Extracellular Vesicles and Aging

Date Posted: January 26, 2018

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Stem cell therapies have been developing and evolving rapidly over the last decade, and extracellular vesicles (EVs) are another innovative approach that researchers are exploring. EVs are being explored for their potential as the basis of new cell therapies, taking the signals generated from various types of stem cells and delivering just those signals, rather than the cells, to the patient.

So what are extracellular vesicles?

EVs are basically membrane-wrapped packages that contain proteins and other molecules and are created and released by cells. Nearby cells intercept these packages and adjust their behavior based on the information contained in the EVs.

Various names have been used to refer to the vesicles being released by healthy cells, including ectosomes, microparticles, and shedding microvesicles. For the purposes of discussion, we will use the term extracellular vesicles (EVs) as a generic term to describe all secreted vesicles.

EVs can broadly be described as either exosomes, microvesicles (MVs) or apoptotic bodies depending on their cellular origin:

	Exosomes	Microvesicles	Apoptotic Bodies
Origin	Endocytic pathway	Plasma membrane	Plasma membrane
Function	Intercellular communication	Intercellular communication	Facilitate phagocytosis
Size	40-120 nm	50-1,000 nm	500-2,000 nm
Contents	Proteins and nucleic acids (mRNA, miRNA and other non-coding RNAs)	Proteins and nucleic acids (mRNA, miRNA and other non-coding RNAs)	Nuclear fractions, cell organelles

Extracellular vesicles have attracted considerable interest in the scientific community due to their role in intercellular communication. It has been known for a long time that cells release vesicles into the extracellular environment during apoptosis. However, the fact that healthy cells also release vesicles into the extracellular environment has only been realized more recently.

A review of extracellular vesicles and aging

Today, we wanted to point out a great review paper discussing the potential of extracellular vesicles and how they could be used to develop new kinds of therapies[1].

It is not hard to imagine that stem cell therapies could evolve to include therapies that use cellular signals without any actual cells being transferred. Indeed, we have seen some studies showing that even cell culture that has had stem cells kept in it retains some beneficial properties that can help facilitate healing.

The clinical data thus far strongly supports that many cell therapies produce beneficial effects via this signaling. Mesenchymal stem cells are a classic example; the cells themselves do not survive in the patient for long, but the signals they give off encourage tissue repair.

Conclusion

It is logical that therapies based on just these signals are the next step forward, though they would not totally replace whole-cell therapies. It is important that we develop efficient ways to transplant stem cells and improve their survival and engraftment rates to deal with organ failure. This will improve with time, and, indeed, progress on this front has been rapid in recent years.

Meanwhile, we can consider the use of extracellular vesicles as yet another string on our bow and an option for therapy in certain cases.

Literature

[1] Robbins, P. D. (2017). Extracellular vesicles and aging. Stem Cell Investigation, 4(12).

Date Posted: January 25, 2018

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TIGIT as a Biomarker for T Cell Senescence and Exhaustion

In a new study, researchers propose that TIGIT is a marker of T cell senescence and exhaustion in the immune system [1]. However, not only is TIGIT just a biomarker, it is also a potential therapeutic target; as the researcher team discovered, lowering levels of TIGIT resulted in the restoration of some lost function in T cell populations that were experiencing high levels of senescence and exhaustion.

Aging is associated with immune dysfunction, especially T-cell defects, which result in increased susceptibility to various diseases. Previous studies showed that T cells from aged mice express multiple inhibitory receptors, providing evidence of the relationship between T-cell exhaustion and T-cell senescence. In this study, we showed that T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), a novel co-inhibitory receptor, was upregulated in CD8+ T cells of elderly adults. Aged TIGIT+ CD8+ T cells expressed high levels of other inhibitory receptors including PD-1 and exhibited features of exhaustion such as downregulation of the key costimulatory receptor CD28, representative intrinsic transcriptional regulation, low production of cytokines, and high susceptibility to apoptosis. Importantly, their functional defects associated with aging were reversed by TIGIT knockdown. CD226 downregulation on aged TIGIT+ CD8+ T cells is likely involved in TIGIT-mediated negative immune suppression. Collectively, our findings indicated that TIGIT acts as a critical immune regulator during aging, providing a strong rationale for targeting TIGIT to improve dysfunction related to immune system aging.

A recipe for disaster

An aged immune system is rife with dysfunction, with too many senescent and exhausted cells causing inflammation and not doing their jobs properly. Many immune cells become specialized to deal with persistent viruses, such as cytomegalovirus, which takes up immune space. This all adds up to a recipe of increasing dysfunction and decline as we age and ultimately leaves us vulnerable to pathogens and infections.

It has been suggested by some researchers that the problem lies with these dysfunctional immune cells and that removing them could be a potential approach to restoring efficient function to the immune system. This would be the same approach as removing senescent cells from any other tissue, and the use of senolytics, drugs that induce cell death in target senescent cells, could also be the solution here.

Another option could be to completely remove the immune system and start over; although while this is currently possible and has been done in some patients undergoing organ transplants, it is a risky procedure and not safe enough to be used in older people. Presently, the method for doing this is to use high doses of immunosuppressive drugs followed by cell therapy to repopulate the immune system. This approach has also been used to treat the autoimmune condition of multiple sclerosis, but the risks are high.

Conclusion

Senescent cells are without a doubt one of the reasons we age, so the discovery of TIGIT as a biomarker is promising. Senescent cells age us by contributing to the background of chronic inflammation known as inflammaging, so their removal is a solid strategy for improving tissue health and preventing diseases.

Now that TIGIT has been identified as a potential therapeutic target, companies like Oisin Biotechnologies could potentially use their programmable gene therapy to attack senescent immune cells. Systems like this also have an advantage over traditional small molecules, as they are faster to configure and deploy against a target gene without the off-target side effects that drugs have.

References

[1] Song, Y., Wang, B., Song, R., Hao, Y., Wang, D., Li, Y., … & Kong, Y. (2017). T‐cell Immunoglobulin and ITIM Domain Contributes to CD8+ T‐cell Immunosenescence. Aging Cell.

Date Posted: January 22, 2018

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Starving Cancer Cells to Death

Novel therapeutic approaches may often require quite a bit of lateral thinking, as researchers at the Salk Institute have recently shown in a study presenting a novel method to interfere with cancer growth.

The problem with cancer

In a nutshell, the reason cancer is such an insidious enemy is that its cells divide uncontrollably, leading to the formation of tumors that keep growing, impair bodily functions, and in a worst-case scenario, metastasize—they spread from their original site, wreaking havoc around the body.

Thus, methods to directly prevent cancer cell division have long been a major research target worldwide. Salk researchers, however, decided to try to intervene a little earlier in the chain of events, messing with cancerous cells’ growth rather than division. To do so, they interfered with cancer’s ability to evade the constraints imposed by the circadian cycle.

What is the circadian cycle?

You can think of the circadian cycle as a sort of internal clock of your body that regulates many different mechanisms. The cycle starts over about every 24 hours (hence the term “circadian”, coming from Latin circa “about” and dies “day”), and among its many functions, it tells cells when they’re supposed to produce and consume nutrients. Healthy cells are normally allowed to do so for about 12 hours a day, in order to prevent them from being overwhelmed by a flood of excessive nutrients.

When cell mealtime is over, levels of the REV-ERB protein rise, which inhibits the cell’s ability to synthesize fats and shuts down autophagy—the cell’s ability to recycle materials, which has implications for longevity and atherosclerosis, for example. When REV-ERB levels go down again, cells resume fat production and start breaking down useless cellular components.

Cancer’s deep appetite

Obviously, in order to keep dividing indefinitely, cancer cells cannot afford the periodic fasting imposed by the circadian rhythm; before they can divide, they need to grow, and in order to grow, they need nutrients. Therefore, furiously paced division requires furiously paced nutrient intake. Hence, all cancers evolve strategies to get around the circadian limitation.

Cancer cells do contain the REV-ERB protein that switches nutrient consumption on and off, but their relevant machinery stays inactive, which allows them to feast all the time and thus grow quickly. This is where Salk researchers intervened.

The team, led by Professor Satchidananda Panda, used two known REV-ERB activators on several different types of cancer cells, including the ill-famed glioblastoma, an extremely dangerous brain cancer. In all cases, the cancer cells, deprived of nutrients, ended up starving to death, whereas healthy cells, which normally undergo this periodic fasting, were unaffected. Tested in a mouse model of glioblastoma, the treatment successfully eliminated cancer cells while seemingly leaving healthy ones alone.

Conclusion

This study may hold the promise of novel anticancer approaches with minimal side effects, if any. However, in order to assess this, follow-up studies will be required to make sure of how exactly REV-ERB activators affect metabolism, particularly the metabolism of the gut microbiome. It should also be noted that this is only one of many possible methods to control cancerous cells’ growth and thus interfere with their ability to proliferate. However, we will follow the development of this research with great interest.

Literature

[1] Sulli, G., Rommel, A., Wang, X., Kolar, M. J., Puca, F., Saghatelian, A., … & Panda, S. (2018). Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence. Nature.

Date Posted: January 19, 2018

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Is Aging Natural, a Disease That We Can Treat, or Both?

Aging is something that we all share, rich or poor; it is something that happens to us all, and we are taught from a young age that it is inevitable. However, some scientists believe that aging is amenable to medical intervention and that such interventions could be the solution to preventing or reversing age-related diseases.

Academics are currently debating whether aging is natural or a pathological disease that we can treat.

In fact, there is now pressure from many academics to classify aging itself as a disease; indeed, doing so could potentially improve funding for aging research and help to speed up progress in finding solutions to age-related diseases.[1] The debate continues, but does it really matter if aging is classified as a disease, or is it largely a matter of semantics?

Fighting a losing battle

Current medical practice sees us trying to treat age-related diseases in the same way we do other diseases; this is the “infectious disease model”, and when it comes to treating age-related diseases, it is a losing battle.

The current approach works like this: as soon as a disease appears, the doctor attacks the disease using everything in the medical armory, and the patient can then continue with life until the next disease happens; this process is repeated until failure. This is an excellent way to deal with infectious diseases, and it has helped to increase life expectancy greatly in the last century; however, there are signs are that this approach is starting to run out of steam.[2-4]

Unfortunately, this “whack-a-mole” approach is a poor choice when it comes to treating the chronic diseases of old age. This is because the damage that the aging processes cause still continues to take its toll; therefore, treating the symptoms will ultimately achieve very little and certainly not cure the disease.

So, given that the aging processes lead to the diseases of aging, it is understandable that scientists are starting to consider aging itself to be a disease. While we do not yet fully understand all the intricacies of aging, we already know a great deal about the individual processes.[5] Certainly, we now know enough about aging to begin developing and testing interventions that directly target the underlying processes in order to prevent or treat pathology.

Treating the underlying processes and repairing their damage, which leads to the familiar diseases of old age, is the basis for the medical approach known as rejuvenation biotechnology, a multidisciplinary field that aims to prevent and treat age-related diseases by targeting the aging processes directly.

Aging is the foundation of age-related diseases

Even if aging is not a disease itself, the individual processes do lead to pathology and age-related diseases, such as cancer, heart disease, Parkinson’s, and Alzheimer’s. So, knowing that these processes create the conditions for diseases to develop, it makes sense to target the processes themselves in order to potentially prevent or treat a slew of age-related diseases at once.

The changes that aging brings vary from one person to another, but the common processes of aging are at work in all of us, albeit with some small variances between individuals. For example, we all suffer wear and tear in our joints due to the loss of cartilage, and we all experience the loss of skin elasticity due to the degradation of elastin and the failure of connective tissues. We all encounter other age-related changes, such as the accumulation of non-dividing senescent cells that cause chronic inflammation and disrupt tissue repair, and we also suffer from the accumulation of metabolic waste products that collect in our bodies over time.

As these changes progress, they eventually lead to the familiar diseases of aging. For example, lipids are critical for the function of our metabolism and are essential as part of our diet; however, over time, these processed lipids begin to accumulate in the blood vessel walls. Macrophages arrive to clear the toxic fatty waste away, but they become immobilized and die. This causes inflammation, attracting more macrophages and continuing the cycle. Ultimately, this debris forms plaques that harden the blood vessels and cause them to narrow; this causes blood pressure to rise and can eventually result in a heart attack or stroke.

This demonstrates that the normal metabolic processes that keep us alive ultimately lead to disease. Importantly, in this case, the early age-related changes that set the scene for disease progression, such as high cholesterol, have no symptoms. Nevertheless, such changes are the precursors of deadly diseases and are considered suitable targets for treatment. The same can be said for the other, more subtle, changes and damages that the aging processes cause.

Age-related conditions, such as arthritis, diabetes, osteoporosis, Alzheimer’s, Parkinson’s and many cancers, all follow this dynamic. Simply put, given the sufficient passage of time, the aging processes will cause us to suffer from multiple diseases. Therefore, we should consider these diseases to be the clinical manifestation of these age-related changes. In fact, medicine has been fighting against age-related changes for a long time, even if it was not obvious. For example, a doctor recommending that his patient should reduce his fat and carbohydrate intake to delay heart disease is already fighting those age-related changes. The diabetic who modifies her diet to better manage blood sugar levels is also doing the same thing.

Some people might contest this point of view, stating that the aging process is “natural” and therefore cannot be a disease. The argument that natural things are always good, the appeal to nature, is a logical fallacy. Such people may see natural and pathological as being mutually exclusive. Thus, what is natural must always be good, and what is pathological is bad, and so it cannot also be natural. This is, of course, false when you consider the meaning of each word. Natural simply means something that follows the normal, established course of events, and pathological means something that is harmful.

Conclusion

So, is aging natural or pathological? Well, by the dictionary definitions, aging can be described as both natural and pathological without contradiction.

Additionally, as it is currently classified, aging could be considered a syndrome, specifically a co-morbid syndrome. This really does describe aging perfectly; it is a group of symptoms that consistently occur together and a condition characterized by a set of associated symptoms. Ultimately, aging is an umbrella term describing a range of pathological changes; it may struggle to be accepted as a disease, but it already qualifies as a syndrome.

However, the question of aging being a disease or not is essentially semantic in nature. What rejuvenation biotechnology seeks to achieve is nothing more than preventing age-related diseases by treating the early stages of pathology, which are considered a natural process. While these early age-related changes have not been given a disease name, they are instrumental in the development of diseases, and surely, when it comes to medical treatment, that is all that matters.

References

[1] Bulterijs, S., Hull, R. S., Björk, V. C., & Roy, A. G. (2015). It is time to classify biological aging as a disease. Frontiers in genetics, 6.

[2] Crimmins, E. M. (2015). Lifespan and healthspan: Past, present, and promise. The Gerontologist, 55(6), 901-911.

[3] Olshansky, S. J., Passaro, D. J., Hershow, R. C., Layden, J., Carnes, B. A., Brody, J., … & Ludwig, D. S. (2005). A potential decline in life expectancy in the United States in the 21st century. New England Journal of Medicine, 352(11), 1138-1145.

[4] Reither, E. N., Olshansky, S. J., & Yang, Y. (2011). New forecasting methodology indicates more disease and earlier mortality ahead for today’s younger Americans. Health Affairs, 10-1377.

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

Date Posted: January 18, 2018

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Distinct Types of Amyloid-Beta Prions in Alzheimer’s Found

In a paper in the Proceedings of the National Academy of Sciences, a research team led by Carlo Condello presented their results from a study of the sliced brain fragments of deceased Alzheimer’s disease (AD) patients. It appears different amyloid-beta prions are uniquely associated with different AD variants [1].

A primer on Alzheimer’s disease

AD is a chronic neurodegenerative disease affecting about 5% of the population above 65 years of age—the time when the first symptoms usually manifest. It is estimated to be the cause of up to 70% of all cases of dementia, which according to WHO projections, by 2050 will be around 115 million.

Initial symptoms may be as apparently inconspicuous as forgetting somebody’s name or being easily confused by unfamiliar situations, but eventually, they become more severe, significantly affecting the patient’s cognitive abilities, impairing speech, inducing immotivated anxiety or aggressive behavior, and even delusions. As the disease progresses, patients become unable to perform fine motor tasks, such as dressing, and to take care of themselves. Eventually, patients become bedridden, incapable of feeding themselves or performing even the simplest tasks. Death usually occurs as a consequence of the complications that eventually arise.

Amyloids and the new study

The exact cause of AD is not clear, but different theories have been proposed, suggesting causes ranging from genetic factors to amyloid-beta and tau protein build-up, to reduced synthesis of the neurotransmitter acetylcholine, to a combination of different possible factors.

However, it is established that Alzheimer’s patients show an abnormally high presence of amyloid plaques—misfolded protein aggregates that build up in the patients’ brains—and since 1991, the hypothesis that this excess may be the root cause of the disease has been one of the most prevailing. More precisely, it is thought that the real culprit might be amyloid-beta prions—a type of infectious protein, in the sense that they can induce other, normal protein to misfold in their same way and thus spread and cause disease, somewhat resembling a viral infection.

In the study by Condello’s team, slices from the brains of 41 deceased AD patients were examined. Researchers used fluorescent probes—chemicals that bind to specific molecules and, by their own fluorescence, “highlight” them—to locate amyloids and confocal spectral analysis to analyze the samples. They found that each patient affected by a certain, specific AD variant exhibited only one or two different strains of amyloid-beta prions; this seems to indicate that initial, more stable strains may take over other prion strains and become dominant, potentially explaining the different features of the various diseases in within the Alzheimer’s spectrum.

In their paper, the team stresses the urgency of developing clinical PET probes sensitive enough to detect different prion strains in patients’ brains, which may allow not only earlier detection of AD—and thus grant more time for a therapeutic intervention—but also tailoring treatments to each individual case.

Literature

[1] Condello, C., Lemmin, T., Stöhr, J., Nick, M., Wu, Y., Maxwell, A. M., … & Bird, T. D. (2018). Structural heterogeneity and intersubject variability of Aβ in familial and sporadic Alzheimer’s disease. Proceedings of the National Academy of Sciences, 201714966.

Date Posted: January 18, 2018

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Could Filtering Our Aged Blood Keep us Young?

There has been a lot of hope and hype around blood transfusions and it being able to reverse aging recently. We decided to take a look at the science behind the idea and talk with a leading expert in the field to see what the reality was.

Is the blood a key to aging?

Due to a recently published study on the effects of young plasma on aged mice, we got in touch with Dr. Irina Conboy of the University of California Berkeley. Dr. Conboy is an Associate Professor at the Department of Bioengineering and an expert in stem cell niche engineering, tissue repair, stem cell aging and rejuvenation. Before we dive into the main topic, let’s familiarize ourselves a little with Dr. Conboy and her work.

Dr. Conboy got her Ph.D. at Stanford University, focusing on autoimmunity. She met her partner in science—and in life—Dr. Michael Conboy at Harvard and they got married before embarking on graduate studies; they celebrated their Silver Anniversary a few years ago. During her postdoctoral studies, she began focusing on muscle stem cells, trying to figure out what directs them to make new healthy tissue and what causes them to lose their ability to regenerate the tissues they reside in as we age [1].

Together with her husband Michael, she eventually discovered that old stem cells could be reactivated and made to behave like young ones if appropriately stimulated. The Conboys’ parabiosis experiments—which consisted in hooking up the circulatory systems of aged and young mice—showed that old age is not set in stone and can be reversed in a matter of weeks [2].

The follow-up work by the Conboys uncovered that age-accumulated proteins, such as TGF-β1, inhibited stem cells’ ability to repair tissues even in young mice, and when TGF-β1 signaling is normalized to its young levels, old mice (equivalent to 80-year old people) have youthful muscle regeneration and better neurogenesis in the hippocampus (the area of the brain that is responsible for memory and learning)[3].

While young blood did appear to be beneficial to old stem cells, their evidence suggested that the real culprit of the broad loss of tissue repair with age was the negative influence of age-accumulated inhibitory proteins in aged tissues and circulation, also called the stem cell niche [4].

The results support that aging is at least partly due to damage accumulation

This conclusion is certainly compatible with the view of aging as a damage accumulation process [5]. As Irina herself pointed out in this interview, in the parabiosis experiments, the old mice had access to the more efficient young organs: lungs, liver, kidneys and immune system of the younger mice, which likely accounted for many of the benefits observed in the elderly parabiosed mice. With respect to the rejuvenation of the brain, the old mice experienced environmental enrichment by being sutured to young, more active parabionts, and this is known to improve the formation of new brain cells, learning, and memory.

An aged niche blocks the action of old and young stem cells alike very quickly; therefore, as Dr. Conboy observed in an article in the Journal of Cell Biology, we can’t treat the diseases of aging by simply transplanting more stem cells, because they will just stop working. Their niche needs to be appropriately engineered as well. Fortunately, there are potential solutions to this problem; such as the use of artificial gel niches and defined pharmacology that are designed to protect transplanted or endogenous stem cells from the deleterious environment of the old body.

This research holds the potential to significantly postpone the onset of age-related diseases and possibly reverse them one day, including frailty, muscle wasting, cognitive decline, liver adiposity and metabolic failure, but Dr. Conboy remains cautious about the possibilities until more data is in. However, she does think that longer and healthier productive lives could improve people’s attitudes towards the environment and treating each other with compassion and respect—a view that we definitely share.

We managed to catch up with Irina and Michael Conboy and talk to them about their work.

For the sake of those new to the topic, what is it in young blood and aged blood that affects aging?

Irina: Numerous changes in the levels of proteins that together regulate cell and tissue metabolism throughout the body.

Mike: We wondered why almost every tissue and organ in the body age together and at a similar rate, and from the parabiosis and blood exchange work now think that young blood has several positive factors, and old blood accumulates several negative, “pro-aging” factors.

A lot of media attention and funding is currently being directed to youthful blood transfusions; how can we move beyond this to potentially more promising approaches, such as filtering and calibration of aged blood?

Irina: People need to understand not just the titles, abstracts and popular highlights of research papers, but the results and whether they support (or not) the promise of rejuvenation by young blood. In contrast to vampire stories, we have no strong experimental evidence that this is true, and there is a lot of evidence that infusing your body with someone else’s blood has severe side effects (even if it is cell-free).

Mike: Translational research!

Some evidence suggests dilution is the most likely reason that young blood has some beneficial effects; what are your thoughts on this recent study[6] in rats that shows improved hepatic function partially via the restoration of autophagy?

Irina: There are certainly “young” blood factors that are beneficial, not just a dilution of the old blood, and this benefit differs from organ to organ. We have published on improved liver regeneration, reduced fibrosis and adiposity by transfusion of old mice with young blood, but these are genetically matched animals, and in people, we do not have our own identical but much younger twins[7].

If dilution is also playing a role here, then can we expect similar or better results from calibrating aged blood?

Irina: Yes, and our work in progress supports the idea.

In your 2015 paper, you identified that TGF-β1 can be either pro-youthful or pro-aging in nature, depending on its level[8]. In the study, you periodically used an Alk-5 inhibitor to reduce TGF-β1 levels and promote regeneration in various tissues. In the study, you showed that TGF-β1 was important in myogenesis and neurogenesis; is there reason to believe that this mechanism might be ubiquitous in all tissues?

Irina: Yes, because TGF-β1 receptors are present in most cells and tissues.

Also, TGF-β1 is only one of a number of factors that need to be carefully balanced in order to create a pro-youthful signalling environment. How many factors do you believe we will need to calibrate?

Irina: There will be a certain benefit from calibrating just TGF-beta 1, but also additional benefits from more than one or just TGF-beta.

How do you propose to balance this cocktail of factors in aged blood to promote a youthful tissue environment?

Irina: We are working on the NextGen blood apheresis devices to accomplish this.

So, you are adapting the plasmapheresis process to effectively “scrub” aged blood clean and then return it to the patient. This would remove the need to transfuse blood from young people, as your own blood could be filtered and returned to you, and no immune reaction either, right?

Irina: Accurate.

This plasmapheresis technique is already approved by the FDA, we believe, so this should help you to develop your project faster, right?

Irina: Exactly.

Do you think a small molecule approach is a viable and, more importantly, a logistically practical approach to calibrate all these factors compared to filtering aged blood?

Irina: Yes, it is a very feasible alternative to the NextGen apheresis that we are working and publishing on.

It is thought that altered signaling is caused by other aging hallmarks higher up in the chain of events; even if we can “scrub” aged blood clean, is it likely to have a long-lasting effect, or would the factors reach pro-aging levels fairly quickly again if nothing is done about the other hallmarks antagonizing them?

Irina: That needs to be established experimentally, but due to the many feedback loops at the levels of proteins, genes and epigenetics, the acquired youthful state might persist.

Ultimately, could a wearable or an implanted device that constantly filters the blood be the solution to these quickly accumulating factors?

Irina: Maybe, but the first step of a day at a NextGen apheresis clinic once every few months might be more realistic.

Filtering seems to be a far more practical solution, so how are you progressing on the road to clinical trials?

Irina: We are collaborating with Dr. Dobri Kiprov, who is a practicing blood apheresis physician with 35 years of experience, and he is interested in repositioning this treatment for alleviating age-related illnesses.

Senolytics and removing senescent cells and the resulting inflammation they cause during the aging process has become a hot topic in the last year or so. What are your thoughts on senolytics as a potential co-therapy with a blood filtering approach?

Irina: Might be good, but we should be careful, as p16 is a normal, good gene that is needed for many productive activities by many cells.

What do you think it will take for the government to fully support the push to develop rejuvenation biotechnology?

Irina: Clear understanding of the current progress and separating the real science from snake oil is very important for guiding funding toward realistic clinical translation and away from the myth and hype.

The field is making amazing progress, but, sadly, it is plagued by snake oil. As much as an “anti-aging free market” encourages innovation, it also encourages hucksters. How can a member of the public tell the difference between credible science and snake oil?

Irina: I was thinking for some time about starting a popularized journal club webpage where ordinary people can see what we typically critically point out in the lab setting about published papers and clinical trials.

How can our readers learn more about your work and support your research?

Irina: The new Conboy lab website is coming up; meanwhile, contact me and Dr. Mike at iconboy@berkeley.edu and conboymj@berkeley.edu

Conclusion

We would like to thank Irina and Michael for taking the time to answer our questions and for providing the readers with a fascinating insight into their work.

Literature

[1] Conboy, I. M., Conboy, M. J., Smythe, G. M., & Rando, T. A. (2003). Notch-mediated restoration of regenerative potential to aged muscle. Science, 302(5650), 1575-1577.

[2] Conboy, I. M., Conboy, M. J., Wagers, A. J., Girma, E. R., Weissman, I. L., & Rando, T. A. (2005). Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature, 433(7027), 760-764.

[3] Yousef, H., Conboy, M. J., Morgenthaler, A., Schlesinger, C., Bugaj, L., Paliwal, P., … & Schaffer, D. (2015). Systemic attenuation of the TGF-β pathway by a single drug simultaneously rejuvenates hippocampal neurogenesis and myogenesis in the same old mammal. Oncotarget, 6(14), 11959.

[4] Rebo, J., Mehdipour, M., Gathwala, R., Causey, K., Liu, Y., Conboy, M. J., & Conboy, I. M. (2016). A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood. Nature communications, 7.

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

[6] Liu, A., Guo, E., Yang, J., Yang, Y., Liu, S., Jiang, X., … & Gewirtz, D. A. (2017). Young plasma reverses age‐dependent alterations in hepatic function through the restoration of autophagy. Aging cell.

[7] Rebo, J., Mehdipour, M., Gathwala, R., Causey, K., Liu, Y., Conboy, M. J., & Conboy, I. M. (2016). A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood. Nature communications, 7.

[8] Yousef, H., Conboy, M. J., Morgenthaler, A., Schlesinger, C., Bugaj, L., Paliwal, P., … & Schaffer, D. (2015). Systemic attenuation of the TGF-β pathway by a single drug simultaneously rejuvenates hippocampal neurogenesis and myogenesis in the same old mammal. Oncotarget, 6(14), 11959.

Date Posted: January 10, 2018

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World Health Organization Puts the Elderly Back in the Picture

Not long ago, we wrote about some complications involving the WHO 13th programme of work. In the initial version of this document, developed by the WHO working group in November 2017, the problems of the elderly were nearly completely overlooked. The joint efforts of our community helped to bring this critical flaw to public attention.

During the meeting of the working group, it was announced that 90% of the comments received by WHO (out of 400) pointed out the need to set healthy aging as one of the priorities of the new programme of work. However, we didn’t know if our demand to focus on the implementation of the global strategy and action plan on aging and health would be fulfilled.

The good news is that the new draft programme published on the WHO site on January 5th (the draft was removed from WHO site some time after this article and incorporated into the 13th program of work) includes several provisions related to aging. Our community managed to persuade these global policymakers to implement the activities listed in the global strategy to help society prepare for the Decade of Healthy Aging (2020-2030). Let’s have a closer look at these provisions.

15. The foundation of WHO’s work is SDG 3: ensuring healthy lives and promoting well-being for all at all ages. WHO is an organization focused principally on promoting health rather than merely fighting disease, and especially on improving health among vulnerable populations and reducing inequities. Leaving no-one behind, the Organization aims to give women and men, girls and boys, in all social groups, the opportunity to live not just long but also healthy lives. WHO will explore measuring this foundation of its work using healthy life expectancy, which could serve as one overarching measure aligned with SDG 3, complemented by the triple billion goal, which leads to three more specific priorities, each with overlapping one-billion people goals.

Healthy life expectancy (HALE) is an assessment of the period of time that a person can live in full health. HALE is usually lower than total life expectancy, and the difference between HALE and total life expectancy is regarded as years of life lost to disease.

As the goal of our community is to prolong the healthy period of life by addressing the root mechanisms of aging and postponing age-related disease, the introduction of HALE as a way to measure WHO activities is a very good outcome. It is very hard to preserve health in older ages without addressing the underlying mechanisms of aging and implementing an extensive program that involves educating the public about healthy lifestyles. This choice of indicator means that WHO will strengthen its efforts to keep people healthy for as long as possible, which will ease the introduction of rejuvenation interventions once they are available, as it will likely be a cost-effective way to achieve a more favorable HALE.

16. Life expectancy at birth has consistently increased since the 19th century, largely due to socioeconomic developments and public health measures such as vaccination, nutrition and sanitation. Today, socioeconomic, political, cultural, environmental and economic forces continue to drive changes in the burden of disease. However, efforts are needed to ensure that their impact is positive. Poor health literacy coupled with weak health-promoting policies make it difficult for people to make healthy choices for themselves and their families. Investment in health promotion and disease prevention allows countries to address economic concerns about the rising costs of the health system and enables potential savings if disease can be avoided.

The WHO draft programme of work refers here to the increasing burden of chronic, non-communicable diseases due to the increasing proportion of people age 60 and over. Indeed, it would be really hard to double or even triple healthcare and pension expenditures for many countries, especially taking into account the ongoing economic crisis. However, this is what aging societies will have to do if HALE does not grow faster.

This is why WHO is only promoting evidence-based interventions that represent the “best buy” scenarios: the most realistic and cost-effective. When it comes to age-related diseases, which can last 20-30 years or longer, prevention could be much cheaper, and it is more humane, as this scenario would reduce unnecessary human suffering. Therefore, we could consider this provision of the new draft programme as supporting our efforts to introduce longevity lifestyles and even “soft” (careful and evidence-based) biohacking.

17. Healthy life expectancy has not increased at the same pace as life expectancy, and increasing age often brings increasing morbidity and reduced functioning, making healthy ageing an important focus. Most disability-adjusted life years in older age are attributable to chronic conditions and the accumulated impact of such conditions can lead to significant loss in function and care dependence in older age. At the same time, there is emerging evidence that healthy ageing depends on early childhood development and is epigenetically determined. Ensuring healthy ageing is an urgent challenge in all countries.

This provision once again underlines how important it is to focus on prevention. I would like to point out that if childhood is perceived as the foundation of healthy lifestyles, longevity advocates receive carte blanche for working with the younger generation. Activists could think of developing corresponding education programs for schools and universities, and this very provision can be a strong argument when offering such a program to educational authorities.

37. Ensuring healthy ageing is central to universal health coverage, just as it is to the other priorities of GPW 13. The number of people over the age of 60 is expected to double by 2050 and this unprecedented demographic transition will require a radical societal response. The Secretariat will support Member States to promote healthy ageing through the actions defined by the Global strategy and action plan on ageing and health (2016), as well as through the Decade of Healthy Ageing that is planned for the period 2020−2030. These actions include aligning health systems to the needs of older populations, with a special focus on enhancing the functioning of older persons and the management of chronic disease; improving access to medicines; developing systems of longterm care including community-based services; promoting palliative care, creating age-friendly environments; and improving measurement, monitoring and understanding of healthy ageing.

This provision is exactly what we were aiming for when calling the members of our community to take part in the Open Consultation or the Draft. As you remember, all mentions of the WHO documents related to aging were absent; this provision clearly shows that we achieved our goal! Even though the global strategy and action plan on aging and health may not be ideal in terms of rejuvenation research promotion, it helps member states navigate the field with more confidence. This global strategy, which we wanted so much to be the foundation of the draft programme provisions related to aging, contains a very important paragraph that every activist should know about:

105. Finally, better clinical research is urgently needed on the etiology of, and treatments for, the key health conditions of older age, including musculoskeletal and sensory impairments, cardiovascular disease and risk factors such as hypertension and diabetes, mental disorders, dementia and cognitive declines, cancer, and geriatric syndromes such as frailty. This must include much better consideration of the specific physiological differences of older men and women and the high likelihood that they will be experiencing mutimorbidities. This could also be extended to include possible interventions to modify the underlying physiological and psychological changes associated with ageing.

Conclusion

Dear friends, this is a victory! Our community managed to influence policymakers at the highest level: the World Health Organization. We managed to ensure that the new programme of work considers aging and age-related diseases to be an important issue, and the resulting global strategy and action plan on aging and health is an effective guide to helping our society adapt to population aging.

In terms of advocacy, this is a complete victory, which shows two important things. First, when we join forces, we can influence global health policy at the highest level. Our community became stronger, and our voice is being heard! Second, this victory shows that dialogue with the UN and its institutions, including decision-makers in these agencies, is possible, and it goes in the directions that we need: more focus on prevention and more focus on public health education related to aging,

I offer special thanks to Dr. Ilia Stambler for initially turning the attention of the community to this issue. I want to thank and congratulate all participants in the Open Consultation with this achievement. Of course, we are still at the beginning of our path to rejuvenation as a public health priority, but outcomes like this one make me believe that there are more victories to come. Let’s keep working, as the main reward is worth it: health, youth, and freedom from age-related diseases for all!

Date Posted: January 9, 2018

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Exercise is Currently the Best Way to Slow Down Aging

We have all heard that exercise is good for our health. However, it can not only keep you healthy, it can also slow down some aspects of aging. Some researchers even think that it might be possible to use this knowledge to develop new therapies against aging. While waiting for that to happen, we need to exercise in order to slow down the effects of aging.

How important is it to keep fit?

So, how beneficial is exercising? Well, one of the best studies conducted on this subject showed that women will live 5.6 years longer and men 6.2 years longer if they exercise between 1 and 2.5 hours per week [1]. This makes exercise a better lifestyle choice than any other, at least as long as you’re not counting avoiding downright dangerous behavior, such as smoking.

The main benefits of physical activity may come from better health for the heart. Exercise lessens the risk for many types of heart disease [2]. It is even more beneficial for people who already suffered age-related conditions, including stroke and coronary heart disease, and it is more effective than any known drug in preventing repeated episodes [3].

The key improvements also include increased muscle strength, stronger bones, better weight control, and improved cognitive function. This means less risk of age-related diseases, such as Alzheimer’s disease, as well as lethal falls, which are a major risk for the elderly.

The conclusion is that exercise helps with a lot of different aspects of your health in several ways, and we can summarize its effects as improving quality of life and increasing healthspan.

How much exercise do you need?

More exercise does not always improve outcomes. Professional athletes exercise more than the rest of us, and they generally live longer than the average person [4]. However, correlation isn’t causation, and robust individuals are perhaps more likely to become athletes, instead of the other way around. There could even be negative effects from too much exercise, although that is far from certain.

Even moderate exercise leads to better health. Half an hour a day seems to be enough to see positive effects, and it is also a common recommendation for the minimum amount of exercise you should get. The biggest difference can be seen between people who hardly move around at all and people who get at least a little exercise a few times a week. Taking the stairs and walking short distances is clearly better than nothing. In fact, some studies show that even light activity, such as housework, can have an effect on mortality risk.

It should also be noted that there are different types of exercise and that these could have different benefits. Jogging increases your aerobic ability, which should, among other things, lead to better heart health. Lifting weights is an anaerobic exercise that improves strength and should bring other benefits, such as stronger bones. A lot of research about this has been done already, but so far, we don’t definitively know the optimal amount and type of training for each particular type of person.

Drugs to mimic exercise

Some of the positive effects have to do with the anti-inflammatory processes that occur when exercising [5]. Other mechanisms appear to be involved, although more research on these mechanisms is needed.

Since the advantages of exercise are clear, the idea has occurred to some researchers that it may be possible to mimic the effects of exercise without doing the hard work and getting sweaty. Research is now being conducted using drugs that target the same mechanisms to try to get the same benefits of exercise.

This typically involves adjusting a part of the human metabolism, which is not an easy matter. However, there have been at least some tentative breakthroughs already, and last year, a team found a drug that boosted the endurance of mice by roughly 70 percent [6]. Where this might lead in the future is not clear, but some positive effects may come from this research.

Will exercise lead to longevity?

Even though exercise is beneficial for your health, there is no guarantee it will keep you alive until you reach 100, although staying fit will almost certainly improve your chances. This is why if we want to remain in good health and live longer, we need to develop rejuvenation biotechnology and therapies that address the aging processes directly. That said, if you want to increase your chances of living long enough to see these therapies arrive, then exercise is the best option you have right now.

Literature

[1] Schnohr, P., Lange, P., Scharling, H., & Jensen, J. S. (2006). Long-term physical activity in leisure time and mortality from coronary heart disease, stroke, respiratory diseases, and cancer. The Copenhagen City Heart Study. European Journal of Cardiovascular Prevention & Rehabilitation, 13(2), 173-179. [2] Jakovljevic, D. G. (2017). Physical activity and cardiovascular aging: Physiological and molecular insights. Experimental Gerontology. [3] Naci, H., & Ioannidis, J. P. (2013). Comparative effectiveness of exercise and drug interventions on mortality outcomes: metaepidemiological study. Bmj, 347, f5577. [4] Lemez, S., & Baker, J. (2015). Do elite athletes live longer? a systematic review of mortality and longevity in elite athletes. Sports medicine-open, 1(1), 16. [5] Fan, W., Waizenegger, W., Lin, C. S., Sorrentino, V., He, M. X., Wall, C. E., … & Auwerx, J. (2017). PPARδ Promotes Running Endurance by Preserving Glucose. Cell Metabolism, 25(5), 1186-1193. [6] Dimitrov, S., Hulteng, E., & Hong, S. (2017). Inflammation and exercise: Inhibition of monocytic intracellular TNF production by acute exercise via β 2-adrenergic activation. Brain, behavior, and immunity, 61, 60-68.

Date Posted: January 3, 2018

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Obesity Found to Cause Lasting Damage to Hematopoietic Stem Cells

You might think that being overweight may cause you health problems only until you finally shed those extra pounds, at which point everything will be fine again. It sounds reasonable, but it might be not so easy. According to a new study published in the Journal of Experimental Medicine on December 27, the negative effects of obesity might last even after that extra weight has been lost.

Yes, it appears that being overweight can have lasting consequences that persist long after the weight comes off. Damage to the hematopoietic stem cells can be caused by being overweight, making it all the more reason to try to maintain a healthy weight as part of your personal health and longevity strategy.

What the study found out

In a nutshell, the study shows that the oxidative stress induced by obesity causes the overexpression of the transcription factor Gfi1 in hematopoietic stem cells (HSCs), pushing them to produce myelocytes that, if you’re out of luck, may well end up becoming preleukemic as well[1].

As if this wasn’t bad enough, the overexpression may persist even if affected HSCs are then transplanted into a normal environment. This means that the damage has a lasting and long-term effect, and even restoring a healthy environment does not fully rectify the damage done.

To explain further, oxidative stress is basically an imbalance between reactive oxygen species (ROS) and the body’s ability to clear them out. ROS are oxygen-containing molecules that, like their name implies, are extremely reactive. Even though ROS have normal, beneficial functions in the body as well, because of their high reactivity, they often end up reacting with molecules better left alone, damaging them in the process or causing them to do things they shouldn’t do.

Obesity tends to increase the body’s oxidative stress, and as the study found out, this causes the production of too much Gf1 in hematopoietic stem cells. As said, Gfi1 is a transcription factor—that is, a protein controlling the rate at which certain genetic information contained in DNA is transcribed into RNA and ultimately translated into specific proteins with a certain job.

Too much Gf1 expression in hematopoietic stem cells—that is, stem cells that “produce” blood and immune cells—will skew the production towards myelocytes, white blood cells that are normally found in bone marrow but appear in circulating blood as a consequence of diseases such as myelogenous leukemia.

Of mice and men

In the mouse model the researchers used in their study, the negative effects of obesity on HSCs lasted even after they were transplanted into a non-obese mouse. This doesn’t necessarily mean that we would observe the exact same results in obese human patients, but it does suggest that using damaged HSCs from obese human donors may present some risk.

The next step will be to determine if human HSCs suffer the same fate as those in mice. It is worth noting that humans have more robust repair systems that allow us to resist and repair ROS damage better than mice. It may be the case that human HSCs could be more resistant to such damage and that you may need to be overweight for a longer time before significant damage occurs.

Conclusion

Naturally, as prevention is always better than cure, you should try your best to maintain a healthy weight and spare yourself—and other people, should you ever be a HSC donor—obesity-induced troubles. Even if human HSCs are more resistant to such long-term damage, there are a myriad of other reasons why maintaining a healthy weight is a good idea for your health and longevity.

Literature

[1] Lee, J. M., Govindarajah, V., Goddard, B., Hinge, A., Muench, D. E., Filippi, M. D., … & Reynaud, D. (2017). Obesity alters the long-term fitness of the hematopoietic stem cell compartment through modulation of Gfi1 expression. Journal of Experimental Medicine, jem-20170690.

Date Posted: January 3, 2018

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The Gut Microbiota Could Contribute to Sarcopenia

We have all seen it, the age-related loss of muscle mass and increasing frailty that generally accompanies advancing age. Recently the World Health Organization classified this age-related muscle wastage as a disease and thus sarcopenia entered official usage to describe it. There are a number of potential causes of sarcopenia and new research suggests that there is a nutritional link between the microbiota and development of the condition.

What is sarcopenia?

Sarcopenia is the condition that causes the familiar, age-related loss of muscle strength and mass in older people, and it leads to ever-increasing frailty. Frailty makes everyday tasks difficult, affects balance, and can lead to falls, which can be very dangerous for older people.

How sarcopenia develops is a more complex matter; there are a number of possible causes for sarcopenia, including reduced protein intake, sedentary lifestyle, chronic inflammation that inhibits cell function and tissue repair, reduced stem cell activity from the same inflammatory signals, mitochondrial dysfunction, and reduced oxygenation resulting from deteriorating blood vessels.

These are only some of the possible factors involved in the onset of sarcopenia, and more research is needed to determine the exact cause, although it currently appears that reduced stem cell activity is a strong contender.

Could the gut influence sarcopenia?

A new study has researchers considering that age-related changes of the gut microbiota may possibly contribute to sarcopenia[1]. In recent years, the role of the gut microbiota in aging has increasingly become the focus of research. In this paper, the researchers focus on age-related changes in these populations of gut microbes in an attempt to explain the link between nutrition and sarcopenia.

There is certainly ample evidence to suggest that changes in the gut microbiota can promote inflammation and contribute to the smoldering chronic inflammation known as “inflammaging”. It may be the case that changes to the microbiota promote inflammation, which inhibits stem cell activity and thus provokes sarcopenia; we know that inflammatory signals do inhibit stem cells, so this is certainly plausible.

Conclusion

The interaction of the gut microbiota with the aging processes and other metabolic systems is intriguing. However, the interplay of the gut microbiome with our biology is highly complex, so it remains to be seen if anything useful will come from this particular line of research in the near future.

As ever, our interest lies in research that focuses on the root causes of aging and has the potential to prevent sarcopenia at its root. A repair-based approach to aging, as proposed in the Hallmarks of Aging and the SENS model, is what we believe could lead to the most significant increases of healthy longevity, making these approaches the ones we consider most worthy of development and funding. That said, research such as this is still intriguing and adds to our scientific understanding, and that is a never a bad thing.

Literature

[1] Ticinesi, A., Lauretani, F., Milani, C., Nouvenne, A., Tana, C., Del Rio, D., … & Meschi, T. (2017). Aging Gut Microbiota at the Cross-Road between Nutrition, Physical Frailty, and Sarcopenia: Is There a Gut–Muscle Axis?. Nutrients, 9(12), 1303.

Date Posted: January 2, 2018

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Stem Cell Trials For Osteoarthritis Repair Cartilage

Mesenchymal stem cells (MSCs) are one of the most thoroughly studied and understood stem cell types. They are used in a wide range of therapies, and the many studies using MSCs have enjoyed varied levels of success, depending on delivery methods, patients, co-therapies and other factors.

Today, we will be taking a look at MSCs and a new human clinical trial focused on treating osteoarthritis, an age-related inflammatory condition that leads to the breakdown of bone and cartilage.

What are mesenchymal stem cells?

Mesenchymal stem cells are multipotent cells, which means that they can differentiate (transform) into a variety of cell types, including osteoblasts (bone cells), chondrocytes (cartilage cells), myocytes (muscle cells) and adipocytes (fat cells)[1]. Sources of MSCs are varied and include bone marrow, which is the original source of MSCs and still the most frequently used; umbilical cord tissue; adipose tissue; amniotic fluid; and molar cells.

MSCs have been used to treat multiple joint and musculoskeletal problems with the goals of reducing inflammation and promoting tissue regeneration. In general, the transplanted MSCs do not tend to survive long in the body; however, they last long enough in most cases to generate anti-inflammatory signals and promote tissue regeneration.

MSCs to treat osteoarthritis in human trials

Today, we wanted to bring your attention to a small open access study that used MSCs to treat age-related osteoarthritis, a common complaint for many older people[2]. This condition is caused by localized inflammation in the joints, leading to the breakdown of bone and cartilage and painful and potentially crippling outcomes for the patient.

The presence of proinflammatory senescent cells are very likely a major factor in how this condition develops, and it will be important to see how senolytic therapies that remove these cells might ameliorate osteoarthritis. It would potentially be even more interesting to see how MSCs and senolytics used as a co-therapy might ameliorate osteoarthritis, given that reducing inflammation enhances tissue regeneration in stem cell therapies.

The study here is also different from the majority of previous studies, as it tracked patient outcomes for two years following MSC therapy, a considerably longer period than other studies. This is important because we need to know more about the long-term effects of these therapies in order to refine and optimize the approaches used. This study was a phase 1 and 2 human clinical trial which essentially means that this approach is both safe and effective at combating osteoarthritis. If you want to you can learn more, check out our topic that explains clinical trial phases.

Conclusion

Mesenchymal stem cell therapies do not address the root cause of osteoarthritis, which is chronic inflammation from senescent cells, cell debris, microbial burden and other sources, but they do locally suppress inflammation long enough to promote tissue repair.

The study results here show that there was a significant improvement in patients with osteoarthritis. Despite the limited number of patients in the study, the therapy was shown to safely increase knee cartilage thickness; this demonstrates its ability to improve the function and structure of joints and shows that it could be an effective therapy for osteoarthritis patients.

Literature

[1] Nardi, N. B., & da Silva Meirelles, L. (2008). Mesenchymal stem cells: isolation, in vitro expansion and characterization. In Stem cells (pp. 249-282). Springer Berlin Heidelberg.

[2] Al-Najar, M., Khalil, H., Al-Ajlouni, J., Al-Antary, E., Hamdan, M., Rahmeh, R., … & Al-jabbari, E. (2017). Intra-articular injection of expanded autologous bone marrow mesenchymal cells in moderate and severe knee osteoarthritis is safe: a phase I/II study. Journal of orthopaedic surgery and research, 12(1), 190.

Date Posted: December 13, 2017

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People Support Living Longer If It Means Remaining Healthy

A number of studies in different countries show that when people are asked “how long would you like to live?”, they respond with a figure equal to or slightly higher than the current life expectancy in a given country [1-4]. So, why does the public often lack enthusiasm for longevity?

These studies have shown that, generally, the public is uninterested in living longer than normal because they believe that these extra years will be spent suffering from the illnesses of old age. This is why the public often reacts to words like ‘longevity’ this way; to them, ten extra years likely means a decade spent in a wheelchair or some other decrepit state robbed of independence and health.

Asking the right question is important if you want the right answer

When asking people about living longer, it is essential to frame the question properly so that a considered response with all the facts can be made. When talking about longevity, it is critical to ask the right question and use the right language.

In a recent study, when it was made clear that continued physical and mental health would accompany these extra years, the responses were generally more favorable towards living longer [5]. In this study in particular, people even changed their responses to support longer life when it was made clear that continued mental and physical health would be part of that extra time.

We surveyed 1000 individuals (through “Ask Your Target Market”) about how long they wished to live (to age 85, 120, 150, or indefinitely), under 3 scenarios: (1) sustained mental and physical youthfulness, (2) mental youthfulness only, (3) physical youthfulness only. While responses to the two partial youthfulness conditions recapitulated the results of previous surveys (Cicirelli, 2011; Kogan et al., 2011; Partridge et al., 2011; Duncan, 2012; Pew Research Center, 2013), i.e., most responders (65.3%) wished to live to age 85 only—under scenario (1) the pattern of responses was completely different. When guaranteed mental and physical health, 797 of 1000 people wanted to live to 120 or longer, and 53.1% of the 797 desired unlimited life spans. Furthermore, 70.1% of the people who responded 85 to scenario (2) or (3) changed their answer to 120 or longer in scenario (1).

A new study once again suggests asking the right question is critical

Today, we see yet more vindication of this in a new study by researchers from the University of Kansas[6]. The team asked ninety elders in China, Germany, and the U.S. about their ideal lifespans.

A larger number of respondents did mention they wanted to extend their lives. Yet less than half of that group noted a specific amount of time they desired to live.
The strongest opinion among that group was the desire to live longer only if they maintained their current or what they deemed to be acceptable levels of health.
Source: KU

Conclusion

Once again, we can see that continued health is very much a proviso of continued longevity. This is a perfectly understandable reaction, and it is fortunate that rejuvenation biotechnology has the same goal: to prevent age-related diseases by targeting the aging processes, thus offering people longer and healthier lives.

Ultimately, the right question to ask is “Would you want to live longer if your continued health is guaranteed for those additional years?” People are generally more supportive of the idea if they know that those extra years will be good years, and most of us really want to be healthy enough to enjoy life.

Literature

[1] Lang, F. R., Baltes, P. B., & Wagner, G. G. (2007). Desired lifetime and end-of-life desires across adulthood from 20 to 90: A dual-source information model. The Journals of Gerontology Series B: Psychological Sciences and Social Sciences, 62(5), P268-P276.

[2] Lugo, L., Cooperman, A., & Funk, C. (2013). Living to 120 and Beyond: Americans’ Views on Aging, Medical Advances, and Radical Life Extension. Pew Research Center, August, 6. URL: https://www.pewforum.org/2013/08/06/living-to-120-and-beyond-americans-views-on-aging-medical-advances-and-radical-life-extension/

[3] CARP Radical Life Extension Poll Report (2013). URL: https://www.carp.ca/wp-content/uploads/2013/09/Life-Extension-Poll-Report.pdf

[4] Financial University of the Government of the Russian Federation, Sociology Faculty (2015). Most of Russians want to live up to 80 years only. (Bol’shinstvo rossijan hochet dozhit’ tol’ko do 80 let).

[5] Donner, Y., Fortney, K., Calimport, S. R., Pfleger, K., Shah, M., & Betts-LaCroix, J. (2016). Great desire for extended life and health amongst the American public. Frontiers in genetics, 6, 353.

[6] Ekerdt, D. J., Koss, C. S., Li, A., Münch, A., Lessenich, S., & Fung, H. H. (2017). Is longevity a value for older adults?. Journal of Aging Studies, 43, 46-52.

Date Posted: December 11, 2017

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Ending Aging – A Book Review

The book I’m reviewing today is pretty much a classic by now. Published for the first time in 2007, “Ending Aging” by Dr. Aubrey de Grey is not only “an audacious blueprint for cheating the reaper”—as Janet Cromley of the Los Angeles Times put it—but also a manifesto, a call to arms, if you will, openly denouncing biological aging as public enemy number one and explaining why and how we should and could put an end to it.

Dr. de Grey’s enthusiasm and confidence are often regarded with skepticism by people who are new to the idea of defeating aging, and while initially the scientific community wasn’t persuaded that the SENS “maintenance approach” was even worth discussing, this paradigm has been confirmed by other academics and is shaping the rejuvenation biotechnologies of tomorrow.

Like every rejuvenation advocate eventually learns, a conversation on the defeat of aging with a newbie is composed of roughly three parts: explaining why aging is a problem, explaining what aging is and how we may conquer it, and finally, addressing the inevitable concerns of the audience. “Ending Aging” does a great job of the first two parts, though it dedicates only little to the third one, replacing it with a more pragmatic discussion of what needs to be done, in terms of advocacy and policy-making, in order to get from here to a world free of age-related diseases. Dr. de Grey normally addresses typical concerns about extended longevity with two general answers without going into the finer points of each specific concern, as he understandably believes that eliminating diseases and saving lives is an absolute priority and no excuses can justify delayed action to address it—or worse, failing to address it altogether.

My personal feeling is that the book might have benefited from even a brief section dedicated specifically to the details of the most common concerns; as it is, “Ending Aging” may well persuade readers that defeating aging is feasible and desirable, but unaddressed worries of some people might deter them from wholeheartedly joining or supporting the cause. Then again, I understand why Dr. de Grey might prefer dedicating more attention to the scientific and technical aspects of the issue and leaving the discussion of related but peripheral matters for more appropriate venues.

Although the book presumes little to no knowledge of biology and goes to great lengths in attempting to make the topic accessible to everyone, its tone is never condescending; rather, it’s friendly, engaging, and peppered with humor, making the readers feel as though they were all part of a single team trying to take aging down—which reflects de Grey’s conviction that only with sufficiently widespread support across the globe can the crusade against aging eventually succeed.

Being aimed at non-specialists, “Ending Aging” is rather non-technical, although the second part—which describes SENS’s seven damage categories and the proposed regenerative interventions against them—can be difficult to get through. Simplified as it may be, it is full of details, and there’s a lot going on that the reader will need to keep track of; I can tell from experience that a second readthrough is very helpful. Readers with strong biology backgrounds will probably wish to investigate further, and they may do so via the extensive references provided at the end of the book or by getting in touch with de Grey himself—which he explicitly invites readers to do, should they have any questions.

While “Ending Aging” is not the first book discussing medical advancements that may spell the end of aging as we know it, to my knowledge, it is the only one so overtly endeavoring to change the public’s perception of defeating age-related diseases from a purely scientific quest fueled by vanity into a global, humanitarian cause. Dr. de Grey correctly identifies the current, skewed perception of aging as something necessary and even desirable and enjoyable as the biggest roadblock on the way to a healthier world, and his book is only part of his efforts to remove this roadblock through advocacy.

Personally, I believe that, without Dr. de Grey’s work, the popularization of rejuvenation biotechnologies might well have been slowed down by decades. In particular, it was this very book that pushed me to become an advocate and grow an interest in biology; for this reason, I think it’s a must-read for every supporter of the cause and a recommended read for just about anyone who’d rather be healthy than sick at any age.

Date Posted: December 11, 2017

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The Best of the SENS AMA

Dr. Aubrey de Grey from the SENS Research Foundation (SRF) did an Ask Me Anything on Reddit on December 7th, and there were many great questions and answers; we thought it would be a great time to summarize some of the best ones and offer a little commentary.

What do you think were the biggest wins of the last couple of years in SENS-relevant advocacy, research, and development? What has moved the needle?
There have been lots. On the research, I would highlight our paper in Science two years ago, which shows how to synthesize glucosepane, and our paper in Nucleic Acids Research one year ago, which shows simultaneous allotopic expression of two of the 13 mitochondrial genes. Both of those projects have been greatly accelerated in the meantime as a result of those key enabling breakthroughs; watch this space.
On advocacy, I think the main win has been the arrival of private capital; I would especially highlight Jim Mellon and his Juvenescence initiative because he is not only a successful, energetic and visionary investor, he is also a highly vocal giver of investment advice.

We are pleased to have been involved with the second project mentioned here, as we hosted the MitoSENS project at Lifespan.io, where it raised 153% of its initial fundraising goal. Less than a year later, after raising this money, it went on to publish the groundbreaking study showing that backup copies of mitochondrial genes could indeed be created in the nucleus. Dr. de Grey originally proposed the idea over a decade ago amid much scepticism; it is really good to see that years later he has been vindicated. This is the power of crowdfunding and how we as a community can make big changes in science by working together.

How do you feel about the impact of groups like LEAF advocating and reporting on rejuvenation biotech? Has the advocacy and reporting of these groups made your life any easier?
Massively! A huge thing that I say all the time is that advocacy absolutely relies upon the diversity of its messengers. Different people listen to different forms of words, different styles of messaging, etc. The more, the better.

It’s good to know that our work is appreciated and helping. Working together as a community is essential for progress, so it was nice to see this question and response from someone we respect a great deal.

We have said many times before effective advocacy efforts are just as important as the research itself. Professional advocacy has the potential to increase public support and funding, paving the way for the arrival of rejuvenation biotechnology. In the past decade or so, advocacy has mostly been left to volunteers and people such as Dr. de Grey.

Popular causes attract celebrities, public support, funding and investment; if we want a revolution in medicine and how we treat aging, then we must popularize the movement. There has been a serious shortage of full-time and organized advocacy; therefore, we decided to create LEAF to support groups like the SRF, advocate to popularize the cause, and help to raise much-needed funds for research efforts. We are only able to do this thanks to the support of the community, and we are extremely grateful to our Lifespan Heroes for helping us to do the work we do.

Aside from funding, what do you consider to be a burden or delay for your type of research?
Nothing. Seriously, nothing at all. We have the plan, and we have the people. It’s all about enabling those people by giving them the resources to get on with the job.

Indeed, funding for research is one of the four major bottlenecks slowing down the development of therapies that address the aging processes. The more funding the field gets, the more projects can be launched, the sooner breakthroughs can potentially happen, and the greater the benefits will likely be for all of us.

Is there anything new you are able to say about the breaking of cross-links in the extracellular matrix?
Absolutely. Short story, we now have a bunch of glucosepane-breaking enzymes, and we are within a few months of spinning the work out into a startup.

A suspected cause of degenerative aging is the accumulation of sugary metabolic wastes known as advanced glycation end-products (AGEs). These are wastes that are, in some cases, hard for our metabolism to break down fast enough or even at all. Some types, such as glucosepane, can form cross-links, gumming together important proteins such as those making up the supporting extracellular matrix scaffold.

The properties of elastic tissues (skin and the blood vessel walls) derive from the particular structure of the extracellular matrix, and cross-links degrade that structure, preventing it from functioning correctly. AGEs’ presence contributes to blood vessel stiffening with age, and it is implicated in hypertension and diabetes.

That SRF now has candidate enzymes is very significant because it means that there are now potential ways to remove these crosslinks from our tissues. There are many types of crosslinks, and we already know of compounds and drugs that can break other kind of crosslinks; the major problem is glucosepane, as it lasts a very long time, and, so far, nothing is known to remove it. Given that other types of crosslinks can be removed, Dr. de Grey rightly thought that there must be ways to remove (cleave) glucosepane from tissues; now, it seems that we are a step closer to that potentially becoming a reality.

If the SRF is successful in finding ways to break glucosepane crosslinks, this has huge implications for diabetes, hypertension and aging. It is great to hear that the organization is now reaching the point at which it is almost time to develop this as a therapy by creating a startup company.

It seems likely that artificial intelligence will be a necessary tool in order to reach longevity escape velocity. I was wondering how much of a role does artificial intelligence play in your research? Is this something you devote many resources to?
We don’t, but that is because other major players in this field (and good friends of mine), such as Alex Zhavoronkov and Kristen Fortney, are doing it so well already (with Insilico Med and BioAge, respectively). Check out the BioData West conference that will occur in SF a couple of days before our Undoing Aging conference in Berlin; I will be chairing a session on this.

We believe that the application of AI and, in particular, machine learning will prove to be a very valuable tool for research in the coming years. Such systems are ideally suited for high-throughput, laborious tasks that also require high attention to detail and would take humans a long time to do. Drug discovery, image analysis and many more tasks in the lab could potentially be automated, saving time and freeing up researchers to work on other critical tasks.

We are proud to have hosted the MouseAge project this year, which is an AI-based visual aging biomarker application that helps researchers determine the age of mice without the use of harmful tests. In a few months, researchers will be able to use the MouseAge application in the lab to help speed research progress up. This is just one example of how AI can be used in aging research and how the community helped to make it happen.

Given current funding, how far away from robust mouse rejuvenation do you think you are?
My estimate is 5-7 years, but that’s not quite “given current funding”. My overoptimism in saying “10 years” 13 years ago consisted entirely of overoptimism about funding – the science itself has not thrown up any nasty surprises whatsoever – but, nonetheless, I am quite optimistic as of now about funding, simply because the progress we have made has led to a whole new world of startups (including spinoffs from the SENS Research Foundation) and investors, so it’s not only philanthropy anymore. Plus, the increase in overall credibility of the approach is also helping to nurture the philanthropic side. We are still struggling, that’s for sure, but I’m feeling a lot surer that the funding drought’s days are numbered than I felt even two or three years ago.

Robust mouse rejuvenation (RMR) has long been a goal for the SENS Research Foundation, going back to when the SENS approach was initially proposed. RMR was originally outlined as being able to demonstrate and replicate SENS to double the remaining life expectancy of an already aged mouse. This would not mean the first RMR would be a total implementation of all the SENS approaches or that rejuvenation would need to be absolute; it would be a first pass to demonstrate the viability of multiple SENS approaches combined to produce robust results.

Being able to achieve a first-pass RMR could do much to convince academia that the repair approach to aging is plausible and attract more funding and interest in the approach. While RMR working in mice may not sound that exciting, it has huge implications for the field and potentially the rate of funding and progress.

How confident are you still in your previous prediction that humans will be able to control aging by 2029?
I think we’ve slipped a few years, entirely because of lack of funding. The tipping point will be when results in mice convince a critical mass of my curmudgeonly, reputation-protecting expert colleagues that rejuvenation will eventually work, such that they start to feel able to say so publicly. I think that’s on the order of five years away.

We think that the tipping point could well be if senolytics have the same result in humans as they have in mice. Enhanced tissue repair and regeneration in older people would be a very strong case for the repair approach to aging and almost certain to convince the academics sitting on the fence.

Certainly, if AGE breakers could be demonstrated to work in humans, this would also go a long way towards not only convincing academia but also grabbing public interest. Removing AGEs from the skin may potentially reverse wrinkles, for example, and restore skin elasticity, offering a very visual demonstration of repair being plausible.

There is almost certainly going to be a tipping point at which the bulk of academic and public support swings in favour of a repair approach to aging; the only question is when? Well, the sooner the basic science can be done and moved to translational research, the sooner we can all potentially benefit from these technologies. This makes supporting both the research and advocacy of rejuvenation biotechnology very important for progress.

Date Posted: December 8, 2017

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Boosting Mitochondrial Quality Control to Combat Alzheimers

Scientists at the École polytechnique fédérale de Lausanne (EPFL) have found a way to make mitochondria more resistant to damage, which could potentially be used to halt Alzheimer’s and other, similar, diseases.

Globally, Alzheimer’s disease is the most common form of dementia and cause of neurodegeneration. It causes brain damage and symptoms such as long-term memory loss. It is an amyloid-based disease, with the characteristic hallmark being the formation of toxic plaques in the brain made from the aggregated beta-amyloid inside the neurons.

Improving mitochondrial quality control

Diseases like Alzheimer’s are the result of the loss of proteostasis, which leads to the creation of sticky misfolded proteins, which form plaques by bonding together. There is still no cure for the disease, and it causes tremendous suffering while posing a considerable burden on the public health system. Many treatments have focused on trying to reduce the formation of the plaques, but, as of yet, the results are inconclusive. One group of researchers has tried a different approach and is looking at Alzheimer’s as a metabolic disease.

The new study focused on the mitochondria, the powerhouses of the cell that produce the energy needed for cellular functions central to metabolism[1]. The research team showed that in worms and mice, they could make the mitochondria more robust and resistant to a particular form of protein stress, allowing them to better protect themselves and, more importantly, reduce the accumulation of amyloid plaques.

During the aging process, cells are exposed to increased levels of damage, and that includes damage to their mitochondria. Damaged mitochondria become dysfunctional, and cells normally replace them via a process known as mitophagy, a selective degradation of the mitochondria by autophagy.

Unfortunately, over time, our cells become increasingly poor at removing these problem mitochondria, thus leaving them vulnerable to Alzheimer’s disease.

The researchers identified two key processes that act as a quality control system for the mitochondria. First, there is the process of mitophagy, which recycles damaged mitochondria, and second, there is the mitochondrial unfolded protein response (UPRmt), which shields mitochondria from stress. Taken together, these processes are one possible solution to reducing mitochondrial damage and could help combat diseases like Alzheimer’s.

Better recycling improves cognition

It has been known for some time that the mitochondria are dysfunctional in the brains of Alzheimer’s patients, but this is the first evidence suggesting that the disease might be combated by boosting these quality control systems. These two processes are present in C.elegans flatworms, mice, and humans, so worm and mouse research could translate well into human beings. The researchers decided to try activating these systems using a drug to see if they could boost protection and quality control in the mitochondria.

They used the antibiotic doxycycline and the vitamin nicotinamide riboside (NR), both known to activate the UPRmt and mitophagy systems in worm models of Alzheimer’s. They noticed that the health and lifespan of treated worms increased dramatically compared with untreated controls, and the formation of plaques was also significantly reduced. Intriguingly, they also observed similar improvements when they activated the same two systems in human neuronal cells in culture using the same two drugs.

Finally, the researchers tested NR in a mouse model of Alzheimer’s disease. They observed the same improvement to mitochondrial function and reduction of plaques as seen in the flatworms. Perhaps most importantly, the researchers noted a dramatic improvement in the cognitive function of the mice.

Conclusion

The usual caveats apply; the results are only so far confirmed in flatworms, Alzheimer’s model mice and human cells in culture. However, the two target quality control systems are present in all three species and can be activated in the same way, which leaves some room for optimism. Will it prove to be more effective than the direct removal of amyloids? Or could it even be a co-therapy for those other approaches? Only time and a clinical trial will tell.

Literature

[1] Vincenzo Sorrentino, Mario Romani, Laurent Mouchiroud, John S. Beck, Hongbo Zhang, Davide D’ Amico, Norman Moullan, Francesca Potenza, Adrien W. Schmid, Solène Rietsch, Scott E. Counts, Johan Auwerx.Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity. Nature 06 December 2017. DOI: 10.1038/nature25143.

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