up to 80 years. Wisdom, a 70 years old albatross has laid eggs again. A parrot (cockatoo) has also reached a similar age (82 years).

Oldest amphibian: the cave salamander (100 years)

Naturalists attribute the longevity of the blind salamander Proteus anguinus to its unusually slow metabolism. Tthis salamander takes 15 years to mature, mates and lays eggs only about every 12 years, and barely moves except when foraging for food. In addition, the damp caves of southern Europe where it lives are virtually free of predators, allowing P. anguinus to live beyond 100 years in the wild.

Reptiles: The famous Galapagos tortoises

In 2012, « Lonesome George » died at over 100 years old. Six years after his passing, the centenarian has made a comeback thanks to the revelations of Yale researchers studying his genome! George was the last representative of a species endemic to a Galapagos island. He always shunned any mating in captivity. The scientists who had sequenced his genome during his lifetime as well as that of another species of giant tortoise, revealed the results in the journal Nature.

The biologists detailed 891 genes in these turtles, involved in the function of the immune system. They show that these animals have developed extra copies of genes that allow them to better respond to oxidative stress, known to be a major factor in aging. They also discovered a gene that allows cells to better defend themselves against foreign cells, as well as tumor suppressor genes that are more numerous than in most vertebrates, and others that are involved in DNA repair.

The study of aging in animals is a source of knowledge for humans. Researchers have found some similarities between the genomes of turtles and centenarians.

Jeanne Calment with her 122 years is the person who lived the longest in the history of humanity…, but certainly not enough to impress an old turtle. The longest living turtle seems to have reached 189 years of age.

Sphenodons are other reptiles that can live past a century.

Fish: 150 years for the orange roughy (Hoplostethus atlanticus)

Hoplostethus atlanticus is called « watchfish ». The animal lives in the world’s oceans at depths between 900 and 1,800 meters, especially in submarine canyons.

The species only reaches sexual maturity between 20 and 30 years of age, which could be explained by a low predation rate and the scarcity of prey in the abysses. Adults can measure 75 cm long and weigh 7 kg and the age of the oldest known specimen, determined by radiometric radiation of the mineral accumulations in its internal ears, is said to  be 149 years.

Echinoderms: 200 years for the giant red sea urchin (Astropyga radiata)

Quite common in the Indian Ocean and in part of the Pacific Ocean, this echinoderm owes its name to its color and its size, which can reach nearly 20 cm in diameter, the largest known among sea urchin species. Some individuals have reached the age of 200 years.

Mammals: 200 years for the bowhead whale (Balaena mysticetus)

Living in Arctic waters, the bowhead whale is a cetacean measuring up to 20 meters and weighing around 100 tons. Its longevity has been estimated at more than 200 years thanks to scars left by old wounds caused by whale hunters. This exceptional longevity could be explained by certain genes. For example, analysis of the whale genome shows unique mutations in the ERCC1 gene involved in the repair of damaged DNA. Another gene, called PCNA and associated with cell growth and DNA repair, contains a duplicate section of DNA. This duplication could slow down cetacean aging.

Sharks: 400 years for the Greenland shark (Somniosus microcephalus)

This rather plump grey shark, measuring five meters, lives in the waters of the Arctic Ocean and is the champion of longevity among vertebrates. Its growth is estimated at about 1 cm per year.

In an article published in Science, an international team of researchers describes how they managed to measure the age of 28 Greenland sharks. The results revealed that the largest shark, a female over five meters long, was 392 years old, although there is a significant margin of error of plus or minus 120 years. The sexual maturity of females is thought to be reached at the age of about 150 years.

According to this research by Julius Nielsen at the University of Copenhagen, published in August 2016, the Greenland shark would therefore be the longest-living vertebrate.

Oldest Mollusc: The Ocean Quahog (500 years)

Scientists have determined that the ocean quahog, Arctica islandica , can literally survive for centuries, as demonstrated by one individual, Ming, which has surpassed the 500-year mark (you can determine a mollusk’s age by counting the growth rings in its shell).

Trees. The Giant Sequoia: over 3000 years old!

Some trees seem to have no senescence mechanism. They remain as fertile at the age of several centuries as in their youth.

The Giant Sequoia is characterized by its longevity since it can reach more than 3000 years. 

Many other species of trees can live for centuries: olive trees, oaks. The absolute record seems to be held by a 5,000 year old Bristlecone pine.

Finally, trees, like other plants, can multiply clonally and form a collective organism. In this sense, the clonal colony of aspen Pando is, at 80,000 years, one of the oldest organisms on the planet.

Microscopic organisms: endoliths (10,000 years)

Determining the lifespan of a microscopic organism is a tricky question: in a sense, all bacteria are immortal, as they propagate their genetic information by constantly dividing (rather than having sex and dying of age).

The term « endoliths » refers to bacteria, fungi, amoebas, or algae that live deep underground in cracks in rocks. 

Studies have shown that individuals in some of these colonies undergo cell division only once every hundred years and can have a lifespan of about 10,000 years. 

Technically, this differs from the ability of some microorganisms to recover from stasis or freezing after tens of thousands of years; in a significant sense. Endoliths are continuously « alive », though not very active. Perhaps most importantly, endoliths are autotrophic, meaning that they fuel their metabolism not with oxygen or sunlight, but with inorganic chemicals, which are virtually inexhaustible in their underground habitats.

Biological immortality in lobsters, hydras, sponges and corals

A small number of multicellular animals seem to have no mechanism of senescence. They do not degrade as they age. For example, their fertility remains constant or even increases.

Hydras, like all cnidarians, can regenerate, which allows them to recover from an injury and reproduce asexually. All hydra cells divide continuously. It has been suggested that hydras do not undergo senescence and, as such, are biologically immortal. In a four-year study, three cohorts of hydras showed no increase in mortality with age.

One species of sponge can live up to 11,000 years, namely Monorhaphis chuni, according to a U.S. study published in the journal Aging Research Reviews in 2014.

Some colonial animals, such as corals, can live more than 4,000 years.

Research suggests that lobsters may not slow down, weaken or lose fertility with age, and that older lobsters may be more fertile than younger lobsters. This does not, however, make them immortal in the sense of no impact of senescence, as they are much more likely to die in a shell molt with advancing age due to their increasing size. 

Their longevity may be due to telomerase, an enzyme that repairs long repetitive sections of DNA sequences at the ends of chromosomes, called telomeres. Unlike vertebrates, lobsters express telomerase in adulthood throughout most tissues, which has been suggested to be related to their longevity.

It has been claimed that some fish, notably the bigmouth buffalo, do not have measurable senescence. However, with the exception of the Greenland shark, no captured fish whose age was measured exceeded 200 years.

Why no biological immortality in vertebrates, even those without predators?

Natural selection, at least for vertebrates, always results in species with limited lifespans. This can be explained by the fact that an animal species without aging would lose its genetic diversity and be eliminated by any environmental change. This also explains sexual reproduction: more genetic mixing means more adaptability to the environment. 

But in a certain sense, systematic aging remains an evolutionary mystery. Indeed, even salamanders or cave fish in an extremely stable environment (hundreds of thousands of years) and without predators do not seem to live much beyond a century.

Cnidaria: biological immortality and rejuvenation for the jellyfish Turritopsis nutricula

Small in size, but long in life expectancy. The jellyfish Turritopsis nutricula measures only 5 mm in diameter, but could live ad vitam æternam. Native to the Caribbean Sea, the species is nowadays very widespread. Several specialists are worried about its proliferation over the whole globe.

Thanks to a particular cellular process called transdifferentiation, the animal is able to stop its aging and even to become younger. It is already known that the best way to push a Turritopsis Nutricula to regenerate is to stress it. For example, in case of an injury, the process starts immediately and within a few days, the jellyfish returns to its juvenile stage and starts a new life.

This makes it an exceptional subject of study for biologists and geneticists, and a subject of interest for some pharmaceutical groups who are already considering the production of a rejuvenating cream containing Turritopsis DNA. « It’s as if a butterfly were able to go back to the caterpillar stage, » says Stefano Piraino, a professor at the University of Salento in Italy.

Dormancy as a longevity strategy

Dormancy is a term that covers all forms of slowed life. 

It is the period in the life cycle of an organism when growth, development and/or physical activity (in animals) are temporarily stopped. This reduces metabolic activity and thus helps the organism to conserve energy.

Especially in extreme environments, or ones of a very seasonal nature, dormancy can only be an adaptive strategy if a stimulus for the seed to move from a « dormant » to a « non-dormant » state is made possible at the « right time ». And indeed, dormancy often does indeed cease when environmental conditions permit.

The longevity of a seed (the length of time it can remain in a dormant state without losing its ability to germinate) is highly variable. In plants, all the intermediaries exist, between the seed of the lotus which holds the record of longevity (about1000 years) and the seeds of cocoa tree, little dehydrated, which must, under pain of death, find, in the few days following their maturation, conditions allowing their germination. Scientists have even managed to germinate seeds of silence (a plant with white flowers) frozen for nearly 32,000 years in the Siberian subsoil! 

Although costly, the dormancy strategy prevents all individuals carrying the same genotype from simultaneously encountering an environment not conducive to their survival or reproduction.

A rotifer survived 24,000 years of freezing in the Arctic permafrost.

Bdelloid rotifers generally live in aquatic environments and have an incredible ability to survive. Russian scientists discovered these creatures in a core of frozen soil extracted from the Siberian permafrost using a drill.

In a study published recently in the journal Current Biology, the Russian researchers used radiocarbon dating to determine that the creatures they recovered from the permafrost (ground that is frozen year-round, except for a thin layer near the surface) were about 24,000 years old.

This is not the first time ancient life has been « revived » from a permanently frozen habitat.

Antarctic moss stems were successfully regenerated from a 1,000-year-old sample and a living campion flower was regenerated from seed tissue, probably stored by an Arctic squirrel, that had been preserved in 32,000-year-old permafrost. Simple worms, called nematodes, were « resurrected » from permafrost at two locations in northeastern Siberia in sediments more than 30,000 years old.

This month’s good news: Private investments for longevity. The European Union announces widespread health data sharing for its citizens by 2025.

• Vitalik Buterin donates over $2 million to the Methuselah Foundation.
• Michael Greve, founder of Forever Healthy, pledges 300 million to advance rejuvenation startups.
• In an unfortunately poorly circulated document, the European Commission announces that it aims to have EU citizens able to share their health data with the healthcare providers and authorities of their choice by 2025. This would mean, if followed through, that European citizens will be able to easily share their data for scientific research, including healthy longevity.

For more information:

• See in particular: heales.org, sens.org, longevityalliance.org and longecity.org.
• Source of image

Thomas Pesquet, the current star of French scientific research: « If we could unlock the key to aging and figure out how to reverse it, that would be super convenient. » (translation)

Theme of the month: Regeneration

All living beings are capable, at different levels, of repairing damage to their organism. 

In biology, regeneration is the capacity of living organisms to rebuild themselves after a natural or accidental destruction of a part of themselves. 

Stem cells: the key to regeneration?

Regeneration can involve cells, organs or functional parts of certain living beings. The ability to regenerate is mainly carried by cells of the body that will reprogram themselves to replace the damaged tissue or organ. Some of these cells called « stem cells » are generated either by the bone marrow and can circulate in the body, or by the tissues themselves.

 Regeneration in humans

The human body is constantly subject to cell death and regeneration. However, this regeneration is not exactly the same depending on the type of organs and cells.

Some cells are completely replaced by new ones in a very short time. For example, the cells of the intestines and stomach are only used for a few days before being evacuated by the body. The skin is completely renewed in a few weeks due to external aggressions. Some cells even live only a few hours, like white blood cells.

On the other hand, some cells are renewed slowly. For example, it takes about ten years for bones to be completely regenerated. Heart muscles regenerate by only 1% each year after the age of 20.

But our body also contains cells that never regenerate! This is the case of oocytes or certain neurons in the cerebral cortex.

We must not confuse regeneration and healing, even if they can be observed together, they are two very distinct phenomena. Healing is only a partial repair of the cells, but does not allow an identical reproduction.

We certainly cannot regrow a leg or an arm, but some animals can regenerate whole parts of their body!

Regeneration in living beings

The regeneration capacities of certain plants, notably trees, are remarkable. But the genetic and physiological functioning is so different from that of animals, and therefore also from that of humans, that there is no prospect of application against human senescence appearing conceivable in the short or medium term.

The ascidian, a curious small marine invertebrate in the shape of a wineskin, has the ability to renew its tissues very quickly after serious injuries. Other invertebrates, such as the flatworm and the planarian, can regenerate their head from a tail fragment and vice versa. These invertebrates are not the only animals with such regenerative powers.

Among vertebrates, too, we can find experts in regeneration. The axolotl, a small amphibian that can regrow its limbs, organs and even parts of its brain. The zebrafish regenerates its heart tissue without needing stem cells. Salamanders regenerate their limbs, heart, tail, eyes, kidneys, brain and spinal cord throughout their lives. 

How do these animals with regenerative abilities manage to regrow such complex structures?

Understanding the regeneration process

After an amputation, stem cells accumulate at the site of injury in a structure called the blastema. A major part of current research focuses on how signals from the injury site indicate to stem cells to form the blastema and begin dividing to rebuild the missing structure. 

But what happens at the level of the stem cells themselves? Do the animals use a single type of blastema stem cell that can differentiate into multiple tissues? Or do different groups of stem cells produce the different tissues required to form the new organ?

Recent research in animals with regenerative abilities has shown that stem cells use a variety of strategies to reconstitute missing body parts from multiple tissues, such as muscle, nerve and skin. 

In this 2014 study, scientists combed through the 23,000 genes of Anolis carolinensis, a lizard about 20 centimeters long. Its complete genetic sequencing had already been completed in 2011. But this time, the study’s researchers scanned all the genes during tail regeneration to isolate those responsible. The result: at least 326 genes are activated in the phenomenon, a real « recipe » in the lizard’s DNA.

Another group of scientific researchers in the United States recently solved the mystery of planarian worm regeneration. They discovered that adult individuals have pluripotent stem cells that can make all types of cells in the animal’s body. 

In addition to stem cells, the regeneration process uses differentiated cells that have stopped dividing and « start » to multiply again to replace lost tissue. This phenomenon is present in zebrafish where a heart muscle cell divides to reconstitute the missing tissue. This regenerative process has also been demonstrated in the heart of young mice, but it quickly disappears as the animal grows.

Future Research and Challenges: Enabling human rejuvenation through regeneration

As adults, humans can regenerate certain organs such as the liver or skin. Unfortunately, many other human tissues do not have this ability. One of the goals of regenerative medicine is to find ways to stimulate tissue regeneration or make replacement tissues. One day, this could be one of the ways to « cure » humans of aging.

In December 2018, the scientist Michael Levin from Tufts University, demonstrated that by changing the electrical pattern between cells in the planarian worm this resulted in activation of cells indicating to the body its shape by guiding regeneration.

How to limit growth to what is useful (avoid cancerous growths)? How to « start », « reactivate » these mechanisms to allow the regeneration of organs that arenot destroyed, but senescent? This research requires a better understanding of the genetic and molecular mechanisms of regeneration. 

Progress in the use of stem cells, gene therapy, and the knowledge of genetic mechanisms linked to regeneration open up considerable perspectives. This could well be one of the avenues studied by the USA in the framework of the initiative announced below.

Good News of the Month: U.S. President Joe Biden Announces Advanced Health Care Agency in First Address to U.S. Congress

« The Department of Defense has an agency called DARPA (Defense Advanced Research Projects Agency), whose mission is to develop advances to strengthen our national security. This agency gave birth to the Internet, GPS and many other things. The National Institutes of Health, NIH, should create a similar agency for advanced research projects in the health field. To develop breakthroughs – to prevent, detect and treat diseases like Alzheimer’s, diabetes and cancer.

This is a personal issue for many of us. I can’t think of a more worthy investment. And I don’t know of anything more bipartisan. Let’s end cancer as we know it. It’s within our power. » (Source)

The DARPA agency specializes in « disruptive » technologies. So this new agency could quickly target « disruptive » research in health and anti-aging.

For more information:

• heales.org, sens.org, longevityalliance.org and longecity.org.
• Source of the image