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

Jed Lye, Molecular physiologist, 2021 Medium.com.

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

Introduction

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

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

Harmful Effects 

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

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

Direct Effect on Aging 

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

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

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

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

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

Conclusion

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

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

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

The good news of the month: AI for longevity Research

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

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

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

For more information

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

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

This month’s theme:  Naked Mole Rats

Introduction

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

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

Do they age ?

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

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

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

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

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

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

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

Transferring the genes of longevity

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

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

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

Conclusion: 

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

The good news of the month: Dublin Longevity Declaration.

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

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

For more information

• Heales, Longevity Escape Velocity Foundation, International Longevity Alliance, Longecity and Lifespan.io 
• Heales Monthly Science News
• Heales YouTube channel
• Source of the image: prompt Dessine un rat-taupe nu dans un laboratoire avec des éprouvettes style Van Gogh
• Contact us

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

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

This month’s theme: Recent Longevity Conferences

Introduction

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

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

One goal: longevity for all, many points of view

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

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

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

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

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

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

Main themes approached during the conferences

Biomarkers 

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

Foods that promote a healthier, longer life 

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

Physical activity 

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

Drugs for longevity

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

A few blind spots

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

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

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

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

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

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

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

Conclusion: 

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

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

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

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

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

For more information

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

“All my possessions for a moment of time.”

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

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

Introduction

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

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

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

Statistics

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

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

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

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

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

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

Primary Cause: COVID 

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

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

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

Direct and Indirect medical consequences

Long Covid

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

No rebound effect, at least until 2022

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

Deficit of other medical interventions

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

No rise in suicides in the older population

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

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

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

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

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

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

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

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

Conclusion: What could longevists do?

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

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

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

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

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

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

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

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

For more information

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

Everything in human history starts out as Science-Fiction. For thousands of years, man has dreamed of flying, and today we fly without paying attention. (…) If we don’t destroy the planet first, what we’re about to see is phenomenal.

(Journalist) So it’s good news? It’s great news. We’re going to merge with technology, which will allow us to live longer and make us smarter. We urgently need to use AI to solve our problems. (…)

-Jeanette Winterson, novelist (translation, source)

This month’s theme: How longevitists could share their health and research data

Introduction

Written language was probably invented to record data more than five thousand years ago. In 2023, each day, we store more data than was conserved during the whole history of humanity before the 20th century. Today, about 30 % of all this data is health data. Medical data about older people, especially in rich countries, is stored for decades in hospitals, and medical laboratories,… and is generally available electronically. It contains detailed data available about hundreds of millions of people. Even better, we now have basic information for the large majority of the inhabitants of the planet (date of birth, vaccination, number of children, main disease and at the end of life, cause and date of death, …). 

In other words, we do not only need data, but first, we need to better share and curate health data. To analyze those data and progress modestly against senescence, we already have tools. In other words, we do not only need better AI for health, we need to have better access to it.

Those questions were already approached in a newsletter 3 years ago. Fortunately, progress is fast, among other things at the European level and also -of course- concerning AI tools.

Access to data: Right to share Scientific Advancement and Intellectual Property Rights

The right to health is a universal right, one of the basic conditions for the right to life. Article 27 of the Universal Declaration of Human Rights establishes the right of everyone to « share in scientific advancement and its benefits ». Similarly, Article 15 of the International Covenant on Economic, Social, and Cultural proclaims the right to « enjoy the benefits of scientific progress and its applications ».

However, international conventions and national laws also create rights related to the protection of the interests of the authors of scientific work. In the medical field, this concerns patents, but also many other complicated rules related to intellectual property.

In theory, patents exist to make an invention known to everybody while protecting the rights of inventors and encouraging them to pursue as many inventions as possible. Practically, concerning medical research, investors generally use it to sell drugs and products invented by others. The information related to the results is often kept partly secret, so that it is more difficult for others to violate the patent rights, but also to create similar or better products.

Concerning data related to the research:

• « Positive » results will be only made public as much as absolutely necessary for the patents. Worst, they will often only be made public when the patent is available because if the information is communicated, the patent could be refused.
• « Negative » results will not be made public because they are not useful for the patents. Worst, they will often be kept secret because of bad publicity related to « failures » of the research.

Privacy, security, informed consent

In this part of the newsletter, we will mainly approach questions related to the European Union and the USA. China and other countries approach these situations in very different ways.

In theory, most European citizens should have access to their own health data. They should also have the right not to share it without informed consent thanks to the famous General Data Protection Regulation (GDPR). Some categories of data are better protected because they are more « sensitive » and health data is among those categories. Finally,  in theory, informed consent is not necessary to use health data in some circumstances, one of them is scientific research.

However, practically in many European places, the situation is very different and can be summarized as:

• The citizens often do not have access to their own medical data in a simple way. In Belgium, for example, the right to access files does exist, but not yet the right to access an electronic file.
• The citizens do not have the opportunity to participate in medical experimentation and share knowledge scientifically, even if he or she wishes to do so out of personal or collective interest and even if he or she has given explicit informed consent. It is possible to participate in clinical studies, but in most cases, the results will not be shared or will be patented.
• Researchers do not have access to the detailed health data of most citizens and they have often to pay to access information.
• Medical data is often the subject of opaque and self-interested commercial transactions. As indicated above, « positive » results can be kept secret to be sold later. « Negative results » can be kept private, because they are not helpful and even could be bad for some companies selling some products.
• The development of research using artificial intelligence and « massive medical data » is slowed down, as biased and sold data potentially contains more inaccuracies.

In the USA, the situation is well described by the renowned lawyer Orly Lobel: Privacy—and its pervasive offshoot, the NDA (non-disclosure agreement)—has also evolved to shield the powerful and rich against the public’s right to know. (…) But there is much more health information that needs to be collected, and privileging privacy may be bad for your health.

Curation

Data curation is a process that improves data that doesn’t meet a quality standard due to missing or incorrect values, thereby reducing the amount of unusable data. This process includes activities like data selection, classification, validation, and remediation of disparate data that comes from multiple sources.

The curation of health data is extremely complicated

There is no single system. Healthcare data originates from multiple sources—and to/from different departments or organizations. Healthcare data exists in myriad formats: paper, digital, images, videos, text, numeric, and more, with little or no standardization. Data structure (or lack thereof) varies.

Some of the data in a health record is entered and captured into fields that can be validated and aggregated, but other information like free text and notes cannot be easily categorized. 

The data is variable and complex. Information from claims data is more standardized; however, not complete as it does not tell the full patient story. But clinical data is more variable and subjective to provider interpretation.

Regulatory requirements are constantly changing. Reporting requirements for agencies continue to evolve and increase, making some data or transmission modes obsolete or less valuable.

Conclusion: What could longevists do?

We live in fascinating times. We have more data than ever. Thanks to the fast progress of AI (and potentially AGI), the search for therapies thanks to data is considerably facilitated. However, due to privacy and patent rules and profit constraints, we are not able to collect and curate enough health data.

Longevists should now publish more information on public places with as much information about how the data was collected and curated as possible.

In the longer term, we could collectively create a system that longevists and scientists can trust, managed by a non-profit organization where by default (opt-out) health data (anonymized or pseudonymized) would be stored and used for research purposes only.

The ultimate goal is, of course, to enable everyone to want to live longer, healthier lives.

The good news of the month:  Discovery of chemical means to reprogram cells to a younger state. Genetic treatment improves cognitive function for old monkeys.

Using Yamanaka factors as the basis, a research team at Harvard Medical School recently published a study showing that they have identified six different chemical cocktails, which, in less than a week restore a youthful genome-wide transcript profile and reverse transcriptomic age without compromising cellular identity.

The next important step would be to introduce rejuvenated cells in old mice (or other animals) and measure their lifespan compared to a control group.

A study published in Aging Nature establishes that recombinant Klotho Treatment Improves Cognitive Function in Old Rhesus Macaques. This gives very good hope that future rejuvenation genetic treatments for humans could not only slow down and hopefully later rejuvenate our bodies but also our brains.    

For more information

• Heales, LEVF, International Longevity Alliance, Longecity and Lifespan.io 
• Heales Monthly Science News
• Source of the image 

This doesn’t mean we won’t die. But all age-related ailments will one day be eradicated. We’ll be able to stay younger for longer, »

Jean-Marc Lemaitre, Director of Research at Inserm and co-director of the Institute of Regenerative Medicine and Biotherapies in Montpellier. (Translation. Le Figaro. June 18, 2023).

This month’s theme: Longevity, Blue Zones, and Adapted Housing

Introduction

According to the WHO, aging, as it develops now, presents both challenges and opportunities. It will increase demand for primary health care and long-term care, require a larger and better-trained workforce, and intensifies the need for physical and social environments to be made more age-friendly. 

Yet, these investments can enable the many contributions of older people – whether it be within their family, to their local community (e.g., as volunteers or within the formal or informal workforce), or society more broadly. Societies that adapt to this changing demographic and invest in healthy aging can enable individuals to live both longer and healthier lives and for societies to reap the dividends.

Blue Zones (already approached in a newsletter in 2021)

The island of Okinawa, Japan; parts of Sardinia; Nicoya, Costa Rica; Ikaria, Greece, and Loma Linda, California are dubbed blue zones (a concept coined in 2005,) where people live the longest and they are healthiest: The concept of blue zones grew out of the demographic work done by Gianni Pes and Michel Poulain outlined in the Journal of Experimental Gerontology, identifying Sardinia as the region of the world with the highest concentration of male centenarians (even if extreme ages could also be explained by bad birth data).

Whilst diet, exercise, and sleep are key factors in longevity, there are other lifestyle traits that Blue Zone inhabitants follow. Having a good social network is intertwined with Blue Zone communities and you will often find grandparents still living with their families. Studies have shown that those who look after their grandchildren are more likely to live longer. Similar to this, communities have strong social networks and each of these lifestyle factors has been linked to living a longer and healthier life.

In addition to exercising and following an adequate diet, sleep is another deciding factor in longevity. Blue Zone inhabitants ensure they get enough sleep during the night and you will often find them taking short naps during the day. In Blue Zones, people tend to listen to their bodies, rather than having set sleeping hours. They sleep as much as their body tells them to. “They discovered that naps as short as twenty-six minutes in length still offered a 34 percent improvement in task performance and more than a 50 percent increase in overall alertness.”

In Blue Zones, exercise is built into everyday life, rather than having a set time for the gym, or to go on a hike. Inhabitants exercise through their daily tasks such as cooking, walking, and gardening. A study was done on men living in Sardinia and it found that raising their farm animals, living on steep slopes, and walking long distances to work was associated with living longer. Benefits from other studies have shown that exercise reduces the risk of cancer, heart disease, and death overall.

Fasting is common in those communities. Intermittent fasting is one of the most well-known types. This involves fasting for certain hours of the day, particular days of the week, or consecutive days of the month. Fasting has been shown to lower blood pressure, reduce weight, and lower cholesterol.

Those who live in Blue Zones often eat a diet that is heavily plant-based. Typically, most of the population are not vegetarians but will limit their meat consumption to around 5 times a month. Their diets tend to be 95% plant-based and they contain vast amounts of vegetables, legumes, whole grains, olive oil, and nuts. In places such as Icaria and Sardinia, inhabitants will often eat substantial amounts of fresh fish. This tends to be high in Omega 3, which is important for keeping your brain and heart healthy. Commonly, those living in Blue Zones follow a calorie-restricted diet, which has been shown to increase longevity. Eating too many calories can lead to weight gain and chronic diseases.

Variety of Retirement Houses

If we were able to live in perfect housing for all who live, how many years of (healthy) life expectancy would we win? Are retirement houses better places for a longer life than being at home with (younger) family members? Or is it the other way around?

Retirement Villages are larger settlements that have been established as an important form of housing provision for older people in the USA, Australia, New Zealand, and South Africa for the last forty years or more, and in some cases, particularly in Florida and Arizona, these settlements can be very large indeed with up to 5000 dwellings. This scale of settlement, a possibility in areas where land is relatively cheap and where planning laws are relatively unrestrictive, means that lavish communal facilities –  golf courses, pools, tennis courts, fitness centers, and much else – can be economically provided and it is these facilities which generate demand for such housing, particularly among the younger retired. Downsizing for those in their late 50s is very much more common in the USA than it is for instance in the UK and this trend is reinforced both by the fact that US  local taxes are very much lower out of town and by the huge climatic advantages that Arizona and Florida can offer.

Another huge advantage of larger retirement settlements is that care can be provided very flexibly as residents get older and frailer either within individual homes by care workers operating from a central hub or in care homes and supported housing provided within the overall retirement complex.

Independent Living services are supposed to offer residents the freedom to live their lives as they see fit, to accommodate their residents’ unique needs. Independent Living is meant to combine the familiar comforts of home with the excitement of new experiences.

Study on personal control and aging in a nursing home, residents who were instructed to think of themselves as more independent and had more responsibility for their daily activities, rather than relying purely on caregiver or nursing staff, lived longer than those who were treated just as nicely but were not provided with activities that would increase their perceived independence. The study demonstrated a significant improvement in the experimental group over the comparison group in alertness, active participation, and a general sense of well-being. 

In a ‘counterclockwise’ study in 1979, the design included eight older men who lived together for 5 days on a retreat as if they were living 20 years back in time (ie, in 1959). This experience resulted in improvements over the baseline on several measures. Hearing, memory, and grip strength improved. 

This collective environment could be also the ideal place for collective studies of new treatments for longevity. This happens far from enough yet, however.

Conclusion

Our environment contributes strongly to the length of our lives. One important aspect is the level of wealth, but many other aspects are important as well. The USA is by far the country with the most medical scientists and the biggest part in percentage and in absolute terms of the GDP used for health. However, life expectancy in the US is far behind most European countries and Canada, but also in some poorer countries.

This means that significant progress toward a longer, healthier life does not require major funding. But we do need more research, more data, and more clinical trials with well-informed elderly people to « reuse » what can be reused, and also to detect/debunk sometimes over-optimistic visions. These studies could also help to detect « weak signals » that could lead to more radical developments in longevity.

The good news of the month:  Taurine supplementation slows aging and extends lifespan in mice

Taurine is an acid widely distributed in animal and human tissues. The concentration diminishes with age. It is now established that supplementation is useful for healthy longevity for mice. A publication in Science mentions that the median life span of taurine-treated mice increased by 10 to 12%, and life expectancy at 28 months increased by about 18 to 25%. 

In this domain, like in many others, clinical trials on well-informed aged volunteers should begin fast.

For more information

• Heales, LEVF, International Longevity Alliance, Longecity and Lifespan.io 
• Heales Monthly Science News
• Source of the image 

There’s no shame in waging war on old age (…) Conquering diseases that appear among elderly people will eventually make life better for everyone Martha Giill. The Guardian May 20, 2023.

This month’s theme: Declining Immunity in Older Population

Introduction

Our bodies would be incredibly fragile without an immune system. The capacity to distinguish between « good and bad », friend or enemy » is extraordinary. Sometimes, this system is not able powerful or clever enough to stop « unamical aliens ». Sometimes, the system attacks bodies that are not enemies. Sadly, the number of those inefficiencies rises with age and is one of the reasons we die of diseases related to old age.

The effects of the aging immune system (immunosenescence) confer immune dysregulation and have both cellular and humoral aspects. Studies show depletion in lymphocyte reserve with increasing age, in particular with fewer naive T cells (not yet exposed to antigens).

Serum levels of lgG and lgA are increased with age, which is conducive to protecting against viral and bacterial infections effectively in older people. Although the generation of naive T/B cells continues to decline, the adaptive immune system adjusts to age-related changes and protects the body from most pathogens. Only later in life does the immune function decline gradually, which increases morbidity and mortality in the elderly 

Differences in the immune system of Elderly and Centenarians

Compared with the elderly, centenarians have more anti-inflammatory molecules, cytotoxic T cells, highly differentiated CD8+T cells and naive B cells, and well-preserved Natural Killer cells, which would be the hallmark of « successful » aging. In centenarian offspring, the number of B cells decreases significantly, but naive B cells and IgM increase, which might be one of the reasons for resisting infection and prolonging lives.

As one grows older, your immune system does not work as well. The following immune system changes may occur: The immune system responds slower. It increases your risk of getting sick. Vaccines don’t work as well or for as long. An autoimmune disorder may develop. This is where the immune system mistakenly attacks and damages or destroys healthy body tissue. Dysfunction of the immune system with age creates inflammation called inflammaging. Healing is slower as there are fewer immune cells in the body to bring about healing and the immune system’s ability to detect and correct cell defects also declines. This results in an increased risk of cancer.

The decline in Thymus; Affects the B and T cell Production

The effects of aging on the immune system are widespread and affect the rate at which naive B and T cells are produced as well as the composition and quality of the mature lymphocyte pool. Declines in lymphopoiesis are influenced by age-related changes in the environment. The precise, age-related environmental factors that result in the depletion of lymphoid-biased HSCs have not been identified, although changes in levels of transforming growth factor β-1 might be involved

At birth, the immune system is equipped with an enormously diverse repertoire of antigen-reactive T and B cells, all of which are so infrequent that they cannot protect the host. Thus, as humans age and are exposed to infectious organisms and cancerous cells, antigen-specific lymphocytes need to expand massively in frequency and switch from a highly proliferative naive cell into a less proliferative effector and memory cell.

Aging is associated with several comorbidities that finally lead to organ failure and death. With the progressive deterioration of protective immunity, older individuals become susceptible to cancers and infections). Interestingly, aging is also associated with an increased incidence of inflammatory disease, most notably cardiovascular disease). Many of the degenerative diseases of the elderly, such as Alzheimer’s disease, Parkinson’s disease, and osteoarthritis, have a vital component of tissue-damaging inflammation. Similarly, the production of autoantibodies is much more likely to occur in older individuals. In essence, immune aging is associated with declining protective immunity combined with an increased incidence of inflammatory disease. There are two main approaches to T cell-based immunotherapy: HLA-restricted and HLA-non-restricted immunotherapy. Significant progress has been made in T cell-based immunotherapy over the past decade, using naturally occurring or genetically engineered T cells to target cancer antigens in hematological malignancies and solid tumors. However, limited specificity, longevity, and toxicity have limited success rates. One of the few positive aspects of aging is that a long life exposes the body to many different pathogens and so enables this body to create more specific antibodies. 

Older adults age 65 or older represent the growing majority of patients diagnosed with cancer. However, older adults are under-represented in clinical trials in general, as well as in the landmark studies that led to the approval of these immunotherapy agents. Because of increasing age, multimorbidity, and impaired functional status, many of these patients seen in community-based oncology practices are not eligible for such studies. Thus, the results of these studies are difficult to generalize to an older patient population with these competing risks. 

TRIIM study was held at Stanford University by Gregory M. Fahy and his team from 2014 to 2015 with two cohorts. The main aim was to regenerate the thymus with a novel drug combination of hormones like Growth Hormone and DHEA (Dehydroepiandrosterone), as well as Metformin. The results showed protective immunological changes, improved risk indices for many age-related diseases, and a mean epigenetic age approximately 1.5 years less than baseline after 1 year of treatment (−2.5-year change compared to no treatment at the end of the study). Using an epigenetic clock called GrimeAge, they also showed a 2-year decrease in epigenetic vs. chronological age that persisted six months after discontinuing treatment

Conclusion

We all saw that the elderly with COVID-19 showed much more rapid clinical progress, high incidence, and mortality compared to the younger population. This was accompanied by heavy systemic inflammation and tissue damage, which would be related to immunosenescence. 

Boosting the immune system by regularly exercising, eating healthy, and suppressing the use the alcohol and smoking can decrease the rate of aging of the immune system. Taking safety measures to prevent injuries and falls is also important as a weak immune system can slow the healing of wounds. In the longer term, we need therapies able to rejuvenate the immune system, especially the thymus. 

Good News of the Month: Dior wants to reverse old age.

Dior announced the creation of an International Reverse Aging Scientific Advisory Board (RASAB). The first goal is to rejuvenate the skin, but the longer-term goal is the rejuvenation of the whole body. Dior has an entire team dedicated to this goal.

For more information

• Heales, SENS, Longevity Alliance, Longecity, and Lifespan.io
• Heales Monthly Science News
• Source of the image DALL-E

« I predict one day it will be normal to go to a doctor and get a prescription for a medicine that will take you back a decade ». Sinclair said at a California event.

“There is no reason we couldn’t live 200 years.” David Sinclair, who runs an aging-research lab at Harvard University, says the new therapies could allow people to live much longer than they currently do. 

This month’s theme: Neurodegenerative Diseases and Aging

Introduction

Among all diseases related to old age, Alzheimer’s disease is probably the most studied. Sadly, it is still also an incurable, very frequent disease.

Would all of us die of degenerative diseases if we were able to suppress all other causes of death related to aging? Probably, and this is not the funniest way to age and die (if there is one). And until now, all promising therapies have been globally unsuccessful even if they were promising discoveries to understand these diseases and even slow down the diseases on animal models.

We need more work, more clinical trials, and more imagination to progress in this domain.

Aging as a risk factor for neurodegenerative disease

The primary risk factor for most neurodegenerative diseases is aging, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Most individuals with AD are aged ≥65 years and its prevalence continues to increase with increasing age. Tissues composed primarily of postmitotic cells, such as the brain, are especially sensitive to the effects of aging. The disease progresses irreversibly and is associated with high socioeconomic and personal costs. The nine biological hallmarks of aging are genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, stem cell exhaustion, and altered intercellular communication.
Aging is the main risk factor for most neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease.

This Cognitive Trajectories and Resilience in Centenarians study was done on  340 self-reported cognitively intact centenarians. Forty-four of these participants went on to neuropathological study and testing was performed with a range for the sample of 0 to 4 years.

There are some important findings from this work. During 1.6 years of follow-up, no decline in cognitive function was observed except for a minor decrement in memory. This suggests that, among this sample of centenarians, the incidence of dementia was low and implies resilience or resistance to AD and related dementias, despite the facts that they have the most potent risk factor in the general population, extreme old age, and that brain amyloid-β and tau deposition generally increase with age.

Various studies support the hypothesis that centenarians benefit from protective mechanisms rather than enjoying a relative absence of neurodegenerative causative factors.

Alzheimer plaques and tau proteins …

Alzheimer’s disease disrupts transmit information via electrical and chemical signals. among neurons, resulting in loss of function. Damage is widespread, as many neurons stop functioning, lose connections with other neurons, and die. Alzheimer’s disrupts processes vital to neurons and their networks, including communication, metabolism, and repair. The beta-amyloid protein involved comes in several different molecular forms that collect between neurons. Proteins clump together to form plaques.

Neurofibrillary tangles are abnormal accumulations of a protein called tau that collects inside neurons. In healthy neurons, tau normally binds to and stabilizes microtubules. In Alzheimer’s disease, however, abnormal chemical changes cause tau to detach from microtubules and stick to other tau molecules, forming threads that eventually join to form tangles inside neurons. It appears that abnormal tau accumulates in specific brain regions involved in memory. Beta-amyloid clumps into plaques between neurons. As the level of beta-amyloid reaches a tipping point, there is a rapid spread of tau throughout the brain.

Tests on mice are promising but never confirmed

One difficulty is the clear inability of current animal models to represent the full range of events identified in human disease, for instance, neuronal loss. It should be noted that a recent report using a Drosophila model suggests that neuronal loss may be protective in AD. This opens the door to a novel hypothesis that if proven would be quite atypical as in other neurodegenerative conditions, e.g. Parkinson’s and Huntington’s diseases, where neuronal loss is the main neuropathological feature.

A new mouse model developed by RIKEN researchers could improve the situation that many compounds that showed promise in mice models of the disease subsequently flopped in clinical trials on people. Because they so rapidly developed the signature brain abnormalities associated with Alzheimer’s disease, the mice should allow researchers to efficiently screen disease-modifying therapeutic candidates.

Do women have more often the disease?

Women living longer than men are probably not the whole answer as to why women are more likely than men to develop the disease. Your chances of developing Alzheimer’s disease late in life are somewhat greater if you are a woman than a man. One study followed 16,926 people in Sweden and found that beginning around age 80, women were more likely to be diagnosed than men of the same age. And a meta-analysis examining the incidence of the disease in Europe found that approximately 13 women out of 1,000 developed Alzheimer’s every year, compared to only 7 men.

A possible reason:

• The amyloid plaques that cause Alzheimer’s disease may be part of the brain’s immune system to fight against infections.
• Women have stronger immune systems than men.
• As part of their stronger immune systems, women may end up having more amyloid plaques than men.

Notably, mitochondria from young women are protected against amyloid-beta toxicity, generate less reactive oxygen species, and release fewer apoptogenic signals than those from men. However, all this advantage is lost in mitochondria from old females. Since estrogenic compounds protect against mitochondrial toxicity of amyloid-beta, estrogenic action, suggests a possible treatment or prevention strategy for AD

Possible therapies

Transplanted stem cells have shown their inherent advantages in improving cognitive impairment and memory dysfunction, although certain weaknesses or limitations need to be overcome. 

The transplanted neural stem cells compensate for the loss of neurons and have a direct effect on the recipient tissue. Moreover, these cells can produce paracrine cytokines to exert an indirect effect on neurogenesis. The function of transplanted cells can be enhanced through preconditioning. For instance, the transplantation of transplanted neural stem cells that express growth factors promotes neurogenesis and improves cognitive impairment can ameliorate spatial memory and slow learning deficits. However, the transplanted cells can also transdifferentiate into non‐neuronal glia, which is an adverse event. 

Organoids

Human neurodegenerative diseases, such as Alzheimer’s disease are not easily modeled in vitro due to the inaccessibility of brain tissue and the level of complexity required by existing cell culture systems. Three-dimensional brain organoid systems generated from human pluripotent stem cells have demonstrated considerable potential in recapitulating key features of AD pathophysiology, such as amyloid plaque- and neurofibrillary tangle-like structures. However, they fail to model complex cell-cell interactions of different regions of the human brain and aspects of natural processes such as cell differentiation and aging. 

First-in-Human Clinical Trial to Assess Gene Therapy for Alzheimer’s Disease

Researchers at the University of California San Diego School of Medicine have launched a first-in-human Phase I clinical trial to assess the safety and efficacy of a gene therapy to deliver a key protein into the brains of persons with Alzheimer’s disease or Mild Cognitive Impairment, a condition that often precedes full-blown dementia.

The protein, called the neurotrophic factor is part of a family of growth factors found in the brain and central nervous system that support the survival of existing neurons and promote the growth and differentiation of new neurons and synapses. This is particularly important in brain regions susceptible to degeneration in AD.

Deep brain stimulation for Parkinson’s

For people with Parkinson’s disease who do not respond well to medications, the doctor may recommend deep brain stimulation. During a surgical procedure, a doctor implants electrodes into part of the brain and connects them to a small electrical device implanted in the chest. The device and electrodes painlessly stimulate specific areas in the brain that control movement in a way that may help stop many of the movement-related symptoms of Parkinson’s, such as tremors, slowness of movement, and rigidity. This works, unfortunately only for a certain time.

Conclusion
We know more about neurodegenerative diseases and especially Alzheimer’s Disease than about other diseases that we can cure. However, we still ignore and must find answers to fundamental questions:

• What is really starting the disease?
• What is precisely accelerating the disease? 
• Are the accumulation of tau proteins and amyloid proteins the cause or the consequence of the diseases (the answer is probably « both », but to what extent?)?
• And of course, what are the working therapies to stop or at least slow down the disease

Good News of the month: Longest living (Sprague-Dawley strain) rat called Sima is 47 months old and is still alive.

Therapeutic that mimics young plasma could signpost the way to longevity wrote the Longevity Technology. The last oldest rat before this experiment died at 45.5 months and was under calorie deficit intervention, the one in the current experiment has therefore already lived longer. The Guardian quotes the well-known scientist, Prof Steve Horvath: “I think the results are stunning, Some people will criticize the results due to the low sample size. One swallow does not make a summer. But I believe the results because several complementary studies support them.” 

Heales sponsored the experiment by Harold Katcher and the startup Yuvan, where the product E5 is purified from younger animals and given to 24-month-old female rats for rejuvenation purposes. 

For more information

• Heales, SENS, Longevity Alliance, Longecity, and Lifespan.io
• Heales Monthly Science News
• Source of the image

Healthy longevity research is crucial for ensuring that as we live longer, we are to live better. By understanding the complex processes of aging and disease, we can develop strategies to promote healthy aging, allowing individuals to live longer lives in good health. This not only improves the quality of life for individuals but also helps to reduce the burden on healthcare systems and maintains economic and social stability. Investing in healthy longevity research is an investment in our collective future

Created by ChatGPT

This month’s theme:  Anti-aging interventions on Mice, ITP, and LEV Foundation

Remark: This month’s newsletter is more on the technical side so please feel free to contact us for further clarification wherever needed.

Aging is a complex and multifactorial process. There are countless theories about why and how aging occurs and many claims to be able to stop the aging process and thus increase lifespan.

Laboratory mice are preferred for research on aging is their short life span, which allows for faster results. Various experiments carried out on mice, as well as numerous genetic interventions, have yielded significant results and have led to a better understanding of the fundamental processes of aging.

Multiple rules and regulations must be followed to ensure that ethics are maintained while using a model organism for experimental purposes. The EU has a set of strict rules and suggestions which must be followed, these are the three Rs– Replacement, Reduction, and Refinement-

Concerning the efficiency of tests, ideally, researchers should follow four main rules:

• Registration of the interventions before starting. This is useful to give ideas to other researchers and to be complete in the description of the goal of the experiment in tempore non suspecto (before other people comment or contest the results).
• Publication of the results, even if unsuccessful. The publication of unsuccessful trials is very useful to « close doors » and give ideas to other researchers as well. 
• Use old mice and keep them alive until they die to be able to measure the real-life extension effect
• Make experiments with a control group of mice and ideally in a « blinded » environment.

A list of the main ongoing and upcoming interventions are:

• Rapamycin treatment
• Metformin
• NAD+ Supplementation
• Growth hormone receptor antagonist treatment
• Methionine restriction
• Telomerase activation
• Stem cell therapy
• Blood Dilution
• Gene editing using CRISPR-Cas9 technology
• Sirtuin activation
• Caloric restriction (and mimetic)
• Exercise
• Mitochondrial uncoupling 
• Mitochondrial biogenesis 
• (Maybe in a close future) Rejuvenation by ultrasound

Details of each can be found in the Scientific Fact Sheet: Importance of mice and rats in longevity research.

The Interventions Testing Program (ITP)

The Interventions Testing Program (ITP) started in 2012 under the Division of Aging Biology. The main goal is testing potential agents that may delay aging as measured by lifespan extension and/or delayed onset/severity of late-life pathologies.  The three testing sites Jackson Laboratory, the University of Michigan, and the University of Texas Health Science Center at San Antonio work closely together with the National Institute on Aging (NIA) to design and execute standard operating procedures (SOPs) that provide consistent experimental protocol adhered to across the program. It is interesting to note that scientists at ITP have mentioned that the data and results collected from all three laboratories often show “significant” differences even when all the parameters are set exactly the same for reasons they do not understand.

Each site also brings specialized expertise to the project, including statistical analysis, pharmacology, toxicology, and optimal diet compounding. The UM-HET3 mice are genetically heterogeneous, the equivalent of a large sibship. Each mouse is observed until its natural death or until it becomes so severely ill that survival for more than an additional week seems very unlikely. The study design includes sufficient numbers of mice to provide 80% power to detect a 10% increase in average lifespan in either sex. 

They have so far identified nine agents that significantly increase median lifespan — acarbose (Harrison 2014, Strong 2016, Harrison 2019), aspirin (Strong 2008), canagliflozin (Miller 2020), captopril (Strong, 2022), glycine (Miller 2019), nordihydroguaiaretic acid (NDGA) (Strong 2008, Strong 2016), Protandim® (Strong 2016), rapamycin (Harrison 2009, Miller 2011, Wilkinson 2012, Miller 2014) and 17α-estradiol (Harrison 2014, Strong 2016, Harrison 2021).

The ITP constantly publishes all the data, including data collected on agents that fail to increase lifespan or delay late-life illnesses, or interventions that have deleterious side effects.

Collaborative Interactions Program 

The collaborative Interactions Program (CIP) was established to provide samples from ITP studies to advance aging research through collaborations with other scientists in the United States and in other countries. These samples are available free of charge (except, in some cases, for shipping charges). Plasma and certain frozen tissues are available from mice sacrificed at 22 months of age in all treatment and control groups from Cohorts 2015 to the present.

Longevity Escape Velocity Foundation (LEV Foundation): Robust Mouse Rejuvenation Study

LEV Foundation is performing large mouse lifespan studies, with the administration of four interventions namely Rapamycin, Senolytic, mTERT, and HSCT. All of these have individually, shown promise in extending mean and maximum mouse lifespan and health span. Their main focus is to test interventions that have shown efficacy when begun only after the mice have reached half their typical life expectancy, and mostly on those that specifically repair some category of accumulating, eventually pathogenic, molecular, or cellular damage. 

The first study in this program is starting in January 2023. 

Goals and Motivations 

LEV Foundation’ultimate goal in this program is to achieve « Robust Mouse Rejuvenation ». The interventions will be applied to mice of a strain with a mean lifespan of at least 30 months and initiated at an age of at least 18 months. The goal is to increase both mean and maximum lifespan by at least 12 months. In each study in this program, the Foundation will examine the synergy of (typically at least four) interventions already known individually to (probably) extend mouse lifespan when started in mid-life. They will determine not only the ultimate readout of lifespan but also the interactions between the various interventions, as revealed by the differences between the treatment groups (receiving different subsets of the interventions) in respect of the trajectories with the age of cause of death, the decline in different functions, etc.

 Interventions

1.  Rapamycin
2.  Hematopoietic Stem Cell 
3. Transplant Telomerase Expression
4.  Senescent Cell Ablation 

Experiment Schedule:

The LEVF will sacrifice 12 mice out of each group of 50 (males or females, for each of the ten treatments) for analyses that require terminally invasive tissue samples. In contrast to most studies, it will schedule these based not on chronological age but on group-specific survival curves. The LEVF believes this will be more informative than the traditional approach since the underlying correlation between biological and chronological age is factored out.

The LEVF considers there is a major chance that the most efficient interventions will be multi-component. That is why there will be 10 groups of mice tested:

1. Controls only
2. Rapamycin only
3. Senolytic only 
4. mTERT only
5. HSCT only
6. All but Rapamycin 
7. All but Senolytic 
8. All but mTERT 
9. All but HSCT 
10. All interventions 

Other interventions in the future will concern

1. Sapheresis or Plasma Dilution
2. Next-Generation Senolytic 
3. T-cell rejuvenation
4. Environmental enrichment

A bright future for mice and humans?

Thanks to the tests organized by the LEVF and hopefully soon other organizations, we could know soon what is useful for the healthy longevity of old mice. And a bit later, for humans,

Good News of the Month: Half-life more for old mice gene therapy.

Bad News of the Month: Longevity treatments do not slow aging./  Mortality increasing in Europe and  China./ Currently, the oldest person in the world is only 115 years old.

Recent studies have demonstrated that partial reprogramming using the Yamanaka factors (or a subset; OCT4, SOX2, and KLF4; OSK) can reverse age-related changes in vitro and in vivo. They show that systemically delivered AAVs, encoding an inducible OSK system, in 124-week-old mice extend the median remaining lifespan by 109% over wild-type controls and enhance several health parameters.

In a new study, researchers have taken a close look at three treatment approaches that have been widely believed to slow the aging process. However, when tested in mice, these treatments proved largely ineffective in their supposed impact on aging. « There is no internal clock of aging that you can regulate with a simple switch — at least not in the form of the treatments studied here, » concludes Dr. Dan Ehninger of the DZNE, the initiator of the study.

The mortality in China in 2022 was the highest since 1976. The mortality in the European Union was higher in 2022 than before the Covid. 

The French sister André died on January 17 at the age of 118 years. Maria Branyas Morera, who now became the dean of humanity, is « only » 115 years old, the lowest age in the world since 2012.

For more information

• Heales, SENS, Longevity Alliance, Longecity, and Lifespan.io
• Heales Monthly Science News
• Source of the image