« 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. 

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This month’s theme: Neurodegenerative Diseases and Aging

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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

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

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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. 

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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

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

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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,

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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.

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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.

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For more information

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

 

Since last year’s RAADfest in October 2021, there have been more initiatives and advances in the fields of age delay and age reversal than in any other 12-month period of time that is what a lot of people don’t realize that are paying attention to the news the politics plague the war and they’re not focusing on what’s really important.

RAADfest 2022 Bill Faloon Age Reversal Research Progress

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This month’s theme:  2022: A review of Longevity News

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In 2022, we saw many new developments in different areas related to longevity. These ranged from new companies, and organizations dedicated to either providing funding or advocacy in longevity to the beginning of worldwide conferences. The research field also made noteworthy advancements and clinical trials have started which we hope will give promising results in the coming years. Sadly, the years 2020 and 2021 saw a decline in life expectancy due to covid-19 pandemic which had the worst effect on the older population but it is good to see some data suggesting that life expectancy will raise again in 2022.

This newsletter is too short to give even brief feedback on all important activities, but this is our subjective shortlist.

Research and important articles

Senolytics

Senolytics come under a class of drugs that clears out senescent cells (SC). Dasatinib (a tyrosine kinase inhibitor), Quercetin (a naturally occurring flavonoid), Fisetin, and Navitoclax were the first senolytic-drugs introduced in the market following a hypothesis-driven approach. A combination of Dasatinib and Quercetin was given to mice for over two years and the results showed fewer senescence-related biomarkers as well as a lower occurrence of disc degeneration. However, this result was seen in young and middle-aged mice, not the older ones. 

Proposal to new hallmarks of aging

Genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, loss of proteostasis, deregulated nutrient-sensing, cellular senescence, stem cell exhaustion, and altered intercellular communication was the original nine hallmarks of ageing proposed by López-Otín and colleagues in 2013. In the nearly past 10 years, our in-depth exploration of ageing research has enabled us to formulate new hallmarks of ageing which are compromised autophagy, microbiome disturbance, altered mechanical properties, splicing dysregulation, and inflammation, among other emerging ones.

ICD 11

In the latest international classification of diseases, codes were introduced for a better understanding of the diseases and within that, XT9T code referred to  “age-related” and MG2A, defined as “Old Age” which was later replaced by “Ageing-related decline of intrinsic capacity” after receiving criticism.

Update on TRIIM-X Study

TRIIM trial started in 2015 and was completed in 2017. As the researchers still had many questions, they started an extension of the same train known as TRIIM-X. It’s being extended by including women, a broader age range with people up to the age of 80 and down to the age of 40.

Some things that are in TRIIM-X which was not noticed in  TRIIM have to do with blood lipids.

Metformin 

It has been considered a wonder drug for the past few years in terms of anti-aging drugs. However, recently, some articles have affirmed that previous studies on metformin had a bias in data collection and that in reality, the drug has almost mild to almost no effect on slowing the aging process. It will be crucial to see as soon as possible the first results from the TAME study to check the credibility of Metformin.

They were also articles and research concerning rapamycin, caloric restriction, and gene therapies against aging, ….

Companies / Organizations

LEV

Longevity Escape Velocity (LEV) Foundation, headed by Aubrey de Grey, was created in 2022 to proactively identify and address the most challenging obstacles on the path to the widespread availability of genuinely effective treatments to prevent and reverse human age-related disease.

Hevolution

Launched in 2021, Hevolution Foundation is a non-profit organization that provides grants and early-stage investments to incentivize independent research and entrepreneurship in the emerging field of healthspan science. Headquartered in Riyadh, with hubs planned in North America, Europe, and Asia.

Altos Labs

Altos is designed to integrate the best features of academia and industry. The focus is on a shared mission, the ability to foster deep collaborations, and the passion and commitment to turn science into medicine. The company works with world leaders in the field including Juan Carlos Izpisúa Belmonte, Steve Horvath, and Shinya Yamanaka,

Chan Zuckerberg Foundation

In December 2021, Chan Zuckerberg Initiative (CZI) co-founders and co-CEOs Dr. Priscilla Chan and Mark Zuckerberg announced a 10-year effort to develop the science and technologies to observe, measure, and analyze human biology in action. Over the next decade, CZI Science will focus on developing new research, institutes, and technologies that measure human biology in new ways to help deepen our understanding of human health and disease.

Vita DAO 

VitaDAO is a DAO collective for community-governed and decentralized drug development. Their core mission is the acceleration of research and development (R&D) in the longevity space and the extension of human life and healthspan. To achieve this, VitaDAO collectively funds and digitizes research in the form of IP-NFTs. Read the WhitepaperCommunity Report 2021.

Longevity Science Foundation

The Longevity Science Foundation is a non-profit membership organization advancing the field of human longevity by funding research and development of medical technologies to extend the healthy human lifespan.

Other companies are very active in the field: Calico Labs (Google), In Silico Medicine, and SENS.

Some conferences 

Longevity Summit Dublin in September

3-day uplifting conference recognizing and celebrating emerging research and developments across the Longevity Industry globally.

Eurosymposium on Healthy Aging in November (Organized by Heales and the International Longevity Alliance)

The Eurosymposium on Healthy Ageing (EHA) is a unique biennial meeting of scientists working on the biology of aging. Toward the end of the two-day conference, a Declaration for Radical Healthspan Extension was adopted.

Aging Research and Drug Discovery Meeting 28 August – 1 September (ARDD)  

10th Aging Research and Drug Discovery Meeting had a great program with global thought leaders sharing their latest discoveries and insights into aging and how we target the aging process ensuring everyone lives a healthier and longer life. 

The weekly Healthy Longevity Webinar Series throughout the year

The NUS Yong Loo Lin School of Medicine, together with Prof. Brian Kennedy and Prof. Andrea Maier hosts the Healthy Longevity webinar series. Every Thursday, they have researchers and CEOs. etc present talks related to aging.

Advocacy

Party for Biomedical  Rejuvenation Research (Partei für schulmedizinische Verjüngungsforschung) formerly known as Party for Health Research (Partei für Gesundheitsforschung)

The German Party for Biomedical  Rejuvenation Research is committed to the faster development of medicine with which people, through rejuvenation, are unlikely to die of old-age diseases or old age and can live thousands of years, physically and mentally healthy. The Party will have candidates for the Berlin elections on February 12, 2023.

Lifespan.io

The Lifespan Extension Advocacy Foundation (LEAF)  has many different operations to perform in its mission to support the development of life extension technologies. Among other things, they are making great videos and podcasts.

Healthspan Action Coalition (HAC)

Bernard Siegel launched the new nonprofit organization, Healthspan Action Coalition (HAC), initiating a global societal movement supporting healthy aging in the USA. Building upon a foundation of trusted and matured connections and networks, the movement will be deployed across a wide spectrum of collaborative efforts promoting favorable policy and funding for scientific research, innovations, and patient engagement.

The Alliance for Longevity Initiatives (A4LI)

This US organization was founded with the goal of creating social and political action around the issues of combating age-related chronic conditions and increasing our number of healthy, disease-free years.

Less Death

LessDeath is a 501(c)3 nonprofit with the mission to mobilize the world’s best talent to work on maximizing a healthy human lifespan. Their programs are designed to reach out to talented, passionate, mission-aligned scientists, engineers, investors, and operators of diverse backgrounds and help them get oriented, get involved, accelerate their impact, and work together to break bottlenecks to progress.

The Healthy Longevity Medicine Society (HLMS)

The Healthy Longevity Medicine Society (HLMS) was established in August 2022 to build a clinically credible framework and platform for longevity medicine that promotes the highest standards of interdisciplinary collaboration in the field. The HLMS is governed by a Council of elected members representing different geographical locations and sectors. The HLMS aims to educate, foster research and professional development, set recommendations and guidelines, and coordinate activities across the various domains of longevity medicine.

Things to look forward to in 2023

Longevity trials on mice were announced by Aubrey de Grey and the Longevity Escape Velocity Foundation. They should begin as soon as January 2023 with 1,000 mice 18-month-old who will follow 4 different therapies. We should have results before the end of 2023.

Many more grants from Hevolution and other organizations should be available for scientists to conduct research and clinical trials. 

Finally, all the other advances could be accelerated notably by the rapid progress of artificial intelligence if they are used for longevity research.

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This month’s good news: An international commission will be convened to assess the challenges presented by global aging and demonstrate how these challenges can be translated into opportunities for societies globally. 

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Global Roadmap for Healthy Longevity (on the site of the National Academy of Medicine) 

Specifically, the commission will:

Consider and put forward avenues for innovative and groundbreaking aging-related research and development across basic, clinical, pharmaceutical, social, and behavioral sciences, bioengineering, information technology, and assistive technologies, and recommend ways to expand research funding and incentivize research in aging. Special consideration will be given to elucidation of the cellular and biological mechanisms of aging and regeneration; advances in information technologies including the development of large databases, machine learning, and artificial intelligence tools that will inform approaches to therapeutic interventions but also enhance the quality of life; merging engineering technologies based on software and mechanical design; new business models for social innovation and social enterprises; and implications for investment in research and development, regulation, commercialization, and scalability, including issues pertaining to ethics and equality.

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For more information

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

Medical, scientific, and technological progress is stronger than ever. However, this has not been enough to improve Healthy Life Expectancy. In 2020 and 2021, we had the first decrease in life expectancy at the world level in the last 75 years. To overcome this loss in life expectancy, we need better scientific cooperation, increased research, and more government-level commitment to progress. Second Brussels Declaration for Radical Healthspan Extension:  After Covid times, rejuvenation times. 6th Eurosymposium on Healthy Ageing.  November 2022.  

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Theme of the month: Frequently Asked Questions about Healthy Longevity

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Since 2016, the Organisation « Partei für Gesundheitsforschung » presents candidates for the German elections. On their website, they present a long text with dozens of frequently asked questions on how to defeat aging. Below, you will read a selection of five of those questions (with slight adaptations).

Q. What is meant by « longevity escape velocity »?

The « first generation » therapies for humans will not be perfect. So they will repair some ageing damage very well, some less than that while others might not work at all. If we simply keep applying the same therapies – no matter how often or thoroughly – the less well or unrepaired damage will continue to accumulate. Ultimately, we will only experience age-related decline and death at an older age.

So, to keep ageing at bay permanently, it is not enough to repeat the therapies at regular intervals. We have to improve them and apply the improved version the next time. This is where the concept of « longevity escape velocity » (LEV for short) comes into play. The term refers to the rate at which we need to improve the thoroughness of repair over time in order to prevent the overall level of damage in the body from increasing further – in other words, to keep our biological age, defined as the amount of damage in our body, constant or to reduce it. If we achieve this rate, we would therefore increase the remaining life expectancy of people receiving the treatment faster than time passes during it (for example, by more than one year per year). A 52-year-old who has a life expectancy of 80 years (i.e. 28 years remaining) would therefore add more than one year of life during his or her 53rd year. His or her life expectancy would increase to more than 81 years, and the next year to more than 82. The expected (age-related) end of their life would thus move away from people faster than they approach it.

It is to be expected that once we reach LEV, (global catastrophes and similar scenarios excepted) we will never fall below this rate again because as therapies become more thorough, the amount of damage that needs to be repaired continues to decrease (after all, the complexity of ageing is finite, not infinite). As a result, the remaining damage takes more and more time to reach a critical level and the speed needed to improve therapies also decreases.

Comparison with jumping off a cliff: the remaining life expectancy of a human being is currently constantly decreasing due to ageing, just as the distance to the ground decreases in a fall due to gravity. If you jump with a jet engine on your back, the situation is comparable to regular « rejuvenation » spurts: At first, it is inactive – so you fall. If you activate the jet engine in time (i.e. if you are not too old when the first therapies are available – we won’t be able to save them with the first therapies because they will already have accumulated too much damage), it will give you lift, slow down the fall and eventually let you climb further and further.

Q. I won’t live to see that anyway, will I?

Encouraging progress is being made and therefore it is not unlikely that a large proportion of the population alive today will benefit from rejuvenation therapies – this is true even for those already at a relatively advanced age.

The objection that people have been trying in vain for millennia to find a fountain of youth or immortality is correct. But the same is true of flight, access to space, the ability to restore paralyzed limbs and freedom from smallpox, polio, and tuberculosis: All these things have been impossible for hundreds of thousands of years until the technology needed was available and used. Now they are already available for most of the human population and are being extended to the rest.

Suppose we do nothing today to accelerate rejuvenation research. In that case, we run the risk of spending our last days wondering if we could have saved ourselves and millions of other people years of unnecessary suffering if only we had decided to act sooner.

Even if these treatments may come too late for some of us, it is still our moral duty to enable our descendants to live without age-related diseases and suffering, and that can only be done if we get to work today.

Q. How close are we?

According to US inventor and futurist Ray Kurzweil, we will reach LEV (longevity escape velocity) in ten to twelve years (as of 2018).

Bioinformatician and theoretical biogerontologist Aubrey de Grey says that we have a 50% chance of reaching LEV around the year 2036. This would mean that people who are healthy enough at that time and subsequently regularly take advantage of the latest rejuvenation therapies will never die from age-related causes.

This is based, among other things, on de Grey’s estimate that we will realize RMR (robust mouse rejuvenation) with a 50% probability in three to five years. According to de Grey, this estimate is based on an assessment of the following factors:

• how fast the individual sub-areas are progressing
• how much research funding will be available in the future
• how often we find out something surprising about ageing
• how often we develop new technologies that make the work we need to do easier
• how difficult it will be to combine therapies when they work individually
• how much we need to rejuvenate people to give scientists time to rejuvenate them better and stay one step ahead of damage

Regardless of these estimates, rejuvenation is a rapidly growing field of research that, as you can read under the next question, has already seen some breakthroughs. The first components of a comprehensive anti-ageing therapy, such as senolytics, are already being tested in clinical trials. Others are on the verge. This should give us confidence that we are in for a revolution in biomedical research – and subsequently in human life – in the next few decades.

Q. Are there already successes?

Yes. The SENS Research Foundation, the leading research institution in the field of the SENS approach to rejuvenation, has a list on its homepage of all publications in scientific journals that originate either from its in-house laboratory or from research projects funded by the foundation.

This Wikipedia article is very helpful in tracing the history of the research field so far.

Here is a roadmap showing which stages of development the individual components of the targeted therapies are in. Not only the scientific but also the organizational, public, and political progress.

Q. What can I do today to age more slowly?

Although there is evidence that some molecules can delay or even reverse individual ageing processes, there is no currently available intervention that has been shown to slow ageing in humans. Leading candidates among currently available interventions include caloric restriction, rapamycin, SGLT-2 inhibitors (especially in men) and 17-alpha-oestradiol (again in men). Even if they work, however, their potential is much lower than that of the direct harm-reversal therapies of the SENS approach, and they cannot be replicated in a similar way.

Q. How can I accelerate progress in this area?

If you want to contribute to the faster development of more effective rejuvenation medicine, you can start in small ways: Creating broader public awareness of rejuvenation therapies by talking about them with friends, school or work colleagues or family members, donating books on the subject to libraries, doctors’ offices or hospitals, and donating money to organizations dedicated to fighting ageing (some of which can be done for free, for example through AmazonSmile).

Of course, if you are a billionaire, a scientist, or a student in fields potentially useful for rejuvenation, or if you have more time for activism, today may be the first day of the rest of your life as a professional longetivist. You could one day save many lives, including your own, your parents or your children’s.

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The good news of the month: 1,000 mice will live as long as possible in good health and a promise of total commitment to longevity

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Longevity trials on mice were announced by Aubrey de Grey and the Longevity Escape Velocity Foundation. They should begin as soon as January 2023 with 1,000 mice 18-month-old who will follow 4 different therapies. We should have results before the end of this year.

Alex Zhavoronkov expressed a beautiful Longevity Pledge : (…) In my opinion, there is no cause more urgent, more altruistic, more impactful, more important, and more ambitious than enabling humans to improve continuously. (…) Therefore, I would like to pledge everything I have now, and what I will get in the future, to only one cause — extending healthy productive longevity for all human beings. Instead of donating just a portion of my wealth and energy to this cause, I would like to do more. I pledge to spend 100% of my time and personal resources to accelerate research and clinical deployment of longevity technologies. (…)

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For more information

• Heales, SENS, Longevity Alliance, Longecity and Lifespan.io
• Heales Monthly Science News

I grew up in New Zealand and lived there until I was 12 years old. I remember one time my grandma came to visit us and I had never hung out with somebody older than the age of 60 before. When she came, I remember for the first time realizing that when I go and play with my brother, I could run around and roughhouse, but for my grandma, just getting up from a chair is really painful for her and that struck me as oh she has a disease like we should try to find a way to cure her so she can come and play with us” and then I remember asking my parents “what disease does grandma have” and they said, “she doesn’t have it, she’s just old” and I said “what disease is that”, They said “you do not understand it is a natural process” and as a kid, I thought that was stupid you know, why is it a natural process that we should all get this disease: Laura Deming, biological researcher, HT Summit 2017.

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Theme of the month: Aging in the International Classification of Diseases (ICD)

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What is a disease and what is the International classification of diseases?

A negative effect on the functioning of the body of an organism and its structure over a prolonged period of time is termed as a disease. Diseases come with a set of signs and symptoms and can either be caused externally (due to a pathogen) or internally (Immune system dysfunction). What is considered a disease changes with medical knowledge, but also with social and cultural evolutions. Historically, some poor areas considered obesity to be a sign of wealth, but in today’s world, we consider it to be a complex disease. In a similar context, homosexuality was also considered a “mental illness” but in 1973, the Diagnostic and Statistical Manual of Mental Disorders (DSM) removed “Ego-syntonic Homosexuality ». 

In 1893, the Bertillon Classification of Causes of Death was introduced to the congress of the International Statistical Institute in Chicago by the French physician Jacques Bertillon and then adopted by several other countries. This system was based on the principle of “distinguishing between general diseases and those localized to a particular organ or anatomical site”. The first edition was published in 1900 and until the sixth version, very few changes were made. In the 6th edition, which came out in 1949, the title was modified to reflect the changes: International Statistical Classification of Diseases, Injuries, and Causes of Death (ICD). From this point onwards, World Health Organization (WHO) started preparing and publishing the revised versions of the ICD every 10 to 15 years. 

Is aging a disease for the ICD?

The question to know if aging is a disease or not is a controversial one.

Aging is slowly killing all humans of the world (who are not dying of other causes). To know if it is a disease or not is a semantic question. What is sure is that is it the common cause of all age-related diseases and an aggravation factor of almost all illnesses.

ICD-10 (in 1990) already included code R54 for Age-related physical debility, R41.81 for Age-related cognitive decline, and F03 for Senile psychosis.

In the latest ICD-11, codes were introduced for a better understanding of the diseases and within that, XT9T code referred to  “age-related” and MG2A, defined as “Old Age” which was later replaced by “Ageing-related decline of intrinsic capacity” after receiving criticism.

In fact, a group of scientists from Latin America opposed the idea of including the broad term of “Old Age” as a disease fearing reinforcement of the widely prevalent ageistic beliefs in society. They argue that aging might lead to some chronic medical or mental health conditions but that other factors play a much greater role in the disease causation rather than age itself. According to them, Frailty is a much more homogeneous and better-defined clinical entity.

Ageism can indeed be a problem in many societies. Still, the immense majority of sufferings due to aging come from diseases and infirmities due to senescence that we cannot yet escape.

On the other hand, a large group of scientists argued that categorizing aging as a disease with a “non-garbage” set of codes will result in new approaches and business models for addressing aging as a treatable condition, which will lead to both economic and healthcare benefits for all. This will also make it easy for researchers to conduct clinical trials as many countries strictly follow the ICD list for approvals and once a disease is recognized in this classification, it is easier for scientists to get their research funded. 

Old Age might be an ageist term, but pathological processes of aging are a major risk factor. Work on developing new and improved therapies, with the purpose of slowing and reversing the damage done by aging is thus very important.

What is now recognized?

The following list of Aging-related codes which are included in ICD-11 was curated by Daria Khaltourina. XT9T is coded for age-related and it is in combination with codes for other diseases. This long list can be useful for researchers wanting to start clinical trials in one specific domain of aging.

• 3C0Y/Z&XT9T- Ageing-related other specified/unspecified diseases of the blood or blood-forming organs
• 4A20.Y/Z&XT9T- Ageing-related other specified/unspecified acquired immunodeficiencies (probably the most useful for clinical trials)
• 9E1Y/Z&XT9T- Ageing-related other specified/unspecified diseases of the visual system
• AC0Y/Z&XT9T- Ageing-related other specified/unspecified diseases of the ear or mastoid process
• BA00&XT9T- Ageing-related essential hypertension
• BA01&XT9T- Ageing-related hypertensive heart disease
• BA02&XT9T- Ageing-related hypertensive renal disease
• DE2Y/Z&XT9T- Ageing-related other specified/unspecified diseases of the digestive system
• CB7Z&XT9T- Ageing-related diseases of the respiratory system, 
• BA80&XT9T- Ageing-related coronary atherosclerosis 
• GA31.1&XT9T- Ageing-related secondary female infertility
• 8A00.2&XT9T- Ageing-related Parkinson-like syndrome/secondary parkinsonism 
• 8A03.3&XT9T- Ageing-related acquired ataxia, unspecified 
• FA01&XT9T- Ageing-related osteoarthritis of the knee 
• 2F34&XT9T- Ageing-related benign neoplasm of male genital organs 
• GB04.Z&XT9T- Ageing-related male infertility, unspecified.
• EE40.31- Age-related skin fragility
• EJ20- Photoaging of the skin
• MB21.0- Age-associated cognitive decline
• EE40.Y- Other specified atrophy or degeneration of dermal or subcutaneous connective tissue
• 9B10.0- Age-related cataract
• 9B75.0- Age-related macular degeneration
• MG2A- Old age Ageing-related decline of intrinsic capacity

Conclusion

ICD is important as it provides a common framework for recording and monitoring diseases universally between different countries, regions, and hospitals. This makes it easy to share and analysis of this data globally. 

The WHO felt that “dialogue helped to find a way forward in this matter” and allocated a dedicated process for review of the term “old age” The review led to the retraction of the term “old age” as a category title and index listings from ICD-11, having been replaced by “aging-associated decline in intrinsic capacity”. Additionally, the use of the term “pathological” as an extension code (XT9T) to describe the normal process of “aging” has been replaced by the much more appropriate term, “biological”.

This inclusion was accomplished in large measure thanks to longevity advocacy, in particular, the years-long advocacy of the International Longevity Alliance and its core activists.

So, aging is now in the ICD and can be officially addressed as a medical condition. 

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The good news of the month: Aubrey de Grey’s announces rejuvenation trials on mice

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The famous biogerontologist Aubrey de Grey’s was interviewed by Phil Newman, Editor-in-Chief of Longevity.Technology. He announced his new foundation will start « rejuvenation trials » on mice.

Innovative combined interventions on 18-month-old mice should be launched. The goal is to double the remaining life span.

This is excellent news. If successful, this type of experimentation offers perfect proof of the effectiveness of longevity therapy in an animal model. 

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For more information

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

I decided early on that aging was bad for you. It made people sick and then they died. It seems so simple and so true. Why do you think many people still don’t take seriously the idea that aging can and should be fought?

People are easily intimidated by scientific information. They get a lot of it, and most of it comes from people who think about aging in a way that appeals to fantasy and wishful thinking. Public figures who talk about aging usually make things up and make a big deal about it, without detailed evidence to back up their words. This makes intelligent people skeptical, and it’s harder for people who actually have information to rise above that in terms of clarity. Richard Miller, gerontologist. May 2022.

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Theme of the month: Effects of aging on the bone system

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Introduction

The bones forming the skeleton, especially the skull, are a symbol of death in many cultures. They are also the last parts of ourselves that will remain, in case of burial, for decades, centuries, millennia,… Finally, the degradation of our bones is also one of the many causes of mortality due to aging.

Definition

The bone system ensures the protection of the internal organs as well as their maintenance. It also serves as a lever for the muscles to allow numerous movements.

The human skeleton is composed of 206 bones in adult life. The skeletal system is made up of cartilage, joints and ligaments in addition to bones.

It represents on average 20% of the body mass. The bones are rigid, but the skeleton is very flexible.

Bone consists mainly of collagen fibers and an inorganic bone mineral in the form of small crystals and between 10% and 20% water.

Changes with age

The aging of the musculoskeletal system is important because it affects one of the major factors of functional independence. It represents 75% of the major health problems of people over 75 years old.

With age, the mineral density of the bones begins to decrease, this is called osteoporosis. The bones lose calcium and other minerals. This loss of bone density accelerates with age, especially in women after menopause.

The spine becomes shorter as the spinal discs gradually lose fluid and become thinner. It becomes curved and compressed.

The long bones of the arms and legs are more fragile due to mineral loss, but they do not change in length. This makes the arms and legs longer than the shortened trunk.

Moreover, as we age, the cartilage inside the joints and its components deteriorate, making them less resistant and more vulnerable to injury. The aging of articular cartilage is dependent on multiple morpho-genetic factors, but also on obesity and repeated microtrauma caused by work or sport. Unfortunately, articular cartilage does not regenerate and this is why prosthetic joint replacement surgery has become so common in both the hip and knee.

Aging also affects the muscles. There is a loss of muscle, called sarcopenia (subject of our monthly letter of January 2022). During this process, the mass of muscle tissue as well as the number and size of muscle fibers progressively decrease.

The effects of these changes

The bones become more fragile, smaller and more brittle.

Joint degradation can lead to inflammation, pain, stiffness and even deformity. Joint changes affect almost all older people.

The result of sarcopenia is a progressive loss of muscle mass and strength. Movement slows down and may become limited. This loss of muscle strength increases the strain on certain joints (such as the knees) and may predispose the person to arthritis or a fall.

Common conditions
Osteoporosis is a common problem, especially in older women. Bones break more easily. Compression fractures of the vertebrae can cause pain and reduced mobility.

Muscle weakness contributes to fatigue, lack of energy and reduced activity tolerance. Joint problems, ranging from mild stiffness to debilitating arthritis (osteoarthritis), are very common.

The risk of injury increases as changes in gait, instability and loss of balance can lead to falls. Falls often result in fractures and the likelihood of death in the elderly. Fracture of the femoral neck is particularly common as a cause of death.

Involuntary movements (muscle tremors and fine movements called fasciculations) are more common in older people. Older people who are not active may have abnormal sensations (paresthesias).

Solutions to prevent the consequences of bone aging
Physical exercise is one of the best solutions to slow down or prevent muscle, joint and bone problems. Exercise helps bones stay strong.

A balanced diet also plays an important role. Especially for women, who need to take special care to get enough calcium and vitamin D as they age.

Curative solutions

There are few new therapies aimed at increasing the longevity of the bone system. However, medical treatments do exist. They act on bone cells by stimulating their reconstruction by osteoblasts. An alternative could be the use of stem cells.

However, these issues are rarely addressed, even in the longevity community. We still have much room for research and rejuvenation in this area.

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The good news of the month: Mammal death is a partially reversible phenomenon

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Scientists at the German University of Bochum have found that blood markers of Alzheimer’s disease are visible up to 17 years before the onset of the disease. These are biomarkers of amyloid-beta protein indicating misfolding.

If this study is confirmed, it is doubly positive. It means that it is long. Window of opportunity to counteract what triggers the disease before it becomes disabling. It also confirms the traditional hypothesis of the origin of the disease.

In this case, it will of course remain to establish the therapy that will succeed in stopping the development of « harmful » proteins and, by a cascade reaction, stop the disease.

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For more information

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