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- A Few Recent Conference Reports from the Aging Research Community
- A Selection of Opposing Views on Cryonics
- The Merits of Attacking Cytomegalovirus
- When Someone Has to Spend Millions on Small Molecule Screening to Get Things Moving
- Examining Mitochondrial Dysfunction in Old T Cells
- The Challenges of Xenotransplantation
- Effective Treatment of Alzheimer's Disease Requires Targeting the Mechanisms of Aging
- Evidence for Pyrophosphate to be the Primary Inhibitor of Vascular Calcification
- Telomerase Activity and Telomere Length Show a Greater Increase After Endurance Training versus Resistance Training
- Can Peripheral Nervous System Regenerative Mechanisms be Introduced into the Central Nervous System?
- Linking Impaired Autophagy to Changes in Polarization of Microglia in Aging
- Searching for Longevity-Related Genes in the Genomes of Parrots
- Macrophages Could Improve Heart Regeneration, but Arrive Too Late Following Injury
- Thoughts on Near Term Rejuvenation Therapies
- More Evidence for TIGIT to Mark a Population of Harmful Immune Cells in Older People
A Few Recent Conference Reports from the Aging Research Community
There are more than enough conferences focused on aging and the treatment of aging these days to collectively be called a conference circuit, I think. A researcher in the field of aging could find two or more scientific events every month to attend, and the business side of conference hosting is catching up. I had to give up noting every event of interest a number of years ago for the sake of space, and I know of at least one individual who provides a service to the community by maintaining what is becoming quite a lengthy calendar of conferences.
That there are more conferences rather than fewer conferences is a sign of health for the field. When people hold conferences, they do so because there is a sizable scientific or professional organization with the funds to spare, or because a for-profit conference host sees an opportunity to make a profit by providing a conference series as a service to the community. As a rough metric of growth, it is helpful. A field with twenty conferences in a year is better funded and moving more rapidly than one with two.
Today I'll point out a small selection of reports that cover conferences held earlier this year. While looking through these, consider that next year will start off much the same way. There is a good selection of longevity-related conferences and meetings early next year: Longevity Therapeutics, a number of other investor-focused events running alongside the big JP Morgan healthcare conference in San Francisco, the Longevity Leaders event in London, and of course Undoing Aging 2019 in Berlin at the end of the first quarter.
A Summary of the 5th Annual Aging and Drug Discovery Forum 2018
"Why do we age?"; "Can we intervene in the aging process?"; and if so, what approaches should aging science take to transform research into viable therapeutic interventions to improve public health? Understanding the mechanisms of aging will be of vital importance to answering these questions. However, several obstacles stand in the way of generating efficacious and safe interventions that extend the period of healthy life. At the 5th Annual Aging and Drug Discovery Forum which was held during the Basel Life Congress, Basel, Switzerland, September 12-13, 2018, leading aging experts from academia and industry came together to discuss top issues in aging research. Here, we provide a brief overview of the presented results and discussion points.
A Report from the 2018 International Society on Aging and Disease Conference
The International Society on Aging and Disease (ISOAD) recently held its third international conference in Nice, France, bringing together researchers - and longevity activists - from around the world. Prof. Gilson founded the Ircan Institute for Research on Cancer and Aging in Nice in 2012. "It was perhaps the first institute that specifically aimed to couple the themes of aging and cancer in the same laboratory, even if the links between them had been known to some extent. That was its originality. We've laid the foundations - to have the expertise, the right people, the right models - and I think we're going to have important answers for the role of telomeres in aging and, more generally, cellular senescence, which is the favorite current target of a lot of pharmaceutical or fundamental research that we are revisiting via our original models."
Thoughts on the 2018 Eurosymposium on Healthy Ageing
When I first learned about the possibility of achieving human rejuvenation through biotechnological means, little did I know that this would lead me to meet many of the central figures in the field during a conference some seven years later - let alone that I would be speaking at the very same event. Yet, I've had the privilege to attend the Fourth Eurosymposium on Healthy Ageing (EHA) held in Brussels on November 8-10, an experience that gave me a feel of just how real the prospect of human rejuvenation is. The first day of the conference was basically a journey into the world of cellular senescence: methods of targeting senescent cells, the SASP, drug delivery systems, and so forth; however, other topics, such as the extracellular matrix, transcriptomics, and stem cells, were also discussed. A great deal more researchers and other people otherwise involved in the community were present on the first morning than there were at the pre-conference meeting; the peak was probably during the second day, which saw a wider variety of topics, including genomics, DNA repair, bioinformatics, and the first panel of the conference.
A Selection of Opposing Views on Cryonics
Cryopreservation via a cryonics provider, such as Alcor or the Cryonics Institute in the US, is presently the only option available to the billions who will age to death prior to the advent of a comprehensive package of rejuvenation therapies. Sadly, it is not yet a well-developed industry, operating at scale. The technology exists to vitrify people immediately following clinical death, preserving the fine structure of brain tissue if the vitrification process is of sufficiently high quality, but very few people choose to take advantage of this opportunity. Every year, tens of millions go to oblivion rather than chose the better option. Given preservation, there is the chance of restoration to life in a more technologically advanced future. The odds of success are unknown, but any chance is better than the certain oblivion of any other end of life choice. The cost of cryopreservation is small, provided that preparations are made decades in advance, as it can be funded via life insurance.
The popular science article noted here presents an array of comments from people for and against cryonics as an endeavor, and captures most of the important divisions. There is the disagreement over whether sufficiently well performed vitrification can preserve the structures that encode the mind, which seems to me to be the case, given the evidence from experiments in nematodes. There is the debate over whether present practices actually constitute sufficiently well performed vitrification. Then there are those who think it is better to go to oblivion than to be restored in a new era, which I can't say I agree with at all. Finally there are those who will never be convinced by any amount of indirect evidence, such as the nematodes or reversible vitrification of whole organs for use in the transplant industry, and will be skeptics until the day that someone is restored to life.
As is the usual case in the popular press, the article title and commentary willfully substitutes "frozen" for "vitrified". These are two very different things. Only the earliest of the preserved individuals were frozen, and we can be rightfully skeptical that there is anything left to restore there. Freezing produces ice crystals that shred cell structures, such as the synapses where it is thought that memory is encoded. Vitrification, on the other hand, involves the use of cryoprotectants that minimize ice crystal formation, turning tissue into a glass-like state. Reversing this process will require advanced nanotechnologies, of a sort that can be envisaged today but will only arise many decades in the future at our current pace of development. For so long as the structure is preserved, then reversal remains a possibility, only waiting on the technical capability to do so.
Will Cryopreserved People Ever Be Revived?
Dr. Joao Pedro de Magalhaes, Biologist at the University of Liverpool and coordinator of the UK Cryonics and Cryopreservation Research Network
I'd say that with today's technology, cryonics severely damages the body's cells. Even under optimal conditions (i.e., the procedure starts right after death), there are several problems in cryonics. In particular, cryoprotectant agents have toxic effects on human tissues with prolonged exposure. Vitrifying large organs like the brain can also result in fractures due to different cooling rates in different parts. Under non-optimal conditions (i.e., if a significant time elapses between death and being cryopreserved) much more damage can occur because cells start to die, and brain cells in particular start to die within minutes after cardiac arrest, due to lack of nutrients and oxygen (called ischemia). Therefore, it will take huge scientific advances in areas like tissue engineering and regenerative medicine to make cryopreserved individuals alive and healthy again. As such, I would say that the chances of cryopreserved individuals ever be revived is low but not impossible. And then the argument is that the worse possible outcome of being cryopreserved is to remain dead, so cryonics gives you a chance of future revival that will not happen if you are buried or cremated.
Mark Kline, Co-Founder and CTO, X-Therma Inc., a company improving cold storage of stem cells, tissues, and whole organs
The hardest thing to solve is: how do you freeze things without damaging them? You mix in all these cryoprotectants - like antifreeze for your car, but geared towards biology - in an effort to prevent ice formation within the cells and tissues. But you need to drastically lower the temperature - down to about -196 degrees C, liquid nitrogen temperature. Preventing ice formation at that temperature, throughout a very large tissue, is very, very difficult. So there's the chemistry problem (preventing ice), the biology problem (tissue damage, connection damage), the physics problem (how do you evenly cool something as large as an organ? And how do you warm it up evenly afterwards, without damaging it?). I think there are much more imminent applications for cryopreservation, like organ preservation. Preserving organs has a high-value impact for the medical system, and also is much more feasible than preserving a whole body. You can save many, many lives with organ preservation.
Nick Bostrom, Professor at the University of Oxford and Director at the Future of Humanity Institute and the Governance of AI program
Technically it seems like it should probably work. The freezing (rather: vitrification or plastination) and storing we can do now. The bringing back part may however require the assistance of machine superintelligence in order to repair the extensive cellular damage that occurs during the suspension process.
Dennis Kowalski, President, Cryonics Institute
The scientifically correct answer is that we do not know, since no one knows the future and what will be possible. However, that is why some people have signed up to preserve their bodies at liquid nitrogen temperatures in hopes that future technology and medicine will be able to answer that very question. New technologies moving forward might mean advanced, AI-guided stem cell therapies that regenerate tissues that have been damaged by aging, freezing, or death itself. Technologically we are advancing at an exponential pace, and this means that things considered impossible even a few decades ago will become reality.
Cathal O'Connell, Researcher in 3D bioprinting and biofabrication at BioFab3D, St Vincent's Hospital, Melbourne
All signs point to no. The freezing-down process is critical. Doing this in a way that preserves cell function - especially regarding connectivity in the human brain - is way beyond our current capabilities. Unfortunately, everyone who has ever been frozen so far is essentially turned to mush. These people will never be revived. Cryonics in its current form is more of a religion than a science. Rather than a divine entity, its followers place their faith in technological progress. The ability of some organisms to survive freezing is a sign from nature that what cryonics promises might one day be possible. But getting there will require a massive investment - billions in funding, thousands of scientists, decades of research. Without a clear economic incentive, that investment is not forthcoming. As my old professor says, a vision without funding is hallucination.
Ralph Merkle, Director of Alcor Life Extension Foundation, the world's leading cryonics organization
The short version is: many of the patients at Alcor will likely be revived sometime this century. Had you asked a random person in 1940 if flight to the moon was possible, you'd likely have been told "no." If asked why, a typical answer was "because there's no air to push against in space." This scientific-sounding but totally false objection was infamous among knowledgeable scientists, and was the basis for the New York Times' 1920 editorial denouncing Robert Goddard. Yet those knowledgeable about space flight had been forecasting flight to the moon for decades before the event. Similarly, those knowledgeable about nanomedicine have also been forecasting the revival of cryopreserved patients for decades, and those forecasts are likewise based on a sound assessment of physical law. Until the structures in the brain that encode our memories and personality have been so obliterated that they cannot in principle be inferred and restored to a functional state, you are not dead. This information theoretic criterion of death is obviously much more difficult to meet than current legal or medical definitions, hence the belief that cryopreserved patients are not actually dead.
Michael Hendricks, Canada Research Chair in Neurobiology and Behaviour and Assistant Professor of Biology at McGill University and wrote "The False Science of Cryogenics" for the MIT Technology Review
If you mean people who have already had their brains, heads, or bodies cryogenically stored after death (or are doing so with current technology): no, they will never be revived. They are dead, and will remain dead forever. Will it ever be possible to store a dead person (or a dead person's brain) in such a way that they can be revived? Almost certainly not. Look at the world. The only good thing we still reliably do for future generations is get out of their way. Let's not take that away from them too... they will have their hands full with all the horrific problems we've left them because of our selfishness and greed. We shouldn't making them responsible for keeping our bodies cold, too.
The Merits of Attacking Cytomegalovirus
Today's research results, published a few months ago, are one of a number of examples from recent years of a possible way to suppress or destroy persistent herpesviruses such as cytomegalovirus (CMV). These viruses cannot be effectively cleared from the body by the immune system; they remain latent to reemerge time and again. CMV itself is of particular interest because it is strongly implicated in the age-related dysfunction of the immune system. Research suggests that in old age an unsustainable fraction of immune cells become devoted to CMV, and since the decline of the thymus and hematopoietic stem cells ensure that the supply of replacement immune cells is reduced to a trickle, too few capable immune cells remain to adequately address other threats.
A range of studies provide evidence for people with greater exposure to CMV have a worse prognosis in later life, but it is far from clear as to whether (a) this is a burden that accumulates over time, and length of exposure is important, as studies of childhood adversity suggest, or (b) the burden arrives near entirely in later life, despite life-long infection with CMV, and requires some initial decline in immune function to start the process in earnest. The interesting question is whether it is worth trying to clear CMV from the body, given that it is largely harmless to young people, or whether the real target is the damage done to the immune system.
That damage, in the form of too many specialized immune cells and too low a rate of generation of new immune cells, will remain in effect even if CMV can be banished from the body of an older individual. The deficits of the aged immune system will have to be addressed via other approaches, such as targeted removal of CMV-specialized cells and regeneration of thymus and hematopoietic stem cells to restore a more youthful supply of new immune cells. Achieving those goals may well make CMV irrelevant. That said, it is worth considering getting rid of CMV might be more or less effective as a way to improve health in later life depending on when and how rapidly the consequent immune damage emerges.
Scientists Find a New Way to Attack Herpesviruses
Human cytomegalovirus is a leading cause of birth defects and transplant failures. As it's evolved over time, this virus from the herpes family has found a way to bypass the body's defense mechanisms that usually guards against viral infections. Until now, scientists couldn't understand how it manages to do so. Normally, when a virus enters your cell, that cell blocks the virus's DNA and prevents it from performing any actions. The virus must overcome this barrier to effectively multiply. To get around this obstacle, cytomegalovirus doesn't simply inject its own DNA into a human cell. Instead, it carries its viral DNA into the cell along with proteins called PP71. After entering the cell, it releases these PP71 proteins, which enables the viral DNA to replicate and the infection to spread.
"The way the virus operates is pretty cool, but it also presents a problem we couldn't solve. The PP71 proteins are needed for the virus to replicate. But they actually die after a few hours, while it takes days to create new virus. So how can the virus successfully multiply even after these proteins are gone?" The researchers found that, while PP71 is still present in the cell, it activates another protein known as IE1. This happens within the first few hours of the virus entering the cell, allowing the IE1 protein to take over after PP71 dies and continue creating new virus. To confirm their findings, the team created a synthetic version of the virus that allowed them to adjust the levels of the IE1 proteins using small molecules.
"We noticed that when the IE1 protein degrades slowly, as it normally does, the virus can replicate very efficiently. But if the protein breaks down faster, the virus can't multiply as well. So, we confirmed that the virus needs the IE1 protein to successfully replicate." The new study could lead to a new therapeutic target to attack cytomegalovirus and other herpesviruses.
Feedback-mediated signal conversion promotes viral fitness
A fundamental signal-processing problem is how biological systems maintain phenotypic states (i.e., canalization) long after degradation of initial catalyst signals. For example, to efficiently replicate, herpesviruses (e.g., human cytomegalovirus, HCMV) rapidly counteract cell-mediated silencing using transactivators packaged in the tegument of the infecting virion particle. However, the activity of these tegument transactivators is inherently transient - they undergo immediate proteolysis but delayed synthesis - and how transient activation sustains lytic viral gene expression despite cell-mediated silencing is unclear.
Using an HCMV mutant, we find that positive feedback in HCMV's immediate-early 1 (IE1) protein is of sufficient strength to sustain HCMV lytic expression. Single-cell time-lapse imaging and mathematical modeling show that IE1 positive feedback converts transient transactivation signals from tegument pp71 proteins into sustained lytic expression, which is obligate for efficient viral replication, whereas attenuating feedback decreases fitness by promoting a reversible silenced state. Together, these results identify a regulatory mechanism enabling herpesviruses to sustain expression despite transient activation signals - akin to early electronic transistors - and expose a potential target for therapeutic intervention.
When Someone Has to Spend Millions on Small Molecule Screening to Get Things Moving
There are any number of reasons why promising lines of research get stuck. Simple abandonment is a surprisingly common one; people outside the scientific community have little appreciation of the degree to which the floor of the forest is littered with valuable raw materials, just waiting for someone to spend the effort to forge them into useful goods. Many researchers have little interest in implementation, or fail to convince funding sources to continue their initial exploration, or the people involved move on, or the tools are hard to use and no-one else wants to make the effort to replicate the discoveries. It is sometimes amazing that anything is accomplished, watching the way in which most academic labs organize themselves.
Another common problem is the lack of suitable tools to manipulate a mechanism of interest, related to disease or aging. Once researchers find a mechanism, and have the means to probe its operation, the next step is to build ways to influence it. Some of the most common traditional tools are genetically engineered animal lineages, in which genes of interest are inserted or removed in the germline, gene therapies that increase or decrease protein levels in cells and adult animals, and small molecules that can increase or decrease protein levels, or interfere in or enhance protein interactions. Of those, only small molecules have traditionally resulted in clear path to clinical application, though gene therapies are starting to become more practical for those purposes.
What happens when researchers have an interesting mechanism, but don't have a small molecule that can manipulate that interesting mechanism? Well, they are stuck when it comes to moving closer to the clinic, unless they can raise a fairly sizable amount of funding for screening, as well as produce a sufficiently cheap screening methodology to allow a very large number of compounds from the standard libraries to be tested. The cost of a comprehensive screening exercise to find candidate small molecule drugs can be a few million, which is why there are a sizable number of companies working on ways to reduce that cost and raise the odds of success. Expending these sizable resources offers no guarantee of finding a viable compound, or even a viable starting point. That is why many projects just stop right there, and remain halted until the slow grind of grant-writing and incremental discovery leads to a potential candidate compound in some other way.
In recent years, the new ability to cultivate arbitrary bacterial species from soil, rather than the tiny minority that has traditionally been the case, has unlocked the door for compound discovery relating to destruction of problem molecules. Every molecule in the human body can be consumed and broken down by at least one species of soil bacteria. Finding the tools that bacteria use for that purpose is low-cost and reliable in comparison to old-style screening from compound libraries: just grab a soil sample, separate the bacteria, drop in the protein that needs destruction, and see which of the bacteria thrive on that diet. A number of research groups have produced proof of principle results with modest budgets.
While that works just fine for targets such as the 7-ketocholesterol associated with atherosclerosis, as well as glucosepane cross-links, both of which are implicated in the aging process, and that we'd be far better off without, the approach doesn't work when the objective is to alter rather than destroy aspects of cellular metabolism. For example, it would be very useful to have drugs that interfere in the operation of alternative lengthening of telomeres (ALT), a mechanism that is only active in cancer cells. All cancers must lengthen their telomeres constantly in order to maintain rampant growth. If both ALT and telomerase-based telomere lengthening could be suppressed, then cancers would wither.
Work on finding ways to manipulate ALT is essentially stuck on the point that someone needs to spend a few million in order to buy a chance at finding a candidate small molecule drug. No-one really wants to take that wager, and would much rather wait on incremental progress in the field to turn up a possible path forward. Perhaps that will happen in a year, perhaps not for twenty years, no-one can tell. It seems to me that for those areas of research blocked in this way, and where success would be very valuable, then paying for the screening would be a sensible act of high net worth philanthropy. For that to take place, however, it would require either a good understanding of the field on the part of more wealthy individuals, or a good packaging of the ideas involved on the part of a non-profit entity.
Examining Mitochondrial Dysfunction in Old T Cells
In older mice and humans, the immune system becomes dysfunctional. It is overactive, producing chronic inflammation that leads to harmful cellular behavior throughout the body, but at the same time it is much less capable when it comes to destroying pathogens and errant cells. In today's open access research, scientists investigate the incapacity of naive T cells in older mice. This population of T cells is necessary for a strong immune response, but their numbers decline due to the involution of the thymus. T cells begin life as thymocytes in the bone marrow, and then migrate to the thymus where they mature into T cells of various types. With advancing age the thymus atrophies, and the active tissue needed for T cell maturation is replaced with fat. The supply of new T cells diminishes, and thus so does the fraction of the overall immune cell population that is made up of naive T cells capable of meeting new threats.
In the research here, it is found that those naive T cells that do remain in old mice are dysfunctional, far less capable than their young counterparts. The mitochondria, the power plants of the cell, are altered and diminished. Many important mechanisms are thus likely compromised, or operating at levels far beneath what is minimally required for adequate cellular function. This mitochondrial malaise is observed in all tissues, but possibly best studied in the context of muscle and brain, both energy-hungry tissues that are greatly affected by a reduced supply of chemical energy store molecules packaged by mitochondria. Clearly similar problems exist in all cells.
Fixing this age-related alteration in mitochondrial structure and function is an interesting challenge. The problem is only peripherally related to the mitochondrial DNA damage of the SENS rejuvenation research program, and appears to be a downstream consequence of some combination of other molecular damage and altered signaling inside and outside cells. There is no clear view of which forms of repair would be most effective, as there is no solid link established between any of the known forms of molecular damage that lie at the root of aging and this general mitochondrial decline. Thus efforts to override specific mitochondrial mechanisms are further ahead as of the moment; providing additional NAD+ to cells, for example, perks up mitochondrial activity. That can be enough to provide incremental benefits to tissue function, as recently demonstrated in a small human trial. There are no doubt other similar possibilities. These are all limited in their upside by the fact that they don't address the underlying causes; there is a great need for more research and development focused on repair of those underlying causes.
The 'Graying' of T Cells
Researchers looked for overall differences between old and young T cells. They isolated T cells from the spleens of young and old mice and noticed that, in general, older mice had fewer T cells. Next, to gauge the cells' immune fitness, the researchers activated the T cells by mimicking signals normally turned on by pathogens during infection. The older T cells showed diminished activation and overall function in response to these alarm signals. Specifically, they grew more slowly, secreted fewer immune-signaling molecules and died at a much faster rate than young T cells. The researchers also observed that aged T cells had lower metabolism, consumed less oxygen and broke down sugars less efficiently. They also had smaller than normal mitochondria, the cells' power-generators that keep them alive
To pinpoint the metabolic pathways behind this malfunction, the scientists analyzed all the different proteins in the cells, including those that might be important for coaxing a T cell from dormancy into a fighting state. The team found that the levels of some 150 proteins were lower-than-normal upon activation of the aged T cells, compared with young T cells. About 40 proteins showed higher than normal levels in aged versus young T cells. Many of these proteins have unknown functions, but the researchers found that proteins involved a specific type of metabolism, called one-carbon metabolism, were reduced by nearly 35 percent in aged T cells.
One-carbon metabolism comprises a set of chemical reactions that take place in the cell's mitochondria and the cell cytosol to produce amino acids and nucleotides, the building blocks of proteins and DNA. This process is critical for cellular replication because it supplies the biologic material for building new cells. The team's previous work had shown that one-carbon metabolism plays a central role in supplying essential biological building blocks for the growing army of T cells during infection. So, the scientists wondered, could adding the products of this pathway to weakened T cells restore their fitness and function?
To test this hypothesis, the team added two molecules - formate and glycine, the main products of one-carbon metabolism - whose levels were markedly reduced in aged T cells. Indeed, adding the molecules boosted T cell proliferation and reduced cell death to normal levels. The researchers caution that while encouraging, the effects were observed solely in mouse cells in lab dishes rather than in animals and must be confirmed in further experiments.
Defective respiration and one-carbon metabolism contribute to impaired naïve T cell activation in aged mice
T cell-mediated immune responses are compromised in aged individuals, leading to increased morbidity and reduced response to vaccination. While cellular metabolism tightly regulates T cell activation and function, metabolic reprogramming in aged T cells has not been thoroughly studied. Here, we report a systematic analysis of metabolism during young versus aged naïve T cell activation.
We observed a decrease in the number and activation of naïve T cells isolated from aged mice. While young T cells demonstrated robust mitochondrial biogenesis and respiration upon activation, aged T cells generated smaller mitochondria with lower respiratory capacity. Using quantitative proteomics, we defined the aged T cell proteome and discovered a specific deficit in the induction of enzymes of one-carbon metabolism. The activation of aged naïve T cells was enhanced by addition of products of one-carbon metabolism (formate and glycine). These studies define mechanisms of skewed metabolic remodeling in aged T cells and provide evidence that modulation of metabolism has the potential to promote immune function in aged individuals.
The Challenges of Xenotransplantation
Xenotransplantation from genetically engineered pigs to humans is one of the potential approaches that is hoped to provide an arbitrarily large supply of replacement organs. Whether or not this becomes a sizable industry depends on how long it takes for competing researchers to complete the alternative route of generating patient-matched new organs from cell samples. While the production of small functional organoids from patient samples is a going concern, the construction of entire organs continues to be held back by the inability to reliably generate the intricate blood vessel networks that are needed to supply large tissue sections. Not that xenotransplantation is without challenges, as this article illustrates. The problems are largely discovered by running into them, as researchers continue the process of testing transplants between pigs and baboons.
Even though humans can give their hearts to compatible persons with little more than a side of immunosuppressants, cross-species transplantation is not so straightforward. More than 60 percent of attempts to replace a baboon's heart with that of a pig ended in the recipients dying within two days. Two important developments pumped hope into the field over the past few years. First, researchers began using the gene-editing tool CRISPR-Cas9 to remove parts of the pig genome that might harm humans or provoke an immune response. Then in 2016 researchers took this further by showing baboons could survive with a genetically engineered pig heart implanted into their abdomens for nearly 1,000 days - if the baboon was on a certain cocktail of immunosuppressants.
For the new work researchers wanted to see if the same genetically engineered pig hearts and immunosuppressant regime could support the life of a baboon. But the first five animals in the new study did not live long. Three died of heart failure almost immediately. It turns out porcine hearts are more vulnerable compared to human hearts. During the period between removal from a pig and implantation into a baboon the heart will sustain damage similar to that caused by a heart attack. Human hearts can often recover from this damage, but the pig hearts could not.
So researchers tried something new with another group of baboons and repeatedly immersed the pig hearts in an experimental nutrient solution for a couple of hours. The researchers think this formulation, originally designed to help transport human hearts long distances, might have helped keep the pig hearts from deteriorating too much. These baboons hung on for about a month before dying - this time because the pig hearts began swelling inside the monkeys' chests, eventually squeezing against the rib cages and failing. "A pig grows to maturity within four months or so, but a baboon takes about 10 years to grow. So the pig heart was growing in the primate as if it was still in a pig. We were just astonished. Nobody had experienced this before - the heart grew like a tumor."
In the third group of baboons researchers added an immunosuppressant drug called temsirolimus, which could also stop the pig hearts' unwanted growth. With the exception of one baboon that died of mechanical heart failure 51 days after surgery, the transplant recipients in this group survived in good health until the researchers euthanized them at 90 or 180 days, an action required under the study protocol approved by officials. The study is invigorating xenotransplantation researchers who, after decades of sometimes dismal attempts, say human trials are finally in sight.
Effective Treatment of Alzheimer's Disease Requires Targeting the Mechanisms of Aging
These days, an ever larger fraction of the research community is waking to the idea that the effective treatment of age-related disease requires approaches that target the mechanisms of aging. This is a good thing, as it begins to narrow the scope of advocacy within the research community to the task of steering scientists towards better rather than worse ways of going about targeting the mechanisms of aging. It remains the case that most of the better supported lines of work related to aging are, in effect, very challenging ways to produce only small benefits at the end of the day - most researchers are working on methods of slightly slowing aging rather than methods of outright rejuvenation.
Attempts to develop calorie restriction mimetics or other therapies capable of upregulating stress responses and cellular maintenance processes are a good example of the type, and they are much on display in this open access paper (currently available in PDF format only), alongside other targets that, while not being root causes of aging, are thought of as being significant enough in the progression of disease to merit effort. While goals such as suppression of chronic inflammation and overriding the dysfunction of vascular cells are seductive, in the sense that many near-term approaches are viable, this sort of work still leaves the underlying causes of aging untouched, and is thus limited in the benefits it can provide.
Geroscience is a multidisciplinary field that examines the relationship between biological aging and age-related diseases. The Trans-NIH Geroscience Interest Group Summit discussed 7 processes that contribute to biological aging: macromolecular damage, epigenetic changes, inflammation, adaptation to stress, and impairments in proteostasis, stem cell regeneration, and metabolism. Intriguingly, these 7 processes are highly intertwined with one another. Thus, targeting the common biological processes of aging may be an effective approach to developing therapies to prevent or delay age-related diseases.
Biological aging is the leading risk factor for the major debilitating chronic diseases of old age that cause morbidity and mortality, including Alzheimer's disease (AD) and other dementias. Drugs that treat fundamental biological mechanisms of aging have been proposed to be useful for most prevalent chronic diseases of aging. In fact, many repurposed drugs are used to treat other age-related diseases. Despite over 75 years of accumulated research on biological aging, the current drug development pipeline is dominated by therapeutics targeting amyloid-β and tau, and there has been proportionately less translation of biological gerontology into our efforts to develop drugs for AD.
Nevertheless, aging biology provides numerous novel targets for new drug development for AD. Because of the multifaceted nature of biological aging, it is unlikely that drugs addressing a single target will be very successful in effectively treating AD. Nevertheless, single drug clinical trials may be needed to demonstrate incremental benefits, even if modest, before combination trials can be pursued. As interventions that target one aberrant system tend to also attenuate others, ultimately, combination therapies that target multiple age-related dysfunctions may produce synergistic activities.
Combination therapies are already the standard of care for other diseases of aging, including heart disease, cancers, and hypertension, and will likely be necessary in treating AD and other dementias. And because the same biological aging mechanisms underpin the common diseases of aging, repurposing drugs already on the market is a rational strategy for testing new therapies for AD and related dementias, including the sporadic forms of frontotemporal dementia and vascular dementia. Novel therapeutics for new and relevant targets will clearly also be needed.
In addition to combination therapies, addressing the multifaceted nature of the relationship between biological aging and AD with drugs possessing pleiotropic effects (simultaneously producing more than one effect) will be advantageous. Many effective drugs act on multiple targets while single-targeted approaches seldom progress to the final stages of clinical trials. For example, statins are widely used to lower cholesterol levels in patients with dyslipidemia, but statins also have pleiotropic effects that are independent of their effects on cholesterol, including improved endothelial function, inhibition of vascular inflammation, stabilization of atherosclerotic plaques, and immunomodulation. To effectively treat AD, pleiotropic drugs may need to hit the right nodes of relevant biological networks affected by aging such that they positively influence those networks and interconnected pathways.
Finally, a parsimonious approach to drug discovery and development with regard to translating knowledge from biological aging to AD is needed. For example, due to the plethora of misfolded proteins that accumulate with aging in the brain, biologics that attempt to address a single misfolded protein may be far less efficacious than drugs that enhance autophagy and clearance of all misfolded proteins. Similarly, age-related inflammation, vascular disease, epigenetic dysregulation, mitochondrial/metabolic dysfunction, and synaptic failure may be upstream causes of neuronal dysfunction and death leading to the classic pathologic hallmarks that have been historically among the first drug targets in AD. A better understanding and translation of the systemic, cellular, and molecular processes of biological aging that precede and increase vulnerability to AD will help identify new strategies and therapeutic targets for drug discovery and development.
Evidence for Pyrophosphate to be the Primary Inhibitor of Vascular Calcification
This open access commentary notes the evidence to suggest that therapies based on raised levels of pyrophosphate in blood vessel walls to reduce age-related calcification. The mineralization of blood vessel walls through deposition of calcium, calcification, is one of the mechanisms that contributes to vascular stiffness with age. It impairs the ability of blood vessels to contract and relax as they should. This is a serious issue, as it breaks the feedback mechanisms that control blood pressure, leading to hypertension, vascular disease, and heart failure as heart muscle grows and weakens.
From my point of view, the work here is an excellent example of the wrong way to go about addressing the issues of aging. Researchers note that a process runs awry with aging, so they analyze the dysfunctional and normal operation of the process to find the proteins that regulate it. Then treatment involves finding ways to safely adjust levels of those proteins, overriding their state in older individuals to try to force the process to deliver better outcomes. As the last half century has demonstrated, it is possible to produce marginal, incremental gains at great expense and a high rate of failure via this strategy. The most impressive results involve methods of overriding our biology to reduce blood cholesterol, blood pressure, and inflammation.
But incremental results are all that can be achieved this way. It is a strategy that completely ignores the cause of the issue. Aging results from forms of cell and tissue damage, and then spirals out through a long and complex and poorly understood chain of consequences. Senescent cells - and the chronic, systemic inflammation that they produce - appear to bias cells in blood vessel walls towards deposition of calcium, for example. But senescent cells cause a wide range of other issues. Trying to override cell behavior in the narrow case of calcification while failing to remove senescent cells leaves those errant cells free to contribute to all of the other issues of aging. You can't force a damaged machine to function as though it were undamaged. There is no future in that approach to aging. The research community must look to causes and repair of damage rather than continuing this expensive, marginal, ultimately futile business of trying to override cell behavior, one tiny fraction of aging at a time.
Vascular calcification is associated with physiological aging and is characterized by the deposition of calcium-phosphate crystals in the aortic media and/or intima, usually as hydroxyapatite, the main component of bone. Vascular calcification reduces aortic and arterial compliance and elastance, hampering cardiovascular system function. It is linked to poor clinical outcomes and contributes to cardiovascular morbidity and mortality. Because tissue mineralization may occur at normal concentrations of calcium and phosphate, regulatory mechanisms exist to limit this process to bone and cartilage. Several endogenous inhibitors of vascular calcification have been identified, including the matrix Gla protein, fetuin A, osteopontin, and pyrophosphate.
Pyrophosphate is a potent inhibitor of calcium-phosphate crystal formation and growth. Vascular tissue mineralization occurs when the synthesis of vascular calcification inhibitors is impaired or when the formation of calcium-phosphate crystals is enhanced, for example, by hyperphosphatemia, the main risk factor for vascular calcification. Despite findings showing that hyperphosphatemia triggers vascular calcification, the effects of hyperphosphatemia on extracellular pyrophosphate metabolism remain unclear. A recent study investigated pyrophosphate metabolism in the context of phosphate-induced vascular calcification. It was found that calcification is a passive process that can be actively prevented by pyrophosphate.
The main conclusion of this new study was that high phosphate concentrations resulted in the increased synthesis of pyrophosphate over time. Moreover, the hydrolysis of pyrophosphate was found to decrease during early stages, but increase during later stages, of hyperphosphatemia. Although overall pyrophosphate production is higher during hyperphosphatemia, it was not sufficient to block calcium-phosphate deposition. A growing body of evidence suggests that pyrophosphate is the predominant endogenous inhibitor of vascular calcification. The results of this study, along with previous findings, suggest that induction of pyrophosphate synthesis may be an easy and effective therapeutic strategy to inhibit vascular calcification associated with aging and other pathological conditions.
Telomerase Activity and Telomere Length Show a Greater Increase After Endurance Training versus Resistance Training
These days a fair amount of scientific work is aimed at quantifying the benefits of various different approaches to exercise. The research here is an example of the type, and compares endurance training (aerobic activity) versus resistance training (to build strength). The authors looked at measures of telomerase activity and telomere length in white blood cells obtained from a few hundred volunteers who carried out different programs of training. Some groups showed greater gains than others.
This should not be taken as robust evidence for effects on aging, as firstly this is more an assessment of immune system activity than of the state of the body as a whole, and secondly telomere length is a truly terrible measure of aging. It correlates very poorly with aging in all but the largest groups. All this really tells us is that aerobic activity fires up the immune system more readily than resistance training. It is known that both aerobic and resistance exercise affect aging, and in different ways, but this study isn't the way to usefully quantify those influences.
Our DNA is organised into chromosomes in all the cells in our bodies. At the end of each chromosome is a repetitive DNA sequence, called a telomere, that caps the chromosome and protects its ends from deteriorating. As we grow older, the telomeres shorten and this is an important molecular mechanism for cell aging, which eventually leads to cell death when the telomere are no longer able to protect the chromosomal DNA. The process of telomere shortening is regulated by several proteins. Among them is the enzyme telomerase that is able to counteract the shortening process and can even add length to the telomeres.
Researchers enrolled 266 young, healthy but previously inactive volunteers and randomised them to six months of endurance training (continuous running), high intensity interval training (warm-up, followed by four bouts of high intensity running alternating with slower running, and then a final cool down of slower running), resistance training (circuit training on eight machines, including back extension, crunch, pulldown, seated rowing, seated leg curl and extension, seated chest press and lying leg press), or to an unchanged lifestyle (the control group).
The participants who were randomised to the three forms of exercise undertook three 45-minutes sessions a week, and a total of 124 completed the study. The researchers analysed telomere length and telomerase activity in white blood cells in blood taken from the volunteers at the start of the study, and two to seven days after the final bout of exercise six months later. Telomerase activity was increased two- to three-fold and telomere length was increased significantly in the endurance and high intensity training groups compared to the resistance and control groups.
Previous research has shown that longer telomeres and increased telomerase activity are associated with healthy aging. However, this is the first prospective, randomised controlled study of the effects of different forms of exercise on these two measurements of cellular aging. A possible mechanism that might explain why endurance and high intensity training could increase telomere length and telomerase activity is that these types of exercise affect levels of nitric oxide in the blood vessels, contributing to the changes in the cells.
Can Peripheral Nervous System Regenerative Mechanisms be Introduced into the Central Nervous System?
The nervous system in general is not particularly regenerative, but peripheral nervous system tissue is more capable of repair than central nervous system tissue. Focusing on neurons that link these two parts of the nervous system, researchers here report on mechanisms involved in repair of nervous system cells, and propose that it might be possible to make central nervous system cells act more like peripheral nervous system cells in this regard. Whether or not this can be achieved safely is another question, however; this is very early stage work, too early to answer many questions about safety and plausibility.
Neurons in the central nervous system - the brain and spinal cord - and the peripheral nervous system are very similar except in their ability to regenerate. Researchers realized that studying peripheral neurons could help us understand why some damaged neurons regenerate and others do not. They turned to a unique kind of sensory cell that spans both nervous systems. Known as dorsal root ganglion neurons, these cells have long tendrils, called axons, with two offshoots. One branch of the axon connects to cells in the body's periphery and can regenerate if cut; the other side links up with cells in the spinal cord and cannot regrow after injury.
The researchers grew mouse dorsal root ganglion neurons in the lab and then cut them to find out what biological processes occur as the cells regrow their axons. They also cut the sciatic nerve - which runs up the leg and into the spinal cord through the dorsal root ganglia - in mice. The researchers then identified a suite of genes needed to be turned off for the axons to regenerate. "Other people also have shown that a big swath of genes is turned down during regeneration, but as a field we've just said, 'Eh' and ignored them to focus on the genes that are activated. Here, we showed that establishing a regeneration program means some genes have to be turned on but a lot have to be turned off."
In particular, a set of genes related to sending and receiving chemical and electrical signals - the primary duty of mature neurons - had to be silenced for the injury to heal. "The injured neuron has to stop functioning as a neuron and focus on repairing itself. This means the neuron has to transition back to an immature state so it can re-engage developmental programs and regrow." The idea that cells must become less mature in order to regenerate is not new, but the study provides evidence in support of that idea. The researchers identified the key molecular and genetic players involved in regressing to a less mature state, and showed that the timing of the regression was crucial to successful recovery. They are now working on developing a more detailed understanding of when and for how long specific genes must be shut off, and whether silencing the genes in neurons from the central nervous system will induce them to regrow after injury.
Linking Impaired Autophagy to Changes in Polarization of Microglia in Aging
The polarization of the immune cells known as macrophages and microglia is a topic of growing interest in the study of aging and age-related disease. A perhaps overly simplistic summary is that polarization describes the state and preferred activities of a macrophage or microglial cell, changing in response to signals and environment. The states of greatest interest are M1, inflammatory and aggressive in pursuit of pathogens, versus M2, a helper in tissue maintenance and regeneration. Both polarizations are necessary in the grand scheme of things, but in older individuals and in tissues affected by age-related disease, a an excess of M1 macrophages or microglia is a common theme. The result is a diminished capacity for regeneration and necessary processes of maintenance.
Too great a number of M1 polarized cells ties in to the chronic inflammation of aging, as inflammatory signals provoke macrophages into this polarization. In this context, researchers are investigating a range of possible strategies to override polarization, forcing immune cells back into the M2 state. Another aspect of this issue is added here in an open access paper linking the quality of autophagy to polarization. Autophagy is the name given to a collection of cell maintenance processes responsible for breaking down and recycling damaged structures and proteins. That it would be linked to immune cell polarization is most interesting, as autophagic activity is known to decline with age. Increased autophagy is associated with increased longevity in a variety of interventions examined in laboratory species, such as calorie restriction. It remains to be seen how strong this relationship is in comparison to the relationship with inflammation, but it seems that they influence one another, and are not independent.
Neuroinflammation and autophagy dysfunction are closely related to the development of neurodegeneration such as Parkinson's disease (PD). However, the role of autophagy in microglia polarization and neuroinflammation is poorly understood. TNF-α, which is highly toxic to dopaminergic neurons, is implicated as a major mediator of neuroinflammation in PD. In this study, we found that TNF-α resulted in an impairment of autophagic flux in microglia. Concomitantly, an increase of M1 marker expression and reduction of M2 marker expression were observed in TNF-α challenged microglia. Upregulation of autophagy via serum deprivation or pharmacologic activators (rapamycin and resveratrol) promoted microglia polarization toward M2 phenotype, as evidenced by suppressed M1 and elevated M2 gene expression, while inhibition of autophagy with 3-MA or Atg5 siRNA consistently aggravated the M1 polarization induced by TNF-α.
Moreover, Atg5 knockdown alone was sufficient to trigger microglia activation toward M1 status. More important, TNF-α stimulated microglia conditioned medium caused neurotoxicity when added to neuronal cells. The neurotoxicity was further aggravated with Atg5 knockdown in cells, but alleviated given microglia pretreatment with rapamycin, suggesting that activation of AKT/mTOR signaling may contribute to the changes of autophagy and inflammation. Taking together, our results demonstrate that TNF-α inhibits autophagy in microglia through AKT/mTOR signaling pathway, and autophagy enhancement can promote microglia polarization toward M2 phenotype and inflammation resolution.
Searching for Longevity-Related Genes in the Genomes of Parrots
One way to identify the important mechanistic links between metabolism and longevity is to examine the genomes of unusually long-lived species. This has long been underway for naked mole rats and some smaller bats, species that live many times longer than similarly sized near relatives. The same sort of longevity occurs in parrots; other birds of their size live for perhaps a decade or two, but parrots exhibit a similar life span to that of humans, given a safe and supportive environment. Scientists here report on their initial investigations of the parrot genome, and a comparison with less long-lived birds. As for the case for all similar research, it remains an open question as to whether any of the findings will turn out to be of practical use when it comes to developing the means to significantly lengthen healthy human life spans.
Parrots are one of the most distinct and intriguing groups of birds, with highly expanded brains, highly developed cognitive and vocal communication skills, and a long lifespan compared to other similar-sized birds. Yet the genetic basis of these traits remains largely unidentified. To address this question, we have generated a high-coverage, annotated assembly of the genome of the blue-fronted Amazon (Amazona aestiva) and carried out extensive comparative analyses with 30 other avian species, including 4 additional parrots.
We identified several genomic features unique to parrots, including parrot-specific novel genes and parrot-specific modifications to coding and regulatory sequences of existing genes. We also discovered genomic features under strong selection in parrots and other long-lived birds, including genes previously associated with lifespan determination as well as several hundred new candidate genes. These genes support a range of cellular functions, including telomerase activity; DNA damage repair; control of cell proliferation, cancer, and immunity; and anti-oxidative mechanisms.
We also identified brain-expressed, parrot-specific paralogs with known functions in neural development or vocal-learning brain circuits. Intriguingly, parrot-specific changes in conserved regulatory sequences were overwhelmingly associated with genes that are linked to cognitive abilities and have undergone similar selection in the human lineage, suggesting convergent evolution. These findings bring novel insights into the genetics and evolution of longevity and cognition, as well as provide novel targets for exploring the mechanistic basis of these traits.
Macrophages Could Improve Heart Regeneration, but Arrive Too Late Following Injury
Macrophages of the innate immune system play an important role in coordinating the intricate dance of cell populations that takes place during regeneration from injury. Differences in macrophage behavior may be key to the exceptional regenerative capacities of species such as salamanders that can regrow entire organs, and possibly also in the few mammalian species and genetically altered lineages capable of noteworthy feats of regeneration.
Researchers here make a most interesting discovery, finding that in mice there are populations of macrophages capable of coordinating greater than normal regeneration following injury to the heart, such as that resulting from a heart attack. This regeneration doesn't take place because the macrophages arrive too late to prevent the formation of scar tissue; regeneration is already well advanced by the time they are present in any significant number. This suggests that regenerative therapies based on manipulation of macrophage behavior are plausible for the near future, as it is always easier to adjust an existing mechanism than it is to build something completely novel.
Macrophages are white blood cells that live in organs and are key components of our immune system. They have a well-established ability to fight infections, but more recently, have been shown to help promote repair and regeneration of tissues. Researchers have found that instead of a single type of macrophage, there are at least four types that live within the uninjured heart, and that number increases to 11 after a heart attack, which indicates the immune system behaves in much more complex fashion than was imagined.
First, they found that neonatal-like macrophage cells are lost after a heart attack in adults, which could explain why the adult heart may not heal itself as well as the neonatal heart. In very young animals, neonatal macrophages increase in number and are very effective at triggering the regrowth of heart muscle and blood vessel cells. "Genetically removing neonatal-like macrophages at the time of the heart attack in adult animals worsens heart function most profoundly at the region of the heart separating injured and uninjured heart muscle - the only zone of the adult heart where they increase in number."
Researchers also found large numbers of macrophages are attracted to the heart after a heart attack, and a small number enter into the neonatal state, except, too late. By the time they arrive on site after a heart attack, a scar has formed in the heart in the place of heart muscle. "Each cell has a unique role to play in the human body, but our next question is: how can we guide a cell that enters the heart into a neonatal state more efficiently and, ultimately, more effectively?"
Thoughts on Near Term Rejuvenation Therapies
At this year's RAADfest event, the interviewer noted here was taking an informal survey of optimistic versus pessimistic attitudes towards progress in the decades ahead. Apparently I was on the pessimistic end of the spectrum. Once past the present highly active development of senolytic therapies to remove senescent cells from old tissues, I think it quite plausible that we'll see a gap of a decade before the next class of SENS-like rejuvenation therapy arrives at the point of availability via medical tourism. The likely candidates include clearance of cross-links and restoration of the immune system via thymic regrowth.
Surprise progress in advance of the end of the 2020s seems implausible, with the exception of the discovery that an existing small molecule drug or otherwise widely available low cost compound breaks down significant amounts of some form of molecular waste, such as oxidized cholesterol or glucosepane cross-links. That is possible to engineer, given the resources, but so far as I know next to no-one is screening the compound libraries with this in mind. It is an expensive task with uncertain chances of success. This present state of the market, that there is a gulf of further required development ahead, is perhaps a little obscured by the excitement over senolytics. There is, however, a continued need for philanthropic support of lines of research that remain poorly funded. If senolytics are to be closely followed by the rest of the rejuvenation toolkit, then we still have a great deal of work to do.
What are the most promising near-term therapies that may actually turn back the clock on biological aging?
Senolytic treatment, obviously, is the one that is here already and is presently available. It is fortunate that some of the first drugs identified to have this effect are, to a significant degree, already widely used and cheap. The animal results are far better in terms of robustness and reproducibility than any of the calorie restriction mimetic and other stress response tinkering work. The first human data from formal trials will arrive late this year or in early 2019. These first-generation approaches are killing only about half of the senescent cells at best (and far fewer than that in some tissues) but are nonetheless very effective in comparison to any other approach to age-related inflammatory disease.
The next approach to arrive that will likely have a similar character and size of effect is breaking of glucosepane cross-links, but since that involves a completely new enzyme-based therapy, we're unlikely to see it in people any sooner than a decade from now. If there is interest in that field, someone might uncover a useful small molecule prior to then, but it seems unlikely.
Other than that, over that same timeframe: (a) advances in stem cell medicine, moving beyond the simple transplantation therapies that do little other than suppress inflammation towards ways to actually replace damaged populations and have them get to work; (b) removal of amyloids through means other than the immunotherapies that are the present staple of that field; (c) forms of immune system restoration, such as via thymic regrowth, replacement or enhancement of hematopoietic stem cells, and clearance of problem immune cells.
I'm not convinced that there is an enormous benefit to be realized from approaches to enhance mitochondrial function, such as NAD+ precursors and mitochondrially targeted antioxidants, that get a lot of hype and attention. They may have a small positive effect on metabolism in later life, which would make them worth taking when cheap and safe. They are not in any way reversing aging - they are forcing a damaged machine to work harder without addressing any of the causes of failure. One can paint the same picture when discussing ways to enhance stem cell function without addressing the underlying damage, such as telomerase therapies and the use of signaling molecules. It may meet the cost-benefit equation, but it also may not, since these are much more expensive propositions.
Why is breaking extracellular crosslinks so important?
This is important because cross-links cause stiffening of tissues. The stiffening of blood vessels is the cause of hypertension, and hypertension is (like inflammation) a major way in which low-level biochemical damage is translated into many different forms of structural damage: pressure damage to delicate tissues; rupture of capillaries in the brain; remodeling and weakening of the heart; increased risk of atherosclerotic lesions causing stroke or heart attack. High blood pressure is very damaging. It is so harmful that ways to reduce blood pressure that work by overriding signaling systems - which do absolutely nothing to eliminate the root cause, the biochemical damage of aging - can still produce large reductions in mortality risk.
All of that can be greatly reduced by cross-link breaking, and there is only one major class of cross-links in humans that needs targeting to obtain that benefit: those involving glucosepane. Thus, like senolytics, once there is some motion towards achieving this end, we should see a very rapid expansion of the industry and delivery of benefits to patients. Glucosepane is hard to work with, so very few groups have done anything meaningful - the first big advance that the SENS Research Foundation achieved in this field was to fund the creation of the tools needed to move forward at all in this part of the field. Even now, there is really only one group working earnestly on it that I know of, David Spiegel's team at Yale, with a couple of others doing some investigative work around the edges of the challenge. The Spiegel approach is to mine the bacterial world for enzymes that degrade glucosepane and then refine the successes into therapeutic drugs. His team is a fair way along, and work is progressing in a funded startup company at this point.
More Evidence for TIGIT to Mark a Population of Harmful Immune Cells in Older People
Earlier this year, researchers provided evidence for expression of TIGIT to mark senescent and exhausted T cells in the immune systems of older individuals. Here, new results reinforce the point that TIGIT-expressing T cells are a burden. These cells cause issues, contributing to the inflammatory and weakened state of the aged immune system. Selectively destroying them should help, and senolytic drugs may achieve this goal, as least insofar as the biochemistry of TIGIT-expressing T cells overlaps with that of better studied varieties of senescent cell in tissues. To what degree this is the case remains to be determined; researchers in the cellular senescence field have far more analysis of this nature in front of them than can possibly be accomplished over the next few years, and this particular case is probably still a fair way down the list by priority.
Researchers have identified that an immune cell subset called gamma delta T cells that may be causing and/or perpetuating the systemic inflammation found in normal aging in the general geriatric population and in HIV-infected people who are responding well to drugs. The team measured many markers on the surface of immune cells in the blood of people either with or without HIV (uninfected controls) that were sub-divided into two groups: younger (less than 35 years) and older (over 50 years) and compared that data with levels of inflammatory proteins in their plasma.
Researchers found a marker on these gamma delta T cells, called TIGIT, that tracked significantly with plasma inflammatory markers in both the HIV+ and uninfected subject groups, and therefore could be targeted to potentially stop this "inflammaging" found in both HIV+ people and the general geriatric population. "Our study indicates that there's a previously uninvestigated cell subset new player in the immune landscape that could be driving widespread illnesses and with targeted gamma delta therapeutics maybe there may be a chance of reducing onset, symptoms, and/or severity of inflammation-related diseases."