Tag: Hallmarks of Aging

U.S. Transhumanist Party Virtual Enlightenment Salon with Abdelhadi Rebbaa on Senolytics – July 28, 2024

U.S. Transhumanist Party Virtual Enlightenment Salon with Abdelhadi Rebbaa on Senolytics – July 28, 2024

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Dr. Abdelhadi Rebbaa
Gennady Stolyarov II
Art Ramon Garcia, Jr.
David Wood
Ben Ballweg

On Sunday, July 28, 2024, the U.S. Transhumanist Party invited Dr. Abdelhadi Rebbaa to discuss his views regarding the potential and limitations for using senolytics to treat aging and go over alternative/complementary approaches to delay senescence onset.

Dr. Abdelhadi Rebbaa received his PhD in Biochemistry from the Université Claude Bernard, Lyon, France. He held research and faculty positions at Northwestern University, the University of Pittsburgh, and Columbia University. Over the course of his career, his research encompassed target and drug discovery and development in the fields of cancer, stem cells, and aging. He served as a Principal Investigator on multiple grants, published over 40 manuscripts, and reviewed manuscripts for several high-impact scientific journals. In his role at Ichor Therapeutics from 2018 to 2021, he oversaw the discovery and preclinical testing of small-molecule senolytics and biomarkers of aging. He then worked for SENS Research Foundation between January 2022 and January 2024, where his role was to conceive, design, and oversee research projects on senescence prevention, senolytics, and partial reprogramming. Now he works as a Project Management Consultant in New Jersey.

***

Timestamps

7:25 – Dr. Abdelhadi Rebbaa’s presentation
58:28 – External versus internal/inherent (e.g. age-related) causes of senescent cells
1:01:51 – Senomorphics versus senolytics
1:03:05 – The need to replace senescent cells that have been destroyed
1:04:03 – Whether senescent cells crowd out potentially worse cells
1:04:56 – When reprogramming helps, and when it does not
1:06:06 – Whether donating blood can reduce senescence
1:07:14 – Pros and cons of academia, for-profit, and non-profit sectors
1:08:41 – Whether senescent cells are worse than the holes where the senescent cells were (if the senescent cells cannot be replaced)
1:10:40 – How close we are to senolytics approved for use
1:11:56 – How it is good to donate blood
1:12:50 – Any non-prescription senolytics available
1:14:32 – Revisiting SA-beta-Gal
1:18:10 – Whether a young blood transfusion is comparable to a blood donation (as far as reducing negative blood components)
1:18:59 – Lifespan.io’s Rejuvenation Roadmap
1:20:21 – The relation of mental stress to senescent-cell accumulation
1:23:00 – Balancing the effects of senolytics
1:25:12 – Potentially less toxic alternatives to galactose-conjugated navitoclax
1:28:25 – Potential direction of research into senescence in the next 5-10 years
1:30:42 – Whether the Hallmarks of Aging will change
1:31:51 – How therapies for aging can best be employed
1:33:31 – Potentially the best way to treat senescent cells
1:35:10 – How the application of senescent-cell treatment is challenging because of the variety of lifespans of our various cells
1:36:58 – Where the best senolytics research is happening
1:40:22 – Whether senolytic therapies stop being beneficial for a person at a certain age
1:42:06 – Whether the loss of the ability of the body to remove senescent cells is indicative of a deeper problem
1:43:48 – What we can gain from knowing how mice respond to senolytic therapies
1:47:14 – Just how complex senescent cells and senescence can be
1:49:38 – How rejuvenating senescent cells could be better than destroying them
1:50:30 – Dr. Rebbaa’s closing remarks

***

See Dr. Abdelhadi Rebbaa’s LinkedIn profile: https://www.linkedin.com/in/abdelhadi-rebbaa-32bb9279/

Join the U.S. Transhumanist Party for free, no matter where you reside: https://transhumanist-party.org/membership/

Why I Hope to Be Alive at 75 – Article by Steve Hill

Why I Hope to Be Alive at 75 – Article by Steve Hill

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Steve Hill

Editor’s Note: In this article, originally published on November 13, 2020, by our allies at the Life Extension Advocacy Foundation (LEAF), Steve Hill explains why the attitude of Joe Biden’s new advisor on COVID-19 strategy, Ezekiel Emanuel, is supremely counterproductive. Emanuel infamously wrote in 2014 that he hopes to die at age 75. Given that COVID-19 is a disease whose toll is greatly amplified by biological aging, Emanuel’s statements render him uniquely ill-suited  to remedy the ravages of the ongoing pandemic. Moreover, his pessimism toward what life is like at age 75 is no longer justified, in light of emerging medical advances that could enable rejuvenation and biological youthfulness for those who are in late middle age today. Perhaps, if he sees these advances become a reality in the not-too-distant future, Emanuel might change his mind regarding the desirability of longer lifespans.

~ Gennady Stolyarov II, Chairman, United States Transhumanist Party, November 17, 2020

2020 has been a strange year for a variety of reasons, but the societal changes that the COVID-19 pandemic has created are probably the strangest. However, it is perhaps even stranger that Dr. Ezekiel Emanuel has been appointed to advise Joe Biden on COVID strategy.

Emanuel is best known for writing a controversial article in the October 2014 edition of The Atlantic, headlined “Why I Hope to Die at 75”, in which he strongly rejects the desire to live beyond the age of 75 and expresses his opinion that continuing to live after such an age is meaningless.

Living too long is also a loss. It renders many of us, if not disabled, then faltering and declining, a state that may not be worse than death but is nonetheless deprived.

Needless to say, I strongly disagree with this baffling point of view and am somewhat concerned that someone who thinks this way of his own life, and presumably the lives of others, may be appointed to a position of influence for a disease whose primary risk group is the elderly. This seems almost as foolhardy as spending a vacation weekend in a caravan with Hannibal Lecter.

Emanuel listed quite a few methods by which people extend their lives and stated that they were a “valiant effort to cheat death and prolong life as long as possible,” but his response to them was, “I reject this aspiration. I think this manic desperation to endlessly extend life is misguided and potentially destructive.”

Age is the #1 risk factor for COVID

The scientific evidence clearly shows that the primary risk factor for contracting and dying from COVID-19 is age, with people over the age of 75 at particularly high risk. This is due to the decline of the immune system, which becomes increasingly weak and dysfunctional with age in a process known as immunosenescence.

Globally, the strategy has been to try to shield these vulnerable people as best as possible due to their weakened immune systems and limit their exposure to the disease while vaccines are developed.

Needless to say, I find Biden’s nomination of him to address a disease that mostly affects seniors ironic in itself, given that he thinks the lives of most people beyond 75 are pointless and that they don’t live meaningful lives and would be better off embracing death rather than desperately trying to extend them. Therefore, I hope for the sake of the older people in our society that he has rethought his priorities.

Why I hope to be alive at 75

Predictably, there is already a storm raging on social media around his appointment, so there is no purpose to adding more fuel to that fire. Instead, I am going to talk about why the future of aging could be very different to the grim picture that Emanuel paints.

At age 63, he is getting closer to the age at which he thinks life is pointless, and I believe that a large reason why he is so pessimistic about life beyond 75, whether he realizes it or not, is based on the current state of medicine. This line of reasoning does not take into account how medicine, and in particular how we treat aging could change in the next decade or two.

Current medicine does a great job at keeping people alive for longer, but they often have to live with one or more chronic diseases. Given that, I am not surprised that Emanuel is not enamored with living a long life, especially as that could entail being disabled, bed-bound, or otherwise suffering a poor quality of life as the result of debilitating age-related diseases.

Thankfully, the world healthcare strategy is slowly starting to shift to one of prevention over cure, but right now, the typical approach is to play whack-a-mole with diseases. As one pops up, it is treated, then the next, and the next, and so on. This strategy works great for infectious diseases, but it is an exercise in futility and diminishing returns when applied to the chronic diseases of aging.

However, things could be different in the not so distant future, and being 75 could see the majority of people far more fit, healthy, and vibrant than ever before in human history thanks to advances in aging research. Therapies that directly target aging could potentially make people biologically younger (in particular their immune systems) and much more able to withstand COVID-19 and other diseases.

As explained on LEAF’s What is Aging? page, aging consists of multiple processes (“hallmarks”) that gradually cause damage to organs and tissues and lead to age-related diseases. Rejuvenation biotechnology is advanced medical technology that directly addresses any of the various aging processes in order to restore tissue and organ function to a more youthful state, thereby ameliorating, delaying, or preventing age-related diseases. Let’s take a brief look at some of the promising near-future research that could bear fruit by the time Emanuel reaches 75 and perhaps change his mind.

Rejuvenating the immune system

The decline of the immune system is a key reason why the elderly are most susceptible to infectious diseases such as COVID, and there has been considerable interest in the rejuvenation of the immune system in recent years.

Dr. Greg Fahy from intervene immune has had some early success with thymus rejuvenation in a small human pilot study and demonstrated that it is possible to cause the thymus, which shrinks and loses its capacity to produce immune T cells during aging, to regrow and resume production of those cells. Dr. Fahy is now moving forward into a larger-scale study, and if the results continue to be positive, it is not hard to imagine that thymus regrowth could become a staple of helping the elderly stay healthy.

Another example of immune rejuvenation is currently being developed by Samumed, a biotechnology company that is developing drugs that target the Wnt pathway to restore it to youthful function. The Wnt pathway is a key pathway that regulates the function of our stem cells and ensures that they supply our tissues and organs with new cells to replace losses from injury, disease, and wear and tear.

If successful, this approach would allow the body to resume efficient repair of tissues, and it would replenish aged and failing tissues and organs with fresh, healthy cells supplied by the rejuvenated stem cells.

Therapeutic plasma exchange

Researchers Irina and Mike Conboy at UC Berkeley have been researching blood factors and their role in aging for over two decades. During that time, they have identified a number of factors present in aged blood that appear to regulate aging.

These factors are also present in younger people, but in typically far lower amounts, and tend to serve useful functions. However, during aging, the levels of these proteins become deregulated, and they often rise to detrimental levels and cause damage to the body, which typically involves preventing stem cells from working and tissue from regenerating.

Decades’ worth of research from the Conboy lab has shown that, in mice at least, it is possible to filter out these harmful pro-aging blood factors and bring them back down to a level similar to younger animals. When this happens, the result is rejuvenation of tissues and the reversal of some of the aspects of aging, making the mice more youthful.

This approach uses an already approved technique known as therapeutic plasma exchange to filter and calibrate these key factors and could be readily modified for human use. Should the results seen in animals translate to humans using this approach, it would have a profound effect on our health as we age and potentially delay, prevent, or even reverse some age-related diseases.

Conclusion

These are only some of the examples of why healthy life expectancy could rise significantly in the near future, and there are plenty of reasons to remain future positive. This is the future direction of medicine and healthcare that we support at Lifespan.io, a world where being 75 does not mean you are thrown on the scrap heap and where people like Emanuel will no longer feel that life has no meaning. I am confident that in such a world, being 75 would not be the burden he thinks it will be, and this is why I hope to be alive at 75.

Steve Hill serves on the Life Extension Advocacy Foundation (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, interviewed over 100 of the leading researchers in the field, hosted livestream events focused on aging, along with attending various medical industry conferences. His work has been featured in H+ Magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Swiss Monthly, 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.

Petition by Biogerontology Global to Declare Aging the Top Global Risk

Petition by Biogerontology Global to Declare Aging the Top Global Risk

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Biogerontology Global

Editor’s Note: The U.S. Transhumanist Party encourages its members to support the petition created by our allies at Biogerontology Global, which aims to declare aging the largest global risk. The U.S. Transhumanist Party holds significant life extension as its first Core Ideal, and biological aging is the greatest barrier to significant life extension. Overcoming biological aging through the progress of science and technology is therefore the greatest moral imperative of our time.

 ~ Gennady Stolyarov II, Chairman, United States Transhumanist Party, August 21, 2020

Sign this petition on Change.org here. 

TL;DR: You have a terminal disease and so does everyone you love. Human aging kills more people (100,000 per day), causes more suffering, and harms society more than anything else – by a large margin. Scientific discoveries and technological advancements are making it clearer by the day that given enough funding and effort, human aging can be cured. In other words, we should cure aging and we can cure aging. For that to happen, however, a large cultural shift must take place in favor and support of the idea – which currently faces significant opposition and neglect. The Global Risks Report is an annual publication released by the World Economic Forum that ranks global risks. It is read by a large portion of world leaders and citizens alike. If human aging were to top this list of risks or, at the very least, make the cut, it would help the world see aging as an urgent threat and potentially save the life of whomever is reading this. Sign this petition if you want to help declare aging the top global risk.

Detailed Description:

Each year, the World Economic Forum, with support from Marsh and McLennan Companies, releases a Global Risks Report. This report, as the name suggests, includes detailed analyses and rankings of the greatest threats facing the world each year. Each major threat is referred to as a risk. The two-part centerpiece of this report consists of a ranking of the top 5 risks in terms of likelihood, and another ranking of the top 5 risks in terms of impact. There are also “trends”. Per the World Economic Forum, a “trend” is defined as a long-term pattern that is currently evolving and that could contribute to amplifying global risks and/or altering the relationship between them. Simply put, trends are not seen as the major global threats, but instead as factors that may influence them. In past years “population ageing” has sometimes been recognized as a trend, but nothing more.

The purpose of this petition is to get the World Economic Forum to not only recognize human aging as a global risk but as the global risk. Human aging kills approximately 100,000 people per day. In developed countries, 90% of all deaths are at the hands of age-related disease. How could it be that the largest cause of human death (by an immense margin) is not seen as the most pressing issue in the world? Not to mention, the amount of human suffering caused by the diseases of old age is arguably unparalleled. Why is this mass suffering and death justified rather than fought?

In 2020, the top 5 global risks in terms of likelihood were all environmental. Solving aging would significantly lessen these risks. Without human aging, people would not be planning to die. They would have a stake in the long-term future of the environment. This radical sociological shift could be the push humanity needs to start consistently making environmentally beneficial decisions. Overpopulation should not be a concern, as we have more than enough land and resources to accommodate a much larger population on planet Earth. More efficient methods of resource allocation are the remedy for current problems that are often falsely attributed to a growing global population. Additionally, emerging agricultural technologies such as hydroponics, which can boost crop yields by up to 11 times, and vertical farming, which can further maximize that factor, will continue to make it even easier to feed more people.

Without human aging, we would no longer have such a substantial portion of society that is sick and unable to work or enjoy the activities that they so loved in their youth. This could work wonders for global productivity. Not to mention, people who are not gripped by old age and stay in the workforce much longer than they do now would become more experienced than the workers of today, boosting global productivity even further.

People would be happier in a world without death by aging. They would have much more time with their loved ones. They would be able to have and achieve long-term goals without the inevitability of death by aging to get in the way. They would have the time to live fuller lives. Happier societies commit less crime, so that is another societal ill that curing aging could help dismantle.

Many of humanity’s greatest threats are directly or indirectly the result of human aging. If we were to solve aging, many of the global risks mentioned in past Global Risks Reports would no longer be major issues.

We tend to think of death by aging as an inevitability of life. However, scientists in the field of biogerontology (the study of biological aging), billionaire businesspeople and philanthropists, technologists, and many other professionals/activists are working to make death by aging optional. Science and technology have already drastically improved lifespan and health in recent years by a considerable margin; however, it can do more. The molecular mechanisms by which we age (The Hallmarks of Aging) have been identified by scientists. Interventions such as senolytic drugs have already been proven to counteract some of these mechanisms. Cellular pathways have been genetically modified to extend the lifespans of model organisms to the equivalent of 500 human years. Google has launched and given over a billion dollars to its subsidiary, Calico, which researches aging. Many other companies and nonprofits, including the SENS Research Foundation and Methuselah Foundation, are tackling aging or its subparts. Growing support and advancement makes it clear that humanity will cure aging eventually, but so many people die each day of aging that eventually is not good enough. We must cure aging as soon as possible to save ourselves and those we love.

This petition recognizes that a cultural shift at every level of society is necessary for leaders and organizations in this space to garner enough support to cure human aging within our lifetimes. If this petition were to succeed, that cultural shift would come easier. Between the large portions of world leaders and citizens that read and respect the Global Risks Report, many more people would recognize aging as a problem they can solve and should solve if the report were to name aging as a global risk. This would lead to increased funding to cure aging, more talented scientists and technologists joining the space, and a greater opportunity to cure aging within our lifetimes!

Aging is objectively the largest global risk to humanity in terms of likelihood and impact. We ask that the World Economic Forum recognize this and act accordingly.

Sign this petition to help forge a better existence for yourself, your loved ones, and all of humanity.

Learn more at @biogerontology on Instagram.

The Hallmarks of Aging: Deregulated Nutrient Sensing – Article by Ariah Mackie

The Hallmarks of Aging: Deregulated Nutrient Sensing – Article by Ariah Mackie

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Ariah Mackie

Editor’s Note: In this article, Ariah Mackie explains that there are four key proteins involved in nutrient sensing that might be key contributors to aging.  This article was originally published by the Life Extension Advocacy Foundation (LEAF).

                   ~ Kenneth Alum, Director of  Publication, U.S. Transhumanist Party, February 15, 2018

As part of our ongoing series covering the hallmarks of aging, we are taking a look at deregulated nutrient sensing today and how these four pathways regulate metabolism and influence aging.

To understand studies on nutrient sensing in the context of aging, let’s introduce four key protein groups. In this post, we’ll explore the pathways they help control and how they affect aging. These key proteins are IGF-1, mTOR, sirtuins, and AMPK [2]. We call these proteins “nutrient sensing” because nutrient levels influence their activity [2].

IGF-1 and the IIS pathway: The Basics

Insulin-like growth factor (IGF-1) inhibits the secretion of growth hormone (GH) by binding to a special receptor on the surface of a cell [1]. Like insulin, IGF-1 takes part in glucose sensing. Both it and insulin are part of the aptly named “insulin and insulin-like growth factor” (IIS) pathway [2].

Attenuation of the IGF-1/GH pathway (IIS) appears to improve lifespan in several model organisms [1]. For example, PI3K mice, which have a weakened IIS pathway, live longer [2]. Additionally, FOXO, a transcription factor (a protein that affects the production of RNA), lengthens lifespans in worms and fruit flies by attenuating IIS signaling [2]. In other studies, IGF-1 improves healthspan even when it does not lengthen lifespan [2].

There’s also evidence of a harmful impact when IGF-1 activity is high. Higher levels of IGF-1 are associated with increased risk of some types of cancer [1]. This increased cancer risk might be due to IGF’s ability to promote pathways that result in increased cell production [1].

IIS and the Not-So-Basics

IGF-1 expression and the IIS pathway are a bit of a paradox. Since it looks like turning down the IIS pathway promotes longevity, you might expect the IIS pathway to be very active in old organisms. It looks like high IIS ages us, after all. However, that’s not the case. In both accelerated and normal aging models, we see that the IIS pathway decreases [2].

One explanation for this weirdness is that it’s a last-ditch measure of the organism to increase its own lifespan. Yet, this short-term decrease in IIS activity can be harmful. In fact, it is so harmful that IGF-1 supplementation is beneficial [2]. What this seems to point to is a dichotomy concerning the expression of IIS. Overall, it looks like turning down the IIS pathway is good over the long term for longevity. This might be because it causes the reduction of metabolism and cell growth, which lessens wear and tear [2]. However, the body’s attempt to do the same in later life goes too far and too late to be truly beneficial.

How IGF-1 affects human lifespan is still fuzzy as well [1]. On one hand, there is an indication of a longevity effect with reduced IGF-1 activity in those with Laron syndrome (who don’t have functional growth hormone receptors), female nonagenarians, and extremely long-lived people [1]. Yet, the epidemiological data is not clear enough to be conclusive on IGF-1’s effects on humans [1]. This is partially due to the difficulty of structuring epidemiological studies on IGF-1, as many external factors, such as nutrition, can confound results [1].

mTOR

Mechanistic target of rapamycin (mTOR) is composed of the mTORC1 and mTORC2 protein complexes. It senses amino acids and is associated with a nutrient abundance [2]. It is a kinase, which means it adds phosphates to molecules [2]. mTOR is a champion regulator of anabolic metabolism [2], the process of building new proteins and tissues. In this way, how it functions is similar to the IIS pathway [2]. At any given moment, the metabolism is either breaking down old parts (catabolism) or building new ones (anabolism). Both mTOR and the IIS are part of the anabolic side of metabolism.

Lower activity of mTOR lengthens lifespan in model organisms, such as mice, yeast, worms, and flies [2]. Along those lines, mTOR activity increases in the hypothalami of aged mice, which promotes late-life obesity. With rapamycin, an inhibitor of mTOR, these effects are ameliorated [2]. As is the case with, IIS, lowered expression of mTOR is not always beneficial. Low expression of mTOR can harm healing and insulin sensitivity and can cause cataracts and testicular generation in mouse models [2].

Sirtuins

Sirtuins are a family of proteins that act as NAD(+) dependent histone deacetylases [2]. To explain what that means, let’s start with histones. Histones are the proteins that DNA wraps around. They serve as a way to compact the DNA (which is very long) in the nucleus, especially during cell division. Histones also help control the expression of genes by spatially making some genes more or less available for proteins like RNA polymerase to attach. On histones, there are lysines, a type of amino acid. It is on these lysines that histone deacetylases remove acetyl groups, which are small molecules. If that sounds too confusing, remember this: adding or removing acetyl groups helps control the expression of genes. In such a manner, sirtuins help control gene expression.

Sirtuins detect when energy levels are low by sensing the coinciding increase of NAD+ [2]. They also help control catabolic metabolism [2]. Upregulating some sirtuins produces anti-aging or health-promoting effects [2]. However, some sirtuins have only weak effects in some species, which makes summarizing their effects difficult. For example, in worms, higher expression of SIR2 yields only slight gains in longevity [2]. Overexpression of SIR2’s most similar counterpart in mice, SIRT1, appears to improve health during aging but not lifespan [2].

Another mouse sirtuin, SIRT6, seems to promote longevity more robustly [2]. Mice deficient in it experience accelerated aging. Conversely, turning it up results in increased longevity [2]. There is also SIRT3, which has been shown to help the regeneration ability of old hematopoietic (blood and immune cell producing) cells when overexpressed [2].

AMPK

AMP-activated kinase (AMPK) senses AMP (adenosine monophosphate) and ADP (adenosine diphosphate). These long-named molecules are present in higher quantities when nutrients are scarce [2].Therefore, it is easiest to remember AMPK as a sensor of fasted or calorie-restricted states and catabolism [2]. Molecularly, AMPK acts by adding phosphates to serine and threonine [3]. By doing so, AMPK helps regulate metabolism [2].

Like sirtuins, higher activity of AMPK has longevity-promoting effects [2]. To illustrate, metformin, a diabetes drug that appears to have a life-extension effect, activates AMPK in mice and worms [2]. Calorie restriction, which is known to increase lifespan in at least short-lived animals, can also increase the activity of AMPK [3]. Conversely, less AMPK sensitivity due to cellular stress results in oxidative stress, reduced autophagy, metabolic syndrome, more fat disposition, and inflammation [3].

Conclusion

In summary, there are four key proteins involved in nutrient sensing that might be key contributors to aging. Turning down the pathways of the first two, IGF-1 and mTOR, promote longevity. Both of these are involved in anabolic metabolism (building tissues) and increase in states of nutrient abundance[2]. Conversely, turning up the activity of the last two, sirtuins and AMPK, helps longevity. They work to promote catabolic metabolism (breaking down tissues) and increase with nutrient scarcity [2].

References

[1] Milman, S., Huffman, D. M., & Barzilai, N. (2016). The Somatotropic Axis in Human Aging: Framework for the Current State of Knowledge and Future Research. Cell Metabolism, 23(6), 980-989. doi:10.1016/j.cmet.2016.05.014

[2] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

[3] Salminen, A., & Kaarniranta, K. (2012). AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Research Reviews, 11(2), 230-241. doi:10.1016/j.arr.2011.12.005

About Ariah Mackie

Ariah received a Bachelor’s Degree in Biomolecular Engineering from the University of California in Santa Cruz in 2016. Her career interests are in regenerative medicine for aging, teaching, computational biology, genomics, and bioinformatics.

About LIFE EXTENSION ADVOCACY FOUNDATION (LEAF)

In 2014, the Life Extension Advocacy Foundation was established as a 501(c)(3) non-profit organization dedicated to promoting increased healthy human lifespan through fiscally sponsoring longevity research projects and raising awareness regarding the societal benefits of life extension. In 2015 they launched Lifespan.io, the first nonprofit crowdfunding platform focused on the biomedical research of aging.

They believe that this will enable the general public to influence the pace of research directly. To date they have successfully supported four research projects aimed at investigating different processes of aging and developing therapies to treat age-related diseases.

The LEAF team organizes educational events, takes part in different public and scientific conferences, and actively engages with the public on social media in order to help disseminate this crucial information. They initiate public dialogue aimed at regulatory improvement in the fields related to rejuvenation biotechnology.

Hallmarks of Aging: Epigenetic Alterations – Article by Steve Hill

Hallmarks of Aging: Epigenetic Alterations – Article by Steve Hill

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Steve Hill

Editor’s Note: In this article, Mr. Steve Hill discusses one of the hallmarks of aging – in this case, Epigenetic Alterations. It is part of a paper published in 2013. It divides aging into a number of distinct categories (“hallmarks”) of damage to explain how the aging process works and how it causes age-related diseases [1]. This article was originally published by the Life Extension Advocacy Foundation (LEAF).

                        ~ Kenneth Alum, Director of Publication, U.S. Transhumanist Party, October 18, 2017

What are epigenetic alterations?

The DNA in every one of our cells is identical, with only small variations, so why do our various organs and tissues look so different, and how do cells know what to become?

DNA is modified by the addition of epigenetic information that changes the pattern of gene expression in a cell, suppressing or enhancing the expression of certain genes in a cell as the situation demands. This is how a cell in the liver knows that it needs to develop into a liver cell; the epigenetic instructions make sure that it is given the right orders to become the correct cell type.

At a basic level, these epigenetic instructions make sure that the genes needed to develop into a liver cell are turned on, while the instructions specific to other types of cells are turned off. Imagine if a heart cell was given the wrong instructions and became a bone cell!

How epigenetic alterations accumulate

The aging process can cause alterations to our epigenome, which can lead to alterations in gene expression that can potentially change and ultimately compromise cell function. As an example, epigenetic alterations of the immune system can harm activation and suppress immune cells, thus causing our immune system to fail and leaving us vulnerable to pathogens.

Inflammation is implicated in epigenetic alterations, and studies show that caloric restriction slows the rate of these epigenetic changes [2]. Metabolism and epigenetic alterations are closely linked with inflammation, facilitating a feedback loop leading to ever-worsening epigenetic alterations. Alterations to gene expression patterns are an important driver of the aging process. These alterations involve changes to DNA methylation patterns, histone modification, transcriptional alterations (variance in gene expression) and remodeling of chromatin (a DNA support structure that assists or impedes its transcription).

In the cell, gene expression is activated by hypomethylation (a loss of methylation) or silenced by hypermethylation (an increase of methylation) at a gene location. The aging process causes changes that reduce or increase methylation at different gene locations throughout the body. For example, some tumour suppressor genes become hypermethylated during aging, meaning that they cease functioning, which increases the risk of cancer [3]. Post-translational modifications of histones regulate gene expression by organizing the genome into active euchromatin regions, where DNA is accessible for transcription, or inactive heterochromatin regions, where DNA is compacted and less accessible for transcription. The aging process causes changes to these regions, which changes gene expression.

The aging process also causes an increase in transcriptional noise, which is the primary cause of variance in the gene expression happening between cells [4]. Researchers compared young and old tissues from several species and identified age-related transcriptional changes in the genes encoding key components of inflammatory, mitochondrial, and lysosomal degradation pathways [5].

 Finally, chromatin remodeling alters chromatin from a condensed state to a transcriptionally accessible state, allowing transcription factors and other DNA binding proteins to access DNA and control gene expression.

Conclusion

If we can find ways to reset age-related epigenetic alterations, we can potentially improve cell function, thus improving tissue and organ health.

One potential approach is the use of reprogramming factors, which reset cells to a developmental state, thus reverting epigenetic changes. We have been doing this for over a decade to create induced pluripotent stem cells, and recent work has seen a therapy based on that technique applied to living animals to reset their epigenetic alterations [6]. This reversed a number of age-related changes, and work is now proceeding with the goal of translating this to humans.

Epigenetic alterations might be considered like a program in a computer, but in this case, it is the cell, not a computer, being given instructions. Ultimately, damage causes changes that contribute to the cell moving from an efficient “program” of youth to a dysfunctional one of old age. If we can reset that program, we can potentially address this hallmark of aging, and a number of researchers are working on that right now.

 

Literature

[1] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

[2] Maegawa, S., Lu, Y., Tahara, T., Lee, J. T., Madzo, J., Liang, S., … & Issa, J. P. J. (2017). Caloric restriction delays age-related methylation drift. Nature Communications, 8.
[3] Maegawa, S., Hinkal, G., Kim, H. S., Shen, L., Zhang, L., Zhang, J., … & Issa, J. P. J. (2010). Widespread and tissue specific age-related DNA methylation changes in mice. Genome research, 20(3), 332-340.

[4] Bahar, R., Hartmann, C. H., Rodriguez, K. A., Denny, A. D., Busuttil, R. A., Dollé, M. E., … & Vijg, J. (2006). Increased cell-to-cell variation in gene expression in ageing mouse heart. Nature, 441(7096), 1011-1014.

[5] De Magalhães, J. P., Curado, J., & Church, G. M. (2009). Meta-analysis of age-related gene expression profiles identifies common signatures of aging. Bioinformatics, 25(7), 875-881.

[6] Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., … & Araoka, T. (2016). In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. Cell, 167(7), 1719-1733.

 

About Steve Hill

As a scientific writer and a devoted advocate of healthy longevity technologies, Steve has provided the community with multiple educational articles, interviews, and podcasts, helping the general public to better understand aging and the means to modify its dynamics. His materials can be found at H+ Magazine, Longevity Reporter, Psychology Today, and Singularity Weblog. He is a co-author of the book Aging Prevention for All – a guide for the general public exploring evidence-based means to extend healthy life (in press).

About LIFE EXTENSION ADVOCACY FOUNDATION (LEAF)

In 2014, the Life Extension Advocacy Foundation was established as a 501(c)(3) non-profit organization dedicated to promoting increased healthy human lifespan through fiscally sponsoring longevity research projects and raising awareness regarding the societal benefits of life extension. In 2015 they launched Lifespan.io, the first nonprofit crowdfunding platform focused on the biomedical research of aging.

They believe that this will enable the general public to influence the pace of research directly. To date they have successfully supported four research projects aimed at investigating different processes of aging and developing therapies to treat age-related diseases.

The LEAF team organizes educational events, takes part in different public and scientific conferences, and actively engages with the public on social media in order to help disseminate this crucial information. They initiate public dialogue aimed at regulatory improvement in the fields related to rejuvenation biotechnology.

Hallmarks of Aging: Genomic Instability – Article by Steve Hill

Hallmarks of Aging: Genomic Instability – Article by Steve Hill

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Steve Hill

Editor’s Note: In this article, Mr. Steve Hill discusses one of the hallmarks of aging – in this case, Genomic Instability. This article was originally published by the Life Extension Advocacy Foundation (LEAF).

~ Kenneth Alum, Director of Publication, U.S. Transhumanist Party, October 17, 2017

What is genomic instability?

The cells of your body produce a constant flow of proteins and other materials; these are built according to the blueprints contained in our DNA and are vital to cell function and survival. A large amount of information contained in the DNA is ignored during this process, and this is thought to be junk DNA, remnants of our evolutionary past that are no longer used.

However, if a part of the DNA important to cell function mutates or is damaged, the cell can experience a loss of proteostasis, in which the cell produces misfolded proteins. These misfolded proteins can be very harmful, such as when neurons in the brain produce masses of the toxic amyloid beta protein, as seen in Alzheimer’s disease.

Now, the odd dysfunctional cell is not really a huge problem; however, as we get older, an increasing number of cells succumb to this damage and begin to accumulate in tissue over time. Eventually, the number of these damaged cells reaches a point where tissue or organ function is compromised. Normally, the body removes these problem cells via a self-destruct sequence known as apoptosis, a sort of kill switch that senses the damage and destroys the cell in conjunction with the immune system.

Unfortunately, some cells evade apoptosis, taking up space in the tissue and pumping out inflammatory signals that damage the local tissue. These cells are known as senescent cells, and we will be covering them in a later Hallmarks article.

Another possible outcome of damaged DNA is cells that mutate and do not become senescent cells or destroy themselves via apoptosis. These cells continue to replicate, becoming more mutated each time they divide, and if a mutation damages the systems that regulate cell division or switches off the safety mechanisms against tumor formation, this can lead to cancer. The unchecked and rampant cell growth of cancer is probably the most well-known result of genomic instability.

How DNA damage accumulates

There are many ways for DNA to become damaged. UV rays, radiation, chemicals, and tobacco are all examples of environmental stressors that can damage the genome. Even chemotherapy agents designed to kill cancer can also potentially cause DNA damage and senescent cells, leading to later relapse [2].

Finally, even if we avoided all the external threats to our DNA, the body still damages itself. Reactive oxygen and nitrogen species produced during the operation of normal metabolism can damage both DNA and mitochondrial DNA.

Thankfully, we have evolved a robust network of repair systems and mechanisms that can repair most of this damage. We have enzymes that can detect and repair broken strands of DNA or reverse alterations made to base pairs. This repair process is not perfect, and sometimes the DNA is not repaired. This can lead to the cell replication machinery misreading the information contained in the DNA, causing a mutation.

As mutations are passed to daughter cells, the cell tries to prevent this from happening by checking DNA integrity before and after replication. Unfortunately, some cells do manage to slip through the net.

The consequences of DNA damage

A large number of age-related diseases are linked to damaged DNA or faulty DNA repair systems. Alzheimer’s, Parkinson’s, Lou Gehrig’s disease (ALS), and cancer are all the result of genomic instability.

Another example are the progeric diseases. Progerias are congenital disorders that result in rapid aging-like symptoms and a dramatically shortened lifespan, with Hutchinson-Gilford progeria syndrome (HGPS) probably being the most well known. The disease is caused by a defect in Lamin A, a major component of a protein scaffold on the inner edge of the nucleus called the nuclear lamina. The lamina helps organize nuclear processes, such as RNA and DNA synthesis, and lamins are responsible for supporting key proteins in the DNA repair process.

This defect leads to HGPS sufferers only living until their early 20s and developing atherosclerosis, stiff joints, hair loss and wrinkles, and other accelerated aging-like characteristics.

Conclusion

Despite the various repair systems we have evolved, our body is constantly being assaulted from exposure to environmental stressors and even damaged through its own metabolic processes. Coupled with this, our repair systems also decline in effectiveness over time, meaning that DNA damage and mutations are inevitable.

There is some evidence to suggest that caloric restriction may help combat this, but as of now, no drugs or therapies are available yet that can prevent or repair DNA damage. The good news is human trials for DNA repair are launching this year at Harvard, and Dr. David Sinclair and other researchers are also working on their own solutions.

For the time being, the best we can do is to avoid risks, such as excessive sun exposure, industrial chemicals, smoking, and, of course, staying away from radioactive waste; there are no comic-book superpowers from these mutations!

Literature

[1] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

[2] Demaria, M., O’Leary, M. N., Chang, J., Shao, L., Liu, S., Alimirah, F., … & Alston, S. (2017). Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer discovery, 7(2), 165-176.

About Steve Hill

As a scientific writer and a devoted advocate of healthy longevity technologies, Steve has provided the community with multiple educational articles, interviews, and podcasts, helping the general public to better understand aging and the means to modify its dynamics. His materials can be found at H+ Magazine, Longevity Reporter, Psychology Today, and Singularity Weblog. He is a co-author of the book Aging Prevention for All – a guide for the general public exploring evidence-based means to extend healthy life (in press).

About LIFE EXTENSION ADVOCACY FOUNDATION (LEAF)

In 2014, the Life Extension Advocacy Foundation was established as a 501(c)(3) non-profit organization dedicated to promoting increased healthy human lifespan through fiscally sponsoring longevity research projects and raising awareness regarding the societal benefits of life extension. In 2015 they launched Lifespan.io, the first nonprofit crowdfunding platform focused on the biomedical research of aging.

They believe that this will enable the general public to influence the pace of research directly. To date they have successfully supported four research projects aimed at investigating different processes of aging and developing therapies to treat age-related diseases.

The LEAF team organizes educational events, takes part in different public and scientific conferences, and actively engages with the public on social media in order to help disseminate this crucial information. They initiate public dialogue aimed at regulatory improvement in the fields related to rejuvenation biotechnology.