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Building a Future Free of Age-Related Disease

NAD+ and Cellular Senescence Pathways Interact

A new publication highlights how the complex interaction of NAD+ and cellular senescence pathways may complicate proposed anti-aging therapies that boost NAD+ using precursors.

What are epigenetic alterations?

One of the proposed reasons we age is the changes to gene expression that our cells experience as we get older; these are commonly called epigenetic alterations. These alterations harm the fundamental functions of our cells and can increase the risk of cancer and other age-related diseases.

The DNA in each of our cells is the same, with only slight differences, so why do our various organs and tissues look so different, and how do cells know what to become?

Gene expression is modified by the addition of epigenetic markers to the DNA changing the pattern of gene expression in a cell, suppressing or enhancing the expression of certain genes in a cell as the situation demands. You might think of DNA as the building blocks and epigenetics as the instruction manual that explains how to assemble those blocks to make a certain structure to suit a particular situation.

This is how a cell in the liver knows that it needs to be a liver cell: the epigenetic instructions make sure that it is given the right guidance 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.

However, as we age, our cells are exposed to environmental factors and are subject to negative changes in their genome through epigenetic mechanisms. Such changes accumulate over time and have been correlated with the decline observed in aging cells.

Epigenetic alterations in aging include changes to methylation patterns and in general, these correlate with a decrease in the amount of heterochromatin and an increase in chromosome fragility and transcriptional alterations (variance in gene expression), remodeling of chromatin (a DNA support structure that assists or impedes its transcription), and transcriptional noise.

The consequences of epigenetic alterations

If epigenetic alterations happen, then the cell could potentially lose its cell memory, forgetting what type of cell it is, or begin to behave in a harmful manner. This appears to be the case with the thymus; when we age, the thymic epithelial cells of that organ start to lose cell identity and begin to change into fat or mesenchymal cells.

Another example of how epigenetic alterations can harm us is the immune system; changes to cell behavior there can interfere with immune cell activation or suppress immune cells, leaving us vulnerable to pathogens.

One consequence of this is the inappropriate activation of the immune system, which causes inflammation and contributes to the age-related background of chronic inflammation. This is known as “inflammaging“, and it harms tissue repair and prevents effective regeneration. Metabolism and epigenetic alterations are closely linked with inflammation, facilitating a feedback loop that leads to ever-worsening epigenetic alterations.

Partial cellular reprogramming appears to be a potential way to fix this aging process and reset the cells to a younger epigenetic state.

Interacting NAD+ and cellular senescence pathways

Essentially, age-related epigenetic alterations can cause cells to become functionally compromised or less efficient as well as potentially dysfunctional. The weight of evidence is increasingly supporting the primary role that epigenetic alterations have during aging and how they drive and interact with the other aging processes.

Two age-related changes driven at least in part by epigenetic alterations that are demonstrably treatable are the accumulation of senescent cells and the decline of NAD+ levels in cells; however, while it is clear that the two are linked, the exact relationship between these two has been unclear.

NAD+

Nicotinamide adenine dinucleotide (NAD) is a coenzyme found in all living cells. It is a dinucleotide, which means that it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base, and the other contains nicotinamide.

NAD+ is created from simple building blocks, such as the amino acid tryptophan, and it is created in a more complex way via the intake of food that contains nicotinic acid (niacin) or other NAD+ precursors. These different pathways ultimately feed into a salvage pathway, which recycles them back into the active NAD+ form.

In metabolism, NAD facilitates redox reactions, carrying electrons from one reaction to another. This means that NAD is found in two forms in the cell: NAD+ is an oxidizing agent that takes electrons from other molecules in order to become its reduced form, NADH. NADH can then become a reducing agent that donates the electrons it carries. The transfer of electrons is one of the main functions of NAD, though it also performs other cellular processes, including acting as a substrate for enzymes that add or remove chemical groups from proteins in post-translational modifications.

NAD plays a central role in metabolism and cell signaling and function facilitating glycolysis, oxidative phosphorylation, the citric acid cycle, and poly-ADP-ribose polymerases (PARPs), sirtuins, and CD38/157 ectoenzymes. NAD facilitates DNA repair via its interaction with PARPs as well as interacting with sirtuins, which are protein deacetylases that regulate cell survival, cell cycle, apoptosis, mitochondrial function, and energy production.

Accumulating evidence suggests that NAD+ systemically declines with age in a variety of organisms, including rodents and humans, which contributes to the development of many age-related diseases.

Quite simply, without NAD, life would be impossible, so it is unsurprising that the decline of NAD is linked to the various proposed causes of aging: DNA damage, mitochondrial dysfunction, loss of proteostasis, deregulated nutrient sensing, stem cell exhaustion, and epigenetic alterations. For this reason, there is a great deal of interest in boosting NAD+ levels via precursors, including nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), with the hope of delaying or even preventing certain aspects of age-related functional decline and diseases.

Cellular senescence

As we age, increasing numbers of our cells enter into a state known as cellular senescence, which, like epigenetic alterations, is one of the hallmarks of aging.

Senescent cells do not divide or support the tissues of which they are part; instead, they emit a range of potentially harmful chemical signals that encourage nearby healthy cells to enter the same senescent state. Their presence causes many problems: they reduce tissue repair, increase chronic inflammation, and can even eventually raise the risk of cancer and other age-related diseases.

Senescent cells normally destroy themselves via a programmed process called apoptosis, and they are also removed by the immune system; however, the immune system weakens with age, and increasing numbers of senescent cells escape this process and begin to accumulate in all the tissues of the body.

Senescent cells only make up a small number of total cells in the body, but they secrete pro-inflammatory cytokines, chemokines, and extracellular matrix proteases, which, together, form the senescence-associated secretory phenotype, or SASP.

By the time people reach old age, significant numbers of these senescent cells have built up, causing chronic inflammation and damage to surrounding cells and tissues via the SASP.

The SASP is thought to significantly contribute to aging and cancer; thus, targeting senescent cells and removing them using senolytic drugs has been suggested as a potential solution to this problem.

NAD and cellular senescence pathways collide

One potential hurdle with NAD-boosting therapies is coming to light, however. The NAD+ and SASP pathways interact with each other, and this is becoming clearer as more research data arrives. The new publication highlights how these two pathways interact and how NAD levels are directly related to the expression of the SASP, which may confound attempts to boost NAD using precursors as an anti-aging therapy [2]. The paper reviews the various studies and takes a look at NAD+ and cancer risk as well as why increasing NAD+ levels using precursors may be a trade-off.

However, perhaps the most interesting part of this paper is the suggestion that senolytics may eliminate the need for NAD+ boosting therapies entirely in the context of anti-aging. This actually makes a great deal of sense.

We talked about how CD38 expression destroys NAD in a previous article and that CD38 is part of the inflammatory SASP, which means that the more senescent cells there are, the more CD38 there is, which leads to less NAD. Therefore, removing senescent cells using senolytics should reduce CD38 and lead to a corresponding increase in NAD; this was certainly shown when CD38 was inhibited using quercetin and apigenin in a 2013 experiment [3].

During human aging, decrease of NAD+ levels is associated with potentially reversible dysfunction in the liver, kidney, skeletal and cardiac muscle, endothelial cells and neurons. At the same time, the number of senescent cells, associated with damage or stress that secrete pro-inflammatory factors (SASP, Senescence-Associated Secretory Phenotype), increases with age in many key tissues, including the kidneys, lungs, blood vessels, and brain. Senescent cells are believed to contribute to numerous age-associated pathologies and their elimination by senolytic regimens appears to help in numerous preclinical aging associated disease models including those for atherosclerosis, idiopathic pulmonary fibrosis, diabetes, and osteoarthritis.

A recent report links these processes, such that decreased NAD+ levels associated with aging may attenuate the SASP phenotype potentially reducing its pathological effect. Conversely increasing NAD+ levels by supplementation or genetic manipulation which may benefit tissue homeostasis, also may worsen SASP and encourage tumorigenesis at least in mouse models of cancer. Taken together these findings suggest a fundamental trade-off in treating aging related diseases with drugs or supplements that increase NAD+.

Even more interesting is a report that senescent cells can induce CD38 on macrophages and endothelial cells. In turn increased CD38 expression is believed to be the key modulator of lowered NAD+ levels with aging in mammals. So accumulation of senescent cells may itself be a root cause of decreased NAD+, which in turn could promote dysfunction. On the other hand, the lower NAD+ levels may attenuate SASP, decreasing the pathological influence of senescence. The elimination of most senescent cells by senolysis before initiating NAD+ therapies may be beneficial and increase safety, and in the best case scenario even eliminate the need for NAD+ supplementation.

Conclusion

The interaction of metabolism is complex, and it appears that careful adjustment of NAD+ levels may be required in order for it to be beneficial rather than harmful. Trying to raise NAD+ with precursors may come with too many downsides, preventing us from both having our cake and eating it; alternatively, researchers may find a way to bypass this issue. Only time and research will tell.

It may be the case that in order to restore NAD+ effectively, we must address the chronic inflammation caused by senescent cell accumulation and other sources of inflammaging. Ultimately, we may need partial cellular reprogramming to reset epigenetic alterations and senolytics to remove senescent cells.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

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] Mendelsohn, A. R., & Larrick, J. (2019). Interacting NAD+ and Cell Senescence pathways complicate anti-aging therapies. Rejuvenation research, (ja).

[3] Escande, C., Nin, V., Price, N. L., Capellini, V., Gomes, A. P., Barbosa, M. T., … & Chini, E. N. (2013). Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome. Diabetes, 62(4), 1084-1093.

Birthday cake

Why I Am Future Positive on My Birthday

Not so long ago, it was my 44th birthday, and I’ve finally decided to write something that I’ve been reflecting on for a while. To some people, a birthday is a cause for celebration; for others, it is viewed as a bad thing.

Yes, if you take the negative view, you could see it as simply a reminder of being another year older and another year closer to the grave. However, this is not how I see it; in fact, I think quite the opposite. I see it as another year closer to our goal: the defeat of age-related diseases due to the progress of rejuvenation biotechnology that offers longer and healthier lives.

From my point of view, viewing birthdays, or, indeed, the passing of time, as a positive or negative thing is largely a question of knowledge and understanding of the aging research field, which ties in with what I want to address today.

Knowledge is power

During my work as a journalist, people often ask me how things are progressing in the field. This is, of course, a perfectly reasonable and understandable question to ask. While I am always more than happy to talk about the field and answer this question, I also urge people to delve deeper into the field so that they can learn and evaluate for themselves rather than simply taking my word for it.

Our website, including the Rejuvenation Roadmap, is a good resource to start learning and to hear the latest news, as are places such as FightAging and the SENS Research Foundation website. Conferences such as Ending Age-Related Diseases and Undoing Aging are also valuable places to learn more about what is happening in the field.

Sometimes, I encounter people outside, but also fairly frequently within, the community who can be somewhat pessimistic about the field and its progress. It is perfectly natural to be cautious about the unknown, but there comes a point at which caution becomes unwarranted pessimism. The “Science Will Not Defeat Aging in My Lifetime, so Why Bother?” argument is a classic example of this, and much of this is caused by a lack of knowledge and understanding of the field.

The Latin phrase scientia potentia est, meaning “knowledge is power”, is particularly apt here. Knowledge and understanding allow us to better evaluate a situation or a proposal and reach a conclusion. It is hard to reach an accurate conclusion about anything without all the facts in place, yet I often see people doing it. Of course, there are always people who will not put in the time and effort required to learn about a topic properly, so they make predictions without all the facts, but there really isn’t much we can do about these people.

However, as advocates and supporters, we can do our best to learn about such things ourselves, and this will also come in useful when speaking to others about the field, as there is nothing like having a good understanding of the topic to help you convey it to others. That does not mean you need to become a biologist and understand things to such deep levels but even a solid understanding of the basics can be a huge help when it comes to engaging with others on the subject and also for understanding where we are currently progress wise.

Future positive

This relates to a second question people often tend to ask me, which is if I think that they or we have a chance of living long enough to see these technologies arrive.

Obviously, no one can predict the future, so this question, by its very nature, is a tricky one to answer. I generally avoid being too specific on the timeframe in which we will reach the goal of longer lives through science, but I am optimistic that people in my age group, even perhaps older, have a reasonable chance of making the cut.

The reason that I am generally optimistic about the future is mostly that, as a journalist who speaks to hundreds of researchers, each focused on a part of the puzzle, I get an almost unique picture of the field. I can see the broader landscape and how and where things in the field or related fields connect or may connect in the future. A breakthrough in a related medical field may not have immediately apparent utility in aging research at first glance, but a deeper look could reveal hidden potential.

This fairly unique insight, combined with the knowledge that I have collected over the years working in the field, makes me fairly optimistic about the future and my place in it. As I have said a number of times in the past, the defeat of age-related diseases will not suddenly happen overnight; there is unlikely to be a single moment at which humanity goes from having no choice about aging to having control. It is far more likely that there will be steady progress, with incremental breakthroughs along the road, that will ultimately reach the goal.

Reasons to be cheerful

I would like to touch upon two of the most promising therapies that I am most interested in and believe may have a big impact in the near future (10-20 years) and that may help pave the way for major changes to how society thinks about and treats aging. Both of these therapies directly address one of the nine proposed causes of aging and thus if they work they have the potential to be transformative in healthcare. Of course, there are more therapies in development and at various stages of progress which also address the other causes of aging but these two are what I am most enthusiastic about presently. I urge you to explore the provided links to resources and learn more about each one.

Senolytics

No list of promising technologies would be complete without talking about the senescent cell-clearing drugs and therapies known as senolytics. Senescent cells are aged or damaged cells that should destroy themselves via a process known as apoptosis but, for various reasons, do not do so; instead, they hang around, sending out inflammatory signals that harm nearby healthy cells, block effective tissue repair, and contribute to numerous age-related diseases.

One proposed solution to these problem cells is to remove them by causing them to enter apoptosis, as originally intended, by using senolytic drugs and therapies. Removing these cells in mouse studies has produced some remarkable results, with mice often living healthier and longer lives as well as reversing some aspects of aging.

The race is now on to bring these drugs to people, and a number of companies are developing them right now. So far, UNITY Biotechnology has seen the most progress, and the company is already conducting human trials of its lead candidate drug (UBX0101) for the treatment of osteoarthritis. It has another candidate drug (UBX1967) closely behind; this drug is poised to enter human trials for the treatment of age-related macular degeneration, diabetic macular edema, diabetic retinopathy, and glaucoma. Based on recent comments from UNITY, we are anticipating the initial results of human trials in the next few months; hopefully, the news will be positive.

With the number of companies working on these therapies, it is fair to be optimistic about their potential to address multiple age-related diseases given that senescent cells are a proposed root cause of aging. You can also check out the Rejuvenation Roadmap to see which companies are working on senolytics and how they are progressing.

Partial cellular reprogramming

Cells can be reverted back to an earlier developmental state, known as induced pluripotency, using reprogramming factors, and this process effectively makes aged cells functionally young again in many ways. Ever since its first discovery, there has been a great deal of interest in this area of aging research.

The problem with inducing pluripotency is that the cell loses its identity and forgets what cell type it currently is, as it becomes a new kind of cell capable of being guided into changing into any other cell type, much like our cells during development. This is great for early human development, but as adults, having our cells forget what they are is bad news. Therefore, researchers have wondered if it is possible to reset a cell’s age without resetting its cell memory, and the answer appears to be yes!

Thankfully, during the reprogramming of a cell back to pluripotency, the cell’s age is one of the first things to be reset before the cell memory is wiped, and it appears possible to partially reprogram the cell so that only aging is reset. We have talked about the potential of partial cellular reprogramming and how it is similar to hitting the reset button on aging in a previous article, but, needless to say, if we can find a way to safely partially reprogram our cells, it could have a dramatic impact on how we age and may allow us to remain more youthful and healthy.

In terms of progress, partial reprogramming has already been demonstrated in mice, and now a number of groups, including Turn.Bio, the Salk Institute, Life Biosciences, Youthereum Genetics, and AgeX, are developing therapies based on partial reprogramming, which is essentially the resetting of cells’ epigenetic states (what genes are expressed) from an aged profile to a more youthful one, again directly targeting one of the proposed root causes of aging.

This approach is likely to be quite a few years away, but I think it is plausible that it could be in human trials in the next decade, and it is probably the approach that interests me the most in the field.

In closing

The truth is we cannot predict the future because it is not set in stone, so we cannot be totally certain if or when rejuvenation technologies will arrive. The best we can do is learn as much as we can about the field and try to reach a reasonable conclusion based on the situation as it is now.

The field is advancing steadily, and we should be optimistic but not complacent about progress. We should be mindful of being too negative and, equally, of being too positive without ample justification. Blind optimism is as bad as blind pessimism, and we should always strive for informed optimism.

That said, given the progress being made, I am optimistic about my chances based on the evidence to date. This is why I do not mind birthdays and why I find them positive experiences rather than negative ones. Arm yourself with knowledge, and perhaps you too will agree with me and understand why I am future positive.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Creating Thymus Organoids Using Tissue Engineering

Today, we wish to highlight a new open access publication in which the researchers take a novel approach to the regeneration of the thymus, a small but vitally important organ that is key to our immune system.

The thymus shrinks as we age

The thymus is one of the most important organs in the body, and it is where thymocytes produced in the bone marrow travel to become new T cells before being trained in the lymph nodes to become the defenders of the adaptive immune system. However, as we get older, the thymus increasingly turns to fat and starts to shrink, causing its ability to produce new T cells to fall dramatically. This process is known as thymic involution and actually begins shortly after puberty, so this is one aspect of aging that begins fairly early in life, although it is many decades later before its decline causes serious health issues.

The fall in production of new T cells from the thymus results in a decline of the adaptive immune system and is part of the collective decline of the immune system called immunosenescence. The end result of immunosenescence is that your body is no longer able to mount an effective defense against diseases and is inappropriately activated, leading to dysfunction and persistent inflammation. This inflammation contributes to inflammaging, a chronic smoldering background of low-grade inflammation, which other age-related sources contribute to as well.

The decline of the thymus has been linked to cancer risk, which rises dramatically as we age as part of the immunosenescence model of cancer. Immunosenescence is also strongly correlated with multiple age-related diseases, which is probably no surprise, given that the aged immune system is no longer able to respond effectively or even appropriately to invading pathogens.

A new approach to an old problem

There have been, and currently are, a number of approaches that seek to regenerate the thymus and cause it to regrow in order to boost the immune system in older people and help them to remain healthy. The majority of these approaches, while taking different paths, generally focus on increasing the activity of the master regulator of thymic growth, FOXN1, in order to spur regrowth and restoration of efficient T cell production. FOXN1 helps the thymic cells to grow and maintain their identity and thus prevents them from turning into fat cells, but the activity of it falls as we get older, so any therapy would need to maintain FOXN1 at more youthful levels or would likely fail.

In a new study, the researchers have taken a different approach to the problem and opted to use tissue engineering to bypass the need to target FOXN1. Because thymocyte cells produced in the bone marrow automatically seek out the thymus once they reach the bloodstream, the location of the thymus tissue is largely irrelevant, as the thymocytes will find it.

The researchers here have created thymic organoids, small but functionally identical versions of the larger organ that they mimic, using modified thymic epithelial cells seeded into a special three-dimensional collagen scaffold that emulates the environment of the thymus and that the thymocytes recognize and home in on.

The research team transplanted these organoids under the skin of mice, and, while the tissue became vascularized, they failed to produce T cells (the process of thymopoiesis), as the structure did not last long enough.

Defective functionality of thymic epithelial cells (TECs), due to genetic mutations or injuring causes, results in altered T‐cell development leading to immunodeficiency or autoimmunity. These defects cannot be corrected by hematopoietic stem cell transplantation (HSCT), while thymus transplant has not yet demonstrated to be fully curative. Here, we provide proof‐of‐principle of a novel approach toward thymic regeneration, involving the generation of thymic organoids obtained by seeding gene‐modified postnatal murine TECs into three‐dimensional (3D) collagen type I scaffolds mimicking the thymic ultrastructure. To this end, freshly isolated TECs were transduced with a lentiviral vector system allowing for doxycycline‐induced Oct4 expression. Transient Oct4 expression promoted TECs expansion without drastically changing the cell lineage identity of adult TECs, which retain the expression of important molecules for thymus functionality such as Foxn1, Dll4, Dll1, and AIRE. Oct4 expressing TECs (iOCT4 TEC) were able to grow into 3D collagen type I scaffolds both in vitro and in vivo, demonstrating that the collagen structure reproduced a 3D environment similar to the thymic extracellular matrix, perfectly recognized by TECs. In vivo results showed that thymic organoids transplanted subcutaneously in athymic nude mice were vascularized but failed to support thymopoiesis because of the limited in vivo persistence. These findings provide evidence that gene modification, in combination with the usage of 3D biomimetic scaffolds, may represent a novel approach allowing the use of postnatal TECs for thymic regeneration.

Conclusion

This is a good proof of concept for the approach, but there is still the challenge of creating a robust and persistent scaffold that integrates and functions in the body remains. Tissue engineering is a field that has undergone rapid advances in the last decade, and it is not beyond the realms of possibility that this hurdle may well be overcome in the years ahead and that a persistent organoid will be produced. Should this be the case, it has the potential to be transformative.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Bortolomai, I., Sandri, M., Draghici, E., Fontana, E., Campodoni, E., Marcovecchio, G. E., … & Catucci, M. (2019). Gene Modification and Three‐Dimensional Scaffolds as Novel Tools to Allow the Use of Postnatal Thymic Epithelial Cells for Thymus Regeneration Approaches. Stem cells translational medicine.

Telomerase Gene Therapy Ameliorates Neurodegeneration in Mice

A group of Spanish researchers, including Dr. Maria Blasco and others at the CNIO, has published a new study that examines the consequences of short telomeres and telomerase deficiency on the brain [1].

This study addresses an aspect of telomere attrition, one of the primary hallmarks of aging. Telomeres are repeating sequences of DNA (TTAGGG) that can can reach a length of 15,000 base pairs and appear at the ends of chromosomes, acting as protective caps. They prevent damage, stop chromosomes from fusing with each other, and prevent chromosomes from losing base pair sequences at their end during cell replication.

Telomere length is influenced by both erosion and addition mechanisms

Telomeres control the number of times a cell can divide; with each division, roughly 25-200 base pairs are lost. When the telomere becomes critically short, the chromosome can no longer replicate, triggering a persistent DNA damage response, which initiates a self-destruct sequence in the cell known as apoptosis. This is the basis of the erosion mechanism of telomeres, which leads to cellular senescence.

Telomeres also have an addition mechanism, which is regulated by the activity of the enzyme telomerase. This enzyme is made of protein and RNA subunits that cause the chromosome to lengthen by adding more TTAGGG sequences to the end of the chromosomes, thus helping to offset the erosion mechanism. However, it is only normally found in fetal tissues, germline cells, and some stem cells; in the regular somatic cells in our body, its activity is so low as to be almost undetectable.

However, if telomerase is activated in regular cells, which can happen in cancerous tumors, the cell can continue to grow and divide indefinitely as long as telomerase is expressed. Therefore, researchers of both cancer and aging find this enzyme and its immortalization of cells interesting, as it can theoretically be used to reset part of cellular aging. This concept has encouraged multiple researchers to investigate ways in which telomerase might be used for regeneration of organs and tissues and to combat age-related diseases.

Telomerase therapy for neurodegeneration

Studies have shown that mice and humans that lack telomerase, and have short telomeres as a result, tend to experience an earlier onset of age-related diseases that are associated with the loss of tissue regenerative capacity in fast-dividing tissues, such as fibrosis. However, there have been few studies investigating the effects of short telomeres in tissues that rarely or do not divide at all, such as the brain.

The Spanish team examined a telomerase-deficient mouse model and compared these mice to ordinary aged mice. Both types of mice had similar symptoms of shortened telomeres that led to neurodegeneration.

The researchers then went on to demonstrate that the delivery of telomerase gene therapy to the brains of these mice caused the amelioration of some aspects of neurodegeneration. The researchers suggest that these findings support that short telomeres are a contributing factor in age-related neurodegenerative diseases and that telomerase gene therapy may be a potential solution to combat such conditions.

Preventing the accumulation of short telomeres may prevent or ameliorate brain aging by allowing stem cells to proliferate and regenerate damaged tissue. We have previously demonstrated that preventing the accumulation of short telomeres through telomerase gene therapy can ameliorate the symptoms of cardiovascular disease, pulmonary fibrosis, aplastic anemia, and aging in general.

Thus, to demonstrate that telomere shortening may be one of the causes of brain aging, here we studied the potential therapeutic effects of a telomerase gene therapy in ameliorating molecular signs of neurodegeneration associated with physiological mouse aging as well as in the context of the telomerase-deficient mouse model.

Our findings demonstrate that AAV9-Tert treatment can ameliorate signs of neurodegeneration with aging in wild-type mice as well as in the context of the telomerase-deficient mouse model with the presence of short telomeres. Our treatment was applied through an IV tail injection, and therefore, many other cell types throughout the body would be infected in addition to the cells in the brain. Improvements of health in other organs may have an impact on the brain and investigating the nature of this relationship could be interesting for future studies. Note also that we did not observe any increased incidence of cancer in the mice treated with AAV9-Tert, which matched our expectations since several other articles have demonstrated that telomerase reactivation alone does not lead to tumorigenesis in vivo.

Of note, the AAV9 serotype used here to express telomerase in the brain primarily transfects neurons and astrocytes but fails to transduce microglia [77]. In our experimental setting, we found that less than 5% of the cells in the brain received the transgene using our vector and delivery method. Interestingly, in spite of the low transduction efficiency, we observed significant effects of AAV9-Tert gene therapy in decreasing DNA damage, increasing neurogenesis as indicated by increased doublecortin expression, as well as decreasing neuroinflammation (decreased GFAP expression). These findings suggest that even a small number of neurons transduced with Tert may increase the health of the environment and benefit cells that were not infected, for instance, through changing the secretory profile of cells. In an analogous manner, factors found in young blood induce a younger phenotype in the recipient cells, as observed from parabiosis experiments with young blood and also treatments with specific factors in young blood such as the GDF11 protein. Nevertheless, even more benefits from telomerase gene therapy may be observed if higher transduction efficiencies are obtained.

Conclusion

Telomerase therapy holds a great deal of potential, especially for resetting cellular aging and some age-related epigenetic alterations. Many people predicted over a decade ago that activation of telomerase, particularly its upregulation in somatic cells, would increase cancer incidence. However, this has proven not to be the case in various animal studies; if anything, the risk of cancer appears to be reduced, as improving telomeres improves the genomic and epigenomic stability of cells, making them functionally younger in some ways.

The trick, of course, is in translating these findings from mice and taking them to clinical trials for eventual translation and human use. There is certainly plenty of enthusiasm for the approach and more than enough reason to be optimistic about it.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Whittemore, K., Derevyanko, A., Martinez, P., Serrano, R., Pumarola, M., Bosch, F., & Blasco, M. A. (2019). Telomerase gene therapy ameliorates the effects of neurodegeneration associated to short telomeres in mice. Aging.

The Future of Pensions and Life Extension

If you work in social security, it’s possible that your nightmares are full of undying elderly people who keep knocking on your door for pensions that you have no way of paying out. Tossing and turning in your bed, you beg for mercy, explaining that there’s just too many old people who need pensions and not enough young people who could cover for it with their contributions; the money’s just not there to sustain a social security system that, when it was conceived in the mid-1930s, didn’t expect that many people would ever make it into their 80s and 90s. Your oneiric persecutors won’t listen: they gave the country the best years of their lives, and now it’s time for the country to pay them their due.

When you wake up, you’re relieved to realize that there can’t be any such thing as people who have ever-worsening degenerative diseases yet never die from them, but that doesn’t make your problem all that better; you still have quite a few old people, living longer than the pension system had anticipated, to pay pensions to, and the bad news is that in as little as about 30 years, the number of 65+ people worldwide will skyrocket to around 2.1 billion, growing faster than all younger groups put together [1]. Where in the world is your institution going to find the budget?

That’s why, whether you work in social security or not, the words “life extension” might make you feel like you were listening to an orchestra playing Beethoven’s Fifth Symphony with forks on a blackboard; we’re likely to have a pension crisis on our hands as it is because of the growth in life expectancy, and some people have the effrontery to suggest that we should make life even longer?!

Why, yes, some people do have the effrontery, and believe it or not, it may actually be a good idea—possibly, and only apparently counterintuitively, the idea that will prevent the pension crisis from happening in the first place.

Why retirement?

Suppose for a moment that human aging never existed and that, barring accidents and communicable diseases, people went on living for centuries—their health, independence, and most importantly, ability to work, remaining pretty much constant over time; in order to tell apart a 150-year-old from a 25-year-old, you’d have to look at their papers.

In a scenario like this, it’s difficult to imagine why any government would go through the trouble of setting up a pension system that works the way the current one does. It would make sense to have measures in place to support people who couldn’t work after being paralyzed by injuries, but paying out money to perfectly able-bodied people to do nothing for the rest of their lives just because they’re over 65 would make no sense at all. It’s surely possible that, after 40 years of work, you’d rather be on vacation forever, but it’s somewhat unrealistic to expect that your country would be prepared to pay you a pension for centuries to come, in exchange for a meager 40 years of contributions, simply because you’re tired of working.

In other words, if people past a certain age have a right to retire until death and receive a pension, it’s essentially because, past that certain age, their health tends to worsen to the point that they’re unfit for work, and it can be expected to worsen in the following years; it’s not because the government or insurance companies feel like sending people on indefinite paid vacations. Depressing, perhaps, but true.

Of course, you could try to put a positive spin on this and look at retirement as a time of financial independence, when, either because you receive a pension or you have enough savings, you can enjoy life without having to go to work every day. This is a much better way to look at it, but we must account for the fact that most people who retire do so either because they hit retirement age or because other circumstances, such as ill health, forced them to retire early [9]—not because they managed to save up enough to retire in their 40s. The health of average retirees doesn’t interfere just with their ability to work but also to enjoy life in general. Most people over the age of 65 suffer two or more chronic illnesses [2,3,4]; the risk of developing diabetes, cancer, cardiovascular diseases, dementia, and so on skyrockets with age [5], and your financial independence (not to mention your life in general) would be a lot more enjoyable if you didn’t have to put up with any of these.

Retirement 101

The takeaway here is that retirement exists out of necessity more than desire, and even if you try to look at it from a different angle, you’ve still got the problem of the burden represented by age-related diseases. Given these facts, it’s important to understand how retirement works before we can establish if and why the feared pension crisis expected in a few decades from now is actually going to happen and whether life extension will make the problem better or worse.

A pension is a regular payment typically paid monthly to retirees. It can be paid to individuals by governments or employers, or it can come from personal savings, often in the form of special individual retirement accounts that provide some tax incentive to save. This three-pillar system, devised around a hundred years ago, exists in several countries around the world. The purpose is to provide an income after people stop working, i.e. during retirement until death.

Often, pensions can be received only after a certain age or number of years of work and would be deferred if you retire before the minimum is reached; if you decide to retire at age 30, well before you hit retirement age or have worked anywhere near the minimum number of years that you were supposed to, you’re going to wait for a while before you see a dime from your pension.

The funding of a pension depends on the type of pension. In the case of government pensions, like those paid by Social Security in the U.S., the funding is a combination of individual contributions (paycheck deductions) and government funding. Federal and state regulations are in place to ultimately ensure that the future pension income “belongs” to each individual contributor, but of course, contributions that you pay out today aren’t simply set aside for thirty years until you can collect them; they’re used to pay the pensions of present-day retirees; similarly, the money owed to pay your pension will come from the contributions of the workforce at the time of your retirement.

Why a crisis might be on its way

This pension system works well under the assumptions made back when it was devised, but, a hundred years later, things aren’t quite the same anymore.

For example, in the 1930—when the US Social Security system was conceived—the average life expectancy at birth was about 58 for men and 62 for women, whereas the retirement age was 65. This doesn’t mean that everyone checked out before they could cash in, because life expectancy at birth was pulled down by a higher infant mortality; in reality, people who reached adulthood had respectable chances to make it to retirement age and go on to collect their pensions for up to about 13 years; that is, just about before they hit age 80. However, in the year 2015, life expectancy at birth in the US was 79.2, which is around the maximum age that people were expected to reach at the dawn of the pension system; in 2014, the remaining life expectancy at age 79 of people in the US was 8.77 years for men and 10.24 for women. Therefore, in a worst-case scenario, people today can expect to live at least well above the maximum expected lifespan of the 1930s, and, in a best-case scenario, ten additional years. (From the point of view of the pension payer, best- and worst-case scenarios are probably the other way around.) The global average life expectancy in 2015 was 71.4, and even though the remaining life expectancy at that age varies depending on the country, it’s not difficult to see why the funding costs of pensions are mushrooming—simply put, people are living for longer; therefore, they need to be paid pensions for longer—longer than the pension system was designed to handle.

This spells trouble already, but there’s more bad news. As noted above, the global number of people over age 60 is projected to increase significantly in a few decades’ time, more than doubling between 2017 and 2050 (from 1.0 to 2.1 billion), whereas the 10-24 age cohort is expected to increase by a meager 200 million (from 1.8 to 2.0 billion) and the 25-59 cohort by 0.9 billion (from 3.4 to 4.3 billion) [1]. In particular, the number of people aged 85 and above is projected to grow more than threefold, from 137 million to 425 million, over the same span of time. Speaking of pensions alone, this is like having a piggy bank that a fast-growing number of people keeps drawing from and a slow-growing number of people puts money into. (As a side note, the number of children aged 0-9 is projected to stay the same between 2030 and 2050—that is, in twenty years’ time, we won’t have any more future contributors than we used to, while the people needing those contributions will have grown by 0.7 billion over the same 20 years.)

These two facts—the increase of life expectancy and the decrease of fertility rates—constitute what is known as population aging, which is pretty much the core of the problem; external factors that make matters worse, as some people maintain, are poor decision-making and unrealistic promises by politicians and, in general, the people managing pension systems. These might be the result of a lack of understanding of the problem or simply not genuinely caring about the consequences, but, in any case, making clear decisions on the actions to be taken is not an easy task, as tinkering with policies and rates relies on hard-to-predict information, such as the average lifespan of pensioners of a specific pension plan.

In addition, unrealistic investment expectations add to this growing pension crisis. The higher the assumed rate of future investment returns, the less funding is needed to have a “fully funded” pension plan. Currently, the high assumed rates reduce the apparent problem. For instance, the average rate of return on US state pension plans is assumed to be 7.5% per year; meanwhile, investment experts would say a return expectation of 6.5% is much more realistic, and if this assumption is correct, then even more pensions are in danger of running out, and others, previously thought to be only somewhat underfunded, become drastically underfunded. The result is that there is much talk of pension reforms, but the political unpopularity of touching retirement pensions or reducing the unrealistic promises causes continued procrastination.

The situation is depressing, in the U.S. and in several other countries. While U.S. Social Security is running low—with the average retiree having only 65.7% of their Social Security benefits remaining after out-of-pocket spending on medical premiums, for example—and expected to run out of money in 2034, Citigroup estimates that twenty OECD countries have unfunded or underfunded government pension liabilities for a mind-boggling total of $78 trillion; China, for example, is expected to run out of pension money shortly after the US, in 2035. In a September 2018 report, the National Institute on Retirement Security warned that the median retirement account balance among working-age Americans is zero and that nearly 60% of working-age Americans do not own any retirement account assets or pension plans. In the press release of the same report, the report’s author, Diane Oakley, stated that retirement is in peril for most working-class Americans, and according to an analysis by Mercer, in a World Economic Forum report, there’s plenty of reasons to believe her, as the US pension funding gap is currently growing at a breakneck rate of $3 trillion a year, reaching $137 trillion in 2050.

World Economic Forum. “We’ll Live to 100 – How Can We Afford It?” May 2017

The icing on the cake: geriatrics

Pensions constitute quite a bit of money paid to people for around two decades until they die, and whether or not we can afford this, it would still be better if we weren’t forced to spend so much money in this way; even worse, we effectively throw even more money out the window by paying for geriatrics, something that most retirees are worried about.

Money spent on healthcare is generally money well spent, but only if it actually improves your health. The problem with traditional geriatrics is that it acts on the symptoms of age-related diseases rather than their causes. The diseases of aging are the result of a on complex interaction between different, concurrent processes of damage accumulation taking place throughout life; this means that, as a rule of thumb, the older you are, the more damage that you carry around. This means that any treatment aimed at mitigating age-related pathologies that does not act on the damage itself or its accumulation is destined to become progressively less effective, like shoveling water with a pitchfork out a lake while a river continually dumps more in.

Generally, geriatric treatments don’t directly affect the damage or its accumulation, so they cannot eliminate age-related diseases and become less and less useful as you age. Some kinds of geriatric treatments are actually geroprotectors—that is, they are able to interfere with the damage or the accumulation of damage and may help prevent diseases—but are often administered too late in the game, when pathologies have already manifested. Geriatrics is decisively not the best bang for the buck, even though it is presently better than nothing at all.

It doesn’t come cheap, either; according to a MEPS report, in 2003, the elderly constituted less than 25% of the Medicaid population but 26% of Medicaid spending; the report finds, unsurprisingly, that chronic conditions contribute to higher healthcare costs, and among the top five most costly conditions are diabetes and heart disease, two diseases typical of old age. Even less surprisingly, in 2002, people over 65 constituted 13% of the US population but accounted for 36% of total US personal health care expenses.

A 2004 study in Michigan found that per capita lifetime health expenditures were $316,000 for women and $268,700 for men (part of the discrepancy is to be attributed to women’s longer lifespans), of which one-third is incurred during middle age and more than another third is incurred after age 85 [6] for people fortunate enough to live that long. Again according to MEPS, in 2016, the average health spending in the US for people over the age of 65 was $11,316; for comparison, the sum total of all the other age cohorts from 0 to 64 was $13,587, only about $2,200 more. The cumulative spending for the 65+ cohort—that is, the average total of yearly expenditures for a US citizen at least 65 years old—was nearly $170,000. Again in 2016, people aged 65 and over accounted for 16% of the US population while constituting 36% of the total health spending.

A report by Milken in 2014 found that, in 2003, about $1.3 trillion was thrown out the window in the US because of the treatment costs and lost productivity related to chronic diseases; the same report projects that, in 2023, the loss will amount to $4.2 trillion.

A 2018 study focusing on out-of-pocket spending for retirees found that the average household that turned 70 in 1992 will incur $122,000 in medical spending over the rest of their lives, and that the top 5% and 1% will incur $300,000 and $600,000, respectively [7]. This paper also found that Medicaid significantly helps the poorest households with their expenses, and it must be noted that, past a certain age, remaining lifetime healthcare costs stop growing and tend to stabilize (for no other reason that the people in question don’t have much life left during which they could spend money on healthcare), but whether the money spent on geriatrics, nursing homes, and so on is a lot or a little, or is spent by you personally or by the government, somebody is going to spend it on something that will not give your health and independence back and is not going to make your life much better. If we must spend it, we might as well do so on something that will actually restore your health.

To top it all, when you consider that American workers aren’t saving that much, a single major medical event past retirement could wipe however little they had set aside.

The costs of caring for older people don’t stop here; they affect their family caregivers as well. As highlighted by the National Center on Caregiving, taking care of a disabled family member may impact the caregiver financially, emotionally, and even health-wise; caregivers are more likely to suffer from stress and depression, are prone to illness themselves, and lose, on average, nearly $700,000 over their course of their lives. When you take into account population aging, it’s clear that this trend can only worsen and put more strain on society.

Life extension: friend or foe?

Now that we have a clearer idea about the potential pension crisis looming ahead and the costs of pensions and geriatrics, it’s time to discuss whether life extension would make the problem better or worse.

It all depends on how you understand life extension. The term per se is somewhat misleading, in that many people often imagine a longer, drawn-out old age in which ill health and the consequent medical expenses and pensions are extended accordingly, just as in the nightmares of social security planners. This is most definitely not what life extension is about, and it’s obvious that extending old age as it is right now would not be a solution to the problem of pensions (or even desirable for whatever other reason). Simply prolonging the duration of life without also prolonging the time spent in good health (if at all possible to a significant extent) wouldn’t solve any problem, and as a matter of fact, it would worsen existing ones; people would be sick for longer, thereby increasing the already exorbitant amount of suffering caused by aging, and they would need pensions and palliative care for longer, probably pushing our social security systems well over the edge. (As a side note, this is what geriatrics does: it delays the inevitable, prolonging the time spent in ill health by making you a wee bit less sick for a longer time.)

However, lifespan and healthspan—that is, the length of your life and the portion of life you spend in good health—aren’t causally disconnected; you don’t just drop dead because you’re 80 or 90 irrespective of how healthy you are. The reason we tend to die at around those ages is that our bodies accumulate different kinds of damage in a stochastic fashion; as time goes by, the odds of developing diseases or conditions that eventually become fatal go higher and higher, even though which specific condition will kill you depends a lot on your genetics, lifestyle, and personal history. The idea behind life extension isn’t to just “stretch” lifespan; rather, the idea is to extend healthspan, that is preserving young-adult-like good health well into your 80s or 90s, and the logical consequence of being perfectly healthy for longer is that you will also live for longer. Significant life extension only follows from significant healthspan extension, and it’s very unlikely that it could ever be otherwise.

Again, the fundamental reason that pensions exist is to economically support people who are no longer able to do it themselves. We need to have such a system in place if we don’t want to abandon older people to their fate. If life extension treatments take ill health and age-related disabilities out of the equation entirely, pensions as we know them today will no longer be needed, because you will be able to support yourself through your own work regardless of your age.

Some people might shudder at the thought of working at age 90, but we can’t help but wonder if they actually realize that the alternative is literally to get sicker and sicker and eventually die; if they prefer that to continuing to work, they probably have more of a problem with the specific line of work they’re in than life extension itself, and they should ask themselves whether they’d trade their health and life in their 40s if it meant that they could quit working earlier. There is, though a better angle to look at this from, and it’s what we mentioned before: retirement as financial independence. Being perfectly healthy for the whole of your life, however long it may be, does not mean you must work each and every moment of it. A longer life spent in good health may more easily allow you to attain sufficient financial independence to retire at least for a while. Unless you’re a billionaire, it’s unlikely that you’ll ever be able to retire for centuries in the current economic system; still, you might be able to enjoy a few years off, and then, say at age 100, celebrate your first century of life in perfect, youthful health by starting off an entirely new career with the same energy and vigor you had when you started the first one in your 20s.

Even if you don’t manage to save enough to retire by yourself, we should not forget that a pension system where people retire for a few years and then go back to work, producing wealth once more rather than just consuming it for decades, is the Holy Grail of social security; governments would have a much easier time paying for your pension for, say, five years, knowing that in five years, you’ll be making your own living again. Your insurance, or whoever pays for your medical expenses, would also be extremely happy to know that you have no chronic conditions to be taken care of—and most importantly, so would you. In a situation like this, a pension crisis is unlikely to happen because pensions would not be a necessity anymore. Even if it happened that pension funds ran dry for whatever reason and push came to shove, people would be able to support themselves through their own work—they’d have to postpone their retirement for some time, but that would be okay, because whatever their age they’d still be fully able-bodied.

This is the best-case scenario: a world where aging is under full medical control, just like most infectious diseases today. There’s also a possibility that this won’t come to pass as soon as we’d like and that we’ll achieve only partial control over aging, for example by successfully extending your healthspan by a few years. Even in this more modest scenario, the financial benefits would be enormous, with an estimated value of over $7 trillion over the course of fifty years [8], which is a benefit worth pursuing whether a pension crisis will happen or not.

Of course, it’s a good idea to sit down and attempt to do the math on a case-by-case basis to see for a fact which countries would effectively have significant economic incentives to endorse, and perhaps even financially support, rejuvenation therapies for their own citizens, but a 2018 report of the International Longevity Centre in the UK provides reasons to be rather optimistic. Titled Towards A Longevity Dividend, the report discusses the effects that life expectancy has on the productivity of developed nations, based on nearly 50 years of demographic and macroeconomic OECD data of 35 different countries; the results of this analysis can be summarized easily: life expectancy is positively correlated with a country’s productivity across a range of different measures. Indeed, the analysis found out that life expectancy seems to be even more important for a country’s productivity than the ratio of young (working) versus old (retired) people. The conclusions of the report’s author are that a longevity dividend, i.e. global economical benefits derived by an extension of healthy lifespans, may be there for society to reap.

We should also not forget that life experience is an asset; while work experience may easily become obsolete time and time again over the course of a very long lifespan, the wisdom and knowledge that older workers may have accumulated may make them excellent mentors and drivers of further progress and innovation.

Summing up

If life extension were simply the prolongation of the period of decrepitude at the end of life, it would make little sense to pursue it. It would do nothing to improve our health, and to add insult to injury, it would exacerbate an already uncertain global financial situation. However, life extension is not this; it’s a significant extension of our healthspan, from which an extension of lifespan logically follows, and as such, it has the potential not just to rid us of age-related diseases altogether but also to solve the financial problems caused by the necessity of pensions and geriatrics by mitigating or eliminating our need for them.

People working in social security can probably sleep more soundly if the undying elderly of their nightmares are replaced with rejuvenated, productive, and independent elderly whose health no longer depends on how long ago they were born.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] United Nations (2017). World Population Prospects: the 2017 Revision. See also World Population Ageing 2017 Highlights, pp. 1 and 6.

[2] Multiple Chronic Conditions Chartbook.

[3] Harris JR, Wallace RB. The Institute of Medicine’s New Report on Living Well With Chronic Illness. Prev Chronic Dis 2012;9:120126.

[4] Bell, S. P., & Saraf, A. A. (2016). Epidemiology of multimorbidity in older adults with cardiovascular disease. Clinics in geriatric medicine, 32(2), 215-226.

[5] Niccoli, T., & Partridge, L. (2012). Ageing as a risk factor for disease. Current Biology, 22(17), R741-R752.

[6] Alemayehu, B., & Warner, K. E. (2004). The Lifetime Distribution of Health Care Costs. Health Services Research, 39(3), 627–642.

[7] Jones, J. B., De Nardi, M., French, E., McGee, R., & Kirschner, J. (2018). The Lifetime Medical Spending of Retirees.

[8] Goldman, D. P., Cutler, D., Rowe, J. W., Michaud, P. C., Sullivan, J., Peneva, D., & Olshansky, S. J. (2013). Substantial health and economic returns from delayed aging may warrant a new focus for medical research. Health affairs, 32(10), 1698-1705.

[9] Munnell, A. H., Rutledge, M. S., & Sanzenbacher, G. T. (2019). Retiring Earlier than Planned: What Matters Most? (No. ib2019-3).

Antibiotics and Vitamin C Halt Cancer Growth

A new open-access study from researchers at the Biomedical Research Centre in the United Kingdom shows how two antibiotics and Vitamin C can be combined to suppress cancer stem cells (CSCs) of the breast [1].

While antibiotics are not normally effective against cancer, and Vitamin C is more well-known for its role in supporting the immune system, this combination has been shown to attack cancer stem cells through a combination of mitochondrial suppression and oxidative attacks on the mitochondria, thus causing mitochondrial growth to falter.

Mitochondria

Mitochondria evolved from symbiotic bacteria that live in our cells, and these “powerhouses of the cell” generate energy in the form of adenosine triphosphate (ATP). This is a small molecule used in cells as a coenzyme, and it is often referred to as the “molecular unit of currency”, as it represents the basic form of chemical energy used by our cells. The majority of cellular processes, such as synthesis of proteins, synthesis of membranes, cell movement, and cell division, need energy in the form of ATP, and without functioning mitochondria, we could not generate the energy we need to survive.

Normally, preventing mitochondrial dysfunction is critical, and damage to mitochondrial DNA (mtDNA) is something we do not want; indeed, the goal of MitoSENS is to move mtDNA into the nucleus in order to protect it from damage.

However, CSCs have a substantially greater mitochondrial mass than normal cells, which is one factor that provides for their uncontrolled growth. Because we do not want these lethal cells to exist at all, attacking them through intentionally inducing mitochondrial dysfunction is a possible strategy for dealing with them.

Productively Using Side Effects

Doxycycline inhibits the small mitochondrial ribosome as a side effect, and one of azithromycin’s side effects is to inhibit the large mitochondrial ribosome. This study shows that by inhibiting both of these ribosomes, this combination (D+A) effectively suppresses the generation of energy in cancer cells. When coupled with Vitamin C, which becomes a pro-oxidant in the presence of iron, the combination causes cancer cells to become “rho-zero-like”, preventing them from properly encoding mitochondrial proteins. This starves them of ATP and forces them into a non-dividing, quiescent state, thus ameloriating their danger as cancer cells.

Surprisingly, this treatment was found to significantly lose effectiveness if some of its components were administered in advance. One week of pre-treatment with either vitamin C or D+A reduced the effectiveness of the full five-day treatment to between 60 and 70 percent. The researchers hypothesize that the increase in oxidative stress led to an antioxidant response, protecting the cancerous cells against the full power of the treatment.

Abstract

Here, we devised a new strategy for eradicating cancer stem cells (CSCs), via a “synthetic-metabolic” approach, involving two FDA-approved antibiotics and a dietary vitamin supplement. This approach was designed to induce a “rho-zero-like” phenotype in cancer cells. This strategy effectively results in the synergistic eradication of CSCs, using vanishingly small quantities of two antibiotics. The 2 metabolic targets are i) the large mitochondrial ribosome and ii) the small mitochondrial ribosome. Azithromycin inhibits the large mitochondrial ribosome as an off-target side-effect. In addition, Doxycycline inhibits the small mitochondrial ribosome as an off-target side-effect. Vitamin C acts as a mild pro-oxidant, which can produce free radicals and, as a consequence, induces mitochondrial biogenesis. Remarkably, treatment with a combination of Doxycycline (1 μM), Azithromycin (1 μM) plus Vitamin C (250 μM) very potently inhibited CSC propagation by >90%, using the MCF7 ER(+) breast cancer cell line as a model system. The strong inhibitory effects of this DAV triple combination therapy on mitochondrial oxygen consumption and ATP production were directly validated using metabolic flux analysis. Therefore, the induction of mitochondrial biogenesis due to mild oxidative stress, coupled with inhibition of mitochondrial protein translation, may be a new promising therapeutic anti-cancer strategy. Consistent with these assertions, Vitamin C is known to be highly concentrated within mitochondria, by a specific transporter, namely SVCT2, in a sodium-coupled manner. Also, the concentrations of antibiotics used here represent sub-antimicrobial levels of Doxycycline and Azithromycin, thereby avoiding the potential problems associated with antibiotic resistance. Finally, we also discuss possible implications for improving health-span and life-span, as Azithromycin is an anti-aging drug that behaves as a senolytic, which selectively kills and removes senescent fibroblasts.

Conclusion

While antibiotics are not normally the first choice for a cancer treatment, and oxidative stress may seem to be an unusual approach with which to combat the proliferation of cancer, the fact that these compounds are already approved by the FDA makes it feasible for this treatment to be released to the public more swiftly than a freshly developed drug would be.

However, one potential problem with this approach may be that it has effects on healthy cells, and only through clinical trials will we be sure that this treatment only affects CSCs without causing undue harm to other cells. In the future, it may be possible to use more targeted compounds that more directly cause oxidative stress in rapidly growing cancer stem cells, thus potentially providing a new avenue of treatment for multiple forms of cancer.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Fiorillo, M., Tóth, F., Sotgia, F., & Lisanti, M. P. (2019). Doxycycline, Azithromycin and vitamin C (DAV): a potent combination therapy for targeting mitochondria and eradicating cancer stem cells (CSCs). Aging, 11(8), 2202-2216.

Anti-Aging Gene Therapy for Dogs Coming This Fall

In an article last May, we covered how Rejuvenate Bio, a startup biotech company led by Professor George Church, was planning to reverse aging in dogs as a step towards bringing these therapies to us. Those plans are now starting to move forward with news of a trial launch in the fall later this year.

Developing anti-aging therapies in dogs is the first step

Back in 2015, the Church lab at Harvard began testing a variety of therapies focused on age reversal using CRISPR, a gene editing system that was much easier and faster to use than older techniques. Since then, Professor Church and his lab have conducted a myriad of experiments and gathered lots of data with which to plan future strategies for tackling aging.

Last year, we learned that Rejuvenate Bio had already conducted some initial studies with beagles and were planning to reverse aging using CRISPR gene therapy. The goal was to move these studies forward to a larger scale as a step towards bringing similar therapies to humans to prevent age-related diseases. Professor Church was so confident that his team would find a solution, he even suggested that he may be one of the first human volunteers once therapies finally reach people.

“Dogs are a market in and of themselves,” Church said during the 2018 Radical Wellness event in Boston. “It’s not just a big organism close to humans. It’s something that people will pay for, and the FDA process is much faster. We’ll do dog trials, and that’ll be a product, and that’ll pay for scaling up in human trials.”

Choosing to develop therapies for dogs helps pave the way for therapies that address the aging processes in humans and could support their approval, which would otherwise be much more challenging. Currently, if you were to tell the FDA that you want to increase lifespan in humans by 20 years, you would need to come back in 20-30 years with the data, which just isn’t practical.

However, if Rejuvenate Bio can produce robust data in dogs showing that some processes of aging have been reversed, it lends considerable justification for human trials. The company is also taking a different tack; instead of focusing on increasing lifespan, it is instead targeting an age-related disease common in dogs, which should be cured if age reversal occurs.

This is based on the concept that in order to treat age-related diseases and cure them, you need to target the root causes of those diseases, which are the underlying aging processes themselves. If Rejuvenate Bio is successful, this would lend additional supporting evidence that directly treating aging to prevent age-related diseases could also work in humans.

Gene therapy trial for mitral valve disease

Rejuvenate Bio has now announced that it will be launching a gene therapy trial in dogs during the fall this year to combat mitral valve disease (MVD), a condition commonly encountered in the Cavalier King Charles Spaniel breed and directly caused by the aging processes. The study will initially focus on this particular breed and expand to include other dogs with MVD as time passes.

We are developing a novel cardio-protective gene therapy to stop the progression of heart failure in dogs. As a part of the technical development, we will launch a study in dogs with Mitral Valve Disease (MVD) in the fall of 2019. This study will provide valuable information that will aid our effort to address MVD.

MVD is due to the failure of the mitral valve in the heart, a one-way valve between the two chambers of the heart that prevents the backflow of blood as it is pumped around the body. As aging occurs, the mitral valve can degenerate, which allows backflow to occur, leading to left atrial chamber enlargement, congestive heart failure, and, ultimately, death.

This gene therapy is focused on adding a new piece of DNA into the cells of the dogs in order to halt the buildup of fibrotic scar tissue in the heart, which is linked to the progression of MVD and other forms of heart failure. Fibrotic tissue is the result of imperfect repair, which occurs when a more complete repair is not possible due to a lack of replacement cells or high levels of inflammation.

The researchers are keen to point out that this new piece of DNA is not passed onto the offspring of the animal and cannot transfer between dogs. This is because the therapy does not alter the DNA in the germline cells, the cells that are involved in reproduction and passing on genetics to an organism’s offspring.

If you wish to enroll your Cavalier King Charles Spaniel in the trial coming this fall, then register your interest with Rejuvenate Bio to learn more about eligibility and how to apply.

Conclusion

This is a very exciting study and the therapy may also be useful for other heart conditions, such as dilated cardiomyopathy (DCM). If the initial results are successful, it would be highly likely that we could see more dog breeds included as well as other conditions, including DCM, added to the program.

We wish Professor Church and Rejuvenate Bio every success, as this forms the basis for potentially moving such therapies into human trials more quickly as well as potentially helping our furry friends to live longer, healthier lives as well. We love our pets, and it is only logical that we should want the same healthy and longer lives for them as we do for ourselves, and the process for them is the same for us: new medical innovations that target the aging processes directly in order to end age-related diseases.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Samumed Begins Phase 3 Trial for Knee Osteoarthritis

San Diego-based biotechnology company Samumed has recently announced that it will be moving to phase 3 clinical trials of its drug lorecivivint (SM04690) for the treatment of knee osteoarthritis.

What is osteoarthritis?

Osteoarthritis is the most common form of arthritis in the knee and a leading cause of adult disability, particularly among older people. This degenerative, “wear-and-tear” arthritis is characterized by the destruction of the articular cartilage and structural changes to the bone, which leads to pain, inflammation, and loss of joint function and mobility. It occurs most often in people who are at least 50 years old, but it may occur in younger people as well.

During the progression of osteoarthritis, the cartilage in the knee joint steadily wears away and becomes frayed and rough, and the protective space between the bones decreases in size. This results in bone grinding on bone, which can create painful bone spurs.

Some estimates suggest that there are around 30 million adults suffering from osteoarthritis, the majority of which is due to aging. The condition robs people of their quality of life and independence while harming workplace productivity and increasing healthcare costs. The current treatment options for patients are very limited in nature, as no approved disease-modifying therapies are available at this time.

Moving to Phase 3

This phase 3 trial, known as STRIDES (SM04690 Trial Evaluating a Randomized Injection for Determination of Efficacy and Safety), will evaluate the ability of lorecivivint to ease the symptoms of knee osteoarthritis, with a focus on patient outcomes and the modification of disease progression.

In the previous phase 2 trial, lorecivivint demonstrated a reduction in pain along with improvement of function and medial joint space width, a marker of disease progression, in patients with knee osteoarthritis. The data was promising and was enough to encourage the launch of this phase 3 trial.

We recently completed the investigator meeting for STRIDES X-ray and anticipate enrolling our first subjects in the near future. Initiating this trial represents a major milestone for lorecivivint, Samumed, and potentially for the millions of patients with OA of the knee. We look forward to providing further updates on this study, as well as the additional STRIDES trials, throughout 2019.

– Yusuf Yazici, M.D., Chief Medical Officer of Samumed

What is Lorecivivint?

Lorecivivint (SM04690) is a small-molecule inhibitor of the Wnt pathway, which regulates crucial aspects of cell fate determination, cell migration, cell polarity, neural patterning, and organogenesis during embryonic development.

Samumed is focused on the part of the Wnt pathway that regulates the self-renewal and differentiation of adult stem cells and is critical for tissue maintenance and organ health. Wnt is an important signaling pathway that controls when stem cells differentiate and thus supports the formation, replenishment, and repair of all bodily tissues.

The problems start when the Wnt pathway becomes dysfunctional and its carefully regulated balance fails, which leads to poor tissue upkeep and repair and, most often, the onset of disease in a particular tissue or organ. Lorecivivint targets the Wnt pathway in order to reset the balance and restore normal function so that healthy tissue maintenance can resume once again.

The company claims that its preclinical data suggests that lorecivivint affects joint health in three key ways: generation of new cartilage material, slowing of cartilage loss, and a reduction of inflammation.

Conclusion

There are currently no approved effective therapies for osteoarthritis that modify disease progression, so a successful drug could improve the quality of life of many older people who suffer from this age-related disease.

As to whether the Wnt pathway is the optimal approach, that is another question; it is likely that a full repair approach, such as one proposed by the Hallmarks of Aging or the SENS Research Foundation, may ultimately prove more effective; however, until such technologies are available, drugs such as lorecivivint at least represent a near-future stopgap, assuming that phase 3 goes well. If it does, then approval may not be far away.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Bone Marrow Transplants Increase Healthy Lifespan in Mice

Stem cell transplants have been of great interest to aging researchers, and, in a new study, they have successfully increased mouse lifespan by using stem cell therapy. While this has been previously achieved, this experiment was more refined than older studies and sheds new light on the potential of tissue regeneration through stem cells.

The significant extension of maximum lifespan could be considered an indication that any intervention is targeting a core hallmark of aging or, in the case of small increases of lifespan, at least indirectly influencing it.

Through bone marrow transplants, the researchers have significantly increased the lifespans of mice and believe that they are directly targeting an aging process directly [1]. Given that stem cell exhaustion is a hallmark of aging, they are likely correct.

While we know a fair amount about tissue-resident stem cells and their role in tissue regeneration and repair, the part that circulating stem cells in our blood play is less well understood. These researchers have conducted prior studies using undifferentiated stem cells, cells that have not yet committed to becoming a particular cell type in the body, and they found that these cells differentiate into specialized cell types based on their environment.

This supports the possibility that tissue regeneration could occur via an injection of undifferentiated stem cells or potentially through approaches such as bone marrow transplants. In some cases, bone marrow transplants appear to treat not only blood diseases but also other conditions, such as mucopolysaccharidosis, senile hearing loss, bullous epidermolysis, and cancer.

A number of previous studies have shown that stem cell transplants appear to slow aging [2-4]; however, this new study is different from these experiments in a few ways. These researchers have used a considerably larger amount of transplant material, the donors and transplantees were genetically closely related due to the mouse strain and inbreeding, and the transplanted cells were not exposed to chemotherapy agents or radiation, which are both harmful to cells and can induce cellular senescence, which is another reason we age.

The researchers wanted to find out what effect bone marrow stem cell transplantation would have on maximum lifespan in mice that had reached an age at which half of their population had already died from age-related diseases. This would be around 70-80 years old in human terms, an age at which the number of stem cells in the bone marrow is a tenth of what it was at birth.

Normally, bone marrow stem cell transplants are preceded by myeloablative conditioning, a medical procedure that consists of either chemotherapy or radiation sufficient enough to destroy the myeloid cells other than red blood cells and platelets, thus paving the way for new bone marrow material to be implanted. However, with this new method, replacement material can be transplanted without myeloablative conditioning.

The result of waiting till the mice were older and had severely depleted stem cell reserves in their bone marrow was an increase of 28% to maximum lifespan, which is a significant amount.

Abstract

The goal of this work was to determine the effect of nonablative syngeneic transplantation of young bone marrow (BM) to laboratory animals (mice) of advanced age upon maximum duration of their lifespan. To do this, transplantation of 100 million nucleated cells from BM of young syngeneic donors to an old non-ablated animal was performed at the time when half of the population had already died. As a result, the maximum lifespan (MLS) increased by 28 ± 5%, and the survival time from the beginning of the experiment increased 2.8 ± 0.3-fold. The chimerism of the BM 6 months after the transplantation was 28%.

For the first time rejuvenation therapy was started so late, at the point when half of the animals had already died, and the high (31 ± 5%) extension in maximal lifespan of the remaining animals was found. Such significant effect on the maximal lifespan, unlike the median lifespan fluctuations, indicates that BM transplantation affects the intrinsic aging mechanism. The life-extending effect was significantly stronger than in earlier works with similar design (no irradiation or chemotherapy, no hereditary pathologies in recipients, advanced age at the start of the BM administration) because of (i) the larger amount of transplanted material and (ii) the close relation of the donors and recipients. The result is encouraging for clinical adaptation for aged humans (70–80-years old).

The observed lifespan extension was accompanied by extension of an active and healthy life period.

The bone marrow chimerism of recipients after BM transplantation was significant (28% of nucleated BM cells were of donor origin) and permanent (it lasted for at least 6 months after the transplantation), indicating that rejuvenation is caused not only by the paracrine effect but also by direct cell replacement.

Conclusion

A number of researchers support the notion of a top-down approach to tissue regeneration, such as using bone marrow transplants to replace age-related stem cell losses. These results clearly show that mouse rejuvenation is happening not only due to the beneficial signals that the stem cells give off, which facilitate healing and reduce inflammation given off, but is also happening as the result of directly replenishing lost stem cells from the pool.

Perhaps the most important thing about this particular study is that it was carried out specifically on older mice who had already lost a considerable amount of their available bone marrow stem cell pools. By replacing those losses, these researchers are directly addressing an aging process, and the result is a large extension of healthy lifespan.

This has implications for treating aged humans who are 70-80 years old, and it supports the notion that the point of no return is considerably later in life if, indeed, there exists a point at which someone cannot be effectively rejuvenated by repair-based approaches to aging.

As a result of their study, these researchers wish to see the rapid implementation of non-ablative stem cell transplantation into the clinic not only for the treatment of pathology but also for rejuvenation in older people. It appears in this case that age-related stem cell depletion makes conditions more favorable for fresh replacement stem cells, so let us hope that this becomes the standard of care soon.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Kovina, M., Khodarovich, Y., Karnaukhov, A., Krasheninnikov, M., Kovin, A. L., Gazheev, S., … & Dyuzheva, T. (2019). Extension of Maximal Lifespan and High Bone Marrow Chimerism After Nonmyeloablative Syngeneic Transplantation of Bone Marrow From Young to Old Mice. Frontiers in Genetics, 10, 310.

[2] Kamminga, L. M., van Os, R., Ausema, A., Noach, E. J., Weersing, E., Dontje, B., … & de Haan, G. (2005). Impaired hematopoietic stem cell functioning after serial transplantation and during normal aging. Stem cells, 23(1), 82-92.

[3] Li, J., Zhang, Y., & Liu, G. X. (2010). Anti-aging effect of transplantation of mouse fetus-derived mesenchymal stem cells. Sheng li xue bao:[Acta physiologica Sinica], 62(1), 79-85.

[4] Shen, J., Tsai, Y. T., DiMarco, N. M., Long, M. A., Sun, X., & Tang, L. (2011). Transplantation of mesenchymal stem cells from young donors delays aging in mice. Scientific reports, 1, 67.

A New Database for Senescent Cells

Today, we want to spotlight a new publication that charts the senescence-associated secretory phenotype (SASP), which consists of the various secreted signals given out by senescent cells during aging.

Senescent cells and the SASP

As we get older, an increasing number of our cells enter into a state known as senescence. They cease dividing and supporting the tissues and organs of which they are part and, instead, secrete a range of harmful chemical signals. This cocktail of harmful signals is known as the senescence-associated secretory phenotype (SASP).

Senescent cells only make up a small number of the total amount of cells in our bodies, but the pro-inflammatory cytokines, chemokines, and extracellular matrix proteases that they secrete do a great deal of damage and help age-related diseases to develop. If this was not bad enough, the SASP can also cause nearby, healthy cells to become senescent; this means that a relatively small number of senescent cells can cause problems far in excess of their numbers, including the degradation of tissue function, increased levels of chronic inflammation, and a greater lifetime risk of cancer.

Senescent cells normally destroy themselves via a programmed process called apoptosis, and they are also removed by the immune system; however, the immune system weakens with age, and increasing numbers of these senescent cells escape this process and build up.

By the time people reach old age, significant numbers of these senescent cells have accumulated in the body, causing chronic inflammation and damage to surrounding cells, tissues, and organs. These senescent cells are one of the hallmarks of aging and are thought to be a key reason why we age and become sick [1-2].

A new class of drugs known as senolytics focuses on removing these cells from the body in order to reduce inflammation and improve tissue function. The hope is that doing so will delay or even prevent certain age-related diseases from developing, as has already been demonstrated in mice [3]. Considering that the SASP is linked to both aging and cancer, there is every reason to be optimistic about senolytics and their potential for increasing healthy human lifespan [4-5].

A new atlas charting the SASP

A new open-access publication from researchers at the Buck Institute for Research on Aging, including Dr. Judith Campisi, is the foundation for a “SASP Atlas” that aims to comprehensively categorize the various secretions that our myriad cell types make [6] This will likely be incredibly useful in tracking the differences in the SASP between various cells.

Essentially, these researchers are creating a database that will collect information about the SASP in one place, giving it the potential to be an incredible scientific resource. The SASP Atlas database is now under construction and we recommend checking it out.

We do not currently fully understand senescent cells and their subtle differences and why these nuances exist in different cells and tissues. We know that transient senescent cells are beneficial in tissue regeneration and, broadly speaking, that persistent senescent cells cause chronic inflammation are a problem, but there is some way to go before we fully understand all that is going on here.

Fortunately, even our incomplete knowledge is allowing us to make good progress and, while somewhat crude, the first generation of senolytics has proven effective in removing senescent cells and reducing the SASP. While these treatments are unable to remove all senescent cells, it is now understood that senescent cells use different pro-survival pathways to avoid destruction, which is why no single drug has yet been able to deal with every senescent cell. This database will include such knowledge and allow senolytics to be increasingly refined, and the goal is for them to become more effective in the near future.

Summary

The senescence-associated secretory phenotype (SASP) has recently emerged as both a driver of, and promising therapeutic target for, multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically monitored by a few dozen secreted proteins, has been greatly underappreciated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present ‘SASP Atlas’, a comprehensive proteomic database of soluble and exosome SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Based on our analyses, we propose several candidate biomarkers of cellular senescence, including GDF15, STC1, and SERPINs. This resource will facilitate identification of proteins that drive specific senescence-associated phenotypes and catalog potential senescence biomarkers to assess the burden, originating stimulus and tissue of senescent cells in vivo.

Conclusion

This new database is a very welcome addition to the research landscape and stands alongside other useful resources, such as the superb HAGR database created by Dr. João Pedro Magalhães and other researchers.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

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] van Deursen, J. M. (2014). The role of senescent cells in ageing. Nature, 509(7501), 439-446.

[3] Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., … & van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232-236.

[4] Freund, A., Orjalo, A. V., Desprez, P. Y., & Campisi, J. (2010). Inflammatory networks during cellular senescence: causes and consequences. Trends in molecular medicine, 16(5), 238-246.

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

[6] Basisty, N., Kale, A., Jeon, O., Kuehnemann, C., Payne, T., Rao, C., … & Schilling, B. (2019). A Proteomic Atlas of Senescence-Associated Secretomes for Aging Biomarker Development. bioRxiv, 604306.

Reversal of Two Advanced Glycation End Products Achieved

Today, we want to highlight a new study that shows, for the first time, that established AGEs can be reversed via therapeutic intervention.

What are AGEs?

Advanced glycation end products (AGEs) are harmful compounds that are created when proteins or fats combine with sugars in the bloodstream in a process known as glycation. AGEs can also be encountered in foods, and foods that have been exposed to high temperatures, such as in grilling or frying, tend to be high in these compounds.

Thankfully, our bodies have ways to eliminate these harmful compounds, including antioxidants and enzymes; however, these mechanisms have their limits, and if we consume too many AGEs, or too many appear through the normal operation of metabolism, they can begin to accumulate, leading to oxidative stress and inflammation [1].

There are various types of AGEs, each with its own unique chemical composition; some of which that the body is able to remove and some that it cannot, as it lacks the biological tools needed to break them down. Both are a problem, and while the former can be somewhat controlled by diet and lifestyle, the latter is something that our bodies cannot deal with.

AGEs can cause random damage by altering protein structure and function, but the inflammation they cause is thought to be a primary contributor to smoldering, chronic age-related inflammation, which typically rises as we age. AGEs interact with the receptor for AGEs (RAGE), causing oxidative stress and the activation of protein complex NF-κB, a master regulator of inflammation, DNA transcription, and cell survival. This activation leads to excessive levels of NF-κB activity and is thought to be responsible for AGE-associated inflammation and cellular damage [2].

High levels of AGEs are linked to a number of age-related diseases, including diabetes, heart disease, and Alzheimer’s [3]. There is also evidence to support that people who have high blood sugar, such as people with diabetes, have a higher risk of producing more AGEs that can accumulate in the body faster than they can be cleared, thus contributing to the decline of multiple organs [4].

So, what is the solution?

It is beyond doubt that large amounts of AGEs are linked to the onset and progression of various metabolic and age-related diseases. However, it has been a challenge for researchers to prove that AGEs are the direct cause of disease, mostly due to the lack of tools needed to investigate and remove established AGEs from the body to see if their removal is a possible treatment.

Multiple researchers have attempted to develop therapies to prevent or slow down the rate of accumulation or to disrupt AGE intermediates before they become established AGEs. However, no researchers had developed a therapy that can break down or repair fully developed AGEs.

This has now changed due to a new study by researchers from the Spiegel Lab at Yale, which was financially supported by the SENS Research Foundation and others. The new study focuses on Nε -(carboxyethyl)lysine (CEL) and Nε -(carboxymethyl)lysine (CML), which are both lysine-derived AGEs.

The presence of CEL and CML are both linked to the progression of various diabetic complications and some neurodegenerative diseases, including Alzheimer’s in the case of CEL. CML is one of the most abundant AGEs found in the renal compartment and is linked to the loss of kidney function in chronic kidney disease.

In this publication, the research team describes an enzyme family known as MnmC that is able to cleave CEL AGE modifications and also CML to a lesser level. This means that it is able to reverse AGE modification and restore the original lysine structure as shown in vitro.

Abstract

Advanced glycation end products (AGEs) are a heterogeneous group of molecules that emerge from the condensation of sugars and proteins via the Maillard reaction. Despite a significant number of studies showing strong associations between AGEs and the pathologies of aging-related illnesses, it has been a challenge to establish AGEs as causal agents primarily due to the lack of tools in reversing AGE modifications at the molecular level. Here, we show that MnmC, an enzyme involved in a bacterial tRNA-modification pathway, is capable of reversing the AGEs carboxyethyl-lysine (CEL) and carboxymethyl-lysine (CML) back to their native lysine structure. Combining structural homology analysis, site-directed mutagenesis, and protein domain dissection studies, we generated a variant of MnmC with improved catalytic properties against CEL in free amino acid form. We show that this enzyme variant is also active on a CEL-modified peptidomimetic and an AGE-containing peptide that has been established as an authentic ligand of the receptor for AGEs (RAGE). Our data demonstrate that MnmC variants are promising lead catalysts toward the development of AGE-reversal tools and a better understanding of AGE biology.

Conclusion

The discovery of enzymes that are capable of reversing these AGEs and restoring their original structure is a world first. This is the starting point towards developing new tools and therapies for the reversal of established mature AGEs in organs and tissues and potentially a step towards combating a number of age-related diseases.

CEL and CML are only two of multiple AGEs we need to tackle, but thanks to funding from SENS Research Foundation, the Spiegel lab at Yale has already identified a lead candidate for cleaving glucosepane, the most abundant AGE in the body. Work continues on synthesizing pentosinane, another common AGE; if this is successful, as it was for glucosepane, this will mean an on-demand source of pentosinane on which researchers can experiment and find enzymes that can break it down.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Uribarri, J., Cai, W., Peppa, M., Goodman, S., Ferrucci, L., Striker, G., & Vlassara, H. (2007). Circulating glycotoxins and dietary advanced glycation endproducts: two links to inflammatory response, oxidative stress, and aging. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 62(4), 427-433.

[2] Xie, J., Méndez, J. D., Méndez-Valenzuela, V., & Aguilar-Hernández, M. M. (2013). Cellular signalling of the receptor for advanced glycation end products (RAGE). Cellular signalling, 25(11), 2185-2197.

[3] Singh, R., Barden, A., Mori, T., & Beilin, L. (2001). Advanced glycation end-products: a review. Diabetologia, 44(2), 129-146.

[4] Semba, R. D., Nicklett, E. J., & Ferrucci, L. (2010). Does accumulation of advanced glycation end products contribute to the aging phenotype?. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 65(9), 963-975.

XPRIZE logo

Success at the Xprize Foundation

On April 29th and 30th, the XPRIZE Foundation hosted an event at its headquarters in Culver City, California that could have a profound effect on the evolving landscape of biorejuvenation research: the Future of Longevity Impact Roadmap Lab.

For those unfamiliar, the XPRIZE Foundation is famous for designing multi-million-dollar, global competitions to incentivize the development of technological breakthroughs, perhaps the most well-known being its first: the Ansari XPRIZE, which offered a $10,000,000 award for the first non-governmental organization to launch a reusable manned spacecraft into space twice within two weeks.

With this event, the purpose of which was to gather subject matter experts to brainstorm a potential longevity-research prize, XPRIZE has turned its focus towards solving the critical problem of age-related diseases on society and extending healthy human lifespan for all. As I was fortunate enough to directly participate in this exciting meeting, I’d like to share some of my experiences with you all.

The Room Where It Happens

The first thing I noticed upon entering the XPRIZE headquarters was how impressive it is, both in terms of size and in its almost museum-like quality of showcasing innovations in which the foundation has had a hand over the past few decades — statues, trophies, a large rocketship model hanging from the ceiling. Simply put, it is a facility designed to make you think “big things happen here”, and the significance of the fact that attendees such as myself were gathered here to “discover innovative and accessible ways to radically extend everyone’s healthy lifespan” was not lost on me. The times are changing, and changing fast — the tide is turning.

The second thing I noticed was just how diverse the group of attendees was, a veritable who’s who of the broader pro-longevity movement: researchers such as Drs. Steve Horvath and Greg Fahy, investors such as Sergey Young (board member of XPRIZE and creator of the $100m Longevity Vision Fund), long-time advocates such as myself, Aubrey de Grey, and Jim Strole, global policy makers, journalists, cryonicists such as Max More, transhumanists such as Zoltan Istvan and Natasha Vita-More, and of course XPRIZE founder Peter Diamandis.

I confess that I was not initially sure how this eclectic group would gel together in the brainstorming sessions to follow, but what was clear to me was that this could be the beginning of a watershed moment for overcoming the diseases of aging. This is the kind of room where it happens.

The Task at Hand

After the stage-setting opening talk by noted futurist Ray Kurzweil, the proceedings quickly shifted to the stated purpose of the gathering: brainstorming the most impactful and audacious ideas to overcome the negative aspects of aging and age-related disease on society.

To facilitate this, the attendees, numbering approximately 70, were divided into tables of four or five — each person tasked with generating a preliminary idea for a longevity-focused XPRIZE and further charged with convincing the rest of their table that their proposed idea should be the one put forth by their table to the rest of the group for consideration. My table happened to include Aubrey de Grey, and thus I knew that a lively discussion was all but assured.

Before beginning to debate the design of an ideal contest, however, it is necessary to understand what qualities and parameters typically make for an effective XPRIZE, and, as such, we were presented with some examples of these — having clearly verifiable goals, the ability to catalyze new markets by targeting specific industry failures, projecting a telegenic vision of hope that the public can rally behind, etc.

The entire group of attendees was also engaged to discuss how the realities of healthy life extension might relate to these various parameters, and, in this exercise, I am glad to note how instrumental the analytical work done by our outreach and writing departments at LEAF was in providing actionable information to the group. One example: when the XPRIZE team asked how the concept of gender inclusivity might relate to an ideal longevity-focused prize, the work of our team allowed me to quickly relay relevant statistics such as how a high percentage of family healthcare decisions are made by women, polling data on the desirability of life extension for both men and women, and how disparities in perception of increased longevity alter depending on how the topic is framed.

When it came time to begin brainstorming, many interesting ideas were discussed at our particular table, including the development of composite biomarkers to validate therapies targeting the aging process, and ways in which blockchain technologies could be used to accelerate drug discovery.

The idea I personally put forth was a conceptually simple one: meaningful physiological remediation of dementia (not just proxy diagnostics or biomarkers) by 2030. I thought this was well suited to the the XPRIZE qualities of “bold, but feasible” and “define the problem, not the solution”, and it has several other factors in its favor, namely that dementia is by far the most damaging aspect of aging in terms of protracted emotional suffering and large-scale socioeconomic effects, it is the one aspect of aging that everyone already unequivocally believes is horrific and needs solving, the existing system has failed to solve it for decades, many promising therapy angles have no traditional profit motive and thus will not come to market without additional incentive, success would be clear to validate, and curing it would create an amazing and hopeful narrative with which to enlist the entire world in overcoming all of the diseases of aging.

Aubrey apparently agreed, and with his vote of confidence, this idea became one of the prize concepts pitched to the entire group for consideration. Ideas arising from the other tables’ groups covered a wide range of topics as well, included growing fully functional organs from stem cells, demonstrating the arrest of epigenetic markers of aging, successful brain transplantation, creation of an ageless mouse, and restoration of homeostatic and damage repair mechanisms in the elderly. After the completion of these presentations, it was time for lunch, with the expectation that upon their return, each attendee would join the table of whichever idea they believed in the most and help to refine it.

It was at this time that I became most uncertain of the future of my own pitched concept, as just prior to the break, one of the organizers mentioned that XPRIZE was already planning an Alzheimer’s-focused contest, and several attendees mentioned during lunch that they had planned to join our table but now supposed that it was better to support a different project instead. Sure enough, when lunch was completed, my table had become empty, but as the contest idea that I was advocating was actually quite different and larger in scope than the mentioned existing initiative, I chose to continue refining it during the ensuing session.

The final activity for the first day was for the team leaders of the newly reorganized tables to present their refined concepts on a poster shown to the entire group of attendees, who would then place stickers to vote for the concepts that they felt most worthy of actually becoming an XPRIZE. There were 18 concepts in total, all interesting, but one that I felt was noteworthy for its difference from the rest was a $5 million “Longevity Peace Prize” for whoever could convince a national government to declare aging to be a disease. This bears similarity to one of the concepts I sent to XPRIZE ahead of the event — to award $10 million to whoever could convince a national government to allocate $10 billion to aging research (a 1000x impact return and in line with other initiatives, such as the Human Genome Project and the Brain Initiative) — and one that I believe is important to have in the running in order to remind the attendees that some of the most impactful initiatives that we could choose may actually not be directly related to research.

When it came time for the actual voting, I confess that my expectations were not high for my own pitched concept, given what had transpired earlier. Thus, I was honestly shocked when it emerged as one of the top three choices along with the arresting of epigenetic markers concept mentioned above and one from Aubrey focusing on limited, but specifically measured, human rejuvenation by 2032.

As some of you reading this may know, the terrors of dementia have had a profound impact on my own family – a story that is now becoming all too common – and it would be a lie to state that seeing the support for eradicating this affliction at an event such as this did not challenge my emotional composure.

Audacity and the Time for Impact

On the second and final day of the event, I happened to meet Aubrey on the road to the venue, as it turned out that both of us preferred to walk from our hotels a few miles away. It was a nice day, and this was a welcome pleasure before returning to meet the rest of the attendees.

Once gathered again at the XPRIZE headquarters, the focus of the group became much narrower than it was on the previous day, as we were tasked to assess the top five highly voted projects from earlier on very specific criteria: How audacious is the concept? How impactful will its success and/or attempts at success be towards achieving the ultimate goal? In what timeframe can we reasonably expect a proof-of-concept? In what timeframe can we reasonably expect wide-scale adoption?

In terms of an ideal XPRIZE contest, the sought-after configuration was maximal impact and audacity, a proof-of-concept expected date achievable within 10 or 15 years, and with the shortest possible time period between proof-of-concept and widespread adoption.

The assigning of these metrics for each proposal involved a discussion among the entire group on each point, and it is interesting to note that, despite the wide diversity of backgrounds represented in the room, there was generally strong consensus on how each concept was ranked in all cases.

When all was said and done, two concepts stood firmly in the upper-right quadrant of the charts that we had collectively made, which denoted “XPRIZE Territory”. These were the aforementioned proposals put forth by Aubrey and myself: limited but specifically measured human rejuvenation by 2032 and meaningful physiological remediation of dementia by 2030.

It was at this time that my emotional composure circuits may have suffered a minor systems failure, but I won’t tell anyone if you won’t.

Now the Turning of the Tide

Of course, with the current exercise completed and the attendees now back to their respective homes and workplaces, it remains to be seen just how the outcome will inform the immediate plans of the XPRIZE Foundation.

Regardless of how quickly a longevity-focused XPRIZE contest is launched, my personal assessment is that this event was an extremely positive one — another clear marker that for whatever battles lie ahead of us to overcome the diseases of aging, some critical battles have already been won. Public perception in terms of the feasibility and desirability of positively affecting the aging processes is profoundly changing, and fast. Influential stakeholders and organizations such as XPRIZE are seeing that the time is now to drive forward a future in which diseases such as Alzheimer’s are just a memory. That is partly because of you, and especially those of you who have been fighting for many years for this cause — take a moment to feel that. Ten years ago, this would not have happened.

Finally, I would like to say that it was a truly humbling and exciting experience to participate in this event, working with a dynamic group of experts to come up with the most impactful and audacious ideas for overcoming the negative aspects of aging on society. Thank you to all who attended and organized; I look forward to meeting again.

NMN Improves Cognitive Function in Aged Mice

Researchers have tested nicotinamide mononucleotide on aged mice to see if it can help reverse age-related cognitive decline by improving blood flow in the brain.

The brain is a hungry organ

Healthy brain function relies on efficient cerebral blood flow (CBF) to wash away harmful waste products for disposal and supply the brain with an adequate supply of oxygen and sufficient nutrients.

The brain is a hungry organ and consumes around 20% of the resting total of oxygen, which is staggering given that it only accounts for about 2% of our total body mass. The demand for oxygen and energy also increases during times of high neuronal activity, which means that the brain needs to quickly adjust the incoming oxygen and glucose levels via CBF.

This rapid response to differing levels of demand by the brain is facilitated by a mechanism known as neurovascular coupling (NVC). NVC refers to the relationship between local neural activity and the subsequent changes in cerebral blood flow (CBF).

One way in which NVC adjusts CBF is via the release of nitric oxide from the cell walls of the microvascular endothelium, the tiny blood vessels that supply brain tissue. Nitric oxide is a vasodilator, meaning that it opens up the blood vessels upon exposure; this allows for a greater flow of blood, leading to more oxygen and nutrients reaching the brain.

As we age, the NVC response appears to decline just as it does in lab mice, and it is thought to contribute to cognitive decline and the ability to coordinate and walk properly.

NAD+ repletion with NMN restores neurovascular coupling

In a new study, a research team including Dr. David Sinclair tested the hypothesis that nicotinamide mononucleotide (NMN) supplementation could rescue NVC responses in aged mice by reducing mitochondrial oxidative stress in the microvascular endothelial cells of the brain [1].

The team’s previous studies had shown that NVC response could be restored in aged mice using mitochondrial antioxidant peptides and SIRT1-activating drugs. This laid the groundwork for suggesting that targeting the cellular mechanisms that contribute to age-related NVC dysfunction could be a potential way to treat cognitive decline in older people.

NAD+ plays a key role in mitochondrial function in all of our cells, which includes the endothelial cells in the brain. As we age, our available levels of NAD+ begin to fall, and with that comes reduced cellular function and critically poorer DNA repair, which NAD+ facilitates.

Some researchers suggest that the decline of NAD+ is one reason we age and that increasing NAD+ to more youthful levels may mitigate some of the negative effects of aging. Certainly, a number of studies support this, and NAD+ repletion therapies have increased healthspan in progeric mouse strains that are engineered to experience a form of accelerated aging.

In the case of NMN, there is good evidence that NAD+ repletion using this compound is able to reverse some aspects of aging in a number of organs, including the eyes, skeletal muscle, and arteries. One of the primary reasons NMN appears effective is due to its reversal of age-related mitochondrial dysfunction [2]. Given that NMN might improve mitochondrial function and have a protective effect on the brain, improving NVC response, the research team set out to test this hypothesis.

The mice were given NMN injections for a two-week period at a dosage of 500 mg NMN/kg body weight per day. The team used aged C57BL/6 mice, a popular strain of lab mouse that is not engineered to experience accelerated aging; this was important for the purposes of this study, as it would mean that any beneficial results would be affecting real aging and not an artificial form of aging, as is the case when using progeric mouse strains.

During the period of treatment, the mice were given cognition and motor coordination tests, both of which are linked to the NVC responses in the brain. They also tested NVC response and how well endothelial cells were performing in the brain’s microvascular system. During this time, the research team also measured biomarkers for oxidative stress, gene expression relating to NVC responses, antioxidant responses in cells, and mitochondrial function.

The researchers found that NMN treatment was able to improve the NVC response of aged mice via improving nitric oxide-mediated vasodilation of the microvasculature in the brain. The increased level of CBF significantly improved cognition and walking ability in aged mice. The researchers conclude that the age-related fall of NAD+ levels facilitates dysfunction in the microvasculature of the brain, leading to a poor NVC response and contributing to age-related cognitive decline.

Abstract

Adjustment of cerebral blood flow (CBF) to neuronal activity via neurovascular coupling (NVC) has an essential role in maintenance of healthy cognitive function. In aging increased oxidative stress and cerebromicrovascular endothelial dysfunction impair NVC, contributing to cognitive decline. There is increasing evidence showing that a decrease in NAD+ availability with age plays a critical role in a range of age-related cellular impairments but its role in impaired NVC responses remains unexplored. The present study was designed to test the hypothesis that restoring NAD+ concentration may exert beneficial effects on NVC responses in aging. To test this hypothesis 24-month-old C57BL/6 mice were treated with nicotinamide mononucleotide (NMN), a key NAD+ intermediate, for 2 weeks. NVC was assessed by measuring CBF responses (laser Doppler flowmetry) evoked by contralateral whisker stimulation. We found that NVC responses were significantly impaired in aged mice. NMN supplementation rescued NVC responses by increasing endothelial NO-mediated vasodilation, which was associated with significantly improved spatial working memory and gait coordination. These findings are paralleled by the sirtuin-dependent protective effects of NMN on mitochondrial production of reactive oxygen species and mitochondrial bioenergetics in cultured cerebromicrovascular endothelial cells derived from aged animals. Thus, a decrease in NAD+ availability contributes to age-related cerebromicrovascular dysfunction, exacerbating cognitive decline. The cerebromicrovascular protective effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective interventions in patients at risk for vascular cognitive impairment (VCI).

Conclusion

NMN therapy appears to have a protective effect on brain microvasculature and improves the production of nitric oxide, which improves blood flow in the brains of aged mice. This opens the door for testing NMN therapy in humans as a potential treatment for age-related cognitive decline.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Tarantini, S., Valcarcel-Ares, M. N., Toth, P., Yabluchanskiy, A., Tucsek, Z., Kiss, T., … & Farkas, E. (2019). Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice. Redox Biology, 101192.

[2] Mills, K. F., Yoshida, S., Stein, L. R., Grozio, A., Kubota, S., Sasaki, Y., … & Yoshino, J. (2016). Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell metabolism, 24(6), 795-806.

One Step Closer to Artifical Lymph Nodes

Scientists from Johns Hopkins Medicine have reported the successful creation of a special type of gel that mimics the lymph nodes in our bodies. This gel recruits and multiplies T cells just like actual lymph nodes do, so it could help in the fight against cancer and immune system disorders.

The lymph nodes are the boot camps of the immune system

There has been a great deal of interest in immunotherapy in the last few years, particuarly in using the T cells, a type of white blood cell, to hunt down cancer and destroy it. Our own immune system is quite literally living medicine, and when it works properly, it can deal with invading pathogens and cancers with ease; this is one reason why the traditional small-molecule approach to cancer has started to fall by the wayside in favor of immune approaches.

Immunotherapy typically increases the amounts of immune cells available or even boosts how well the cells work in order to fight off disease. Cancer often hides in plain sight and uses various tricks to fool the immune system into ignoring it, so immunotherapy often focuses on improving how well our immune cells detect cancer or help it to see past the tricks it uses to hide.

In order to do this, the immune cells must first be trained to detect the key molecular markings on the surfaces of cancer cells. This normally happens in the lymph nodes, which function almost like army boot camps where the new T cell recruits are trained for battle; this follows their initial training in the thymus.

The lymph nodes are small, bead-like glands that are distributed around the body in order to provide a comprehensive network of defenses. In patients with immune system disorders or cancer, this training does not happen or is incomplete, so the resulting T cells cannot do their job properly. With aging, the lymph nodes become increasingly dysfunctional as they become fibrotic and deteriorate.

Currently, the solution to this lack of training is to take the T cells from the patient and activate them through genetic engineering or drugs that complete the training so that the cells can identify cancer cell surface markers properly. This is, by its nature, challenging and costly to undertake and only possible through specialized labs, and it can take several weeks to do. Furthermore, once the T cells are given back to the patient, they do not last long before more need to be processed in this way.

Moving towards an artificial lymph node

In the new study, researchers developed a type of hydrogel, a jelly-like polymer, to serve as a platform for T cell training and which mimics the lymph node environment [1]. The hydrogel contains two chemical signals that encourage T cells to locate and eliminate foreign targets, and it acts similarly to real lymph nodes in training these cells. Compared to the T cells activated in standard Petri dishes, the cells on the hydrogels produced an impressive 50 percent more activation cytokines.

The team also experimented with different grades of hydrogels, ranging from very soft consistency to harder more rigid ones. They found that the T cells favored a softer gel environment over the more tightly packed rigid gels. Over 80 percent of the T cells in the soft gel divided, while those in the rigid gel did not.

To put this into perspective, this translates to taking a handful of cells and having them multiply to around 150,000 cells in just a week. The team also compared this with the Petri dish method of activating and multiplying T cells, which only reached around 20,000 cells in the same period. This makes this gel approach much more efficient, and the potential price point of therapy could be considerably lower with this method.

Finally, the researchers studied mice with a lethal form of melanoma and injected them with T cells from both the hydrogel and the regular Petri dish cultures. The tumors in the mice given gel-derived T cells stabilized and did not grow in size, while an injection of regular Petri dish T cells led to continued tumor growth in most of the mice.

Abstract

T cell therapies require the removal and culture of T cells ex vivo to expand several thousand‐fold. However, these cells often lose the phenotype and cytotoxic functionality for mediating effective therapeutic responses. The extracellular matrix (ECM) has been used to preserve and augment cell phenotype; however, it has not been applied to cellular immunotherapies. Here, a hyaluronic acid (HA)‐based hydrogel is engineered to present the two stimulatory signals required for T‐cell activation—termed an artificial T‐cell stimulating matrix (aTM). It is found that biophysical properties of the aTM—stimulatory ligand density, stiffness, and ECM proteins—potentiate T cell signaling and skew phenotype of both murine and human T cells. Importantly, the combination of the ECM environment and mechanically sensitive TCR signaling from the aTM results in a rapid and robust expansion of rare, antigen‐specific CD8+ T cells. Adoptive transfer of these tumor‐specific cells significantly suppresses tumor growth and improves animal survival compared with T cells stimulated by traditional methods. Beyond immediate immunotherapeutic applications, demonstrating the environment influences the cellular therapeutic product delineates the importance of the ECM and provides a case study of how to engineer ECM‐mimetic materials for therapeutic immune stimulation in the future.

Conclusion

This early, proof-of-concept work is one step closer towards injecting these artificial gel lymph nodes into people who would benefit from an improved level of immune system response, and it opens the door to fighting cancer and other diseases. The study highlights the importance of the substrate on which cells are placed in influencing them and thus the importance of the extracellular matrix (ECM).

The researchers discuss how this study not only improves current immunotherapy cell expansion methods but also lays the groundwork for creating ECM-mimetic materials for therapeutic immune stimulation in the future. This is only an initial step towards creating lymph nodes, but studies like this demonstrate the concept’s plausibility and so bring such things closer to becoming a reality.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Hickey, J. W., Dong, Y., Chung, J. W., Salathe, S. F., Pruitt, H. C., Li, X., … & Gerecht, S. (2019). Engineering an Artificial T‐Cell Stimulating Matrix for Immunotherapy. Advanced Materials, 1807359.

Jerry Shay on Telomere Measurements

Professor Jerry Shay of the Shay/Wright lab is perhaps most well-known for his research on telomeres and telomerase and their relation to cancer and aging.

He has been instrumental in the development of telomerase inhibitors, which turn off the expression of telomerase in cancer cells; this expression is one way in which cancer cells become immortal and divide constantly. His team is also developing another treatment, a small molecule that can uncap the telomeres of cancer cells.

Telomeres are a proposed primary hallmark of aging, but their role in aging is often misunderstood as simply being a replicative clock. However, it seems that their role in regulating gene expression and their contribution to genomic and epigenomic stability is more important.

We had the opportunity to interview Professor Shay at the recent Undoing Aging conference in Berlin.

Can you explain how telomeres regulate gene expression via TPE and TPE-OLD?

TPE is a term that has been around for decades. It stands for telomere position effect. This concept is that the chromatin near telomeres is different from the rest of the genome and generally involves silencing of genes. In yeast, if one moves an actively expressed gene near a telomere, then it becomes silenced. We reasoned that in humans, telomere length changes could also change gene expression so that when telomeres are long (early in human life), certain genes are repressed, and with increased age and progressive telomere shortening, then certain genes (perhaps near telomeres) could become active. We call this TPE-OLD (over long distances) or telomere looping.

We have shown that the gene regulating the protein (catalytic) component of telomerase is very close to a telomere in humans and all large long-lived mammals. Using a variety of cell and molecular techniques, we published in PloS Biology a few years ago that the TERT (telomerase) gene was regulated by TPE-OLD [1].

This has great explanatory values for an aging concept called antagonistic pleiotropy. This means that things that could be beneficial early in life may have unexpected harmful consequences late in life. Thus, we need telomerase during early development when there is rapid tissue growth, and when telomeres reach human typical size, the telomere loops over and silences the TERT genes. As we age and telomeres shorten, then the telomere can no longer influence the repression of telomerase, and thus telomerase may become reactivated in mostly older individuals as part of cancer progression.

What do you think is the best method of measuring telomeres?

We call the most sensitive assay TeSLA, for telomere shortest length assay. Most scientists use a Q-PCR assay that is not very reliable but easy to use. It is well established that it is the shortest telomeres that leads to replicative senescence. There are thousands of published papers using the Q-PCR making extraordinary claims based on very small differences in average telomere length. Other methods include TRF and Q-FISH, and these are intermediate in their ability to see some but not all the shortest telomeres.

Leukocytes are often the cells of choice to measure telomeres with, but telomeres appear to be highly dynamic in these cell types so may not be ideal for rejuvenation studies. For the purposes of aging biomarkers, what would be the ideal cell type to test the telomeres of?

There is nothing wrong with looking at peripheral blood leukocytes. The telomeres in leukocytes reflect the divisions that have occurred in the bone marrow. Many years ago, we demonstrated that the bone marrow stem cells also shortened during human lifespan, and this is reflective in the peripheral blood. Thus if your telomeres are longer in your leukocytes, it is probably better than if they are shorter. Depending on the reason they are shorter in the peripheral blood, it is possible this can be reversed from a stem cell that has somewhat longer telomeres. Thus, someone who smokes may have shorter telomeres in the peripheral leukocytes, and if this person stopped smoking the telomere may appear to be elongating.

A more complicated question is “Does this have anything to do with overall human longevity?” I am cautious and say first that telomeres cannot explain everything about human aging. If telomeres represent let’s say 10% of what causes tissues to decline with age, and if we understand them and can manipulate them, this may result in some improved healthspan or, potentially, lifespan. This is currently where we are today, and the experiments that need to be done are currently in progress.

However, we published in Aging Cell last year that high-performing centenarians have longer telomeres compared to more frail or low-performing centenarians and believe that this may be biologically meaningful. Others have published that the telomere lengths in leukocytes are similar to other tissues, such as skin and muscle.

What are your thoughts on restoring telomere length using transient telomerase induction as a therapeutic approach to aging?

It is a reasonable idea, and we are currently doing such experiments. Initially, it will be done ex vivo, e.g. in the cell culture lab, to prove it works and does no harm. We can then give individuals back their own cells, potentially with slightly elongated telomeres.

We have recently seen some researchers testing in vivo partial cellular reprogramming using OSKM induction, which appears to reset telomere length as it resets epigenetic markers. Are you optimistic about this approach to resetting cellular aging?

Not at all. This approach may reset a lot of things we do not want to reset. Super-elongating telomeres via reprogramming and having high levels of telomerase could have unexpected consequences. It has been shown that many epigenetic changes are also altered that may not be desirable using this approach. It is a good basic biology approach to study specific diseases but is unlikely to be used in a practical sense at least for now.

It seems that telomeres and epigenetic alterations are linked via an axis and that adjusting one appears to influence the other. So, if partial cellular reprogramming resets telomeres, might we expect that resetting telomeres may reset epigenetic markers?

That is correct.

There is often a concern about cancer whenever inducing telomerase is mentioned; however, some studies support that longer telomeres mean a more stable genome and epigenome, which would help to prevent cancer. Do you expect cancer to be a concern with telomerase therapies?

That is why introducing telomerase transiently and in a tissue or cell-specific manner will be safer.

It appears that cancer uses TERT and ALT in order to spread without control and that blocking these pathways may be a way to halt most if not all cancers. How are things progressing with developing such inhibitors?

We have now published at least five recent papers using a compound called 6-thio-deoxyguanosine (6-tho-dG), a nucleoside that uses telomerase to incorporate an alter G into the telomeres, leading to immediate toxicity to cells expressing telomerase but not normal cells. I am very optimistic that this approach will have utility in treating cancer patients (especially those that have failed other therapies), and we are moving forward with preclinical studies to get this into human trials in the near future.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Kim, W., Ludlow, A. T., Min, J., Robin, J. D., Stadler, G., Mender, I., … & Shay, J. W. (2016). Regulation of the human telomerase gene TERT by telomere position effect—over long distances (TPE-OLD): implications for aging and cancer. PLoS biology, 14(12), e2000016.