Date Posted: October 22, 2017
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Why Eradicating Age-related Disease Could Benefit You and Your Family
As I wrote in a different article, rejuvenation biotechnology promises a range of benefits for individuals. Lest anyone thinks that’s all rejuvenation has to offer, I reckon it’s worth discussing other ways that this technology would benefit larger groups of people—namely, your friends and family. If you are rejuvenated, that’s all good for you, but is there anything good coming out of it for your dear ones? Oh, yes.
Two burdens relieved with a single shot
The ill health of old age is a formidable sword of Damocles looming over us all, and when it falls down, it typically does not hit just us; the elderly are certainly the primary victims, but their family are collateral casualties. When people lose their health and independence to aging, their families have to go through the pain of seeing their loved ones becoming more and more fragile, sick, dependent, perhaps even demented. Adding insult to injury, the troubles caused by aging don’t stop here, because a sick and dependent person needs looking after. Thus, the family of an elderly person needs to step in themselves to take care of their relative; if this is not possible, a nursing home is likely going to be the only option left.
Personally taking care of a sick elder is no joke. It requires patience, effort, and most of all, time. It’s a real challenge, especially so for people who have young kids of their own to look after. Let’s also not forget that it is emotionally very taxing.
The nursing home option may partly solve the problem, because there, somebody else does the caring for you, but telling your elders that you can’t take care of them any more isn’t the best feeling in the world, for you or for them. This can be a rather costly solution, too—and as much as every last penny spent to take care of a loved one is well spent, a typical family only has so many pennies, and just because they need them for grandpa, it doesn’t mean they can conjure money out of thin air.
As things stand, when we’re going to be old, our dear ones will be faced with the issues above; however, if a decent rejuvenation platform was in place by then, none of these issues would materialize, because we’d be healthy and independent in spite of our age. We would never be a burden on our dear ones, and the time we’d spend together would be quality time for us and for them.
Be there for those who care about you
Luckily for me, I’m still very far from that stage of life when all your friends of a lifetime keep dying. I like to think that there would be more than one person grieving for my loss, and I believe that would actually be the case for most of us. If we exclude few, rare scenarios, your friends, and family would probably rather have you alive and well than inside a coffin. Thanks to rejuvenation, your spouse, your children, your grandchildren, and your friends may benefit from your presence, life experience, and persona for a much longer time. This would be a benefit for you as well, because you could live through your 80s, 90s, and who knows how much longer, without having to bury a dear friend a few times a year.
Somebody think of the children!
Unlike what I discussed above, what follows is not an indirect benefit of your own rejuvenation for someone else; still, it may be a benefit for your dear ones that you may want to think about.
I certainly understand why we need to think of ‘the children’ specifically—they’re too young to take care of themselves. However, I say we should go a little further and care for them not only when they’re still children, but even later on; we should care for them as people. And your children, old or young, will always be your children; you spend a good chunk of your life protecting them and keeping them away from unnecessary suffering. Once they’re grown-ups, this is something they can do pretty much on their own, but they won’t be able to protect themselves from aging; nobody can do that. However, future children—future people—may never have to worry about their or anyone else’s aging, if we only put enough effort into rejuvenation research and advocacy today. Adults of today aren’t guaranteed to escape the grip of aging, but today’s children stand a much better chance. This, I think, is something we should all remember when we look at kids around us, particularly our own.
Why Rejuvenation Biotechnology Could Benefit You
I’m sure you’ve noticed that LEAF has been shouting from the rooftops for quite a while that rejuvenation biotechnologies need to happen, and we’re doing our best to make them happen as soon as possible. The job isn’t easy; the fact that numerous people still raise concerns about the idea doesn’t make it any easier, and we invest part of our time duly addressing those concerns.
Speaking of concerns, I’m a bit concerned that the discussion about what might go wrong or how to prevent this or that hypothetical problem might draw attention away from another, possibly even more important question: Why do we strive to make rejuvenation a reality? There’s not much point in doing something if it doesn’t yield any benefits, especially if that something requires as much hard work as this cause does; so, what are the expected benefits of rejuvenation?
The benefits are many; some are obvious, and some are less so. The ones I’ll discuss in this article are the ones I see as obvious—tangible, immediate benefits for the people undergoing rejuvenation.
Health
We’ve kind of made a rather big deal of this one, haven’t we? Rejuvenation, we have said time and again, is pretty much all about health. The causal link between biological aging and pathologies is well established, and even when we account for the few elderly who are exceptionally healthy for their age, we’re left with the obvious fact that the older you are, the sicker you are—and even the aforementioned exceptions aren’t in the best of shape.
To the best of my knowledge, the number of people who actively wish to be sick at some point tends to be fairly small; so, when you think that a truly comprehensive rejuvenation platform would allow people to maintain youthful health irrespective of their age, the health benefits of rejuvenation become crystal clear. To be honest, this benefit alone would be enough for me, and I wouldn’t even need to look into the other ones.
Independence
Frailty, failing senses, weakness, and diseases aren’t good friends of independence, but they are good friends of old age. That’s why nursing homes exist in the first place—to take care of elderly people who are no longer independent. Again, even the few exceptional cases who manage on their own until death don’t have it easy. Having people doing things for you can be nice in small doses, but having to have people doing things for you, not so much. Rejuvenation would eliminate the health issues that make the elderly dependent on others, which is a rather evident benefit.
Longevity
As odd as it may sound, longevity is really just a ‘side effect’ of health, because you can’t be healthy and dead. The longer you’re healthy enough to be alive, the longer you’ll live. Since rejuvenation would keep you in a state of youthful health, the obvious consequence is that you’d live longer. How much longer exactly is hard to say, but as long as you’re healthy enough to enjoy life, it’s safe to say that longevity would be a benefit; you’d have more time and energy to dedicate to what you love doing, and you could keep learning and growing as a person for an indefinitely long time.
You would not have to worry about the right age to change your job, get married, or start practicing a new sport because your health wouldn’t depend on your age, and the time at your disposal would not have a definite upper limit. If the first few decades of your life weren’t as good as they could have been for one reason or another, you would still have time ahead and a chance of a better future, which sounds more appealing than ten years in a hospice with deteriorating health to me. (Let’s face it: If your life isn’t very good to begin with, a disease is hardly going to make it better.)
Additionally, a longer life would allow you to see what the future has in store for humanity. I wouldn’t be too quick to think the future will be all doom and gloom: Today’s world is more peaceful and prosperous than it was in the past, and while there’s no certainty it will be at least this good in the future, there’s no certainty that it won’t be worth living in either. I would argue it’s best not to cross our bridges before we get there, and we shouldn’t opt out of life before we actually reach a point when we don’t care for it anymore, if ever. I don’t think I will ever have a reason to give up on life or get bored with it, but I accept that somebody might think otherwise. Even so, I think being able to choose how long you want to live, and always living in the prime of health, is a much better deal than the current situation of having a more-or-less fixed lifespan with poor health near the end.
Choice
Ultimately, all of these perks can be summarised into one: choice. If we had fully working rejuvenation therapies available and were thus able to keep ourselves always perfectly healthy, regardless of our age, we could choose whether we wanted to use these therapies or not. Those who wish a longer, healthier life could avail themselves of the opportunity and escape aging for as long as they wanted; those who prefer to age and bow out the traditional way could just as easily not use the therapies.
Rejuvenation would give us an extra option we currently don’t have; everyone is forced to face the burden of aging and eventually die of it, for the moment. Being able to choose what we wish for ourselves is one of the most fundamental human rights and an obvious, unquestionable benefit.
Cytomegalovirus the Enemy Within
Cytomegalovirus (CMV) is a β-herpesvirus that infects the majority of people in the world, lying dormant and waiting for an opportunity to strike. This persistent virus remains in people for their entire lives once they are infected. it is thought that CMV contributes to microbial burden as we age, and our dwindling immune cell populations are tied up keeping it under control.
Today, we are going to have a look at what CMV is, how it works, and what we can do about it.
Cytomegalovirus, the dormant timebomb
CMV is part of the β-subfamily of herpesviruses, a family of viruses that are believed to have been co-evolving with their hosts for around 180 million years[1]. CMV infection is asymptomatic, meaning that it produces no symptoms and is a latent infection; in other words, it lies dormant in the cell awaiting activation under set conditions[2].
Reactivation from this dormant state is believed to happen periodically and so requires constant, lifelong immune surveillance to keep the body free from disease. Patients who have compromised immune systems are at greater risk for CMV reactivation, and this can lead to an increase of morbidity and mortality[3].
CMV is spread primarily via exposure to infected secretions and subsequent mucosal contact, which then acutely infects various cell types. After this acute infection, the virus spreads and then becomes dormant throughout the body.
In order to reactive and awaken from this dormant state, CMV, like all herpesviruses, progresses through an ordered cascade that starts with the expression of intermediate-early genes, which serve as a trigger for further (early and late) viral gene expression[4]. Studies have shown that CMV periodically expresses these intermediate-early genes at random during its dormant (latency) period[5-6]. This means that there is always a background level of CMV reactivation.
Once these initial genes are expressed, the cycle moves to express genes for host manipulation, DNA replication, and viral packaging. The expression of the intermediate-early genes is closely linked to proinflammatory transcription factors, such as Nuclear Factor Kappa beta (NF-κB), TNFα and interleukin-1β. Not surprisingly, these inflammatory signals can reactivate CMV as a result of this link[7-8].
So in this manner, CMV is sensitive to its environment, and its activity is regulated by local inflammatory factors. This means that injuries and other sources of inflammation can reactivate CMV from its dormant state just by the presence of inflammatory signals, and it uses this inflammation as a way to further reproduce and spread.
What can we do about CMV?
Even in people with healthy immune systems, constant CMV reactivations are potent stimulators of CMV-specific T cells. Perhaps more intriguingly, recombinant CMV viruses are currently being explored as a potential basis for vaccine vectors. A recombinant virus is a virus produced by recombining pieces of DNA using recombinant DNA technology.
This may be used to produce viral vaccines or gene therapy vectors. These vaccine vectors can then be used to generate large numbers of T cells against infectious diseases and cancer. Some CMV-based vaccines have been tested in nonhuman primate models of HIV infection [9-10].
A number of studies show that T cells play a crucial role in the control of CMV and prevent it from reactivating from its latent state by suppressing the viral gene expression cascade discussed earlier[11]. As we age, the numbers of T cells we have dwindle, so this suppression almost certainly dwindles as we get older.
Various studies have shown that adoptive therapy can restore CMV immunity, reduce the risk of CMV infection and treat infections resistant to antivirals[12]. Infusions of CMV-specific T cells can restore CMV-specific immunity in people[13], and, likewise, adoptively transferred (cells from either the patient or another person) T cells have also been shown to be able to control the spread of CMV[14].
This means that transferring CMV-specific T cells to infected patients could be a potential approach to dealing with CMV and could quickly restore immunity and prevent CMV-related deaths.
Controlling the spread of the virus is critical because CMV has been shown to tie up a huge number of T cells devoted to suppressing it in the circulation of infected adults[15]. This large number of required cells is likely due to the systemic nature of the virus and the fact that the immune system has to have CMV-specific T cells everywhere in order to keep it suppressed.
Conclusion
A huge amount of your immune system is devoted to keeping CMV in check, and as we age, that is a losing battle. Finding a way to destroy CMV could be very beneficial indeed to the immune system, as it would free up resources to fight other infections.
Adoptive immunotherapy is a promising approach in this respect, and with our ability to produce essentially unlimited numbers of CMV-specific T cells outside the body in culture for transplant, it might be the ideal solution.
Literature
[1] McGeoch, D. J., Cook, S., Dolan, A., Jamieson, F. E., & Telford, E. A. (1995). Molecular phylogeny and evolutionary timescale for the family of mammalian herpesviruses. Journal of molecular biology, 247(3), 443-458. [2] Fields, B. N., Knipe, D. M., Howley, P. M., & Griffin, D. E. (2007). Fields virology. 5th. [3] Crough, T., & Khanna, R. (2009). Immunobiology of human cytomegalovirus: from bench to bedside. Clinical microbiology reviews, 22(1), 76-98. [4] Hermiston, T. W., Malone, C. L., Witte, P. R., & Stinski, M. F. (1987). Identification and characterization of the human cytomegalovirus immediate-early region 2 gene that stimulates gene expression from an inducible promoter. Journal of Virology, 61(10), 3214-3221. [5] Grzimek, N. K., Dreis, D., Schmalz, S., & Reddehase, M. J. (2001). Random, Asynchronous, and Asymmetric Transcriptional Activity of Enhancer-Flanking Major Immediate-Early Genes ie1/3 andie2 during Murine Cytomegalovirus Latency in the Lungs. Journal of Virology, 75(6), 2692-2705. [6] Henry, S. C., & Hamilton, J. D. (1993). Detection of murine cytomegalovirus immediate early 1 transcripts in the spleens of latently infected mice. Journal of Infectious Diseases, 167(4), 950-954. [7] Hummel, M., Zhang, Z., Yan, S., DePlaen, I., Golia, P., Varghese, T., … & Abecassis, M. I. (2001). Allogeneic transplantation induces expression of cytomegalovirus immediate-early genes in vivo: a model for reactivation from latency. Journal of Virology, 75(10), 4814-4822. [8] Cook, C. H., Trgovcich, J., Zimmerman, P. D., Zhang, Y., & Sedmak, D. D. (2006). Lipopolysaccharide, tumor necrosis factor alpha, or interleukin-1β triggers reactivation of latent cytomegalovirus in immunocompetent mice. Journal of virology, 80(18), 9151-9158. [9] Hansen, S. G., Sacha, J. B., Hughes, C. M., Ford, J. C., Burwitz, B. J., Scholz, I., … & Malouli, D. (2013). Cytomegalovirus vectors violate CD8+ T cell epitope recognition paradigms. Science, 340(6135), 1237874. [10] Hansen, S. G., Piatak Jr, M., Ventura, A. B., Hughes, C. M., Gilbride, R. M., Ford, J. C., … & Gilliam, A. N. (2013). Immune clearance of highly pathogenic SIV infection. Nature, 502(7469), 100. [11] Simon, C. O., Holtappels, R., Tervo, H. M., Böhm, V., Däubner, T., Oehrlein-Karpi, S. A., … & Reddehase, M. J. (2006). CD8 T cells control cytomegalovirus latency by epitope-specific sensing of transcriptional reactivation. Journal of Virology, 80(21), 10436-10456. [12] Nicholson, E., & Peggs, K. S. (2015). Cytomegalovirus-specific T-cell therapies: current status and future prospects. Immunotherapy, 7(2), 135-146. [13] Einsele, H., Roosnek, E., Rufer, N., Sinzger, C., Riegler, S., Löffler, J., … & Kleihauer, A. (2002). Infusion of cytomegalovirus (CMV)–specific T cells for the treatment of CMV infection not responding to antiviral chemotherapy. Blood, 99(11), 3916-3922. [14] Holtappels, R., Böhm, V., Podlech, J., & Reddehase, M. J. (2008). CD8 T-cell-based immunotherapy of cytomegalovirus infection:“proof of concept” provided by the murine model. Medical microbiology and immunology, 197(2), 125-134. [15] Sylwester, A. W., Mitchell, B. L., Edgar, J. B., Taormina, C., Pelte, C., Ruchti, F., … & Nelson, J. A. (2005). Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. Journal of Experimental Medicine, 202(5), 673-685.
Longevity Promotion a Multidisciplinary Perspective
There’s no doubt that Dr. Ilia Stambler’s Longevity promotion: multidisciplinary perspective is a thorough book that all kinds of advocates of healthy longevity may find very useful. The book reads pretty much like a collection of academics papers, each dealing with a different aspect of the matter, including science, history, social and moral implications, legislation, and advocacy. Just like you would expect from an academic work, each section of this book is complete with exhaustive sources that will indubitably prove helpful should you wish to dig deeper into the topic being discussed.
The first section of the book focuses on advocacy, discussing typical concerns raised in the context of life extension, outreach material, and initiatives, and it offers suggestions for effective policies to promote aging and longevity research. The latter part of this section was one of the hardest for me to read since policies and legislation are not at all my strongest suit, but I do believe that professional lobbyists and advocates who have legal and regulatory backgrounds and wish to take action will find numerous ideas in it.
The longevity history section discusses the progression of longevity science during the last century. It was surprising to learn that quite a few well-established scientific disciplines of today, such as endocrinology, owe their existence to early efforts to create rejuvenation treatments. This section discusses other aspects as well, such as the holism vs reductionism controversy in the history of longevity research and the legacy of Elie Metchnikoff, a pioneering immunologist and microbiologist who can safely be regarded as the father of gerontology and made no mystery of his conviction that aging should be considered a disease and treated as such.
However, the topic I found most engaging was the historical evolution of evolutionary theories of aging; antagonistic pleiotropy, disposable soma, and mutation accumulation are all presented here, and their merits and shortcomings are discussed from a neutral perspective.Readers who have religious beliefs or are otherwise interested in religious traditions may find the longevity philosophy section of special interest, for it explains how the pursuit of healthy longevity may fit in the context of the main monotheistic religions, often in surprising ways. Superficially, one might think religions should be against life extension, as it might represent an obstacle on the way of the afterlife or reincarnation, for example; yet, the author makes interesting points about how religious philosophies have strong connections to the pursuit of longevity, sometimes even encouraging it and presenting it as a worthy goal.
The fourth and final section of the book is a treatise on longevity science. It discusses possible intervention to ameliorate age-related conditions, the current state of research, and especially the importance of agreeing on a diagnostic framework for aging. As the author himself points out, it is impossible to cure that which cannot be diagnosed; therefore, the task of curing aging, or the diseases of old age, will be much harder without widely agreed-upon criteria to establish which biomarkers are the most reliable and what their optimal values should be. In absence of such parameters, it won’t be possible to effectively assess whether any rejuvenation therapy is actually doing its job or not, and Dr. Stambler rightly stresses this fact.
In closing of the fourth section, the reader will find a short discussion of several other resources for further reading.
As the author’s writing style is rather formal and academic, some readers may find this book a ‘heavy read’. The text may also appear slightly repetitive on occasion, but, in my perspective, this may well be a feature rather than a bug: Together with the content structure, it helps make each section of the book independent of the others. Readers may safely skip any parts in which they’re not interested and move on to what they find more appealing, without fear of missing out on any crucial bit of information.
Using Artificial Intelligence to Rapidly Identify Brain Tumors
The use of artificial intelligence and, in particular, machine learning is becoming increasingly popular in research. These systems excel at high-speed data analysis, interpretation, and laborious research tasks, such as image assessment.
One of the areas in which machine learning has been enjoying success is image recognition. Now, researchers have begun to use machine learning to analyze brain tumors.
Training a machine to recognize tumors
Primary brain tumors include a broad range that depends on cell type, aggressiveness, and development stage. Being able to rapidly identify and characterize the tumor is vital for creating a treatment plan. Normally, this is a job for radiologists who work with the surgical team; however, in the near future, machine learning will play an increasing role.
George Biros, professor of mechanical engineering and leader of the ICES Parallel Algorithms for Data Analysis and Simulation Group at The University of Texas at Austin, has spent almost a decade developing accurate computer algorithms that can characterize gliomas. Gliomas are the most common and aggressive type of primary brain tumor.
At the 20th International Conference on Medical Image Computing and Computer-Assisted Intervention (MICCAI 2017), Professor Biros and collaborators presented the results of a new, automated method of characterizing gliomas. The system combines biophysical models of tumor growth with machine learning algorithms to analyze the magnetic resonance (MR) imaging data of glioma patients. The system is powered by the supercomputers at the Texas Advanced Computing Center (TACC).
The research team put their new system to the test at the Multimodal Brain Tumor Segmentation Challenge 2017 (BRaTS’17), which is a yearly competition at which research groups present new approaches and results for computer-assisted identification and classification of brain tumors using data from pre-operative MR scans. The new system impressively managed to score in the top 25% in the challenge and was near the top rankings for whole-tumor segmentation.
The goal of the contest is to be able to take an image of the brain and have the computer analyze it and automatically identify different kinds of abnormal tissue, including edema, necrotic tissue, and areas with aggressive tumors. This is a little like if you took pictures of your family and used facial recognition to identify each person, only here the images are brain scans, and it is tissue recognition that must be done automatically by the computer.
The team were given 300 sets of brain images to calibrate their systems with; this is known as “training” in machine learning terms and is how the machine is taught to identify features.
During the last part of the contest, the researchers were given 140 new brain images from patients and had to identify the location of tumors and divide them into different tissue types. They were given just two days to do this; for humans, doing the job would be a monumental amount of work.
The image processing, analysis and prediction pipeline they used has two main stages: a machine learning stage assisted by humans, in which the computer creates a probability map for the target classes it needs to identify, such as whole tumor and edema, and a second stage in which these probabilities are combined with a biophysical model which represents how tumors grow; this serves to impose limits on analyses and aids correlation.
Using supercomputers to characterize brain tumors
The system used the supercomputers of TACC, so they could use employ large-scale nearest neighbor classifiers, a machine learning method. For every voxel, or 3D pixel in an MR image of the brain, the system tries to locate all similar voxels in the 300 brains it had previously seen during training to determine if an area of an image is a tumor or not.
This translates to 1.5 million voxels per brain image, and with 300 brain images to assess, the computer system had to look at half a billion voxels for every new voxel of the 140 unknown brains it had been given in order to determine if a voxel was a tumor or healthy tissue. This was possible thanks to the use of the TACC supercomputers and represents a huge amount of computing power.
Each individual stage in the analysis pipeline utilized different TACC computing systems; the nearest neighbor machine learning classification component used 60 nodes at once (each consisting of 68 processors) on TACCs latest supercomputer Stampede2. The Stampede2 supercomputer is one of the most powerful computer systems in the world, and Professor Biros and his team were able to test and refine their algorithm on the new system in the spring of this year. They were some of the first researchers to gain access to the computer, and they needed the sheer power to perform these highly complex operations.
The end result of having access to this power was that Professor Biros and his team were able to run their analysis on the 140 brains in less than four hours. They correctly characterized the data with an accuracy of almost 90%, which is comparable to human radiologists doing the job and in a fraction of the time. The process is also completely automatic once the system algorithms are trained, and it can then assess image data and classify tumors without any further need for human intervention.
The system is being installed at the University of Pennsylvania by the end of this year in partnership with project collaborator Christos Davatzikos, director of the Center for Biomedical Image Computing and Analytics and a professor of radiology at the university. While the system will not replace radiologists and surgical staff, it will help to improve reproducibility of assessments and could potentially lead to faster diagnoses.
Conclusion
This is yet another example of how machine learning is being employed in research and medicine, and the methods the team has developed here have the potential to go beyond brain tumor analysis. The system could be used for other medical applications of a similar nature though transfer learning, so the possibilities are fairly endless.
If you are excited about how AI and machine learning can change research forever, you may be interested in a related project on Lifespan.io. The MouseAge project is seeking support to develop a visual recognition and assessment system that will allow researchers to determine the age of mice without the need for invasive testing. If you are interested in helping us create a system that could speed up aging research and reduce animal suffering, check it out.
A Potential Path to Treating Inflammation-related Aging and Cancer
The link between inflammation, cellular senescence, aging, and cancer is a complex relationship, but a new study sheds light on how these four interact.
The light and dark side of inflammation and cellular senescence
Cellular senescence is a protective mechanism that helps us to stay healthy and avoid cancer by removing damaged and aged cells from the cell cycle while preventing them from creating damaged copies of themselves. Senescent cells are disposed of via a self-destruct process known as apoptosis.
However, cellular senescence has a dark side. As we age, the immune system slows down, becomes dysfunctional, and ceases to remove senescent cells, allowing them to accumulate.
The accumulation of senescent cells in aged tissues is a hallmark of aging and one of the processes that causes us to age[1]. As senescent cells build up, they trigger the immune system to generate excessive inflammation, which, in turn, impairs healthy tissue regeneration and drives the aging process ever faster.
This contributes to the smoldering and chronic age-related inflammation known as “inflammaging”. Other sources of inflammaging include microbial burden, cell debris and protein crosslinking. This chronic inflammation contributes to age-related diseases, including cancer, heart disease, and neurodegeneration.
The focus of current research efforts is to find ways to periodically remove senescent cells from the body using senolytic therapies or to reduce inflammation by manipulating the immune response.
Chromatin leaking leads to inflammation
A new study by researchers from the Perelman School of Medicine at the University of Pennsylvania found that chromatin – a structure in the cell nucleus where genes are housed – can become misplaced[2]. The traditional view is that chromatin as a cell component remains within the nucleus in order to regulate gene expression. However, the team found that there were misplaced chromatin fragments outside the nucleus that had been pinched off from nuclei present in senescent cells.
This misplaced chromatin causes a DNA-sensing pathway called cGAS-STING to become activated in its presence. The cGAS-STING pathway is based outside the nucleus and is known for its ability to combat microbial invasion from bacteria and viruses. It appears that in the case of cell senescence due to aging, the chromatin leaks outside the nucleus and triggers the cGAS-STING pathway, which reacts to this the same way it does to microbial infection. The leaking chromatin triggers an “alarm signal”, leading to inflammation.
Inducing short-term inflammation is useful in fighting infections and preventing cancers from developing; the problem begins when that inflammation becomes chronic, such as in aging. It leads to loss of tissue repair and ultimately can even help cancer spread.
The researchers used cellular stressors, such as DNA-damaging agents, activated oncogenes, and regular aging cells, to set off the alarm signal. They found that cells responded by shutting down and entering cellular senescence and calling the immune system to dispose of them. This depends on the immune system working properly, and while it is designed to clear away senescent cells, if uncontrolled, it can do more harm than good.
Sounding the alarm
The team observed that when mice with disabled cGAS-STING alarm pathways are exposed to cancer-inducing stressors, their cells do not summon the immune system for help. This is a problem because those damaged cells lead to the formation of tumors.
In normal mice exposed to stressors that induce aging, the accumulation of senescent cells causes a continual call for the immune system, leading to an excessive immune response and chronic, long-term inflammation. This then induces tissue damage, failure of tissue repair and premature aging.
Months after receiving stressors, the normal mice with an active alarm system showed masses of grey hair, a sign of aging in mammals, including humans. In contrast to this, mice lacking the alarm system had normal black hair, which shows exactly what the light and dark sides of cellular senescence are.
The researchers are now searching for molecules that target the always-on cGAS-STING alarm pathway in the hope of finding ways to manipulate the inflammatory response.
Conclusion
Science is steadily unraveling the exact mechanisms behind cellular senescence and how it contributes to chronic inflammation and aging. Of the two approaches to dealing with senescent cell accumulation, the removal of them seems the more direct approach over attempting to mediate the inflammation by tweaking various pathways, as these researchers are attempting to do.
While we find out more about how this complex interaction plays out, there are human trials for senolytics launching this year, and some studies are already in progress in some cases. In our view, removing the root of the problem seems to to be the more practical approach than modulating the signals from senescent cells without actually removing them.
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] Dou, Z., Ghosh,K.,Grazia, M. et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature (2017) doi:10.1038/nature24050.
The Good Sides of Aging?
Sometimes, and especially in articles aimed at mitigating people’s fear of aging, it is said that aging doesn’t come just with downsides, such as frailty and diseases, but also with upsides—for example, wisdom and a long life experience.
It is often subtly implied that these two very different aspects are two sides of the same coin, that you can’t have one without the other, and perhaps even that the ill health of old age is a fair price to pay for the benefits that also come with it.
Nothing could be further from the truth.
Setting the record straight
There are plenty of good reasons to be afraid of aging, because the diseases and disabilities it causes are very real and far from being observed only in exceptional cases. It would be foolish not to fear cancer, for example, because it is an extremely serious and often fatal condition; in the same way, and for the same reasons, it is foolish not to fear aging; perhaps, an even stronger fear is justified, because aging can and does give rise to many diseases, including cancer itself.
There’s nothing wrong with fearing aging, because it may help us steer clear from its inherent dangers, just like the fear of any other harmful thing keeps us away from it. This is true so long as by ‘aging’ we mean biological aging, which is not at all the same as chronological aging. It is very important to draw a line between the two so that we don’t end up accepting the downsides of the former, which are neither necessary nor sufficient to enjoy the benefits of the latter.
What’s the difference?
Chronological aging is a rather fancy term to indicate a very mundane thing, namely the passing of time. For as long as time will keep passing, everything will age chronologically. This is obviously a good thing because if time did not pass, the universe would stand still and nothing at all, including ourselves, would ever happen.
However, it is easy to see how chronological and biological aging are not the same thing by means of a simple observation: Although time runs essentially uniformly everywhere on Earth, different life forms have different health- and lifespans. If time passes at the same rate for me and for a cat, and yet I’m (biologically) old at age 80 while a cat is (biologically) old already at age 15, clearly there must be something else than just the passing of time that accounts for this discrepancy.
This ‘something else’ is metabolism—the intricate set of chemical reactions the bodies of living creatures perform on a daily basis for the very purpose of staying alive. As we have discussed in other articles, what we call biological aging is really just a process of damage accumulation; this damage, which eventually leads to pathologies, is caused by metabolism itself, and therefore a faster metabolism means faster aging. Different species have different metabolic rates; as a rule of thumb, the smaller the species, the faster its metabolism and thus its aging, leading to shorter health- and lifespan. This is, in a nutshell, why a cat ages faster than I do.
As a confirmation of this fact, one may observe that species in a regimen of caloric restriction tend to live longer (sometimes much longer) than their normal lifespan, and the insurgence of age-related diseases is delayed accordingly: A lower caloric intake causes metabolism to slow down; consequently, the aging process follows suit.
Interestingly, some lucky species, the so-called negligibly senescent organisms, don’t show any signs of biological aging at all with the passing of time.
At this point, you don’t have to be clairvoyant to see that biological aging implies chronological aging, but not vice-versa. No chronological aging means no time passing, and no time passing means nothing takes place, metabolism included. However, since different creatures age differently (or not at all) despite time passing at the same rate for all of them, chronological aging doesn’t imply biological aging. Quite simply, they’re not the same thing.
Render unto Caesar the things which are Caesar’s
Having cleared the difference between chronological and biological aging, we must now correctly attribute the aforementioned pros and cons of old age to each of them.
From the very definition of biological aging above, it’s clear that it is the culprit responsible for the cons—the diseases of old age.
Speaking of the pros, all possible benefits of old age—life experience, wisdom, sense of accomplishment—certainly do not come from the damage that metabolism has wrecked throughout your body over the years. Clearly, they depend on the events of your life, and thus they’re not at all granted to happen, no matter how long you live. If you spent your life in isolation doing nothing, avoiding new experiences and not learning anything new, your wisdom as an eighty-year-old would hardly compare to that of a well-traveled, seasoned scientist or philosopher of the same age, for example. Ultimately, the benefits traditionally attributed to old age obviously depend on the passing of time (i.e., chronological aging), and most of all on the use you made of your time. Just because you’re old, you’re not automatically wise, accomplished, or well-learned.
What’s more, the debilitation that comes with biological aging makes it harder for you to relish and expand the wisdom and experience you’ve accrued over the years. So, not only does biological aging bring no benefits; it is a hindrance as well.
In conclusion, the pros and cons of old age are due to different causes, and, as such, they aren’t interdependent. The diseases of old age are not a currency you can use to buy yourself the wisdom of the aged, and thanks to the emergence of rejuvenation biotechnologies, you might relatively soon be able to enjoy the pros of old age without having to pay any undue and unfair tolls.
Dr. Greg Fahy – Rejuvenating the Thymus to Prevent Age-related Diseases
The thymus gland is located at the top of the breastbone and is where the majority of T cells are produced by the immune system. One can think of the thymus as being like an army camp where new soldiers are trained and given their weapons to fight invading forces; in this case, the T cells are those soldiers, and the battlefield is your body.
As we age, the thymus begins to shrink, and fewer numbers of T cells are created and trained to fight. This structural decay of the thymus is one of the main reasons why we become increasingly vulnerable to infectious diseases, such as influenza and pneumonia. The other reason is immune cells becoming senescent.
There are a number of possible solutions to this problem. Firstly, engineering new healthy and youthful thymic tissue might help to restore the immune system, and indeed a number of groups are working towards this.
Secondly, some researchers are focused on encouraging the aged thymus to regrow using various approaches, such as stem cell transplants, cellular reprogramming or chemical compounds. Dr. Greg Fahy is involved in researching this second approach, and we had the opportunity to speak to him about this work.
Introducing Dr. Greg Fahy
Hailing from California, Dr. Fahy holds a Bachelor of Science degree in Biology from the University of California at Irvine and a Ph.D. from the Medical College of Georgia in Augusta. Dr. Fahy used to be the Head of the Tissue Cryopreservation Section of the Transfusion and Cryopreservation Research Program for the U.S. Naval Medical Research Institute in Bethesda, Maryland, where he developed the original concept of ice blocking agents.
Before his time at 21st Century Medicine, where he currently is Vice President and Chief Scientific Officer, Dr. Fahy pioneered the practical use of cryopreservation by vitrification and invented a computer system to apply this technology to organs at the American Red Cross.
With over 30 years of experience in cryobiology, Dr. Fahy is considered a world expert in organ cryopreservation by vitrification[1-3]. He introduced the modern successful approach to vitrification for the cryopreservation process to cryobiology[4-8], and also managed to prove that restoration of organ function after cryopreservation is possible.
Dr. Fahy is also a biogerontologist and is the originator and Editor-in-Chief of The Future of Aging: Pathways to Human Life Extension, a multi-authored book about the future of biogerontology.
For 16 years, Dr. Fahy worked as a Director of the American Aging Association and for 6 years as the editor of AGE News, the organization’s newsletter. He currently serves on the editorial boards of Rejuvenation Research and the Open Geriatric Medicine Journal.
Dr. Fahy kindly agreed to tell us about some of the exciting things he has been working on and, in particular, about the studies he has been conducting on rejuvenating the thymus in humans.
Hi, Greg, thank you for finding the time to talk to our readers about your work. So from around age 20 (or younger) the thymus begins to shrink and loses the ability to produce T cells, why does this happen?
Nobody knows why thymic atrophy, or involution, occurs, but it happens in all vertebrates, starting really at the age of puberty. Some have suggested that it happens to save energy, since the production of properly qualified T cells is very energy intensive and inefficient, and of course, at puberty, the body begins to devote more energy to reproduction, which might require a tradeoff against using energy for immune maintenance.
This could be adaptive since, in nature, humans would not have lived long enough for immune system collapse to set in, even though today, the situation is different. Regardless of the evolutionary reason for it, the most immediate biochemical cause of involution seems to be mostly a drop in thymic FOXN1 expression, although some have pointed to a decline in intra-thymic IL-7 and the negative influence of circulating sex hormones, for example.
Can you please give our readers a few examples of which age-related diseases are promoted by the decline of thymus function.
The job of the immune system is to fight infectious disease and cancer, and a healthy immune system also knows how to do these things without attacking self. With immunological aging or immunosenescence, all three of these functions weaken. T-cell-based immunity begins to collapse in the 60s, and this goes virtually to completion before 80. Coincident with this, we see, for example, more than 90% of seasonal flu deaths and most hospitalizations for the flu in the US taking place in people over 65 years of age, and the response to vaccination becoming poorer as well.
Pneumonia, also, begins to become particularly deadly. In the 20th century, the mean human lifespan was greatly increased in large part by public health measures that radically diminished the death rate from infectious diseases like tuberculosis, polio, smallpox, diphtheria, etc., but you might also say that what also happened was to just postpone death from infectious diseases to after 60-65 years of age, which means that the same basic problem still remains. Perhaps this problem can, finally, be largely conquered by maintaining thymic function.
Twenty years ago, the role of the immune system in controlling cancer was not fully appreciated, but today, it is clear that a key job of the immune system is to attack and eliminate cancerous and precancerous cells. In fact, some of the best cancer therapies ever created are cancer immunotherapies, in which the patient’s own immune cells are harnessed to target and kill cancer cells. So it is probably not a coincidence that in older people, the incidence of cancer skyrockets at the same time T cell immunity fails. The implication is that if thymic and immunological regeneration can be accomplished, perhaps cancer incidence can be kept low throughout life, and on top of this, if cancer does occur, perhaps immunotherapies for cancer will be more effective.
Finally, it is now accepted that the third function of the thymus, which is to prevent the immune system from attacking its host, also declines with age. This allows chronic autoimmune reactions to accumulate with age, and presumably contributes to the age-related chronic inflammation that is observed to occur, which is sometimes called “inflammaging”. This condition has many detrimental effects.
You recently ran a human clinical trial to regrow the thymus gland. Can you please tell us what is the main goal of the project and what is the progress?
The trial was conducted under an FDA-approved IND and with review from multiple scientific and ethics committees. It consisted of a 12-month treatment course for 9 men divided into two cohorts, with the first cohort starting in October of 2015 and the second ending in April of this year. Our goal was to gather preliminary evidence indicating that it is possible to safely regenerate the normal aging human thymus and restore its functions, essentially reversing the process of age-related immunological deterioration.
We chose to work with healthy men in part because this was a small trial, which required a reasonably uniform population, and in part because more information was available for men than for women. We chose an age range of 50 to 65 years because this range extends from several years before to a few years after the threshold age at which the immune system tends to collapse. Success would therefore suggest the possibility of preventing or even reversing the early stages of immune collapse. In future trials, we intend to enroll both women and older men.
The outcome measures included MRI evaluation of thymic density before and after treatment, simple and sophisticated assessment of T cell population distributions, measurements of many serum factors related to immune system function and general health, lymphocyte telomere length distributions and telomerase activity, and biological age based on the Horvath epigenetic clock. Regarding our results, first of all, when you’re working with human beings, safety has to be the top priority, so I’m glad to be able to say that we met or exceeded all of our safety targets.
Regarding thymic imaging results, preliminary analyses indicate that there was a consistent and substantial increase in thymic density, which indicates replacement of thymic fat with more water-rich material, and in previous studies on human immunodeficiency patients, this coincided with improved thymic function. Superficial tests of immune system aging showed improvements in 8 out of 9 men, and we were able to identify a possible correctable reason for the failure of the 9th volunteer. Men of all ages were able to respond positively and to avoid side effects. However, the most definitive endpoints of our study are still being analyzed at four different locations around the world, so we won’t really know the final results of our study for probably another month or two.
Are we going to see a publication anytime soon?
I’m not sure about soon, but certainly, as soon as we can. This will be a complicated paper with lots of authors and lots of data to present, but also with top-tier academic co-authors who can help us go through the scientific review process quickly. In any case, we certainly want to make sure that any novel results are shared with the broader medical and scientific communities.
Our readers are curious, what are other promising approaches to restore thymus function. Why did you choose human growth hormone over using stem cell transplants like the 2015 experiment[9] where they used TECs to regrow a mouse thymus?
We choose methods based on safety, efficacy, and speed. A simplified version of our treatment has been independently proven to work with safety in HIV patients, so there is already extensive human clinical data suggesting that our approach will be effective in people. There is really no alternative approach that has already been tested with success on people, and moving from mice to people is usually costly, uncertain, and very time-consuming.
Take the TEC experiments you mentioned, for example. Only TECs from mouse embryonic day 14.5 to postpartum day 1 engrafted adequately into the thymus of adult mice, and TECs from later ages failed. Parabiosis also failed to regrow the adult thymus. So, how would you apply this to humans? Mouse embryonic day 15 corresponds to the middle of the human third trimester of gestation, so you’re not going to get the needed cells from human fetuses. You might try to create the needed cells from scratch, but nobody knows how to do that yet. Maybe someday, someone will figure this out, and maybe someday, long after that, the FDA will actually approve that treatment, after all of the presently-unknown safety issues have been worked out.
And the same is true of most of the other approaches you may have heard of or thought of yourself, the actual human application is not likely anytime soon. An example of a potentially short-term alternative that frequently comes up is surgical or chemical castration. However, although gonadectomy regrows the thymus on some level, it doesn’t always restore immune function.
Furthermore, testosterone reduces cardiovascular morbidity and mortality in men, ovariectomy shortens lifespan in mice, and transplantation of young ovaries to old mice increases their lifespan, so for both sexes, gonadal ablation may have lifespan-shortening effects, which would partly defeat the goal of thymic regeneration, not to mention the negative effects on quality of life! So this is an example of treatments that might positively modulate thymic activity but have side effects that partly or completely outweigh the benefits or that may take a long time to define. In contrast, our treatment is generally very well tolerated and even has some “positive side effects” that volunteers actually enjoy.
What we see is that we’re losing huge numbers of people to aging every day, so we can’t wait. We need something we can use right now, almost this minute. That’s why we use agents that the FDA already likes, or will easily like. This should greatly simplify and speed the approval process, and maximize the chances of success. We’re on the job, and looking at every possible practical way forward. Stay tuned!
We would like to thank Dr. Fahy for taking the time to speak to us about his exciting work, and we are very excited to hear that there has been positive progress. We look forward to seeing the published results in the future.
Literature
[1] Fahy, G. M., Wowk, B., Wu, J., Phan, J., Rasch, C., Chang, A., & Zendejas, E. (2004). Cryopreservation of organs by vitrification: perspectives and recent advances. Cryobiology, 48(2), 157-178.
[2] Fahy, G. M., Wowk, B., & Wu, J. (2006). Cryopreservation of complex systems: the missing link in the regenerative medicine supply chain. Rejuvenation research, 9(2), 279-291.
[3] Fahy, G. M., Wowk, B., Pagotan, R., Chang, A., Phan, J., Thomson, B., & Phan, L. (2009). Physical and biological aspects of renal vitrification. Organogenesis, 5(3), 167-175.
[4] Fahy, G. M., & Hirsh, A. (1982). Prospects for organ preservation by vitrification. Organ Preservation, Basic and Applied Aspects, MTP Press, Lancaster, 399-404.
[5] Fahy, G. M., MacFarlane, D. R., Angell, C. A., & Meryman, H. T. (1984). Vitrification as an approach to cryopreservation. Cryobiology, 21(4), 407-426.
[6] Rall, W. F., & Fahy, G. M. (1985). Ice-free cryopreservation of mouse embryos at− 196 C by vitrification. Nature, 313(6003), 573-575.
[7] Fahy, G. M. (1986). Vitrification: a new approach to organ cryopreservation. Progress in clinical and biological research, 224, 305.
[8] Mullen, S. F., & Fahy, G. M. (2011). Fundamental aspects of vitrification as a method of reproductive cell, tissue, and organ cryopreservation. Principles & practice of fertility preservation. Cambridge University Press, Cambridge, 145-163.
[9] Kim, M. J., Miller, C. M., Shadrach, J. L., Wagers, A. J., & Serwold, T. (2015). Young, proliferative thymic epithelial cells engraft and function in aging thymuses. The Journal of Immunology, 194(10), 4784-4795.
Juvenescence: Investing in the Age of Longevity
Jim Mellon and Al Chalabi are back with another successful venture into the world of science investment. Following their acclaimed 2012 book “Cracking the code”, whose spotlight was on the life sciences industry, Juvenescence takes us on a compelling journey through the dawning market of longevity and rejuvenation biotechnology, which the authors predict will be the biggest “money fountain” to hit the financial world in the coming years.
Juvenescence: Investing in the Age of Longevity is a visionary book, debunking the sometimes questionable past of longevity research and steering us towards a ‘brave new world’ in which advances in medicine are already leading to clinical trials whose aim is to extend human lifespan to unprecedented levels.
Mellon and Chalabi come across as eloquent devotees of cold, hard science, and for a book targeted primarily at investors, biologists and experts will be hard-pressed to find inaccuracies in the many heavily technical sections. The authors explain the science of aging in an engaging and accessible manner, bridging the gap between the lab and the public with ease and tact. They employ elegant metaphors to explain complex processes as well as some light-hearted ones, including the “Deadly Quintet”, which reads more like the title of a long-lost Tarantino film, or the “Actuarial Escape Velocity”, a reference to the controversial “Longevity Escape Velocity” promoted by Aubrey de Grey. Mellon and Chalabi use state-of-the-art research whenever possible, with recent, fresh-from-the-lab studies making up the majority of sources.
It’s almost like two books for the price of one
In a way, Juvenescence feels like getting two books for the price of one. Whether you are a businessman looking for a new venture or a young researcher wishing to learn more about the biology of aging, this book offers an invaluable treasure trove of information. On one hand, investors wishing to get a grasp on the market need only look at the portfolios at the end of the book, which contains a short introduction to each company, including market valuation, and contains handy recommendations on investment opportunities.
There is even a practical guide to key opinion leaders and relatable bite-size information on their affiliated companies, making Juvenescence an up-to-date ‘who’s who’ guide to longevity.
On the other hand, scientists and the curious alike will enjoy the scientific tone and conscientious detail of Juvenescence. Written in an accessible language complete with a full glossary of technical terms, Mellon and Chalabi give us the lowdown on CRISPR, telomeres, GDF-11, hormone replacement, Myc, and many more, as well as some lesser-known genes, such as KL and INDY.
It’s good but lacking in some areas
Experts on longevity may find that the section on theories of aging falls somewhat short of the mark, however, particularly the focus on evolutionary theories of aging, which comes across as outdated. The theories of aging seem picked and mixed about almost at random, as do the explanatory boxes in the book, while some important hallmarks of aging, such as nutrient sensing and cellular communication, are left almost entirely out of the picture.
That being said, Juvenescence offers the reader a reliable, if sometimes surprisingly technical, overview of the contemporary landscape of aging research.
Finally, Juvenescence includes a discerning practical guide to personal longevity for anyone looking to get started on the path to a longer, healthier life, including diet and exercise tips which have long been shared by the longevity community. Mellon and Chalabi demystify “superfoods” and “wonder vitamins”, and they are careful to point out the potentials and risks in equal measure, giving us a no-frills account of the best longevity practices without the hype.
All in all, Juvenescence is a well-researched bird’s-eye view of the latest advances in medical science, and, although hardly exhaustive, gives us a generous glimpse into this fascinating field. Mellon and Chalabi literally ‘look forward’ to an age when biomedical advances will render us young, healthy, and – if we follow their advice – very rich!
If you are interested in learning more check out an advocate’s review of the same book, but written from the perspective of a non-biologist.
Review of Juvenescence: Investing in the Age of Longevity
Only two years ago, when I launched my advocacy website Rejuvenaction, I didn’t think I would read a book like Juvenescence so soon; yet, the topic of rejuvenation biotechnologies has already become mainstream enough to lead investors of the calibre of Jim Mellon and Al Chalabi to devote a whole book to it.
As Juvenescence is a book aimed at potential new investors in rejuvenation biotechnologies, I expected it to be an extremely technical and detailed account of things I don’t understand, such as finance, markets, and funds. To my delight, this was not the case. Rather, the details Juvenescence dives into are primarily those of the emerging field of rejuvenation science (alas, still something whose details I don’t fully understand).
The book explains the paradigm shift that is currently taking place and changing the way science sees aging—no longer as an inevitable fact of life but rather as a disease to be eradicated like any other—and goes through a biology 101 crash course for the benefit of readers who might be not too well versed in the science of life.
After describing the various, converging views of modern science on what the key processes of aging are and the innumerable ailments they cause, the authors introduce us to many of the most prominent figures of aging research, including Aubrey de Grey, David Sinclair, and Craig Venter, and the approaches these luminaries are painstakingly following to bring aging under comprehensive medical control.
Eventually, the focus of the book shifts to the more technical aspects of the biology of aging, and finally to what a world where extreme longevity is the norm could have in store for humanity—how working life, demographics, the trajectory of life, etc, will all change as a consequence of vastly increased lifespans.
Though, as said, this book isn’t a dry investment textbook, and readers looking for new ventures to invest in needn’t worry; Mellon and Chalabi do provide their opinions and suggestions on financial matters in an unobtrusive way throughout the book, and there is a section dedicated to biotech companies’ financial data as well.
As a non-biologist, I don’t have the expertise to give an opinion on the most technical biology parts of the book, though the little that I already knew on the subject and that I expected to find in Juvenescence was exactly where it should be. Non-technical readers be warned: Juvenescence may not be a biology manual, but it does delve into quite a bit of detail and may prove hard to follow if you don’t pay full attention.
The authors clearly did their bit trying to keep it as simple and straightforward as possible, but the topic is complex and requires an attentive reader. While I cannot personally vouch for the solidity of the science in this book, its illustrious scientific reviewers, including Dr. Aubrey de Grey, Dr. João Pedro de Magalhães, Prof. David Gems, and Franco Cortese, can for sure.
Readers looking for ways to increase their chances of ‘making the cut’ and live long enough to benefit from rejuvenation biotechnologies will find lots of useful information in Juvenescence, in the form of an account of different types of diets and the benefits they may have, a discussion of different potential geroprotectors (i.e., substances that protect against some of the effects of aging) and the foods where they can be found, and other useful tips for living a healthier, longer life. It goes without saying that cautious readers will discuss any changes to their lifestyles with their doctors first.
With its wealth of information and a slightly flashy layout, Juvenescence might be a book to make the fight against aging yet more popular with the greater public, particularly with investors. While I do not like to see health and longevity as business opportunities to profit from, huge investments are absolutely necessary in order to make much-needed progress in the lab and eventually bring rejuvenation therapies to the wider public. It is therefore imperative to attract the attention of investors to this field, and I think Juvenescence stands a good chance of doing exactly that.
If I had been completely new to the topic when I picked up Juvenescence, I would probably have been quite confused and overwhelmed by all the information it contains; it is thus perhaps not the best starting point for newbies, but it is a good addition to the library of any rejuvenation advocate and whoever wants to learn more about the science of longevity.
The book is available in the US at Amazon and at www.harriman-house.com and in the UK on amazon and on their website here. There is also a Facebook page supporting the book here if you wish to keep up with the latest news from Jim and Al. You can find our other review of this book by a biologist here.
Forget ‘live fast, die young’ – do the opposite instead
So far, the only intervention that is known to consistently increase lifespan across multiple species is caloric restriction (CR). Caloric restriction is known to increase lifespan in the majority of mouse strains tested [1] and many other species. The effects of CR have even been shown to influence how primates age and reduce the incidence of diabetes, cancer, cardiovascular disease, and brain atrophy [2]. Whilst there are other compounds that do increase lifespan in animals none is as consistent as CR.
Science has known about the effects of CR since the 1930s, when rat experiments first showed researchers this phenomenon [3]. However, despite the various health benefits of CR, how it delays aging has remained a mystery. A new study suggests that epigenetic drift may be the answer.
Epigenetic alterations drive aging
You might have wondered why your various organs and tissues are so different from each other, since every single cell in your body shares the same DNA with exactly the same genetic information stored in it.
The reason is that they are modified by epigenetic information that changes how they appear and function by turning different gene expression on or off, depending on the tissue type. This epigenetic information comes in the form of DNA methylation (DNAm) patterns, and this is how gene expression is turned on or off.
So if for example, a cell needs to become a lung cell, the epigenetic information ensures that the correct genes for being a lung cell are expressed while turning off the genes relating to other types of cells.
As we age, the genomic landscape of DNA methylation (DNAm) gets altered, a process sometimes called ‘epigenetic drift’. The Hallmarks of Aging proposes that these epigenetic alterations are one of the primary reasons we age and, indeed, recent experiments appear to support this [4-6].
Changes to DNAm patterns during the aging process can cause dysfunction; for example, in the immune system, it could shift the balance from activating to suppressing immune cells, leaving us vulnerable to pathogens. It could also cause cell types to change their function and type as the methylation patterns shift.
So what can we do about epigenetic drift?
We already know that age-related epigenetic changes can be reset during the creation of induced pluripotent stem cells (iPSC) using cellular reprogramming factors. When we create new iPSCs from adult cells, it resets the DNAm patterns, reverting them to those of functionally young cells, and these new cells behave as young cells do. But the big question was, could the same approach be applied to living animals?
Late last year, researchers at the Salk Institute were successful in resetting age-related epigenetic changes in living animals, effectively resetting the DNAm changes that aging made and increasing their healthy lifespan.
Such solutions are potentially the answer to the problem of epigenetic drift, and researchers are working to translate this to humans, now that they know cells can be reset in living animals and not just in a dish. Of course, it will be some time before such therapies are developed and available, so what can we do in the meantime?
A new study suggests that CR as an intervention can potentially reduce the rate of epigenetic drift and that this is the basis for the health benefits that have been observed for decades when testing CR in other species [7].
The researchers studied CR data and DNAm status using genome-wide DNA profiling for mice, rhesus monkeys, and human blood cells. They found a strong correlation between lifespan and the rate of epigenetic drift in all species. Finally, they showed that CR protects against DNAm changes, thus slowing down the rate of epigenetic drift.
Conclusion
While some readers may not be overly thrilled about the idea of caloric restriction, it does appear to be one of the few accessible and cost-effective measures we can take now in order to slow down the rate of epigenetic drift.
Our understanding of aging is advancing at a rapid pace, but there are no guarantees when the first repair based technologies will arrive. Some therapies, such as senolytics, are entering human clinical trials now and could also impact the rate of DNAm changes, as inflammation is known to influence the rate of epigenetic drift [8].
However, right now there is nothing available, bar the basic things to help keep us alive and healthy long enough to benefit from the more advanced medicines and technologies currently in development. Along with exercise, CR is worth considering as part of your personal health and longevity strategy while you wait for true rejuvenation technologies to become available.
Literature
[1] Swindell, W. R. (2012). Dietary restriction in rats and mice: a meta-analysis and review of the evidence for genotype-dependent effects on lifespan. Ageing research reviews, 11(2), 254-270.
[2] Colman, R. J., Anderson, R. M., Johnson, S. C., Kastman, E. K., Kosmatka, K. J., Beasley, T. M., … & Weindruch, R. (2009). Caloric restriction delays disease onset and mortality in rhesus monkeys. Science, 325(5937), 201-204.
[3] McCay, C. M., Crowell, M. F., & Maynard, L. A. (1935). The effect of retarded growth upon the length of life span and upon the ultimate body size one figure. The journal of Nutrition, 10(1), 63-79.
[4] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.
[5] Marión, R. M., de Silanes, I. L., Mosteiro, L., Gamache, B., Abad, M., Guerra, C., … & Blasco, M. A. (2017). Common telomere changes during in vivo reprogramming and early stages of tumorigenesis. Stem cell reports, 8(2), 460-475.
[6] Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., … & Araoka, T. (2016). In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. Cell, 167(7), 1719-1733.
[7] Maegawa, S., Lu, Y., Tahara, T., Lee, J. T., Madzo, J., Liang, S., … & Issa, J. P. J. (2017). Caloric restriction delays age-related methylation drift. Nature Communications, 8.
[8] Issa, J. P. J., Ahuja, N., Toyota, M., Bronner, M. P., & Brentnall, T. A. (2001). Accelerated age-related CpG island methylation in ulcerative colitis. Cancer research, 61(9), 3573-3577.
Open Consultation of the WHO on Research Priorities for Healthy Aging
Very recently, the World Health Organization, which is essentially the United Nations’ agency for coordinating international health-related efforts, has launched The Global Online Consultation on Research Priority Setting for Healthy Aging. A corresponding survey is available on the WHO website and can be filled until September 30. As WHO is the main source of policy recommendations for the UN member states, its position can significantly influence the allocation of state funding to different areas of scientific research.
This is why we at LEAF urge you to step in and fill out the WHO survey; our community needs to demand more focused efforts to understand the basic mechanisms of aging, to develop innovative therapies to address these mechanisms, and to remove the barriers delaying the implementation of rejuvenation technologies into clinical practice.
Why is this important
While UN and WHO strategic documents, such as the world report on ageing and health (2015), the global strategy and action plan on ageing and health (2016) and the new set of Sustainable Development Goals include some provisions to encourage scientific research and development of new medicines, studies on biological aging and development of rejuvenation biotechnologies have never been made one of the main priorities.
Furthermore, the application of medical technologies able to slow down, postpone and reverse the main mechanisms of aging has not been considered a viable approach to cope with the growing morbidity of age-related diseases provoked by rapid population aging. Instead, the main measures suggested to prepare our society to these demographic changes are to stimulate the birthrate while adapting healthcare systems and transforming living environments to become more age-friendly.
This situation is mostly a result of slow dissemination of information from academia to the general public and different decision makers. Even though studies on aging have a long history, there have been very recent breakthroughs, such as senolytics, Yamanaka factors, and gene therapies to extend telomeres.
Due to remarkable progress in taming several hallmarks of aging, we might see the first powerful rejuvenation therapies enter the market in the next 5 years. The more prepared our society will be to support their development and implementation, the better. The most efficient way to accomplish this is to make an opinion leader like WHO accumulate the corresponding data faster and to form an official position that will be delivered right to the heads of the ministries of health and science around the globe.
Step in to help set longevity-friendly research priorities!
We encourage every member of our community to fill out the form – you don’t need a background in science for your response to be taken seriously. This is an open consultation, a disseminated “think tank” to provide the working group at WHO with a spectrum of ideas. If our opinion is represented in a significant share of surveys, we shall see it appear in the resulting WHO recommendations. The input of our community here could be vital, shifting the focus of research towards fundamental and translational gerontology and true control of the aging process for decades to come.
LEAF volunteers have prepared a series of answers to inspire your own response to the different questions presented in the form. You can find these below, in the section entitled “Examples for response”. We need to send no fewer than 200 forms to be heard. However, there are only 20 people on the LEAF team. Please give us a hand and fill out this survey before September 30!
Examples for response
Priority Area 1: Developing age-friendly environments (This focuses on creating environments that are age-friendly and fostering functional ability, including enabling older people’s participation and autonomy.)
Recommended answers in the field Q5 and Q6 (choose one for each field):
What is the best way to make anti-aging therapies and preventive programs accessible to everybody in all areas, with the goal being that people advancing in age could live independently in all environments and settlement types to the maximum degree possible?
What is a feasible age-friendly environment that includes easily accessible qualified medical care services and healthy lifestyle-oriented facilities (gyms, beaches, public swimming pools) to facilitate the use of therapies that prevent or treat the diseases of aging?What is the cost-effectiveness of building an age-friendly environment compared to developing and implementing into clinical practice the drugs and therapies to slow down, stop and reverse the main mechanisms of aging (hallmarks of aging)?
How does building an age-friendly environment affect the economic growth in a given country?
What is the most effective way to encourage city and regional authorities to facilitate the development of aging-related clinical trials and medical cohort studies and promote the accessibility of corresponding health-maintaining therapies?
Priority Area 2: Aligning health systems to the needs of older populations (This focuses on transforming health systems to ensure affordable access to integrated services that are centred on the needs and rights of older people)
Recommended answers in the field Q7 and Q8 (choose one for each field):
What is a good framework for clinical practice guidelines that to prevent and treat not only aging-related diseases but aging as a pathological process per se (i.e. clinical practice guidelines for systemic primary prevention in middle and old ages)?
What kind of drugs and therapies to slow down, stop and reverse age-related damage accumulation have a sufficient level of evidence to be immediately and globally implemented into clinical practice, and which drugs and therapies are expected to enter the market during the Decade of Healthy Aging?
How can WHO enable medical practitioners to prescribe anti-aging, evidence-based lifestyle interventions, medicines and other therapies, with the goal of ultimately enabling every person to have access to such therapies?
What are the main reasons why the existing approaches to slow down, stop and reverse age-related damage accumulation are not yet implemented into clinical practice, and how could the member states remove these barriers for faster adoption of these innovative medical technologies?
What is an effective way to facilitate the introduction and development of national electronic medical record systems and AI-based medical information systems to give researchers and clinical practitioners access to anonymized medical record databases, thereby ensuring better medical advice in terms of effective preventive measures?
What is the most feasible way to encourage hospital and healthcare providers to initiate clinical trials on damage-repair, aging-preventive therapies that follow the Hallmarks of Aging model? What should WHO do to encourage governmental health organizations to initiate, lead and finance such trials involving medical universities and research institutions?
What warnings should WHO give to life insurance companies, who may be interested in diversifying their investments into aging-related clinical developments as a way to balance financial risks they already might face due to increasing life expectancy?
Priority Area 3: Developing sustainable and equitable systems for long-term care (This focuses on the systems of long-term care that are required if older people with significant losses of capacity are to live lives of meaning and dignity – this can take place within their homes, communities, or institutions)
Recommended answers in the field Q9 and Q10 (choose one for each field):
What is the cost-effectiveness of developing long-term care institutions compared to developing and applying evidence-based interventions to slow down, stop and reverse the main processes of aging (hallmarks of aging) and age-related damage accumulation to a significant share of population?
What steps must be taken to ensure that elderly people in community care or retirement homes have, in addition to necessary care, access to evidence-based and experimental therapies and lifestyle interventions that can reverse some age-related damage and alleviate their health impairment? How could WHO encourage, through information and clinical practice guidelines, medical personnel and social workers in these facilities to offer such therapies?What is the best way to ensure that care recipients, caregivers and care providers are properly informed about the potential and advancement of R&D related to aging and longevity, thereby becoming able to make informed health decisions? How can care providers and people in community care and retirement homes get involved in ethical clinical trials on anti-aging interventions that have a high benefit/risk ratio?
Priority Area 4: Improving measurement, monitoring and research for Healthy Ageing (This focuses on strengthening capacities, evidence, frameworks and mechanisms to monitor progress and fill in evidence gaps on what can be done to support Healthy Ageing worldwide, in diverse contexts and populations)
Recommended answers in the field Q11 and Q12 (choose one for each field):
How can the concept of biological aging be shifted from an unavoidable damage accumulation to a process that can be manipulated to the point of a significant delay, deceleration and partial reversal? What steps should the academic community undertake to encourage this shift in the perception of the general public in accordance with the existing evidence?
What can be the benefits and downsides of classifying aging as a disease in the ICD-11, and how will this affect R&D related to aging and healthy longevity?
What is the most feasible way to support large cohort and other studies of the biomarkers of aging, which are needed to monitor and develop adequate health solutions, including interventions to stop, prevent or reverse age-related diseases? What research must be done to develop a consensus on the biomarkers of aging? How should genetic trait analysis be integrated into these biomarker systems to significantly contribute to health improvement and ensure more effective development of gene therapies and other medical solutions in the near future?
Priority Area 5: Commitment to action on Healthy Ageing in every country (This focuses on creating national policies and frameworks for action, enabling countries and governments to access and use existing evidence, and making concrete efforts to tackle ageism as an essential step in fostering Healthy Ageing)
Recommended answers in the field Q13 and Q14 (choose one for each field):
What should be done to improve national and international coordination on biomedical research on aging and development of drugs and therapies to address the root causes of aging and to prevent, postpone and reverse age-related diseases? What should be the local and the global priorities for both fundamental and translational research on aging?
What are the main bottlenecks decelerating the development of evidence-based anti-aging interventions (drugs and therapies addressing the hallmarks of aging)? What measures can the governments undertake to identify these barriers and remove them?
How can informing the population about the advancements of gerontology (namely, the pipeline of evidence-based anti-aging interventions) affect decision making and policy making about research priorities?
Additional Priority Areas?
Q15. Are there other priority areas or themes, for research that should be added, beyond the 5 listed? Please indicate up to 3.
Priority Area 1: Developing age-friendly environments
Priority Area 2: Aligning health systems to the needs of older populations
Priority Area 3: Developing sustainable and equitable systems for long-term care
Priority Area 4: Improving measurement, monitoring and research for Healthy Ageing
Priority Area 5: Commitment to action on Healthy Ageing in every country
Recommended answers in the field Q15 (three additional priority areas):
Inclusion of aging as a disease into the ICD-11.
The World Health Organization should promote research necessary to include aging into the International Classification of Diseases (ICD). Advanced aging, specifically “Senility”, already has an ICD-10 code of R54 (World Health Organization, 1992). However, this code refers only to the late stages of the pathogenesis of aging. This definition lacks enough detail to facilitate the development of new life-saving technologies to address aging. The beta version of the ICD-11 includes MJ43, “Old age”, instead of the ICD-10 code. This code is even less functional, as clearly, a person’s calendar age is an objective parameter and cannot be treated as a health condition.
Therefore, there should be a new parent category of “Aging and aging-related pathological changes and processes”, which would include both new and old categories, as this is allowed by the new “multiple parenting” principle introduced in ICD-11.
Promote fundamental research into the root causes of aging and translational research to develop damage repair therapies that permanently and systematically address the root causes of aging. Accelerate clinical trials of promising anti-aging interventions, such as senolytics, stem cell therapies, gene therapies, Yamanaka factors activators, anti-amyloid therapies, and cross-link breakers.
Assess the cost effectiveness of geroprotective interventions (addressing the root causes of aging and preventing age-related diseases) as compared to the existing means to treat age-related diseases. Assess the long-term impact of geroprotective interventions on demographic trends (population aging, life expectancy, healthy life expectancy) along with social and economic development.
SECTION 2 This section proposes criteria for prioritising research questions in each of the priority areas addressed in Section 1, and asks if other criteria are needed.
Q16. How important is each criterion in assessing global priority research questions and their fit towards Healthy Ageing?
Recommended shares:
0% Answerability (will get an answer)0% Feasibility (can be done in many countries)
0% Applicability (results will matter)
100% Impact on intrinsic capacity and/or functional ability (Healthy Aging will improve)
0% Improving Equity (reducing unfair differences)
Q17. Is there another criterion that should be used to assess global priority research question and their fit towards Healthy Ageing? Please indicate.
Recommended answer in the field Q17
Healthspan extension
Maximum lifespan extension
Life expectancy changes
Q18. In your opinion which research designs to advance Healthy Ageing would draw the attention of funders the most? (select up to 3).
Recommended answers in the field Q18
longitudinal research (research that documents information on the same people repeatedly over a long period of time, to study events throughout lifetimes and to better understand cause and effect)
cluster or randomized trials (clinical or community based research design that minimizes bias and includes comparison groups to better determine any effects of the treatment or intervention)
basic science research (research on the physical and the natural world – such as biology, physics, chemistry, earth sciences, etc. — that advance fundamental knowledge about Healthy Ageing)
Thank you very much for finding time to fill out this survey!
Providing policymakers like WHO with our vision is very important. This way, we help disseminate information about rejuvenation biotechnologies in our society while we encourage more people to support the researchers and to start using the interventions that are already available.
We would like to thank the International Longevity Alliance for bringing this matter to our attention through its own article on this topic – if you would like to see more versions of answers for inspiration, you are welcome to look at its site.
Investing in the Age of Longevity
Today, we are pleased to announce the imminent arrival of Jim Mellon and Al Chalabi’s new book Juvenescence, which covers the field of rejuvenation biotechnology. The book focuses on technologies that will soon arrive, therapies that may increase healthy lifespan, and guidance for investors.
The book offers a comprehensive overview of aging research and how to invest in and profit from rejuvenation biotechnology, a field that is poised to become the next mega-industry.
This book could be very important in promoting rejuvenation biotechnology
This is a very important book, and it has the potential to engage new audiences and increase interest in our fascinating field. Many people are not aware what is happening in the labs right now and how close we are to some truly stunning, game-changing medical advances. This could help to enlighten and enthuse a wider audience and bring in important development capital to help drive progress and scientific advancement.
We were also very pleased to hear that proceeds from the book will go towards supporting charities working in the rejuvenation biotechnology field. This is a really nice gesture and yet another reason to buy the book.
The book will be available on September 25th in the US at Amazon and at www.harriman-house.com and in the UK on Amazon and on their website. There is also a Facebook page supporting the book if you wish to keep up with the latest news from Jim and Al.
We will completely review and discuss this superb book nearer to the September 25th release. Meanwhile, here is a great summary of the book from the authors.
Investing in the age of longevity
“The science of aging is catching up with the aspiration of ultra-long lives”
Is there anyone who doesn’t want to live longer than the apparently allotted time of around 80 years? Is there anyone who wouldn’t want to live in a “wellderly state” right up till when they die? Not many of us wouldn’t want ultra-long and healthy lives. Well, very soon scientific advances will allow just that. Juvenescence is not just a book or a phenomenon, it’s about to be a fact.
Jim and Al, authors of Fast Forward, Cracking the Code and of Wake Up, alert readers of their new book to the amazing science of Juvenescence, to the prospects for all of us to live much longer than most people expect, and to the ways in which we can prosper as investors in this new era of longevity.
They forecast that average life expectancy in the developed world will rise to 110-120 within twenty years and thereafter, much higher. The old life paradigm of born, learn, earn, retire and expire is about to be radically changed. The entirety of our lives will be upended; we will learn continuously, we will start families later, we will enjoy multiple careers and we will have more time for leisure and self-development.
As technology and biology fuse into ever greater capabilities, the conventional wisdom of life’s trajectory will be totally ditched. Retirement will be so last century – people will work till at least 85, and they will be needed and valued.
The diseases of aging that debilitate so many people after the age of 65 or so will be gradually conquered and rendered rare or chronic. Ageing will soon be regarded as a disease in itself, and therapies designed to “cure” it, some available now, will be commonplace. New techniques, including organ transplantation as a matter of routine, cell therapies and genetic engineering will become mainstream.
Deep learning strategies to develop personalized drugs and to accelerate the development of therapies will sit alongside genetic screening and transform medicine.
Jim and Al describe in detail the processes involved in getting older. Ageing is marked by the progressive loss of physical integrity, lessened functionality and increased vulnerability to disease and to frailty. Ageing is the single biggest risk factor in contracting one or more of the deadly quintet of diseases which are responsible for more than 60% of all deaths in developed countries – cancer, diabetes, cardiovascular, neurodegenerative and pulmonary disease. At present, there is no central unified theory as to what causes aging at the molecular and cellular level, but with fast advancing tools and analysis, a definitive picture will surely emerge.
This is a time of true transformation and we are lucky to be living through it.
Prophets in the wilderness, such as was Aubrey de Grey until recently, are increasingly being recognized as visionaries and the transcribers of the scientific advance that will be known as Juvenescence.
Jim and Al have conducted dozens of interviews, many face to face, have traveled extensively in the US and in Europe and have distilled a complex science into layman’s language.
Their book is necessarily quite science heavy, as it has to convey differing opinions and strands of research. it is also a primer on the investment opportunities for all those who would like to prosper from Juvenescence. And it seeks to show readers how they can keep themselves in the best possible shape using existing science in order to bridge the gap between today’s knowledge and tomorrow’s opportunities.
Long life beckons for all, and for the readers of this book, a long life lived in prosperity is more than just a possibility.
If we are all indeed going to live much longer lives, how are we going to be able to afford it? As Juvenescence is a book for investors, Jim and Al have identified the most exciting investment opportunities and companies that will hopefully provide readers ultra-long-lived portfolios alongside their ultra-long lives!
The biotech recommendations in Cracking the Code, for instance, have served investors very well, and the authors believe that the stocks identified in Juvenescence could do even better.
So, in summary, the book does three things: firstly, describes the current or soon to be marketed treatments that will enable everyone to live much longer than actuarial table currently suggest. Secondly, it outlines the technologies that have the potential for extending life, such as genetic engineering and stem cell therapy. And lastly, Jim and Al have carefully curated three portfolios for interested investors to consider.
This book provides a comprehensive, curated and peer-reviewed compendium of everything readers need to know about aging and how to profit from the rapid evolution in the science of biogerontology.
Live long and prosper!
Reviewing Stem Cell Therapies for Osteoporosis
Osteoporosis is a crippling condition provoked by an imbalance between the creation of new bone tissue and the destruction of the old, which becomes worse as we age.
What causes osteoporosis to develop and progress?
Osteoporosis is the failure of tissue maintenance in the bones, causing them to become weak and fragile. This increases the risk of falls and drives age-related frailty. The National Osteoporosis Foundation estimates that low bone mass due to osteoporosis is a threat to public health for nearly 44 million men and women aged 50 and older in the United States. During the progression of osteoporosis, the balance between the destruction of old bone tissue and the creation of new bone tissue gets disrupted. The bone structure is maintained by osteoclasts, the cells that break down bone tissue, and osteoblasts, which create new bone tissue. Bone tissue is in a state of balance between removal and renewal, but as we age, this balance shifts in favor of osteoclasts and the removal of bone tissue. So, why does this happen? Senescent cells are known for causing inflammation via a cocktail of proinflammatory signals known as SASP, so they are thought to be one of the causes of osteoporosis.A new stem cell review
We have talked about how recent progress has been made in treating this disease by removing senescent cells in mice. In this new review, the authors take a look at delivering stem cells to the bone tissue to try to address the imbalance[1].
The idea of increasing the numbers of bone-building stem cells and replacing those lost with age is a plausible approach.
However, this approach is far from complete, as it only addresses one aspect of osteoporosis that causes bones to weaken. Replacing lost stem cells alone is unlikely to solve the problem, as the underlying causes, such as senescent cell accumulation and resulting inflammation, are not being addressed.
Conclusion
As the authors here mention, there are many current stem cell trials, in which researchers are investigating other diseases, that may influence the progression of osteoporosis. This gives us the chance to learn a great deal about stem cell therapies for osteoporosis with some additional effort. It is plausible that the combination of senescent cell removal therapies and stem cell therapy could be a potent force in treating osteoporosis.
Literature
[1] Kiernan, J., Davies, J. E., & Stanford, W. L. (2017). Concise Review: Musculoskeletal Stem Cells to Treat Age‐Related Osteoporosis. Stem cells translational medicine.