Human Pilot Study Results for Senolytics Published – Article by Steve Hill

Human Pilot Study Results for Senolytics Published – Article by Steve Hill

Steve Hill


Editor’s Note: The U.S. Transhumanist Party features this article by Steve Hill, originally published by our allies at the Life Extension Advocacy Foundation (LEAF) on January 7, 2019. This article presents the results of a human pilot study that involved the consumption of two promising senolytic drugs, dasatinib and quercetin, to target idiopathic pulmonary fibrosis. The results are promising and constitute a great step forward for senolytics being tested in human clinical trials. Another promising approach is the TAME trial, which is a double-blind randomized controlled clinical trial, to test if Metformin can treat various age-related diseases. 

~Bobby Ridge, Assistant Editor, July 4, 2019

The results from a human pilot study that focused on treating idiopathic pulmonary fibrosis with senescent cell-clearing drugs has been published. The drugs target aged and damaged cells, which are thought to be a reason we age and get sick, and remove them from the body.

Senescent cells and aging

As we age, increasing numbers of our cells become dysfunctional, entering into a state known as senescence. Senescent cells no longer divide or support the tissues and organs of which they are part; instead, they secrete a range of harmful inflammatory chemical signals, which are collectively known as the senescence-associated secretory phenotype (SASP).

Dr. Judith Campisi from the Buck Institute for Research on Aging, along with her research team, identified that senescent cells secreted the various harmful chemicals that characterize the SASP in 2008, which was when interest in senescent cells really began [1]. In 2010, building on this initial research, Dr. Campisi went on to show the link between the SASP and cancer [2].The SASP increases inflammation, harms tissue repair and function, causes the immune system to malfunction, and raises the risk of developing age-related diseases such as cancer. It can also encourage other nearby healthy cells to become senescent via the so-called bystander effect. Therefore, a small number of these cells can cause a great deal of harm.

Normally, senescent cells destroy themselves by a self-destruct process known as apoptosis before being cleared away by the immune system. Unfortunately, as we age, the immune system becomes weaker, and senescent cells start to build up in the body. The accumulation of senescent cells is considered to be one of the reasons why we age and develop age-related diseases.

It has been suggested that the clearance of senescent cells might help address a number of age-related diseases at once, as senescent cells are thought to be one of the fundamental reasons that we age. Drugs that can remove these unwanted, damaged cells are known as senolytics.

Human trial results for senolytics

This new publication by researchers at the Mayo Clinic, including James Kirkland, one of the pioneers of senolytic drugs, shows the results of a pilot study that uses dasatinib and quercetin to treat idiopathic pulmonary fibrosis [3].

Pulmonary fibrosis causes scarring of the lung tissue, which leads to the progressive loss of lung function over time. When the disease’s origin is unknown, it is called idiopathic pulmonary fibrosis, or IPF. The treatment options for this disease are extremely limited with no currently known cure.

The researchers in this new study tested a combination of dasatinib and quercetin, one of the earliest senolytic drug combinations that was tested in mice and shown to have beneficial results, particularly for the cardiovascular system [4-5]. It was also shown in a previous study that clearing senescent cells using dasatinib plus quercetin was able to alleviate idiopathic pulmonary fibrosis (IPF)-related dysfunction in a mouse model of the disease.

Fourteen patients with IPF were recruited for this pilot study, and the initial results, while leaving room for improvement, are promising.

Physical function evaluated as 6-min walk distance, 4-m gait speed, and chair-stands time was significantly and clinically-meaningfully improved (p < .05). Pulmonary function, clinical chemistries, frailty index (FI-LAB), and reported health were unchanged. DQ effects on circulating SASP factors were inconclusive, but correlations were observed between change in function and change in SASP-related matrix-remodeling proteins, microRNAs, and pro-inflammatory cytokines (23/48 markers r ≥ 0.50).

It should be noted that this was only a small pilot study and that the optimal human dosage and frequency is yet to be established. Typically, the next step is to launch a larger-scale study to establish this dosage.

The researchers also note that these results warrant evaluation of dasatinib plus quercetin in larger, randomized, and controlled trials for senescence-related diseases. In other words, they would like to test senolytics in larger studies for various age-related diseases, and the results certainly support doing exactly that.

Conclusion

These initial results are positive, despite there being plenty of room for improvement. The combination of these two drugs also appears to favor particular cell and tissue types over others, much like other senolytic drugs, which were discovered after dasatinib and quercetin were originally shown to clear senescent cells. It may be that a combination of different senolytics will be needed as a “cocktail” of sorts to fully clear out all the unwanted senescent cells, as different senescent cells appear to use various survival pathways to evade apoptosis, and no single drug can target them all.

We greet these early results positively and look forward to the beginning of larger-scale studies for multiple age-related diseases. Given how senescent cells appear to be implicated in most if not all age-related diseases, there are some exciting possibilities ahead.

Literature

[1] Coppé, J. P., Patil, C. K., Rodier, F., Sun, Y., Muñoz, D. P., Goldstein, J., … & Campisi, J. (2008). Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS biology, 6(12), e301.

[2] Coppé, J. P., Desprez, P. Y., Krtolica, A., & Campisi, J. (2010). The senescence-associated secretory phenotype: the dark side of tumor suppression. Annual Review of Pathological Mechanical Disease, 5, 99-118.

[3] Nambiar, A., Justice, J., Pascual, R., Tchkonia, T., Lebrasseur, N., Kirkland, J., … & Kritchevsky, S. (2018). Targeting pro-inflammatory cells in idiopathic pulmonary fibrosis: an open-label pilot study of dasatinib and quercitin. Chest, 154(4), 395A-396A.

[4] Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., … & O’hara, S. P. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell, 14(4), 644-658.

[5] Roos, C. M., Zhang, B., Palmer, A. K., Ogrodnik, M. B., Pirtskhalava, T., Thalji, N. M., … & Zhu, Y. (2016). Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging cell.[/column]

Steve Hill serves on the LEAF Board of Directors and is the Editor-in-Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic as well as attending various medical industry conferences. In 2019 he was listed in the top 100 journalists covering biomedicine and longevity research in the industry report – Top-100 Journalists covering advanced biomedicine and longevity created by the Aging Analytics Agency. His work has been featured in H+ Magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Keep Me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project. In 2015 he led the Major Mouse Testing Program (MMTP) for the International Longevity Alliance and in 2016 helped the team of the SENS Research Foundation to reach their goal for the OncoSENS campaign for cancer research.

 

U.S. Transhumanist Party / Transhuman Party General Discussion Thread for the Third Quarter of 2019

U.S. Transhumanist Party / Transhuman Party General Discussion Thread for the Third Quarter of 2019

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The purpose of this post is to facilitate member comments pertaining to transhumanism and the U.S. Transhumanist Party / Transhuman Party (USTP), which might not specifically fit the subjects of any other post or article on the USTP website. This is the place for members to offer suggestions or converse about any areas of emerging technologies and their political, moral, societal, cultural, and esthetic implications. The general discussion thread is also an ideal location to suggest or propose platform planks that may be considered for future platform voting, and/or bring our attention to emerging legislative and societal developments that may affect the course and impact of emerging technologies.

The USTP will endeavor to open one of these general comment threads per quarter. This comment thread pertains to the months of July, August, and September 2019.

Type in your comments below. Please note that, to protect against spambots, the first comment by any individual will be moderated. After passing moderation, a civil commenter should be able to post comments without future moderation – although we cannot guarantee that the technical aspect of this functionality will work as intended 100% of the time.

Will Increased Lifespans Cause Overpopulation? – Article by Elena Milova and Steve Hill

Will Increased Lifespans Cause Overpopulation? – Article by Elena Milova and Steve Hill

Elena Milova
Steve Hill

Editor’s Note: The U.S. Transhumanist Party features this article by our guests Elena Milova and Steve Hill, originally published by the Life Extension Advocacy Foundation (LEAF) on October 30, 2016. In this article, both authors provide evidence that if aging was cured, then overpopulation would not be an issue. Not only is there a common trend among industrialized nations, in which, when the citizens become healthier, wealthier, and educated, they have fewer children, but there are also projections showing that global population growth is gradually falling and will come to a halt around the time the world’s population reaches 11 billion people.
***
~ Bobby Ridge, Assistant Editor, July 3, 2019

Any discussion of rejuvenation biotechnology almost certainly includes the subject of overpopulation and the objection that medical advances that directly address the various processes of aging will lead to an overpopulated world. Such dire predictions are a common theme in many discussions involving advances in medicine that could increase human lifespans.

Overpopulation is a word that gives the simple fact of population growth a negative connotation. It implies that an increase in the number of people will harm our lives in different ways, such as famine, scarcity of resources, excessive population density, increased risks of infectious diseases, and harm to the environment.

This concern, first raised by the work of 18th century reverend and scholar Thomas Malthus, has been a constant theme in both popular fiction and early foresights related to population growth. However, is it actually well-founded? We will be taking a deeper look at the historical and present population data and showing why overpopulation is unlikely to happen.

To get you started, this video with Bill Gates summarizes some of the key points about population and why a longer-lived and healthy society is good for keeping population growth in check.

What is the population, and how will it grow in the future?

Since the 1960s, both birth rate and population growth have been gradually falling. This will probably lead to a complete halt at 11 billion people near the year 2100. Here is a chart from the United Nations Population Prospects 2015 edition showing the corresponding projections [1].

Fig 1. Population of the world: estimates, 1950-2015, medium-variant projection and 80 and 95 percent prediction intervals, 2015-2100.

Here we can see the continuous, red trend line gradually leveling out into a straight horizontal line. However, before talking about why population growth is predicted to stop, let’s investigate why the population is even growing.

In order to ensure population growth, the number of children born per year must surpass the number of deaths in a given country. Typically, a fertility rate index equal to 2.1 is enough for the population to renew without growing in numbers, but a higher birth rate will lead to stable population growth.

In the illustrations below, you can see the global map of fertility and the projection of population growth by major regions [2]

Fig 2. World Population 2010-2100 United Nations, Department of Economic and Social Affairs, Population Division (2015). World Population Prospects: The 2015 Revision, Data Booklet. ST/ESA/SER.A/377.

Fig 3. Total fertility 2010-2015 United Nations, Department of Economic and Social Affairs, Population Division (2015). World Population Prospects: The 2015 Revision, Data Booklet. ST/ESA/SER.A/377.

The biggest contributors to the present level of population growth globally are India and several African regions, while many countries (especially in Europe) face depopulation because of their low birth rate. In the future, most of the population growth will be due to Africa.

Our intuition may tell us that it is unlikely that the least developed countries would be producing most of the population; after all, the standards of living in developed countries make for better conditions to have more children.

However, in reality, there are many factors that can lead to a decline in birth rate during the transition to a developed country: education (access to education for women typically postpones marriage and childbirth), unemployment (families try to control their family size to use fewer resources), and access to contraceptive techniques and cultural norms of using them, to name just a few [3].

Economic development is known to affect the time of birth; for example, recession encourages childbirth later in life [4]. National policies to combine work and family life also represent an important factor that may affect fertility rate in both directions. Globalization will “deepen” (in a world-systems theory sense) the less technologically advanced countries, making it very likely that the “higher birth rate” issue in these countries will also decline.

There is supporting evidence showing that moving to an advanced, industrialized economy changes the birth rate of immigrants. The fertility rates of immigrants to the US have been found to decrease sharply in the second generation [5]. Other studies demonstrate that the presence of immigrants does not compensate for declining birth rates [6].

Fig 4. Declining birth rate leads to gradual slow down of the population growth. The chart shows a UN projection in population size change in percent until 2100 for major regions[7].

The relationship between the level of the development of a country and fertility can be seen in the next chart. It is worth noting that when the Human Development Index (HDI) becomes higher than 0.85, country development starts promoting the birth rate again [8]. However, this kind of situation is very rare, historically, and therefore not significant enough to shape global population projections.

Fig 5.  Fertility vs HDI Index. Data source: United Nations Human Development Index (HDI), UN – Population Division (Fertility), 2015 Revision, Gapminder. Source: OurWorldInData.org/fertility/.

Thus, the least developed countries are more likely to have higher birth rates because people there have no reason to postpone childbirth, nor are measures for contraception widely accessible. The only factor holding back population growth in these regions may be the high level of child mortality and overall mortality due to infectious diseases and undernourishment.

With sustainable development goals focused on the solution of both problems, Africa has the potential to become the biggest human factory in our history. However, taking into account how fast fertility rates can fall because of the adoption of new technologies, this is far from certain.

Fig 6.  How long did it take for fertility to fall from more than 6 children per woman to fewer than 3 children per woman?  Data source: The data on the total fertility rate is taken from the Gapminder fertility dataset (version 6)  and the World Bank World Development Indicators. Source: OurWorldInData.org.

But won’t we run out of space?

In all projected future scenarios for Africa, its population will continue to grow. Today, there are 7.4 billion people on Earth. We are used to thinking that this is already too much, but is that true? First of all, let’s see how much space on Earth we humans actually take up. In 2012, the team of the project “Per Square Mile” led by Tim de Chant produced an infographic showing how big a city would have to be to house the world’s 7 billion people.

The city limits change drastically depending on which real city is used as the model and what its population density is, but this still gives us an idea of how much of our beautiful planet is really inhabited and how much spare space we still have.

If the projection of population growth by the United Nations is correct, in the next 84 years, there will be about 11 billion people. This means that if all of humanity were concentrated in a land area with a population density similar to New York, it would at most occupy the size of 3 US states by 2100.

2012                                                         2100

Fig 7.  7 bln city with population density of New York/11 bln city with the same population density. From the “Per Square Mile” project by Tim de Chant. Note: the picture at right is modified by the article authors to illustrate the potential growth. The state of Texas is about 700,000 square kilometers, which corresponds to about 7 billion people. The states of Texas, New Mexico (about 315,000 km^2), and Louisiana (about 135,000 km^2) combined represent 1,150,000 square kilometers, which corresponds to about 11.5 billion people by 2100.

Does this mean that population growth is not an issue? From the point of view of the space we humans need, likely so. However, our species’ survival is dependent on many other factors, such as the environment necessary to produce our food and other goods.

Are we going to run out of food?

We should admit that it is about fifty years too late to be concerned about extensive population growth and its consequences, such as famine, because the highest birth rate and population growth was observed from the 1960s to the 1980s. Our population grew by one billion people in just 14 years (going from 3 to 4 billion); however, no big societal or economic challenges were encountered.

Moreover, the next two billion increases in population appeared in 13 and 12 years, respectively [9], but once again, no famine caused by the deficiency of global food production followed [10]. The famines of the second half of the 20th century were provoked by how the food was distributed. Factors such as administrative incompetence of local governments, wars and natural disasters happening several years in a row played the greatest role in creating famine during this period.

Today, global society is taking measures to eradicate hunger worldwide by 2030. This is very likely to be the case, as the number of people suffering from hunger is decreasing fast. In 2012, it was one in eight, while in 2015, it was already one in nine, which corresponds to 795 million people. Below, you can see the Hunger Map by the World Food Program illustrating the progress.

Fig 8. FAO, IFAD and WFP. 2015. The State of Food Insecurity in the World 2015. Meeting the 2015 international hunger targets: taking stock of uneven progress. Rome, FAO. Sources: www.fao.org/publications/sofi/en/ Undernourishment data: FAO Statistics Division (ESS) – www.fao.org/economic/ess

If we compare the food supply in 1965 and in 2007, we can clearly see that overeating is more of a global issue than undernourishment, as in most countries, the calorie intake has grown significantly. This could not have happened if our society was suffering from food underproduction, as the food would not be available to overeat, and problems such as obesity would not be so prevalent.

Fig 9.  Food supply 1965 vs 2007 Source: Gapminder statistics (www.gapminder.org/)

Astoundingly, this means that a population explosion has passed relatively unnoticed – all thanks to the “Green Revolution” (rapid development of new agriculture techniques, such as fertilizers, irrigation and selection). The concern that there will be a food shortage in the future neglects further technological advances such as aquaponics, hydroponics, aeroponics, vertical farming, 3D-printed housing, algae farms, and many other technologies that could provide enough food for all.

The need for more food production represents an excellent opportunity for entrepreneurs, so it is unlikely that the development process of new technologies would suddenly stop, especially taking into account the objective need for rapid changes due to environmental issues.

According to a report by the Food and Agriculture Organization of the United Nations, “Livestock’s long shadow”, in 2006, livestock represented the biggest of all anthropogenic (i.e., due to human activity and with potentially harmful side effects) land uses, taking up to 70% of all agricultural land and 30% of the ice-free terrestrial surface of the planet [11].

Scientists admit that while it is still possible to expand agricultural land in some countries in accordance with the increasing need for food, this expansion cannot go beyond the limits of the carrying capacity of our planet. The report states that livestock is responsible for about 18% of the global warming effect, 9% of total carbon dioxide emissions, 37% of methane and 65% of nitrous oxide. Water use for livestock represents about 8% of all human water use (7% of this being used for feed irrigation).

New technologies can provide solutions for the numerous environmental issues related to traditional farming. For instance, hydroponics offers around 11 times higher yields while requiring 10 times less water than conventional agriculture [12]. The energy needs of a hydroponic facility are much higher (up to 80 times more), but thanks to emerging clean renewable energy technologies, this increased demand may not be an issue [13].

Today, there are many companies engaged in the creation of lab-grown meat, such as Supermeat and Memphis Meats. Making a laboratory into a farm is beneficial in many ways, starting from less pollution and fewer greenhouse gas emissions (mostly caused by animal digestion processes).

Sterile conditions in the lab lead to decreased risk of infections and allow the exclusion of antibiotics from the process of meat production. Lab-grown meat can be designed to contain less fat or even fats and proteins with new characteristics (for instance, essential Omega fatty acids).

With less space necessary for laboratory meat production and no waste, it will be possible to ensure disseminated local production in order to cut transportation time and reduce the usage of preservatives. The same system can be used to grow fish meat as well, thus reducing the impact of fishing and fish-farming on the environment. It is interesting to note that not only meat but also other animal-derived products, such as leather, can be produced in a lab, like is done by Modern Meadow.

There are attempts to create new edible products that taste like meat but are completely without animal ingredients, such as Impossible Foods. The recently created vegan ‘Bloody Burger’ by Impossible Foods “uses 95% less land, 74% less water and emits 87% fewer greenhouse gas emissions than its cattle-derived counterpart”. By concentrating on the heme molecule, the mixture apparently “looks like meat, tastes like meat and sizzles like meat“.

These solutions are also great from an ethical point of view, as this technology can reduce animal suffering. The rate of transition to these new ways of animal product creation is widely dependent on political will and social support. It is important to note that there is also significant progress regarding access to drinking water. During the Millennium Development Goals period (1990-2015), it is estimated that, globally, use of improved drinking water sources rose from 76 per cent to 91 per cent. 2.6 billion people have gained access to an improved drinking water source since 1990.

The MDG target of 88 per cent was surpassed in 2010, and in 2015, 6.6 billion people used an improved drinking water source. There are now only three countries (all located in sub-Saharan Africa and Oceania) with less than 50 per cent coverage, compared with 23 in 1990 [14]. New technologies for cheap water desalination and water collection from the air are also helping to improve the situation.

If population growth is not exactly an issue, then what is?

What we really should be concerned about is the age structure of the population. Regardless of the level of technological development, its core are the people of working age who are producing goods, paying taxes, and supporting the non-working groups, such as children and the elderly – the latter needing the most resources because of the state of their health.

Due to population aging, the share of working-age people is shrinking while the share of people who are at least 60 years old is growing. Population structure change is the most evident in Europe and Northern America, while the “Global South” has not experienced it yet – but will experience it in the next few decades.

Fig 10. Percentage of population in broad age groups by major area in 2015. Source: United Nations, Department of Economic and Social Affairs, Population Division (2015). World Population Prospects: The 2015 Revision, Data Booklet. ST/ESA/SER.A/377

Soon, one third of the population worldwide is going to be aged sixty or over, which means more social protection and healthcare expenditures and more working age people involved in nursing the elderly. However, it would be wrong and unjust to see the elderly as a burden, while these people have contributed so much to the incredible progress that our society has made.

They have all the same human rights as everyone, including the right to life and right to health. As age-related health deterioration is the main reason why society has to provide so much support to the elderly, it would be only logical to see the development of rejuvenation biotechnologies as the way to improve the situation.

What would life be like if we introduced rejuvenation technologies globally?

Before the era of universal medicine, people who managed to reach their sixties were still in relatively good health. However, once the onset of age-related diseases began, they died very quickly.

Modern medicine has changed that by slowing down the development of age-related diseases, hence extending the period of productivity. The downside is that this has also extended the period of illness, because treatments to prevent age-related diseases are not yet introduced into universal clinical practice.

In the near future, new interventions to slow down the aging process will become accessible, and then a shift will occur: the period of youth and adulthood will be extended due to better health, and the period of illness will be significantly postponed. In their sixties, people will remain as strong and vital as 40-year-old people are today. Some leading scientists predict that this may also lead to maximum lifespan increases of up to 150 years or more.

This is, of course, hard to prove, because as with many other things in human history, it is a unique situation that has never happened before, but some studies have proposed how aging would look given these three scenarios [15].

Fig 11. A:Pre Universal Medicine, B: Current medicine, C: Slowing aging. Source: Blagosklonny, M. V. (2012). How to save Medicare: the anti-aging remedy. Aging (Albany NY), 4(8), 547-52.

Whilst it is too early to be overly optimistic, we still should mention that apart from these three scenarios, there is a fourth possibility called negligible senescence. Negligible senescence in nature happens when a species does not display signs of aging, regardless of the passage of time. A number of species exhibit negligible senescence, including the rougheye rockfish (Sebastes aleutianus).

The ocean quahog (Arctica islandica) and some kinds of turtles are also negligibly senescent, but they still die because the expansion of their shell ultimately limits their movement. More examples can be found here at the excellent HAGR (Human Ageing Genomic Resources) database.

At some point in time, medical technologies may become so sophisticated that they will be able to bring all of the processes of aging under medical control. If that is the case, then aging will always remain at a subclinical stage, because the repairs to our bodies will keep up the pace with damage accumulation, allowing people to look and feel young for an indefinite period of time.

Most likely, it will take decades for medical science to progress this far, but we should also admit that some of the technologies necessary for this transition already exist, e.g., stem cell therapies, early nanorobots, CRISPR and gene therapies, immunotherapies, senolytics, and geroprotectors (drugs that slow down the aging process).

How will increased lifespan affect population growth?

The possibility of significant life extension using medical interventions was not even considered by the academic community until recent years, so there were not many projections of how increased lifespans and negligible senescence would affect population growth. However, a few years ago, such a projection was done for Sweden.

One of the more realistic scenarios is one where only a small share of the population accepts negligible senescence technologies at the beginning (this could be due to a slow dissemination process, ethical or religious objections that people have to overcome, or a high cost of the new technology) with a gradual increase (1% added to the negligibly senescent group each year). It is assumed that some small share of the population will never accept these technologies and will age in the traditional way.

In this case, population change in Sweden will not lead to population growth but can, to some extent, mitigate the process of depopulation over 100 years of medical innovations [16].

Fig 12. Population projection for a scenario of growing acceptance of antiaging interventions. Projection of the Swedish population until year 2105, assuming the negligible senescence scenario for initially small proportion of population (10%), with growing acceptance rate over time. Life extension interventions start at age 60 years, with 30-year time delay from now.

This might be the likely scenario in most developed countries. Taking into account that new technologies tend to be expensive even for developed countries’ middle classes, the developing countries most possibly will reach the same level of implementation later in time, when their fertility rate will be already affected by the index of development. In this case, the fall of their population growth will be smaller due to decreased population mortality.

In a more optimistic scenario, where all the population has access to negligible senescence technologies and they are applied to everyone who is at least 60 years old, population growth in 70 years will be around 22%. The earlier the application, the bigger the population growth. If negligible senescence technologies are applied at the age of 40, then the estimated population growth will be nearly 47% in 70 years.

Fig 13. Projection of the Swedish population until the year 2105, assuming the negligible senescence scenario. Life extension interventions start at age 60 years, with a 30-year time delay from now.

There are three main conclusions we can make based on this data.

  1. The growing share of people using negligible senescence technologies could help optimize the balance between workforce and retirees, hence maintaining economic development. People who are at least 65 years old will be about one-third of the global population in 2100, so we are talking about 3-4 billion old people who could be healthy and productive or ill and frail, depending on which strategy that global society implements.
  2. Negligible senescence is a synonym of good health, which means that the burden of age-related diseases and their social consequences will be mostly eliminated.
  3. Population growth, surprisingly, will not be as dramatic as is often imagined, leaving a significant period of time for adaptation, adequate measures of population growth control, and new territories’ development.

Is mitigating aging not only a need but also a legal obligation?

Even if negligible senescence remains a long-term goal, the emerging technologies to address the various aging processes [17] represent a unique opportunity to maintain older people in good health, allowing them to enjoy healthier lives, remain active, learn new skills, and contribute to the development of society. We owe them our present well-being. Not only have these people contributed a lot to create the things we have now, including better nutrition, healthcare, and a comfortable and safe habitat, they have also worked hard to change traditions and wisdom and helped to carry the concept of equal human rights forwards. This is why it is especially poignant to understand that geroprotective technologies and their potential are being underestimated and that they are not receiving the level of social approval and support that they rightly deserve.

According to the World Health Organization (WHO) Constitution, the objective of the WHO is “the attainment by all peoples of the highest possible level of health”. It is worth noting that WHO defines health as “a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity” [18]. While this definition may seem quite spacious, it was made this way purposefully to ensure that member states’ activities in improving the health of their people would never stop.

Conclusion

The need for constant improvement of health is now a universal consensus.

Aging represents the root cause of severe diseases, such as cancer, Alzheimer’s, stroke, Parkinson’s, heart disease, COPD, type 2 diabetes, osteoarthritis and atherosclerosis, leading to disability of the elderly and to a wide range of negative social consequences, which makes it the perfect target for the global healthcare system [19].

These diseases can only be cured if the actual aging processes are directly addressed and halted while the damage is repaired or reversed by medical interventions. Therefore, according to WHO and United Nations policy, this means that global society has an obligation to eventually cancel aging in order to achieve the highest possible level of health for all people.

Literature

  1. United Nations, Department of Economic and Social Affairs, Population Division (2015). World Population Prospects: The 2015 Revision, Volume II: Demographic Profiles (ST/ESA/SER.A/380).
  2. United Nations, Department of Economic and Social Affairs, Population Division (2015). World Population Prospects: The 2015 Revision, Data Booklet. ST/ESA/SER.A/377.
  3. Mather, M. (2012). Fact sheet: The decline in US fertility. Population Reference Bureau, World Population Data Sheet.
  4. Lanzieri, G. (2013). Towards a ‘baby recession’ in Europe?. Europe (in million), 16(16.655), 16-539.
  5. Nargund, G. (2009). Declining birth rate in Developed Countries: A radical policy re-think is required. FV & V in ObGyn, 1, 191-3.
  6. Camarota, S., & Ziegler, K. (2015). The Declining Fertility of Immigrants and Natives. Center for Immigration Studies.
  7. United Nations, Department of Economic and Social Affairs, Population Division (2015). World Population Prospects: The 2015 Revision, Key Findings and Advance Tables. ESA/P/WP.241.
  8. Myrskylä, M., Kohler, H. P., & Billari, F. C. (2009). Advances in development reverse fertility declines. Nature, 460(7256), 741-743.
  9. United Nations, Department of Economic and Social Affairs, Population Division (1999). The World At Six Billion. ESA/P/WP.154.
  10. Gráda, C. Ó. (2007). Making famine history. Journal of Economic Literature, 45(1), 5-38.
  11. FAO, U., & Steinfeld, H. (2006). Livestock’s long shadow: Environmental issues and options. Rome:[sn].
  12. Barbosa, G. L., Gadelha, F. D. A., Kublik, N., Proctor, A., Reichhelm, L., Weissinger, E., … & Halden, R. U. (2015). Comparison of land, water, and energy requirements of lettuce grown using hydroponic vs. conventional agricultural methods. International journal of environmental research and public health, 12(6), 6879-6891.
  13. REN21. 2016. Renewables 2016 Global Status Report (Paris: REN21 Secretariat).
  14. Unicef. (2015). Progress on Sanitation and Drinking-Water: 2015 Update and MDG Assessment. World Health Organization: Geneva, Switzerland.
  15. Blagosklonny, M. V. (2012). How to save Medicare: the anti-aging remedy. Aging (Albany NY), 4(8), 547-52.
  16. Gavrilov, L. A., & Gavrilova, N. S. (2010). Demographic consequences of defeating aging. Rejuvenation research, 13(2-3), 329-334.
  17. López-Otín, Carlos et al.(2013). Hallmarks of Aging. Cell , Volume 153 , Issue 6 , 1194 – 1217
  18. World Health Organization. (2014). Basic documents. World Health Organization.
  19. Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., … & Rando, T. A. (2014). Aging: a common driver of chronic diseases and a target for novel interventions. Cell, 159(4), 709.
Elena Milova: As a devoted advocate of rejuvenation technologies since 2013, Elena is providing the community with a systemic vision how aging is affecting our society. Her research interests include global and local policies on aging, demographic changes, public perception of the application of rejuvenation technologies to prevent age-related diseases and extend life, and related public concerns. Elena is a co-author of the book Aging prevention for all (in Russian, 2015) and the organizer of multiple educational events helping the general public adopt the idea of eventually bringing aging under medical control.
***
Steve Hill: Steve serves on the LEAF Board of Directors and is the Editor-in-Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic as well as attending various medical industry conferences. In 2019 he was listed in the top 100 journalists covering biomedicine and longevity research in the industry report – Top-100 Journalists covering advanced biomedicine and longevity created by the Aging Analytics Agency. His work has been featured in H+ Magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Keep Me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project. In 2015 he led the Major Mouse Testing Program (MMTP) for the International Longevity Alliance and in 2016 helped the team of the SENS Research Foundation to reach their goal for the OncoSENS campaign for cancer research.

Alzheimer’s Disease Reversed by Editing a Single Gene – Article by Steve Hill

Alzheimer’s Disease Reversed by Editing a Single Gene – Article by Steve Hill

Steve Hill


Editor’s Note: The U.S. Transhumanist Party features this article by our guest Steve Hill, originally published by our allies at the Life Extension Advocacy Foundation (LEAF) on April 13, 2018. In this article, Mr. Hill reviews a new study published in Nature that supports the idea that Alzheimer’s disease research efforts should target the ApoE4 gene, and not consider the ApoE3 gene as much, even though  previous research that focused on the ApoE3 gene cured Alzheimer’s disease in mice models. This is a promising step forward for Alzheimer’s research.

~Bobby Ridge, Assistant Editor, July 2, 2019

Researchers at Gladstone Institutes in San Francisco report that a gene variant associated with Alzheimer’s works differently in mice and humans, and they also demonstrate how modifying this gene could potentially prevent the plaques associated with Alzheimer’s from forming and damaging the brain. The new study was published in the journal Nature in January 2018 [1].

An ApoE3 gene variant is associated with Alzheimer’s disease

The gene apolipoprotein E3 (ApoE3) has a variant known as ApoE4, which is associated with the development and progress of Alzheimer’s disease. People with just one copy of the ApoE4 gene are at twice the risk as people without this gene variant. Some people even have two copies of the ApoE4 gene, which makes their risk of Alzheimer’s a staggering twelve times greater.

Both the ApoE genes produce their own forms of ApoE protein, which differ in structure. The ApoE4 protein is fragile and fragments because it cannot function in the same way as the regular ApoE3 protein in human nerve cells. These fragmented protein pieces are associated with the increased production of amyloid-β peptides and tau phosphorylation that are typical of Alzheimer’s disease.

The researchers wanted to find out how ApoE4 is linked to Alzheimer’s disease. They considered the possibility that the increased amyloid-β and tau phosphorylation from the fragmentation of ApoE4 drives disease progression. Another possibility involved the negative consequences of a lack of ApoE3 proteins, as they were replaced by the ApoE4 variant. The team also considered a combination of both of these possibilities.

The team investigated these potential answers by examining the effects of ApoE3 and ApoE4 on human nerve cells. Neurons were created by using pluripotent stem cells taken from volunteers who had either two copies of ApoE3 or two copies of the ApoE4 gene, and the researchers programmed these cells to become the desired type of neuronal cell.

The team compared the ApoE3 and ApoE4 neurons against neurons that were unable to produce either type of the ApoE protein. They discovered that neurons that produced no ApoE protein worked the same as those that produced ApoE3. This confirmed that it was not a lack of ApoE3 causing the problem but that ApoE4 protein alone was linked to Alzheimer’s disease.

This finding also sheds light on why treatments for Alzheimer’s that work in mice fail to translate to humans. The production of amyloid-β in mice is not influenced by ApoE4; this means that treatments that prove effective in mice may not work in humans, as the mouse models of the disease do not emulate the ApoE4-related form of Alzheimer’s that humans get. However, therapies that focus on reducing amyloid-β have worked in mice [2], so while ApoE4 functions differently in mice and humans, this is not the full story of Alzheimer’s. This research does, however, clearly show a way in which mouse models differ from humans, helping to guide future research.

Converting ApoE4 to ApoE3

The results of the study suggest that therapies that seek to modify the ApoE4 gene protein before it fragments might be a way to combat Alzheimer’s. This is how traditional medicine would generally approach the problem, treating the symptoms and not the cause.

However, the researchers took this one step further to a far more robust solution. Rather than simply attempting to treat the consequences of having an ApoE4 gene producing sub-par proteins, they completely removed the problem by using gene therapy to edit the genes and convert them from ApoE4 to ApoE3.

The converted genes ceased to produce the unstable ApoE4 protein and produced the stable ApoE3 version of it instead. This served to correct the problem at the root rather than trying to slap a band-aid on the consequences.

Conclusion

With so many failures to combat Alzheimer’s disease, it is easy to become disillusioned. We have seen mice cured of the disease numerous times, but these cures have failed to translate to humans. These new findings help to progress knowledge in the field and offer potential new ways to defeat Alzheimer’s.

What is refreshing about this study is how the researchers have opted to attack the problem at the root cause: the production of misfolded proteins that lead to the progression of the disease. It is becoming ever more clear that if we are going to make progress on ending age-related diseases, we must target the aging processes themselves, which cause these diseases.

Literature

[1] Yuang, Y. et al. (2018) Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nature Medicine doi:10.1038/s41591-018-0004-z

[2] Hu, X., Das, B., Hou, H., He, W., & Yan, R. (2018). BACE1 deletion in the adult mouse reverses preformed amyloid deposition and improves cognitive functions. Journal of Experimental Medicine, jem-20171831.

Steve Hill serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic as well as attending various medical industry conferences. In 2019 he was listed in the top 100 journalists covering biomedicine and longevity research in the industry report – Top-100 Journalists covering advanced biomedicine and longevity created by the Aging Analytics Agency. His work has been featured in H+ Magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Keep Me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project. In 2015 he led the Major Mouse Testing Program (MMTP) for the International Longevity Alliance and in 2016 helped the team of the SENS Research Foundation to reach their goal for the OncoSENS campaign for cancer research.

U.S. Transhumanist Party Chairman Gennady Stolyarov II Speaks with Steele Archer of Debt Nation

U.S. Transhumanist Party Chairman Gennady Stolyarov II Speaks with Steele Archer of Debt Nation

Gennady Stolyarov II
Steele Archer


Watch this wide-ranging discussion between U.S. Transhumanist Party Chairman Gennady Stolyarov II and Steele Archer of the Debt Nation show, addressing a broad array of emerging technologies, the aspirations of transhumanism, and aspects of both broader and more personal economic matters – from the impact of technology on the labor market to how Mr. Stolyarov paid off his mortgage in 6.5 years. This conversation delved into Austrian economics, techno-optimism, cultural obstacles to progress, the work and ideals of the U.S. Transhumanist Party / Transhuman Party, life extension and the “Death is Wrong” children’s book, science fiction, and space colonization – among many other topics.
Meanwhile, in the 1600s… – Hypothetical Dialogue by Nicola Bagalà

Meanwhile, in the 1600s… – Hypothetical Dialogue by Nicola Bagalà

Nicola Bagalà


Editor’s Note: The U.S. Transhumanist Party features this article by our guest Nicola Bagalà, originally published by our allies at the Life Extension Advocacy Foundation (LEAF) on January 24, 2019. This article provides an example of a family in the 1600’s having to deal with their children contracting and dying from a fever to shed light on anyone’s contemporary contention for curing age-related diseases. It’s easy for most of us in today’s age to completely support innovation that heals another from their fever before they die, when many would have considered that vile and blasphemous hundreds of years ago. Hopefully we can learn from history and accept that curing all diseases through medical science and innovation is morally superior. 

~Bobby Ridge, Assistant Editor, July 1, 2019

Many people are at the very least iffy about the idea of extending human healthy lifespan through medical biotechnologies that prevent age-related diseases essentially by rejuvenating the body. Even people who accept the possibility that such therapies can be developed are not convinced that developing them is a good idea, and there are only a few arguments that most people use. These arguments can actually be easily adapted to make a case against the medicine that already exists, which the vast majority of people on the planet currently benefit from—and the consensus is virtually universal that people who do not yet benefit from it should be given this opportunity as soon as possible.

The question is: would people who accept these arguments as valid objections to rejuvenation accept them also as valid objections against “normal” medicine? For example, how many present-day people would agree with what these two people from the 1600’s are talking about?


A – Did you hear about John’s son?

B – Yes, he came down with a fever and never recovered. What a tragedy.

A – Indeed. He and his wife had lost three other children to a fever before.

B – Oh, that’s terrible. Did they try to ask for a doctor’s help?

A – They couldn’t afford it for the other children, but when a fourth one became ill, they were so desperate about it that they did all they could to find the money. Anyway, not even the doctor could save the child’s life, even with all the leeches and poultices at his disposal.

B – Of course, I know nothing about medicine, but sometimes I think doctors don’t either. Their practices are a bit… scary, and as far as I have heard, most people they treat die anyway.

A – That may be, but doctors still have the best wisdom and techniques, at least for those who can afford them.

B – Who knows, maybe one day, doctors will actually know how to cure us for real. It could be as simple as drinking a potion or eating some sort of biscuit containing specific medicinal herbs, and in a few days, you’re back on your feet, no matter the disease.

A – That seems like fantasy to me. Doctors have existed for centuries, and they never managed to perform such miracles. If this were at all possible with knowledge and technique alone, wouldn’t one of them have managed to do so by now? Besides, perhaps it is for the best to leave things the way they are; doctors have gone far enough into God’s domain, and I don’t even want to imagine what would happen if they went even farther.

B – That is true. Surely, there must be a reason for all the diseases that plague us. Common folks are more affected, true, but they also take nobles on occasion. It’s difficult to say if this is because commoners sin more than nobles and that this is God’s way of punishing them or because they are more pious and God wants to call them to Himself sooner, but it is obvious that the will of Providence is at play.

A – Exactly. But I think there is more than this to it. Maybe the reason why diseases exist is to make our lives less miserable. Maybe they are blessings in disguise.

B – I don’t understand. They do cause a lot of suffering, not only to the diseased but also their families.

A – That is true, but how much more suffering would they endure if they went on living, especially among us commoners? It might explain why diseases affect common people more than the nobility. They live better lives, so it makes sense for them to live longer and enjoy it; but what about us? Our lives are harder and deprived of all the comforts and luxuries that rich people can afford. Is it worth living longer for us?

B – You speak truth, and I also think that if, one day, doctors will really be able to cure everyone of certain ailments, this will only make poor people’s lives worse. Very few people can afford the services of doctors even though they aren’t of much use; imagine how expensive it would be if they actually could cure you! Rich people would be healthy, and the rest of us would simply have to die knowing that they could be saved if only they had the money.

A – You are right, it is definitely better if there is no cure for anyone rather than a cure that is only for some. But, still, I dream of a day when medicine eventually becomes cheaper, or maybe the commoners won’t be so poor.

B – A day when even the likes of you and me could live in a fairly comfortable house, with our basic necessities covered, without having to work so hard every day to bring just a little food to the table, and while being able to afford the services of a doctor whenever we need one? You dream of Heaven on Earth, friend; it won’t happen until Judgment Day.

A – We won’t be able to achieve this ourselves, even centuries from now?

B – Again, it hasn’t happened until now, I don’t see why it should happen later. Even if it did, the consequences would be even more dire. It’s hard enough as it is to produce enough food for everyone, and if doctors could cure all diseases and everyone was able to afford these cures, there would be far too many mouths to feed. Therefore, in His infinite wisdom, the good God has decided that some of us must fall prey to disease.

A – I see your point, but in such a world where doctors can treat all ailments with their own knowledge, maybe we would be able to produce more food with less work, so that hundreds of millions, maybe even billions, could eat every day, while farming would not be as laborious.

B – You sure have a wild imagination! And how could that be accomplished, pray tell?

A – Perhaps there might be more machines that do work in place of animals, faster and better. Possibly even in place of people.

B – Machines that work the fields without a person maneuvering them? Walking water mills? Clockwork horses? Oh! How about a sewing machine to go with our spinning wheel? My wife would love such a thing, if it could ever exist.

A – We have some machines for some tasks. Why could we not have more?

B – Because they could never work, that’s why. I sure hope you’re never going to talk such nonsense with others, because not everyone has my sense of humor.

A – Maybe you are right. It was a bit of a stretch; windmills and water mills must sit where they are, after all. Diseases may be a necessary evil, as well. I’ve seen people who survived ailments like the one that killed John’s son, and as they grew older, their lives became more and more miserable. Old age was killing them more slowly and with far more cruelty than fever or plague. A poor old man dies on the street if he has no family to care for him or if his family cannot afford it. I would rather die the way John’s son did, surrounded by my loved ones, than as a crippled old man begging under a bridge.

B – Now you’re talking sense, and this is probably one of the most compelling reasons why we should leave diseases alone. Again, maybe it makes sense for the royalty to live that long, because they will not end up dying like old beggars, but for the rest of us, that would be a curse.

A – True. Besides, I suppose that at some point, one would get tired of living and would rather go. I guess this must be why even people who don’t die early in life eventually die of old age; even if you are part of the upper class, what can you possibly look forward to after you’ve seen your children and grandchildren grow up? Even if you know how to read and have a taste for music and the theatre, there are only so many books and so many composers and playwrights.

B – Precisely.

A – Yes, while being able to cure diseases might appear to be a good thing at first, when you think about it, you realize that it would not be.

B – Indeed, and this is what we must always remind ourselves of when disease does strike and sorrow makes us lose our objectivity.


The arguments presented by our two friends from the 1600’s are fundamentally the same ones that a lot of people bring up when they try to rationalize and justify the diseases of old age, saying that the defeat of aging might, at first, appear to be a good thing, but would actually not be that good after all. However, given the knowledge we have today, it is very easy to counter their arguments; in any event, not too many people would agree that the conversation above would have made a good case against vaccines and modern medicine, which have brought infectious diseases under strict control and save countless lives that would otherwise be lost on a daily basis.

Just like the arguments in the conversation above would not be a valid reason to give up on the medicine we are used to, they are not a reason to give up on the medicine of the future—the rejuvenation biotechnologies that might soon prevent and reverse the course of age-related diseases. Claiming otherwise is nothing but a double standard.

Nicola Bagalà is a bit of a jack of all trades—a holder of an M.Sc. degree in mathematics; an amateur programmer; a hobbyist at novel writing, piano and art; and, of course, a passionate life extensionist. After his interest in the science of undoing aging arose in 2011, he gradually shifted from quiet supporter to active advocate in 2015, first launching his advocacy blog Rejuvenaction before eventually joining LEAF. These years in the field sparked an interest in molecular biology, which he actively studies. Other subjects he loves to discuss to no end are cosmology, artificial intelligence, and many others—far too many for a currently normal lifespan, which is one of the reasons he’s into life extension.

Dr. Nichola Conlon and James Strole Discuss the Biggest Reported Increase of NAD in Humans

Dr. Nichola Conlon and James Strole Discuss the Biggest Reported Increase of NAD in Humans

Nichola Conlon
James Strole


Dr. Nichola Conlon, Nuchido CEO & Co-founder, spoke with James Strole, Director of the Coalition for Radical Life Extension, about what she’s bringing to RAADfest 2019:
***
Increasing NAD+ levels to a level comparable with people 17 years younger. 
***
NAD is a natural molecule found within every living cell of your body. Without it, your body couldn’t generate the energy it needs to survive or kick-start its natural cell maintenance and repair systems. In its youthful state, your body naturally makes and retains high levels of NAD. But as you age, these levels are not maintained and the amount of NAD in your body drops by 50% every 20 years. This decline has been scientifically linked to the increasing effects of aging.
***
Recent scientific breakthroughs have shown that one of the best ways to combat aging is to maintain high levels of NAD.
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Nuchido has pioneered the use of systems pharmacology and clinical research to boost and maintain NAD. In a scientific world-first, the team achieved the biggest increase of NAD in humans reported by any scientific group.
***
Hear what she has to share, and meet her at RAADfest 2019, October 3-6:

To find out more and register, visit the RAAD Fest website at https://www.raadfest.com/.


Watch the U.S. Transhumanist Party’s prior appearances at RAAD Fests in 2017 and 2018 below.

RAAD Fest 2017

The U.S. Transhumanist Party – Pursuing a Peaceful Political Revolution for Longevity – August 11, 2017

Advocating for the Future – Panel at RAAD Fest 2017 – Gennady Stolyarov II, Zoltan Istvan, Max More, Ben Goertzel,

RAAD Fest 2018

The U.S. Transhumanist Party: Four Years of Advocating for the Future – Gennady Stolyarov II at RAAD Fest 2018 – September 21, 2018

Gennady Stolyarov II Interviews Ray Kurzweil at RAAD Fest 2018 – September 21, 2018

U.S. Transhumanist Party Meeting at RAAD Fest 2018 – September 22, 2018

Andrés Grases Interviews Gennady Stolyarov II on Transhumanism and the Transition to the Next Technological Era – September 23, 2018

Register for RAAD Fest 2019 here

U.S. Transhumanist Party Presidential Primary Candidates Johannon Ben Zion and Rachel Haywire Discuss Policy, the Democratic Debates, and Transhumanist Advocacy

U.S. Transhumanist Party Presidential Primary Candidates Johannon Ben Zion and Rachel Haywire Discuss Policy, the Democratic Debates, and Transhumanist Advocacy

Johannon Ben Zion
Rachel Haywire


Two 2020 Third-Party Candidates dissect the “First Democratic Debate” from Johannon Ben Zion on Vimeo.

On June 28, 2019, two of the U.S. Transhumanist Party / Transhuman Party Presidential primary candidates, Rachel Haywire and Johannon Ben Zion, conversed about the juxtaposition of techno-progressive and public-health goals, policy-making, and organizing.

This thoughtful and constructive policy-oriented discussion is a worthy precursor to the forthcoming July 6 Virtual Debate (which the public can watch here), where candidates including Johannon Ben Zion and Rachel Haywire (as well as Charles Holsopple and Dan Good) will be articulating their visions of transhumanist policy to the public. The caliber and civility of discourse in the Ben Zion / Haywire conversation stand out as being immensely higher than what was observed during the Democratic primary debates, where it seems that many of the candidates were at one another’s throats. Once again, transhumanists have shown that they can do better. This discussion is a valuable building block for the outcome that we hope will happen once the U.S. Transhumanist Party / Transhuman Party Electronic Primary is concluded in mid-August – that all of the candidates will collaborate with the nominee, no matter who wins, and work toward maximizing the influence and impact of transhumanist ideas and policy proposals.

Steve Hill Interviews Sarah Constantin of The Longevity Research Institute

Steve Hill Interviews Sarah Constantin of The Longevity Research Institute

Sarah Constantin
Steve Hill


Editor’s Note: The U.S. Transhumanist Party features this article by our guest Steve Hill, originally published by our allies at the Life Extension Advocacy Foundation (LEAF) on May 9th, 2018. In this article Mr. Hill interviews Dr. Sarah Constantin, a researcher with a focus on machine learning at The Longevity Research Institute. This is an excellent article, especially if you want to learn more of the hard science behind longevity research. The topics of the interview range from deep learning being applied to pharmacology, to optimal mouse strains, and ideal areas of research to target age-related diseases.

~Bobby Ridge, Assistant Editor, June 30, 2019

Today, we have an interview with the Longevity Research Institute, a new group that launched in April 2018. The goal of the Institute is to identify therapies that can demonstrably extend healthy human lifespan by 2030 at the latest.

Searching for longevity

There are dozens of compounds and therapies that have been demonstrated to increase the lifespan of mammals. Recently, there have been some impressive examples of rejuvenation in animals using a variety of approaches, including partial cellular reprogramming, stem cell therapy, and senescent cell removal. More importantly, in many of these studies, age-related diseases have been delayed or even reversed.

Unfortunately, very few of these studies have had independent follow-ups or replication, and that is slowing down progress. The Longevity Research Institute is aiming to bridge the gap between basic science and commercial drug development.

It has chosen the field of aging research as its area of focus for one simple reason: age-related diseases are the leading cause of death globally. Heart disease, stroke, cancer, diabetes, Parkinson’s, Alzheimer’s and many more diseases are all caused by the various processes of aging.

The data from hundreds of animal studies tell us that aging is not a one-way process and that the rate of aging is something we can slow down or even reverse. Experimental results show that we can increase the healthy lifespan of animals significantly and delay the onset of age-related diseases in doing so. If we could translate those findings to humans, we could potentially increase the healthy period of life, known as health span, or even increase our lifespan beyond current norms while remaining healthy.

The majority of aging research consists of basic science that focuses on the mechanisms of aging, studies involving invertebrates like worms or fruit flies, and experiments that examine the effect of therapies on biomarkers of aging. However, the Longevity Research Institute believes that the way to find effective treatments that could translate to humans is by testing interventions on mammals to see if they increase lifespan or if they delay or reverse symptoms of aging, such as frailty, cognitive decline, and the prevalence of age-related diseases. Robust mammalian lifespan studies are quite rare in aging research due to their long duration and thus cost; the Institute believes they are worth doing despite this challenge.

Its philosophy is to be skeptical of results that depend on too many uncertain assumptions, such as particular mechanisms of aging or analogies between invertebrate and human biology. It believes that the closest way to measure the health and lifespan of a human is to measure the same things in mammals.

Replicating and Extending Lifespan Results

The majority of studies that have been shown to increase lifespan are rarely independently replicated to confirm the findings. There are therapies that, decades later, still have had no follow-up, and the Longevity Research Institute would like to change this situation.

To that end, it will be engaged in grant writing to obtain funds so that researchers studying aging will be able to conduct lifespan studies in mice and rats. The Longevity Research Institute also plans to commission its own studies and contract research organizations to carry them out.

It has a long list of promising interventions and is considering becoming involved with carboxyfullerenes, epithalamin, and stem cell transplants, for example. It is also interested in testing combinations of therapies to see if they have synergistic effects.

As translational research on aging is really a new, uncharted territory, the Institute is working with the Interventions Testing Program and METRICS to design reproducible animal studies. As part of that process, it will be testing genetically heterogeneous animals and using blind, randomized studies to reduce bias. A blind experiment is an experiment in which information about the test is hidden from participants, to reduce or eliminate bias, until after a trial outcome is known.

Best practices and transparency

Establishing best practices and protocol for translational aging research is a top priority here, and its work could help set the stage for future translational efforts. If superbly designed research protocols can be designed and made accessible to everyone, then they could be a real help in standardizing aging research and ensuring that the quality of results is the best it can be.

As part of its commitment to transparency and knowledge sharing, a condition of funding projects is that all experimental data will be made freely available to the public, as will pre-registration of experimental designs. The Institute will further protect this open science initiative by using blockchain technology to make immutable, publicly accessible records of everything it does.

We had the opportunity to talk with Sarah Constantin, Ph.D. and one of the key figures at the Longevity Research Institute, about their work. Sarah is a data scientist specializing in machine learning.

Your group believes that we need to conduct lifespan studies in mice in order to confirm that something might translate. However, some researchers believe that using multiple biomarkers of aging allows them to project, within a reasonable margin of error, changes to potential lifespan. This is becoming more relevant as the accuracy of biomarkers, and the use of comprehensive biomarker panels, becomes more commonplace. How do you respond to this?

There’s some very interesting stuff going on with biomarkers of aging.  We’re able to predict mortality with AUCs of 0.8-0.9, which is quite good, with aging biomarkers, including things like blood panels of inflammatory and metabolic markers, DNA methylation, and phenotypic markers such as BMI and frailty. Some of these biomarkers are things we’re planning to measure in our animal studies, and they should give us interim results on whether the interventions we’re testing affect the predictors of aging. I still believe that we can be most confident in whether a treatment promotes longevity when we’ve tracked its effects throughout an organism’s lifespan. We do know of examples (such as calorie restriction in primates) in which it’s equivocal whether the treatment extends lifespan but it clearly improves age-related biomarkers, and you have to do a lifespan study to distinguish those cases.

Advances in deep learning and systems pharmacology are allowing us to project interactions and potential therapies far more efficiently than ever before. What are your thoughts on these approaches, and will you be looking to use them in your work?

The deep learning and systems pharmacology approaches are actually where I started in biotech; I did machine learning at Recursion Pharmaceuticals, which is taking those approaches for doing phenotypic screens for genetic disease treatments. I think they’re really useful for drug discovery, at the beginning of the pipeline, where they can enable you to search a wider space of drug candidates. At LRI, we’re starting all the way at the other end of the pipeline, with drugs that have already been tested and shown promise in vivo. However, once we make some progress on those, then yes, it could make sense to start doing some of these machine learning-enabled approaches.

What is the ideal mouse strain for aging research, particularly lifespan studies, in your view?

Well, the Interventions Testing Program at the National Institute of Aging is using three-way heterozygous mouse crosses, which I think is the ideal. A single inbred strain of mouse doesn’t have much genetic diversity, so often what you’re testing is the effect of a treatment on that particular strain of mouse, and the results won’t transfer to another strain.

The use of progeria mice is common in aging research due to the shorter study time, but these models are often criticized as not being representative of true aging; what are your thoughts on the prevalence of progeria mice in aging research, and are they a relevant model for what we are trying to achieve?

I think progeria mice are an imperfect proxy. There are a lot of different kinds of progeria, and they exhibit some but not all of the typical symptoms of natural aging.  I’d have more confidence in studies done on aged mice than progeric mice.

We see that you have a strong commitment to ensuring public access to scientific knowledge. What inspired you to make such a wonderful and strong commitment to open science?

Well, coming from a data science background, I’m hyper-aware of how easy it is to fool yourself with data.  You can massage anything into a spurious result if you test enough hypotheses and pick your subgroups artfully. Really, the best way to guard against that is to share the raw data so that people can run their own analyses. Making science more open is how you make it more trustworthy.

Is there a publically viewable list of the targets that you are interested in testing?

The list is still evolving, but some of the first things we’re looking into testing are carboxyfullerenes, which seem to have neuroprotective and life-extending effects, and epithalamin, which is a pineal gland-derived peptide that’s been reported to extend lifespan and even reduce human mortality. Both of these are sort of in the sweet spot of not being the subject of that much research to date, but what there is is very promising, so the value of information is high.

What is likely to be your first target for studies, and what is the rationale behind your choice?

I think people should know that there’s a lot of low-hanging fruit in aging research — treatments that we have reason to believe might work but that we’d still have to test. The misperceptions are either that life extension is so speculative that we’ll never get there or that we already know how to do it and you just have to take the right supplements to live forever. I think the reality is that we’ll have to do a lot of experimental work, but it’s highly possible that, in time, we might find something that extends healthy lifespan in humans.

We would like to thank Sarah for taking the time to do this interview with us, and we look forward to seeing her team’s progress in the near future.

Steve Hill serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic as well as attending various medical industry conferences. In 2019 he was listed in the top 100 journalists covering biomedicine and longevity research in the industry report – Top-100 Journalists covering advanced biomedicine and longevity created by the Aging Analytics Agency. His work has been featured in H+ Magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, and, Keep Me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project. In 2015 he led the Major Mouse Testing Program (MMTP) for the International Longevity Alliance and in 2016 helped the team of the SENS Research Foundation to reach their goal for the OncoSENS campaign for cancer research.

Not Classing Aging as a Disease is Not a Major Problem – Article by Steve Hill

Not Classing Aging as a Disease is Not a Major Problem – Article by Steve Hill

Steve Hill


Editor’s Note: The U.S. Transhumanist Party features this article by our guest Steve Hill, originally published by at the Life Extension Advocacy Foundation (LEAF) on July 19, 2018. In this article, Mr. Hill does an excellent job explaining why the lack of the definition of aging as a disease under the FDA is not so bad as is sometimes feared. Personally, I do not agree with this. Relying on off-label use is not a good idea because that is much slower of a process than doctors quickly seeing that a drug has FDA approval. Once the FDA considers aging as a disease, pharmaceutical companies will quickly enter this arena and make increasingly better drugs. Mr. Hill makes some excellent points, though, and I highly recommend this article. 

~ Bobby Ridge, Assistant Editor, June 29, 2019

A common concern in the community is that the FDA, the EMA, and other bodies, such as WHO, do not classify aging as a disease and that this poses a problem for developing therapies that target aging. However, this is not really as serious an issue as some people would suggest; today, we will have a look at why that is.

Why this will not stop progress

Aging is a variety of distinct processes, damages, and errors; therefore, simply treating aging in clinical terms is not a viable endpoint. For a clinical trial to be conducted, it requires a verifiable indication, and aging is too general for the FDA and EMA to classify it as a disease.

It also is not a major challenge for damage repair-based approaches, such as those proposed by SENS and the Hallmarks of Aging, as these approaches are not focused on an all-in-one therapy with the indication of “aging”. They are based on a strategy of dividing damages into manageable groups and developing a suite of rejuvenation therapies that addresses each of them.

No single therapy will reverse or halt all of the aging processes when used alone, nor will it prevent all age-related diseases that accompany them. So, to have aging as an indication in any clinical trial would be pointless for any damage repair therapy.

Researchers are free to target aging processes

That said, researchers are very well aware that the processes of aging, which lead to the familiar diseases of aging, are a problem, and this is where the focus lies. There has been considerable effort to classify these processes and precursors of pathology as diseases themselves.

A prime example is the inclusion of sarcopenia (frailty and muscle loss) in the World Health Organization International Classification of Diseases (ICD) a few years ago thanks to lobbying by members of our community. Adding more general codes to the ICD that include these aging processes and precursors is an ideal solution, as it could potentially make it easier to organize trials and develop drugs that target the aging processes.

Back in June 2018, the World Health Organization released the new International Classification of Diseases (ICD-11). The previous version, ICD-10, was published in 1983, and the new ICD-11 will likely be the standard for years to come. The new ICD-11 now includes the extension code “Ageing-Related” (XT9T) for age-related diseases, and this should go a long way towards making focusing on aging easier for future drugs and therapies. Again, this is thanks to work by members of our community, who have spent countless hours researching and pushing for change.

Most aging hallmarks are very clearly linked to specific age-related diseases, such as beta-amyloid protein and malformed tau in Alzheimer’s, lysosomal aggregates in foam cells in atherosclerosis, and alpha-synuclein in Parkinson’s disease. Companies are perfectly welcome to target these aging processes directly, and indeed more and more researchers and big institutions are doing just that in order to treat age-related diseases.

Therefore, not classifying aging itself as a disease poses few barriers to developing therapies that address aging; it’s simply a case of working within the existing framework. UNITY Biotechnology is a prime example; this company is targeting senescent cells and applying its method to multiple age-related diseases; as everyone gets senescent cells, these therapies will be broadly applicable once they become available, and off-label use is likely to expand rapidly.

Also, rejuvenation therapies could, at first, be licensed as treatments for genetic disorders, even though the root cause of the pathology underlying those diseases is not aging. An example of this is the inherited mitochondrial disorders, known as mitochondriopathies, many of which are caused by mutations in the mitochondrial DNA (mtDNA). While these mutations are inherited and are not the result of age-related, deleterious damage to the mtDNA, the same repair-based approach can be applied: the allotopic expression of the protein in the nucleus, as proposed by MitoSENS, could potentially be used to repair the mtDNA allowing normal cellular function to resume.

The majority of damage repair therapies, if not all, could be developed as therapies for diseases with accepted indications and verifiable endpoints, which should satisfy bodies such as the FDA and EMA. Therefore, whether regulatory agencies perceive aging as a disease or not is of no consequence to the development of rejuvenation biotechnologies that address the aging processes.

This does not mean regulatory changes are not needed

Even though classifying aging as a disease is unnecessary, significant reform in the regulatory system is still needed in order to encourage investors and companies to put the time and money into researching and developing rejuvenation therapies.

One area in need of reform is the establishment of aging biomarkers, which indicate the repair or removal of age-related damage, as acceptable endpoints for rejuvenation therapies. Studies that use these biomarkers would also need to include long-term follow-up studies to ascertain the effects of a therapy over a longer period of time.

This would deviate from regulators’ normal requirements that therapies have to prove an effect on hard outcomes to be approved. In an ideal situation, patients should get rejuvenation therapies long before they are in immediate danger and once diseases have manifested, but this makes trials more time consuming and more costly to run.

However, back in February 2018, the FDA published a new guidance document detailing how early-stage Alzheimer’s patients might be identified, which, if accepted, would represent a significant change in policy and a step in the right direction. The document suggests that the results of imaging tests or suitable biomarkers could be enough to consider Stage 1 Alzheimer’s patients as suitable subjects for clinical trials.

This is a positive move as it means that therapies can be tested on people in the very early stages of Alzheimer’s rather than on those who have already suffered considerable if not irreparable damage to the brain, damage that no therapy could hope to address alone. This could mean that these early-stage patients could enroll in a clinical trial and take a therapy that could potentially prevent the disease from ever progressing further or reaching the point where cognitive decline begins.

In the case of repair-based therapies, it would then be a case of demonstrating that the early stages of Alzheimer’s disease were improved via the removal or repair of the underlying age-related damage, and suitable biomarkers would show this.

Moving with the times

Another area where regulatory bodies have struggled is keeping up with the rapid march of technology and medicine. Technologies such as gene therapies have struggled to gain traction due to an antiquated regulatory framework struggling to cope with them. Thankfully, this is also being acknowledged, and the regenerative medicine advanced therapies (RMAT) framework published earlier this year seeks to address this issue and make large-scale changes to how its regenerative medicine policy framework operates as a whole.

According to new FDA regulations, a drug is eligible for designation as an RMAT if:

  • The drug is a regenerative medicine therapy, which is defined as a cell therapy, therapeutic tissue engineering product, human cell and tissue product, or any combination product using such therapies or products, except for those regulated solely under Section 361 of the Public Health Service Act and part 1271 of Title 21, Code of Federal Regulations;
  • The drug is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition; and
  • Preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for such disease or condition.

While the FDA created these new guidelines, we joined forces with the Niskanen Center to submit comments to the agency so that it would hear the voice of our community.

Conclusion

Aging not being classified as a disease by the FDA, EMA, etc. is not a major issue; the real need is for policy changes that make developing drugs and therapies that target the aging processes easier and more financially viable. It is good that changes are being made to current frameworks and that progress will almost certainly continue in these areas.

Meanwhile, we can continue to support the development of repair-based approaches to aging knowing that such therapies, if they work, will be approved even in the current regulatory landscape.

Steve Hill serves on the LEAF Board of Directors and is the Editor-in-Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic as well as attending various medical industry conferences. In 2019 he was listed in the top 100 journalists covering biomedicine and longevity research in the industry report – Top-100 Journalists covering advanced biomedicine and longevity created by the Aging Analytics Agency. His work has been featured in H+ Magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, and, Keep me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project. In 2015 he led the Major Mouse Testing Program (MMTP) for the International Longevity Alliance and in 2016 helped the team of the SENS Research Foundation to reach their goal for the OncoSENS campaign for cancer research.