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- The Million Year Life Span
- The Mechanisms of Extended Longevity through Increased p53 Activity
- A Demonstration of Chimeric Tissue Farming: Mouse Pancreatic Tissue Grown in Rats
- Tackling Cellular Senescence as a Treatment for Aging
- Keeping a Careful Eye on When You Cease to be You
- Latest Headlines from Fight Aging!
- Investigating the Early Stages of Inflammation in Arthritis
- Are We Terrible at Advocacy, or is it Actually Hard to Persuade People of the Merits of Living Longer in Good Health?
- A Less Effective Compensatory Response to Mitochondrial DNA Deletions Observed in Parkinson's Disease Patients
- Why Work to Dismantle Arguments Made Against Increased Healthy Longevity?
- The Methuselah Foundation's Bioprinting Program
- Bioprinting Human Skin Cuts the Time Needed from Weeks to Minutes
- An Example of Transplanted Neurons Integrating into the Brain
- News of Another Possible Tau Clearance Therapy
- A Profile of Researchers Working on Heart Decellularization
- More Evidence for Exosomes to be Important in the Outcome of Stem Cell Therapies
The Million Year Life Span
[This is a lightly edited reprint of an article originally published at h+ Magazine, descending from an older Fight Aging! post, and returned again now in order to preserve it for posterity.]
I'm not going to try to convince you that the foreseeable future is a wondrous place: either you accept the implications of the present rate of technological progress towards everything allowed by the laws of physics, in which case you've probably thought this all through at some point, or you don't. Life, space travel, artificial intelligence, the building blocks of matter: we'll have made large inroads into bending these all to our will within another half century. Many of us will live to see it even without the benefits of medical technologies yet to come: growing up without the internet in a 1960s or 1970s urban area will be the new 1900s farmboy youth come 2040. Just like the oldest old today, we will be immigrants from a strange and primitive near-past erased by progress, time travelers in our own lifetimes.
A century is an exceptional life for a human, but far greater spans of years will be made possible by the technologies of the 21st century. I'll plant a flag way out there on the field and claim a million years: a life of a length hard to envisage. I am an advocate for engineered human longevity, and I started on the path that led to Fight Aging! and related projects from the position that (a) immortality would be an unalloyed good if achieved, and (b) our understanding of cosmology does not yet rule out a damn good attempt at actual immortality - the "no death, ever" dictionary definition - or at least a life span of millions of years on the way to that end goal. If a million years is not long enough to figure out the aspects of the problem that cannot be answered today, I'm not sure what would be.
Despite being out there, the million year life span is not an unsupported pipe dream. Living for a million years is a goal that can be envisaged in some detail today: the steps from here to there laid out, the necessary research and development plans outlined, and the whole considered within the framework of what is permissible under the laws of physics, and what the research community believes can be achieved within the next 20, 50, or 100 years.
Biotechnology is the first necessary step on this road of a million years: the biotechnology revolution, still in its early years, is a gateway to the future insofar as it will enable us to extend our healthy life spans by repairing the evolved world of nanoscale machinery within our cells and other vital biological systems. The future is only golden for you and I personally if we live to see it, and for many of us that will require rejuvenation biotechnologies like those worked on by the SENS Research Foundation. This golden future is one in which our biochemistry does our bidding, aging can be repaired, and molecular manufacturing is in full swing. It will be an age of bioartificial bodies, minds transferred to new and more robust mechanisms, artificial general intelligences, an end to most scarcities, and indeed, anything you might imagine that the laws of physics permit and enough time has passed to develop.
A philosophy of first things first is a good way to temper visions of the far future - and explains why I spend my time talking about rejuvenation biotechnologies, cryonics, and even basic common sense health practices that might stop you cutting a mere decade from your life expectancy. If we don't complete the first rung of the ladder, that being sufficient control over our biochemistry to slow and then repair aging, then all the rest of our thoughts on radical life extension are for nothing. If I'd been born twenty years earlier, I'd have ended up primarily a cryonics advocate and volunteer. As it is, it looks like these first decades of the 21st century are the era in which the first rung on the ladder of simply remaining alive forever - which is to say building the means to continuously repair the biological damage of aging in these bodies of ours - can actually be achieved. If we can live another 50 years, grabbing a year here with good health and a year there through incremental advances in geriatric medicine, and if we can build a large enough research community interested in serious work on rejuvenation along the way, then we may live in restored youth and vigor for centuries longer.
If you project forward into the future based today's accident rates, you'll find that an ageless human sustained by biotechnologies of cellular and biochemical repair has a life expectancy in the range of 1,000 to 5,000 years. Sooner or later that piano is going to fall upon your head hard enough that even advanced medical technology cannot fix your injuries in time. So the million year life span: how could that be achieved? The short and not terribly informative answer is that it will be accomplished by using advancing technology to dramatically reduce your vulnerability to fatal accidents, murder, and other unfortunate events that produce the same outcome. Once you start looking at living for even 100,000 years in much the same shape as you are today, it becomes apparent that almost any activity bears an unavoidable minimum level of risk that will jump up and kill you. Eating, swimming, walking ... breathing. Stretch out the timeframe far enough and the improbable and fatal will eventually occur.
The way past these risks is to change your form: your risk of fatality for any given activity is a function of your human physiology. Once the research and development community has achieved the goal of practical biotechnologies for the repair and reversal of aging, that will give us all a few hundred years of life in comparative statistical safety. Technological progress will continue across that long period of time, and I can't imagine that much of the toolkit needed for the next step in long-term risk reduction will remain beyond the capabilities of the human civilizations of the 2200s. Your own personal preferences for that next step will no doubt vary, but I would get my neurons replaced - slowly, one at a time over time, to ensure continuity of the self - with some form of much more robust, easily maintained nanoscale machinery. That allows for a range of new engineering possibilities: swapping out the body for whatever machinery of transport and support best minimizes risk; moving most of the business of life into a virtual world; physically separating my neurons while still remaining alive, conscious, and active.
It shouldn't be terribly controversial at this point to talk about machines that can do the job of a neuron, store all of the same information as a neuron, and integrate fully with surrounding real neurons. Researchers in recent years have assembled lobster neuron simulators from Radio Shack components, grown proof of principle neuron-circuit interfaces, designed and simulated nanomachine replacements for other cell types, and made great inroads into manipulating the internal machinery of cells. These are toys and clunky barnstorming exercises in comparison to what lies ahead, but my point is that this is an active line of research, worked on by thousands of scientists and developers. Similarly, I would hope that interacting via virtual worlds and splitting up one's machine neurons between various locations follows fairly straightforwardly from having machine neurons in the first place. If your brain is made up of artificial neurons, why not throw in an internet connection, adjunct computer hardware, and encrypted wireless communication protocols?
Physical distribution of the self across many disparate locations is in fact the key point when it comes to considering risk over the long term. Locations have much the same issues with time, probability, and bad events as people do. Meteorites are a risk to consider, as are landslides, earthquakes, war, and volcanoes. The way to reduce your location-based risk dramatically is to spread out. You might imagine a wireless brain, using whatever the most robust communications technology of the time happens to be, scattered in a thousand separate machine bodies or vehicles across a continent, or even the whole planet. That might be good for many millennia of falling pianos of various types. However, once you start digging back into the geological and astrophysical history of the solar system, it becomes clear that spreading out over an entire planet still leaves you at risk on longer timescales. Probably not from impact events: I'll be surprised if humanity and its machine descendants fail to solve that problem within the next few centuries. But there will always be war, nearby supernovae, large solar flares, unusually massive volcanic events, and other unpleasant line items, however. Supernovae are the biggest of the known concerns, given that I expect it to be a long, long time before preventing them is a practical and ongoing business for the civilizations that follow man.
What to do about all of this astrophysical and grand geological risk? Spreading out is an option once again. Increase the size of your vehicles and neuron-machines to shrug off the worst case radiation projections for a nearby supernova. Provide them with the means to move about the solar system, and become a spacefaring entity, spread out over a sizeable selection of orbits. By that point in time, your physical presence resembles a small country of machinery, automation, and layers of delegation: perhaps you are a million heavily shielded self-powered containers and transmission systems distributed beyond Pluto's orbit. There is a trade-off for spreading out so far, however, and that is that you must slow down. The speed of thought is determined by the speed of communication between the neurons and sections of your brain. If your brain is light hours wide, you will live very slowly indeed - but with a life expectancy so long that you come out far ahead in the end.
There are other paths forward with varying degrees of risk. You might decide not to spread out, but rather live very fast by running your machine neuron brain on more capable hardware, for example; if you can pass a hundred years of subjective time in a year of real time then you have reduced your subjective risk for many fatal occurrences a hundred-fold. That would be a pleasant enough life as a part of a community of people all running at the same speed, and there is even room for technological development and research to occur at a fair pace under such a scenario. At present our still young computing technology is very, very far removed from the known theoretical limits on computational efficiency. There is a great deal of headroom for the approach of living more rapidly.
But to return to the immortality question: is immortality impractical? Given existing mortality rates and the uncertainties in the timeline for completing efforts to repair and reverse the damage of aging, it may be unlikely for many of us alive today. If progress is too slow, or we are simply unlucky in matters of health, then we won't get past the first step on the path. In other words, we will die - or at best undergo cryosuspension and its attendant risks - before the advent of sufficiently good rejuvenation biotechnology. As for the bigger picture, it is far too early to say whether immortality, the "no death, ever" version, is actually impossible. That requires further research into cosmology - so you might give it a million years or so and ask me again. Regardless, the slope of technology and possibility is curving up ahead of us to great heights, and it'll be a wild ride either way. Missing out on any of it would be a real downer, so why not spend more of your time and resources helping to get the first step accomplished? We should all support the development of rejuvenation biotechnology, as it is the gateway to a life that may ultimately prove to have few limits.
The Mechanisms of Extended Longevity through Increased p53 Activity
The activity undertaken by many important genes is quite subtle and conditional. Simply raising or lowering the amount of protein produced by that gene is rarely as effective as hoped in initial studies, and can be entirely counterproductive. The important activities of any specific protein might be very tissue-specific, and thus thwarted by being altered globally, or they might depend on other proteins and circumstances. The tumor suppressor p53 is a good example of the type; more p53 activity at the right times and in response to the right signals can both extend life and reduce cancer risk in mice. On the other hand, generally increased p53 activity shortens life.
The p53 protein is a part of the complex and shifting tradeoffs made between suppression of cellular replication and encouragement of cellular replication. When there is a greater risk of cancer, when cells are damaged or the cellular environment is toxic, more p53 encourages both greater repair and resistance to cellular damage and a more aggressive removal of cells most at risk by forcing them into senescence. In the normal course of regeneration and tissue maintenance, however, too much p53 suppresses the efforts of the cells that should be replicating, speeding the onset of frailty and organ failure, and over time the presence of larger numbers of senescent cells also leads to an acceleration of the aging process. Senescent cells cause a great deal of harm when they are not efficiently destroyed, either by the immune system or through programmed cell death.
It has been a decade since researchers first demonstrated a way to selectively enhance p53 activity only when needed, producing extension of life in mice. Since then, I think most of the groups involved have been quite distracted by work on telomerase gene therapies, which started in earnest at around the same time and among many of the same researchers, but which has since consumed ever more of the available time and interest. You might recall a merger of these two lines of research in which mice with enhanced telomerase and enhanced p53 activity were found to balance out with a longer life span. Since then the telomerase research has forged ahead, as I'm sure you've all noticed, but I can't say that work on selective increase of p53 activity as a method of modestly slowing aging has advanced all that much at all. The papers today are covering essentially the same ground as was covered a decade ago, and still with little impetus towards building some form of therapy from this:
Increased Arf/p53 activity in stem cells, aging and cancer
Cancer is the consequence of an aberrant gain of cellular fitness linked to the accumulation of stress and cellular damage of acute intensity. This damage occasionally provides aberrant advantages to certain cells, which can eventually lead to cancer development. The Ink4/Arf locus and p53 are regarded as the most relevant tumor suppressors based on their ubiquitous and frequent inactivation in human cancer. The Ink4/Arf locus encodes three tumor suppressor genes p15Ink4b, p16Ink4a, and p14Arf (p19Arf in mice). On one hand, p15Ink4b and p16Ink4a (called Ink4 hereafter) inhibit the formation of the cyclin-dependent kinases (CDK4 and CDK6) and cyclinD complexes during the G1 phase of the cell cycle. Hence, they prevent the transcription of genes involved in the transition to S phase, importantly the Rb/E2F1 pathway, so regulating cell cycle progression. On the other hand, Arf exerts its tumor suppressive action by inhibiting Mdm2, a ubiquitin ligase considered the major p53 regulator, thereby contributing to the activation and stabilization of p53.
The Ink4/Rb and Arf/p53 pathways are major sensors of stress that play a crucial role in early detection and elimination of cells that have suffered different types of stress including oncogene activation, DNA damage, oxidative stress, etc. While the activation of Ink4/Rb pathway induces reversible cell cycle arrest or irreversible cellular senescence-associated changes, the activation of p53 elicits a cellular response that might vary from restoration of cellular homeostasis by a transient blockade of the cell cycle to allow for DNA repair, senescence, or apoptosis. The activation of these responses depends in a complex manner, on the intensity of the triggering stress and on the cellular context. In agreement with this damage protective role, the individual or combinatory deletion of these genes promotes cancer susceptibility in multiple tissues and contexts. On the contrary, enhanced Ink4/Arf and p53 activity preserves mice from spontaneous or chemically induced cancers.
Although cancer and aging may seem opposite processes, they can be regarded as two different manifestations of the same underlying process, namely the accumulation of cellular damage. Moreover, cancer and aging may share common origins. There are several genetic or pharmacological manipulations that simultaneously modulate cancer and aging. These proofs demonstrate that cancer protection and longevity can be simultaneously modulated using different strategies and molecular mechanisms. In recent years, this is deepening the knowledge of the implications that the Ink4/Rb and Arf/p53 pathways have on the management of cellular damage associated with the aging process. The observation that several manipulations simultaneously modulate longevity and cancer protection establishes an interesting parallel with the expression of members of the Ink4/Rb and Arf/p53 pathways, which are silent or very low during development and postnatal life, while progressively increase from adulthood to old age in a broad range of tissues and species.
There is little additional information regarding p53 and aging in human, yet there is no evidence of a pro-aging function. Indeed, it has been documented that p53 is not involved in human premature aging disorders such as Hutchinson-Gilford Progeria, and it has been postulated that well-preserved p53-mediated responses are likely a key factor contributing to protection from diseases and cancer in centenarians. The above raises the possibility that Ink4/Rb and Arf/p53 pathways might have a role in aging. Thus, stress conditions cause an accumulation of DNA damage at the cellular level. Ultimately, it leads to the final activation of the Ink4/Rb and Arf/p53 pathways in order to achieve various adaptive responses to this situation. Amidst such responses is the transient block of the cellular cycle to try to repair the damage, inducing a state of senescence, or even apoptosis. Therefore, the empowerment of Ink4/Rb and Arf/p53 pathways might play an important role not only on surveillance and suppression of tumors, but also on the accumulation of cellular damage and aging. Therefore, it is reasonable to surmise that Ink4/Rb and Arf/p53 play a role also in the response to age-associated chronic stress and consequently affects aging. As activation of the Ink4/Rb and Arf/p53 pathways triggers a protective mechanism against tumor-induced stresses, they could also have anti-aging activity by alleviating the load of age-associated damage.
Significant efforts have been made to determine the impact of Ink4/Rb and Arf/p53 tumor suppressor pathways. While their protective function against cancer is firmly established, their role in aging remains controversial. In mice, it has been demonstrated that modest increases of regulated Arf/p53 activity are anti-aging while deregulated activation of p53 promotes aging. These observations are not in conflict per se and indicate that the activity of Arf/p53 could be beneficial or detrimental for aging depending on their intensity and regulation. It has recently been demonstrated that these effects are mediated through the activity of stem cells, indicating the concept of a reciprocal trade between tumor suppression, aging, and stem cell biology. Based on this, we postulate a model by which high or deregulated Arf/p53 impacts on lifespan by a decline in tissue stem cell regenerative function, but modest and regulated increases in Arf/p53 result in systemic organismal benefits ameliorating stem cell aging and maintaining tissue homeostasis. Additional work is necessary to establish the detail role and mechanism of action of p16Ink4a in aging and stem cell biology.
A Demonstration of Chimeric Tissue Farming: Mouse Pancreatic Tissue Grown in Rats
Today I noted the report of a proof of principle demonstration of the creation of chimeric animals that grow the organs of another species. This not the first such demonstration, but it is another step along the way to larger goals in tissue engineering. One of the potential approaches to building a large supply of new organs and tissues for transplantation is to grow humanized tissues in other species, such as pigs. This might be accomplished in many different ways, ranging from implanting seed cells or organoids into genetically altered adult animals, to creating engineered animal lineages in which all of the desired organs are at least partially humanized, compatible enough for xenotransplantation. That may involve as little as removing a few problem proteins in the case of porcine organs, but it remains to be seen how much concrete progress will be made by the current research programs with this specific focus. In the years ahead, this branch of technology will compete with therapies to regenerate organs in situ, as well as decellularization of donor organs, and efforts to grow or print suitable tissues for transplantation using only the patient's own cells as a starting point. It remains very unclear as to which of these approaches will prosper first.
Creating individual animals with one or more organs from another species requires some genetic engineering, to prevent the growth of the normal organ, followed by implantation of suitable seed cells in embryos early in the developmental process. If expanded into an industry, this methodology doesn't seem likely to result in a cost-effective supply of patient-matched tissues, given that it would require at minimum a few years to create a patient-matched organ for transplantation. It might, however, lead to multiple lines of animals, each possessed of humanized organs that can be transplanted, with little immunosuppression required, into one of the various human immunological groups. As is the case for many of the near future options for organ creation and xenotransplantation, this would be a great improvement over present shortages of donor organs, but it falls a long way short of the ideal future in which existing organs can be repaired and regenerated through some form of cell therapy or similar treatment.
Rat-grown mouse pancreases help reverse diabetes in mice
Growing organs from one species in the body of another may one day relieve transplant shortages. Now researchers show that islets from rat-grown mouse pancreases can reverse disease when transplanted into diabetic mice. The recipient animals required only days of immunosuppressive therapy to prevent rejection of the genetically matched organ rather than lifelong treatment. The success of the interspecies transplantation suggests that a similar technique could one day be used to generate matched, transplantable human organs in large animals like pigs and sheep.
To conduct the work, the researchers implanted mouse pluripotent stem cells, which can become any cell in the body, into early rat embryos. The rats had been genetically engineered to be unable to develop their own pancreas and were thus forced to rely on the mouse cells for the development of the organ. Once the rats were born and grown, the researchers transplanted the insulin-producing cells, which cluster together in groups called islets, from the rat-grown pancreases into mice genetically matched to the stem cells that formed the pancreas. These mice had been given a drug to cause them to develop diabetes.
The mouse pancreases were able to successfully regulate the rats' blood sugar levels, indicating they were functioning normally. Rejection of the mouse pancreases by the rats' immune systems was uncommon because the mouse cells were injected into the rat embryo prior to the development of immune tolerance, which is a period during development when the immune system is trained to recognize its own tissues as "self." Most of these mouse-derived organs grew to the size expected for a rat pancreas, rendering enough individual islets for transplantation. Next, the researchers transplanted 100 islets from the rat-grown pancreases back into mice with diabetes. Subsequently, these mice were able to successfully control their blood sugar levels for over 370 days, the researchers found. Because the transplanted islets contained some contaminating rat cells, the researchers treated each recipient mouse with immunosuppressive drugs for five days after transplant. After this time, however, the immunosuppression was stopped.
After about 10 months, the researchers removed the islets from a subset of the mice for inspection. "We examined them closely for the presence of any rat cells, but we found that the mouse's immune system had eliminated them. This is very promising for our hope to transplant human organs grown in animals because it suggests that any contaminating animal cells could be eliminated by the patient's immune system after transplant." Importantly, the researchers also did not see any signs of tumor formation or other abnormalities caused by the pluripotent mouse stem cells that formed the islets. Tumor formation is often a concern when pluripotent stem cells are used in an animal due to the cells' remarkable developmental plasticity. The researchers believe the lack of any signs of cancer is likely due to the fact that the mouse pluripotent stem cells were guided to generate a pancreas within the developing rat embryo, rather than coaxed to develop into islet cells in the laboratory. The researchers are working on similar animal-to-animal experiments to generate kidneys, livers and lungs.
Interspecies organogenesis generates autologous functional islets
Islet transplantation is an established therapy for diabetes. We have previously shown that rat pancreata can be created from rat pluripotent stem cells (PSCs) in mice through interspecies blastocyst complementation. Although they were functional and composed of rat-derived cells, the resulting pancreata were of mouse size, rendering them insufficient for isolating the numbers of islets required to treat diabetes in a rat model. Here, by performing the reverse experiment, injecting mouse PSCs into Pdx-1-deficient rat blastocysts, we generated rat-sized pancreata composed of mouse-PSC-derived cells. Islets subsequently prepared from these mouse-rat chimaeric pancreata were transplanted into mice with streptozotocin-induced diabetes. The transplanted islets successfully normalized and maintained host blood glucose levels for over 370 days in the absence of immunosuppression (excluding the first 5 days after transplant). These data provide proof-of-principle evidence for the therapeutic potential of PSC-derived islets generated by blastocyst complementation in a xenogeneic host.
Tackling Cellular Senescence as a Treatment for Aging
The research community is now well and truly woken up when it comes to senescent cells and aging, after long years of ignoring this corner of the field, the paper linked below is illustrative of the sort of reviews on the subject being written nowadays. It took quite a while to achieve this awakening. Good evidence for senescent cell accumulation as a contributing cause of degenerative aging has existed for decades, and on the basis of that evidence clearance of senescent cells from old tissues was included in the SENS rejuvenation research proposals when they emerged at the turn of the century. Nonetheless, even as recently as five years ago researchers still struggled to raise the funds needed for the animal studies to prove the point. Once the first of those studies was completed, in 2011, things began to move, and now we have can observe an increasing pace of investment, development of practical therapies by numerous companies, and publication of new data on the biology of senescent cells. Life extension has been demonstrated in normal mice, and a recent studies demonstrate that removing senescent cells should help to slow or reverse the progression of specific age-related diseases and turn back numerous metrics of tissue aging. It is all very promising.
How do senescent cells cause harm? Largely through signaling, it appears, as they do not make up a large fraction of cells in any particular tissue even by the end of a natural life span. If even 1% of the cells in an aged tissue have become senescent, that is enough to cause significant issues. Senescent cells generate a mix of signal molecules that, in greater volume, can become very harmful; this is known as the senescence-associated secretory phenotype (SASP). It promotes chronic inflammation, alters the behavior of nearby cells for the worse, and can damage the structure of the extracellular matrix, among other issues. Why do we accumulate senescent cells? The phenomenon of senescence in old tissue appears to be an adaptation of an embryonic development process, now turned to cancer suppression. Indeed, much of its destructiveness makes more sense in the context of embryonic growth, where tissues must be removed or growth halted in order to correctly define organ structures. Cells become senescent at the Hayflick limit on division, or in response to damage or a toxic environment. In moderation this serves to reduce the risk of cancer by shutting down replication in the most vulnerable cells, those most likely to become cancerous. Levels of cellular damage and stress increase with aging, which will in turn increase the rate at which senescent cells arise. Further, senescent cells are largely destroyed either by the immune system or their own programmed cell death mechanisms. With advancing age, the immune system becomes ever more dysfunctional due to its own burden of damage, however, and thus less capable of removing senescent cells.
Therapeutic interventions for aging: the case of cellular senescence
Cellular senescence is a stress response characterized by the induction of a permanent cell cycle arrest. Senescence represents an important barrier to tumorigenesis by limiting the growth of potentially oncogenic cells. Senescence-associated growth arrest (SAGA) is accompanied by an overactive secretory phenotype known as the senescence-associated secretory phenotype (SASP). The SASP consists of numerous cytokines, growth factors, proteases and extracellular matrix components that, depending on the physiological context, can be either beneficial or deleterious. During early stages, SASP components promote the migration and infiltration of effector immune cells through the secretion of cytokines and facilitate tissue repair and remodeling by release of growth factors and proteases; however, in later stages, persistent senescent cells negatively impact the surrounding microenvironment by impairing tissue homeostasis through complex cell and non-cell autonomous effects.
In a cell-autonomous manner, selected SASP components such as interleukin (IL)-6 and IL-8 can reinforce SAGA through autocrine pathways. However, the same secreted components can act in paracrine signaling to neighboring cells, propagating the senescent phenotype and thus potentially hampering the regenerative capacity of surrounding tissue. Similarly, in a non-cell-autonomous manner, SASP cytokines promote infiltration of immune cells, yet persistent signaling can result in disruptive chronic inflammation, a hallmark of aging and major contributor to age-related dysfunctions. Indeed, senescent cells accumulate late in life and at sites of age-related pathologies, and genetic interventions enabling the effective clearance of senescent cells in genetically engineered animal models is sufficient to delay a number of age-related phenotypes.
Accordingly, a prolonged healthspan is obtained by pharmacological interventions using a novel class of drugs termed senolytics, used to selectively ablate senescent cells. Senolytic interventions not only demonstrated the feasibility of extending healthspan but also evidenced the alleviation of a wide range of pre-existent age-related symptoms including: improved cardiovascular function, reduced osteoporosis and frailty; enhanced adipogenesis, reduced lipotoxicity and increased insulin sensitivity; improved established vascular phenotypes associated with aging and chronic hypercholesterolemia; as well as radioprotection and rejuvenation of aged-tissue stem cells.
Although regeneration capacity deteriorates with age in mammals, it remains intact in other species such as salamanders. Surprisingly, salamanders show a significant induction of cellular senescence during limb regeneration; however, rapid and effective mechanisms of senescent cell clearance operate in regenerating tissues. Accordingly, the number of senescent cells does not increase upon aging, in contrast to mammals. However, very recently senescent cells have been shown to promote tissue regeneration also in mammals, probably through secretion of specific SASP factors. Thus, pharmacological or localized assisted immunological clearance of senescent cells might potentially aid regeneration of dysfunctional aged tissues.
The various beneficial effects resulting from the administration of drugs to selectively eliminate senescent cells, or suppress the deleterious aspects of the SASP, encourage their use in the treatment of age-related disabilities and chronic diseases as a group. Unfortunately, many challenges are still to be overcome for a successful drug development program, including increased selectivity and reduction of off-target effects. The optimization of therapeutic dosage in already approved drugs, now repurposed for aging interventions, appears promising in the reduction of unwanted side-effects, as demonstrated for rapamycin using lower intermittent doses. Additionally, the development of appropriate animal models capable of demonstrating the beneficial effects using clinically relative outcomes is imperative. These models would ideally be capable of distinguishing on-target from off-target effects to enable a correct assessment of safety and efficacy at a preclinical level, and ultimately grant their use in human clinical trials. In the near future, it is most likely that interventions against cellular senescence will only be prescribed on a case-by-case basis, for specific age-related dysfunctions, in patients with a favorable risk:benefit tradeoff; as is already the case in oncology where many identified senolytics are currently under investigation. Promisingly, however, human clinical trials are already underway to evaluate pharmaceutical impacts on longevity and human aging as a whole, extending our understanding on the human biology of aging and suggesting antiaging interventions could be closer than expected.
Keeping a Careful Eye on When You Cease to be You
As I opened the week with a reprint of the Million Year Life Span, it seems fitting to end the week with a short article that focuses on one important aspect of much the same topic. After aging is conquered, the pursuit of exceptional longevity will require us to move beyond biology. Given present accident rates, ageless humans will only live for a few thousand years. Even with vastly reduced accident rates, sooner or later the vulnerable human physiology will succumb to misfortune. To live for very much longer, for tens and hundreds of thousands of years, we must transcend our biological origins in some way. The operation of our minds must move to a far more robust and easily maintained machine infrastructure, each neuron a device. But as those who favor uploading and emulation of the mind in software would point out, physical existence based on machines taking the place of neurons is only one of the many options for transcendence that will open up with progress in technology. To my eyes, the vital, the only question to ask at each stage of the process of becoming greater and vaster than before is whether you will still be you afterwards: is your continuity as an individual preserved?
Becoming Immortal: The Future of Brain Augmentation and Uploaded Consciousness
Let's say you replace a single neuron in your brain with one that functions thousands of times faster than its biological counterpart. Are you still you? You'd probably argue that you are, and even a significant speed bump in a single neuron is likely to go largely unnoticed by your conscious mind. Now, you replace a second neuron. Are you still you? Again, yes. You still feel like yourself. You still have the continuity of experience that typically defines individuality. You probably still don't notice a thing, and indeed, with only a couple of overachieving neurons, there wouldn't be much to notice. So, let's ramp it up. You replace a million neurons in your brain with these new, speedy versions, gradually over the course of several months. Sounds like a bunch, right? Not really; you've still only replaced 0.001% of your brain's natural neurons by most estimates. Are you still you?
You may find you're reading books a teensy bit faster now, and comprehending them more easily. An abstract math concept that once confused you now begins to make some sense. You're still very much human, though. But why stop there? You're feeling pretty good. You feel the tug of something greater calling you. Is it the curiosity, the siren call of improving one's own intelligence? You embark on a neurological enhancement regimen of two billion fancy new neurons every month for a year. After this time, you've got on the order of 24 billion artificial neurons in your head, or about a quarter of your brain.
Are you still you? Your feelings and emotions are still intact, as the new neurons don't somehow erase them; they just process them faster. Or they don't, depending upon your preference. About half-way through this year, you began noticing profound perceptual changes. You've developed a partially eidetic memory. Your head is awash in curiosity and wonder about the world, and you auto-didactically devour articles at a rapid clip. Within weeks you've attained a PhD-level knowledge of twenty subjects, effortlessly. All art becomes not just a moving experience, but an experience embedded in a transcendental web of associations with other, far-removed concepts. Synesthesia doesn't begin to cover what you're experiencing. But here's the thing; it's not overwhelming, not to your enhanced, composite brain and supercharged mind.
You reason (extraordinarily quickly at this point), that since you don't seem to have lost any of your internal experience, you should seek the limit or its limitlessness, and replace the rest of it. After all, at this point, everyone else is, too. It's getting harder to find work for someone who's only a quarter-upgraded. Over the next three years you continually add new digital neurons as your biological ones age, change, and die out. Are you still you? Following this, you are a genius by all traditional measures. Only the most advanced frontiers of mathematics and philosophy give you pause. Everything you've ever experienced, every thought that was ever recorded in your brain (biological or otherwise) is available for easy access in an instant.
Years pass. The same medical technology that allowed your neurons to be seamlessly replaced, aided and accelerated by a planet full of supersavants, has replaced much of your biological body as well. You're virtually immortal. Only virtually, of course, because speeding toward Earth at a ludicrous velocity is a comet the size of Greenland. There is general displeasure that the Earth will be destroyed (and just after we got smart and finally cleaned her up!), but there's a distinct lack of existential terror. Everyone will be safe, because they are leaving. How does a civilization, even a very clever one, evacuate billions of people from a planet in the space of years? It builds some very large machines that circle the Sun, and it uploads everyone to these machines. Uploads? People? Why sure, by now everyone has 100% electronic minds. These minds are simply software; in fact, they always were. Only now, they're imminently accessible, and more importantly, duplicable.
Billions of bits of minds of people are beamed across the solar system to where the computers and their enormous solar panels float, awaiting their guests. Of course, just as with your neuronal replacements all those years ago, this is a gradual process. As neurons are transferred, their counterparts in your skull are disabled. The only difference you feel is a significant lag, sometimes on the order of minutes, due to the millions of miles of distance between one half of your consciousness and the other. Eventually, the transfer is complete, and you wake up in a place looking very familiar. Are you still you?
What is the difference between a process of gradual replacement that resembles the neurogenesis and cell death that already happens in the brain and a process that kills you in order to create a duplicate? Where does the Ship of Theseus, in which it seems sensible to argue it is the same ship if a single plank is replaced, become the grandfather's ax, where we start to have doubts about continuity when replacing the head or handle? Further, how fast and transformative a replacement of neurons can take place before we call it death rather than transcendence? The essential nature of slow replacement that argues for continuity is that (a) the new replacement is a small part of the whole, and (b) the replacement comes to equilibrium with the existing structure before the next replacement takes place. The neuron integrates into neural circuits, the plank is taken voyaging. Large replacements and rapid replacement are both problematic. Few people would be comfortable swapping out a quarter of the brain at once, or running a process of neuron by neuron replacement for the entire brain in an hour. Nor should they be. What use is it if a pattern survives when you, yourself, do not?
In the decades ahead, it will become possible to copy and dramatically alter the mind, as well as to replace neurons with machinery. That doesn't mean that every such implementation is a sound path to exceptional longevity, a continuity of the self far beyond the limits of biological human agelessness. Many of them will be expensive ways to achieve a subtle form of suicide. A copy of you is not you, and for that matter it is far from clear that an emulated mind running in software is in fact a discrete and continuous entity rather than an ongoing flicker of partial, immediately destroyed shades. That depends entirely on the computational architecture. Unless data is tied to physical structure in the same way as occurs in neurons and the human mind, it is hard to argue for an emulation to be alive, a discrete individual in the way we are. No mainstream computational architecture is heading in that direction, and it seems likely that the first emulations will run many layers of abstraction removed from questions of physical storage models. This is a horrible tragedy, but those who disagree with my metaphysics will no doubt go ahead and do it anyway.
I believe that an important existential challenge will arise in the next phase of human longevity, after aging is cured, driven by the economics of mind emulation and other neurotechnologies yet to be developed. Emulations, and other people willing to break continuity of the self by altering the data of the mind in similar drastic ways, such as by running multiple copies with periodic reintegration through overwriting data, will have a considerable economic advantage over those who strive to be certain in retaining continuity of identify. They can change themselves to circumstances, and undertake far more activities per unit time. If present opinions and trends are any guide, there is the risk of humanity dwindling to only a handful of long-lived entities, lost amidst a sea of transient and ever-changing ghosts that pretend to continuous existence but in fact destroy themselves over and over, more rapidly than they form thoughts. It will be the death of identity, and the death of all of those who once lived, but then chose to transform themselves into the basis for such a computational wilderness, where there is only oblivion writ large and repeated, not life as we understand it.
Latest Headlines from Fight Aging!
Investigating the Early Stages of Inflammation in Arthritis
Researchers here examine the biochemistry and behavior of immune cells in the early stages of arthritis, a condition that is strongly associated with age-related increases in chronic inflammation. Inflammation in turn is associated with growing dysfunction of the immune system with age, a progressive failure that occurs for a variety of reasons, including the presence of metabolically active excess visceral fat tissue that is so common this age of cheap calories; a reduced supply of new immune cells due to declining stem cell activity and involution of the thymus; and dominance of the immune cell population by cells devoted to persistent pathogens such as cytomegalovirus, which cannot effectively assist in responding to new threats. Reducing inflammation should be helpful for arthritis patients, and some of the more common forms of stem cell therapy that achieve this outcome so far appear to be more effective than other options for many of those who undergo the treatments. For much the same reasons, senolytic therapies that target senescent cells for destruction will most likely first enter human trials as arthritis treatments, as senescent cells are another prominent cause of inflammation.
Using a novel approach for imaging the movement of immune cells in living animals, researchers have identified what appear to be the initial steps leading to joint inflammation in a model of inflammatory arthritis. "Inflammatory arthritis is caused when immune cells are recruited from the blood into the joint in a highly regulated process controlled by chemoattractants and adhesion receptors. But when the disease has become symptomatic, it is difficult to determine the initial steps that set off the recruitment of immune cells into the joint and the specific roles of the different chemoattractants. Our study was designed to more fully understand this process. The control of immune cell entry into the joint represents a major point at which new therapies could be developed to reduce the symptoms of inflammatory arthritis."
Inflammatory arthritis includes a number of autoimmune diseases of the joints - including rheumatoid arthritis and lupus - and in many cases is caused by a type of inflammation called type III hypersensitivity. That reaction results when a localized accumulation of immune complexes - antibodies bound to their antigens - is deposited in tissue and sets off an inflammatory response involving the infiltration and activation of immune cells, initially the neutrophil. Current thinking regarding type III hypersensitivity is that immune cells within tissues sense the presence of these immune complexes (ICs) through specific receptor molecules and release inflammatory factors called cytokines that activate the endothelial cells lining adjacent blood vessels to promote the recruitment of neutrophils.
To better determine the role of specific chemoattractants in type III hypersensitivity, researchers used multiphoton intravital microscopy to follow in real time the development of IC-induced arthritis in a mouse model of rheumatoid arthritis. Their experiments revealed that the presence of ICs within the joint space induces the generation of complement C5a, a component of the innate immune system, which is then displayed on the inner walls of adjacent blood vessels. C5a directly initiates the adherence of neutrophils to the vessel walls through interaction with the C5a receptor on neutrophils, which then pass into the joint space and set off inflammation. Once the inflammatory process has been initiated, neutrophils within the joint space release interleukin-1, which induces cells lining the joint space to produce chemoattractants called chemokines that further facilitate the movement of neutrophils into the joint space. Neutrophils within the joint also directly produce chemokines that amplify the cells' recruitment to and survival within the joint space.
Are We Terrible at Advocacy, or is it Actually Hard to Persuade People of the Merits of Living Longer in Good Health?
For those of us who immediately understand, at first recognition, that the opportunity to live a longer life in good health would be a fantastic thing, and in fact so wondrous that we should jump up and do something to make it happen, it is a continual puzzle that we find ourselves in a minority. How is it that we live in a world in which the majority simply doesn't care, or if prompted on the topic, declares their desire to age, suffer, and die on the present schedule? After a few years of this, one might be forgiven for thinking that we are just not very good at advocacy. But given a second consideration, we might ask why we should have to be good at advocacy at all in this situation. Isn't more good health and vigor, and an absence of horrible, debilitating age-related disease, an obvious and unalloyed good? Isn't the whole point of medicine to defeat disease and prolong health? Isn't it the case that all of these people in favor of aging and age-related death nonetheless go out and visit the doctor when they get ill, while supporting research into treatments for cancer and other age-related diseases? I don't think that we are the irrational ones in this picture.
After going on fifteen years of writing on this topic, I don't have much more of an idea than I did when I started as to why greater human longevity isn't an obvious and highly important goal for everyone. The same questions and theories back then are still here today, and there is still little data to pin down their accuracy: fear of frailty, of overpopulation, of any change, even positive, and so forth. Since it was an immediate and evident revelation for me, rather than a gradual conversion, perhaps I am not the right person to achieve that understanding. I am, however, pleased to see that despite the challenges our community of iconoclasts, heretics, revolutionaries, and rational thinkers on the subject of longevity science is greatly expanded these days. More of these folk than ever are writing and persuading, both inside and outside the scientific community. We have progressed and grown as a community, alongside progress in the state of the science.
For today, I see that the Life Extension Advocacy Foundation has set up a blog in order to help bring spread our message to new audiences. As noted by the author here, the best evidence so far suggests that the fear of being old and decrepit for longer as a result of life extension therapies is the most important factor in public opposition to greater longevity, despite the fact that scientists and advocates have repeatedly disclaimed this as a goal, and that many have noted that such an outcome is implausible to achieve even if someone was trying. On the one hand that suggests that it is simple ignorance that might be dispelled, but on the other it seems very resistant to the efforts already made, over and again, by near every public figure involved in the aging research community.
Most advocates of life extension report facing resistance to the idea of increased lifespans by medical means when trying to disseminate this idea among general public. Resistance manifests itself in many forms, ranging from concerns such as overpopulation to concerns about unequal access to life extending treatments. But the most unexpected thing is probably that people often don't want an increased lifespan at all. Surveys in different countries show, that when people are asked "how long would you like to live?", they often give a number equal to or slightly higher than the current life expectancy in a given country. But wait ... Isn't extending life for more decades a good thing that everyone should strive for? In reality we often do not see enough enthusiasm for the idea in general. So why is this?
It turns out that the reaction of general public to the idea depends on how the message is formulated. When only life extension is offered, without details of how healthy, mentally sound and good-looking an individual could become, people express less support for the idea. But when life extension is proposed as a combination of perfect physical and mental health, it changes the response dramatically, leading to many more people accepting the idea, and also showing support for the development of corresponding medical technologies. It is important to note, that there are also other factors that influence higher support for life extension and related medical innovations, reported by researchers. An interest in science, for example, appears to be the strongest predictor of a positive attitude towards medical interventions to extend life.
In some surveys, where the message did not include a promise of perfect health combined with longevity, males were found to be more likely to support life extension than females. Most likely, this can be explained by different perception of the risks. Males are found to be more likely to take the risks, so they can cope better with the risks emerging from using an innovative technology, when the long-term effects are still unknown and the volume of benefit is not clear. In other studies, however, when healthy life extension (with a "utopian" scenario) was offered, this difference between the sexes did not remain consistent, males and females were equally supportive of life extension technologies. It could be that a positive scenario does not engage the mechanisms of risk avoidance. But then, it means that solely by adding perfect health to life extension in our messages, we can significantly widen the number of our supporters. Studies like this illustrate the importance of analyzing how the nature of the message matters in furthering our cause. The advocates of rejuvenation biotechnology, including research groups and fundraisers for aging biology research, should carefully consider the messages they are using, as some of them are more efficient to encourage an informed and engaging discussion with society about the benefits of bringing aging under medical control.
A Less Effective Compensatory Response to Mitochondrial DNA Deletions Observed in Parkinson's Disease Patients
Mitochondria, the power plants of the cell, evolved from symbiotic bacteria, and still carry a remnant genome of their own, entirely separate from the nuclear DNA found in the cell nucleus. Unfortunately, mitochondrial DNA is prone to deletion mutations, either due to replication errors or oxidative reactions, and some types of deletion can form the basis for runaway cellular dysfunction. This process is one of the causes of degenerative aging, and doing something about it is one of the line items on the SENS rejuvenation research agenda. As it happens, mitochondrial DNA damage accumulates more readily in some tissues than in others. It is known that this is the case in the substantia nigra, for example, and that this susceptibility is connected to the development of Parkinson's disease, a condition caused by the loss of dopamine-generating neurons in that area of the brain. Researchers here provide evidence to support the contention that Parkinson's patients are distinguished from their comparatively healthy peers not by more mitochondrial damage, but rather by the lack of a compensatory generation of more undamaged mitochondrial DNA in the affected neurons:
Somatic mitochondrial DNA (mtDNA) damage has been associated with both normal aging and neurodegeneration. Accelerated mtDNA mutagenesis causes a premature aging phenotype in mice and somatic mtDNA deletions have been shown to accumulate with advancing age in post-mitotic tissues including the brain, heart and skeletal muscle. In the brain, the dopaminergic substantia nigra is particularly susceptible to somatic mtDNA deletions, which accumulate there at substantially higher levels compared with other areas of the brain. This predilection has led to the hypothesis that mtDNA damage plays a role in the pathogenesis of Parkinson disease (PD), where neurodegeneration of the substantia nigra is the main pathological hallmark and widely accepted as the cause of the cardinal clinical features.
mtDNA deletions were shown to accumulate at similar levels in both individuals with PD and healthy controls however, and therefore do not provide a sufficient explanation for the specific vulnerability of the substantia nigra in PD. Mice accumulating high levels of mtDNA deletion due to an error-prone mtDNA-polymerase (POLG) show a concomitant increase in mtDNA copy number which is associated with nigrostriatal survival and even resistance to mitochondrial respiratory chain complex-I inhibition. Although a similar protective mechanism has not yet been identified in humans, the importance of mtDNA copy-number regulation is highlighted by the vulnerability of the substantia nigra in inherited mtDNA-depletion disorders and the increased risk of PD associated with genetic variation in genes encoding key factors of mtDNA maintenance, such as the mtDNA polymerase γ (POLG) and mitochondrial transcription factor A (TFAM). Nevertheless, the precise mechanism by which mtDNA copy-number loss contributes to brain aging and neurodegeneration remains unclear.
We hypothesized that dopaminergic substantia nigra neurons in PD are rendered vulnerable to the effects of age-dependent mitochondrial mutagenesis due to an underlying dysregulation of mtDNA homeostasis. To test our hypothesis, we employed an integrative approach to study the complete spectrum of mtDNA changes in individual neurons from individuals with PD and controls. Our sample was derived from a population-based, prospectively collected and extensively characterized cohort. To ensure our sample was homogenous and representative for sporadic PD, we excluded known monogenic causes of PD by whole-exome sequencing. Neuropathological examination confirmed Lewy-body disease in all PD samples, whereas control samples were negative for neurodegenerative markers. Our results show that dopaminergic substantia nigra neurons of individuals with PD accumulate higher levels of somatic mtDNA deletions, but not point mutations, compared with age-matched controls. Moreover, in healthy individuals, mtDNA copy number increases with age, thus maintaining the pool of wild-type mtDNA population in spite of accumulating deletions. Conversely, mtDNA copy number does not increase in individuals with PD, resulting in depletion of the wild-type mtDNA population. Our findings suggest that mtDNA homeostasis is impaired in the substantia nigra of individuals with PD.
Why Work to Dismantle Arguments Made Against Increased Healthy Longevity?
Many varied arguments are made against attempts to extend human life spans through medical science: overpopulation, economic impacts, boredom, stasis, that people would be aged and decrepit for longer, and so forth. The only thing they have in common is that they are all fairly ramshackle, and tend to fall apart in the face of even a mildly rigorous look at the data and the evidence. Not that this state of affairs seems to have converted all that many people to our side of the tracks. Arguments against living longer in good health have more to do with emotion, comfort zones, and signaling to peers than anything else, I'd say. The same people who, when prompted, declare that everyone should age to death on the same schedule that exists today also visit doctors when sick, would rather not live with the life expectancy of a few hundred years past, and are generally supportive of efforts to defeat age-related diseases such as cancer, Alzheimer's disease, heart disease, and so forth. They are very inconsistent in word and deed.
I see opposition to life extension as just one of many manifestations of the inherent tendencies towards conservatism and discomfort with change, any change, that are deep-set parts of the human mentality. People who are essentially comfortable here and today tend to want things to stay as they are, no matter what that state might be. If that means closing one's eyes to tens of millions of unpleasant deaths every year and the ongoing suffering of hundreds of millions more, then so be it. Yet aging and its consequences are not set in stone, and they can be changed through medical research and development. All this death and pain need not continue. That is why it is important to dismantle the half-hearted and ill-thought objections to treating aging as a medical condition and thereby extending healthy life spans. Most of the death and disease in the world could be swept away in the decades ahead, given the support and investment to do so, but today so very much of that support has instead buried its collective head in the sand.
Arguments against rejuvenation only sound reasonable because they appeal to our fears and to the blame-the-humans attitude of so many people. If you trust only your gut feelings and don't bother examining facts and data, anti-rejuvenation arguments can easily seem obviously true. Accepting an anti-rejuvenation argument requires far less mental work than understanding why the same argument isn't as sound as it appears, but that doesn't make anti-rejuvenation arguments any more 'obviously true' than their rebuttals. It is impossible to know for a fact whether or not rejuvenation will cause any given problem before we get there.
Proving that no problems will arise as a consequence of defeating ageing is not the point of rebutting objections to rejuvenation. That's not what any of my answers does. All they do is showing that objections to rejuvenation rely more often than not on fallacious reasoning, ignorance, fears, misconceptions, and wrong assumptions taken for established fact. In short, what we do when rebutting objections to rejuvenation is showing they aren't valid reasons to let ageing continue crippling and killing us. At the same time, answers to objections show why all those predictions of doom and gloom aren't as likely as they may appear. There's no certainty to be found anywhere, but this doesn't really matter-had we refrained from doing anything that wasn't proved to be 100% risk-free throughout history, we'd probably still be living in caves.
Remember: Objections to rejuvenation are about hypothetical future problems that are far from being certain. Ageing and all the suffering and deaths that come with it are a very tangible fact, happening here and now. This alone should be sufficient to forget about objections altogether and focus only on putting an end to ageing. However, rebutting objections has also another purpose: It fuels discussion. Apart from raising awareness of the problem of ageing and the feasibility of its defeat, discussion prepares us to face the new challenges an ageless future might bring. The way to a world without ageing is still long, which gives us all the time we need to prevent eternal dictators, overpopulation, and all sorts of dystopian scenarios from ever materialising.
The Methuselah Foundation's Bioprinting Program
The Methuselah Foundation was an early investor in tissue engineering company Organovo, and continues to have a strong interest in accelerating progress in this field through initiatives like the New Organ programs. A while back the Methuselah Foundation kicked off their 3D bioprinter program in collaboration with Organovo, putting bioprinters into academic departments where they can be used to speed up the development of new tissue engineering methodologies. At some point in the decades ahead the research community will be capable of rapidly printing or growing near any type of tissue using a patient's own cells, and the aim here is to help bring that day closer.
Organovo, a three-dimensional biology company focused on delivering scientific and medical breakthroughs using its 3D bioprinting technology, today announced a collaboration with the Murdoch Childrens Research Institute, The Royal Children's Hospital, Melbourne, Australia to develop an architecturally correct kidney for potential therapeutic applications. The collaboration has been made possible by a generous gift from the Methuselah Foundationas part of its ongoing University 3D Bioprinter Program. "Partnerships with world-class institutions can accelerate groundbreaking work in finding cures for critical unmet disease needs and the development of implantable therapeutic tissues. This collaboration is another important step in this direction. With the devoted and ongoing support of the Methuselah Foundation, leading researchers are able to leverage Organovo's powerful technology platform to achieve significant breakthroughs."
We have developed an approach for recreating human kidney tissue from stem cells," said the Theme Director of Cell Biology at Murdoch Childrens Research Institute. "Using Organovo's bioprinter will give us the opportunity to bioprint these cells into a more accurate model of the kidney. While initially important for modelling disease and screening drugs, we hope that this is also the first step towards regenerative medicine for kidney disease. We are very grateful to Organovo and the Methuselah Foundation for this generous support, which will enable us to advance our research with the first Organovo bioprinter in the southern hemisphere." Under Methuselah Foundation's University 3D Bioprinter Program, Methuselah is donating at least 500,000 in direct funding to be divided among several institutions for Organovo bioprinter research projects. This funding will cover budgeted bioprinter costs and key aspects of project execution.
Bioprinting Human Skin Cuts the Time Needed from Weeks to Minutes
Skin is one of the easier starting points for 3D bioprinting, the application of rapid prototyping technologies to the construction of living tissue. Since skin is a thin tissue, the challenging issue of producing the intricate blood vessel networks needed to supply inner cells with oxygen and nutrients can be skipped. Thin tissue sections can be supported in a suitable nutrient bath, and after transplant, patient blood vessels will grow into the new skin. Further, there is a fairly large and long-established research and development industry involved in various forms of skin regeneration. Numerous forms of prototype skin-like tissues have been created over the years, lacking many of the features of the real thing, but still useful in the treatment of, for example, burn victims. Further, skin structure is by now well understood, and considerable progress has been made in deciphering the signals and environment needed for suitable cells to self-assemble into the correct arrangements. All told, it should not be a complete surprise to see significant progress emerge in this part of the field.
Significant progress has been made over the past 25 years in the development of in vitro-engineered substitutes that mimic human skin, either to be used as grafts for the replacement of lost skin, or for the establishment of in vitro human skin models. In this sense, laboratory-grown skin substitutes containing dermal and epidermal components offer a promising approach to skin engineering. In particular, a human plasma-based bilayered skin generated by our group, has been applied successfully to treat burns as well as traumatic and surgical wounds in a large number of patients in Spain. There are some aspects requiring improvements in the production process of this skin; for example, the relatively long time (three weeks) needed to produce the surface required to cover an extensive burn or a large wound, and the necessity to automatize and standardize a process currently performed manually. 3D bioprinting has emerged as a flexible tool in regenerative medicine and it provides a platform to address these challenges.
In the present study, we have used this technique to print a human bilayered skin using bioinks containing human plasma as well as primary human fibroblasts and keratinocytes that were obtained from skin biopsies. We were able to generate 100 cm2, a standard P100 tissue culture plate, of printed skin in less than 35 minutes (including the 30 minutes required for fibrin gelation). We have analysed the structure and function of the printed skin using histological and immunohistochemical methods, both in 3D in vitro cultures and after long-term transplantation to immunodeficient mice. In both cases, the generated skin was very similar to human skin and, furthermore, it was indistinguishable from bilayered dermo-epidermal equivalents, handmade in our laboratories. These results demonstrate that 3D bioprinting is a suitable technology to generate bioengineered skin for therapeutical and industrial applications in an automatized manner.
An Example of Transplanted Neurons Integrating into the Brain
Many types of cell therapy largely work through signaling; the transplanted cells do not last long and very few successfully integrate with the patient's tissue. They do, however, release signals that produce a temporary beneficial alteration in local cellular behavior, such as a suppression of inflammation in the case of more widely available mesenchymal stem cell therapies. This isn't really the desired outcome, however. It would be far better for the majority of transplanted cells to survive and take up residence, replacing or augmenting the activities of local cells. This is actually necessary for meaningful benefits to be produced in many cases, such as for age-related diseases in which some of a patient's cell populations are malfunctioning or diminished in number. A fair amount of work in the research community is focused on finding reliable ways to make this happen:
Today, a stroke usually leads to permanent disability - but in the future, the stroke-injured brain could be reparable by replacing dead cells with new, healthy neurons, using transplantation. Researchers have taken a step in that direction by showing that some neurons transplanted into the brains of stroke-injured rats were incorporated and responded correctly when the rat's muzzle and paws were touched. The study used human skin cells. These cells were re-programmed to the stem cell stage and then matured into the type of neurons normally found in the cerebral cortex.
A couple of years ago, the research team had already proven that transplanting this type of cells to the cerebral cortex enabled stroke-injured rats to move better. At the time, however, it was unclear whether the host brain really formed functioning connections with the transplanted nerve cells. Now the new study has proven that this is indeed the case. The research team used several advanced methods in the study - electron microscopy, virus-based tracing techniques, registration of activity in the transplanted cells and optogenetics. The results show that various parts of the host brain form normal, functioning connections with the transplanted neurons and that the latter change their activity when the animal's muzzle and paws are touched.
"This is the first time anyone has been able to show such a result. That some of the new nerve cells receive signals from the host brain in a normal way indicates that they have been incorporated into the stroke-injured rat's brain. In it, they have been able to replace some of the dead nerve cells. This is basic research, and it is not possible to say when we will be ready to start experiments on patients. But the objective is clear: to develop a treatment method which can repair the stroke-injured brain. Currently, there is no effective treatment which can restore function in a stroke patient once the first hours following a stroke have passed."
News of Another Possible Tau Clearance Therapy
Tauopathies, a category that includes Alzheimer's disease, are neurodegenerative conditions characterized by the accumulation of altered forms of tau protein into solid neurofibrillary tangles. This is only one of a range of proteins that exhibit this sort of behavior with advancing age, such as the various forms of amyloid, and any comprehensive future toolkit for rejuvenation will have to incorporate the means to clear out this unwanted and damaging metabolic waste. In recent years, a few signs of progress towards tau clearance therapies have emerged, and while aimed largely at treating the later stages of Alzheimer's disease at the present time, a successful therapy of this class is something that probably should be applied to everyone on a periodic basis in later life. We all accumulate altered tau, and the only differences between someone with a tauopathy and someone without are matters of degree and time.
Under ordinary circumstances, the protein tau contributes to the normal, healthy functioning of brain neurons. In some people, though, it collects into toxic tangles that damage brain cells. Such tangles are a hallmark of Alzheimer's and other neurodegenerative diseases. But researchers have shown that levels of the tau protein can be reduced - and some of the neurological damage caused by tau even reversed - by a synthetic molecule that targets the genetic instructions for building tau before the protein is made. The findings suggest that the molecule - known as an antisense oligonucleotide - potentially could treat neurodegenerative diseases characterized by abnormal tau, including Alzheimer's.
Researchers studied genetically modified mice that produce a mutant form of human tau that easily clumps together. These mice start showing tau tangles at around 6 months of age and exhibit some neuronal damage by 9 months. To reduce tau, the researchers used an antisense oligonucleotide, a kind of molecule that interferes with the instructions for building proteins. Genes in the DNA are copied into RNA, a messenger molecule that carries the instructions for building a protein. Antisense oligonucleotides bind to the messenger RNA and target it for destruction before the protein can be built. Such oligonucleotides can be designed to target the RNA for almost any protein.
The researchers administered a dose of the anti-tau oligonucleotide to 9-month-old mice every day for a month and then measured the amount of tau RNA, total tau protein and tangles of tau protein in their brains when the mice were 12 months old. The levels of all three were significantly reduced in the treated mice compared with mice that received a placebo. Importantly, levels of total tau and tau tangles in the brains of treated 12-month-old mice were lower than in untreated 9-month-old mice, suggesting that the treatment not only had stopped but reversed the buildup of tau.
By the time this strain of genetically modified mice reaches 9 months of age, the hippocampus - a part of the brain important for memory - typically is visibly shrunken and shows dying neurons. But with the oligonucleotide treatment, the shrinkage and cell death were halted. There was not, however, any evidence of reversal of neuronal death. The treated mice lived an average of 36 days longer than untreated mice, and they were better at building nests, which reflects a combination of social behavior, cognitive performance and motor capabilities. All of these functions can be impaired in people with Alzheimer's disease and other tau-related neurodegenerative diseases.
The researchers were intrigued by the possibility of designing studies to lower tau in people, but first they needed to see how the oligonucleotide worked in an animal more similar to people than a mouse. The researchers treated groups of healthy cynomolgus monkeys with two doses of placebo or oligonucleotide, one week apart, directly into the cerebrospinal fluid that surrounds the spinal cord and brain, just as would be done with human patients. Two weeks later, they measured the amount of tau protein and RNA in the monkeys' brains and cerebrospinal fluid. The oligonucleotide reduced both tau RNA and protein in the brain, and this reduction was mirrored in the cerebrospinal fluid.
A Profile of Researchers Working on Heart Decellularization
This article is a profile of one of the research groups working on decellularization and reconstruction of the heart. As is more often the case in this field these days, those involved are willing to talk about timelines for putting this research into practice. Decellularization is a promising shortcut to the creation of patient-matched organs for transplantation. A donor organ is stripped of cells until only the extracellular matrix structure and its chemical guides and signals is left. That is then populated with the patient's cells, which grow into place and rebuild the tissues. Once the technical challenges have been solved, and the methodologies made reliable, this can potentially expand the pool of donor organs to include a sizable fraction of those that at present are discarded as unsuitable due to tissue damage. It should also be possible to use animal organs as well, such as from pigs, as the decellularization process removes near all of the sources of incompatibility.
Th first thing visitors to the Texas Heart Institute's Regenerative Medicine Research labs see is a pair of large photographs. In one, a lined hand of Denton Cooley, founder of the institute, who died last November, holds a mechanical heart much like the one that he was the first to implant into a human in 1969. In the other, Doris Taylor's gloved hand holds a pig's heart so stark-white, it matches her lab coat. It is a Ghost Heart, scrubbed clean of all cells, leaving only collagen, fibronectin and laminin, which provide a protein scaffold on which to build a new human heart very nearly from scratch. One day, it will cure far more patients with bum tickers than Cooley's earlier invention ever did.
Taylor and her 25-person multidisciplinary team decellularize seven or eight hearts, mostly from rats, a week, then inject the DNA-free scaffolds with stem cells. Because muscular heart cells do not divide, they cannot regenerate on their own like, say, the bladder, an organ which has been regenerated and implanted in humans. In the case of the heart, stem cells (as opposed to heart cells) adhere to the surface of the scaffold, growing into living, functioning organs inside machines known as bioreactors, which replicate the warm, oxygen-rich environment of a heart inside a mammal's body.
The goal, of course, is to build viable organs that will pump blood through an adult's body without assistance and without the threat of rejection, since the heart will be made with the recipient's own cells. Current testing in rats has involved implanting a second heart alongside the original, in hopes that the new organ will strengthen enough inside the body to take command. Taylor estimates that it will be only 10 or 15 years before a functioning heart is implanted into an adult (pediatric hearts are smaller and require less muscle, so that could happen sooner) - "if we do it right. And what I mean by that is that although it's sexy to be first, it's better to be best." Taylor expects a fully functioning liver made from a recipient's own cells will precede the heart by several years.
More Evidence for Exosomes to be Important in the Outcome of Stem Cell Therapies
Stem cell therapies produce benefits, but for most of the presently available treatments this appears to be the result of changes in the signaling environment rather than any other activity on the part of the transplanted cells. The newly introduced stem cells fail to integrate with local tissues and typically don't last long after transplantation. So what exactly produces the observed beneficial changes in cellular behavior, level of inflammation, and degree of regeneration? There are no doubt many distinct mechanisms, as nothing is ever simple when it comes to cell biology, but of late researchers have focused on a role for exosomes. These are membrane-wrapped packages that cells pass between one another, and they appear to be involved in many cellular processes, though at present are only very partially cataloged and understood. If it turns out that they are a primary mechanism by which transplanted stem cells alter the behavior of local cells, then it should be possible to build therapies that deliver only exosomes:
Exosomes are tiny membrane-enclosed packages that form inside of cells before getting expelled. Long thought of as part of a cellular disposal system, scientists have more recently discovered that exosomes are packed with proteins, lipids and gene-regulating RNA. Studies have shown that exosomes from one cell can be taken up by another by fusing with the target cell's membrane, spurring it to make new proteins. Exosomes also facilitate cell-to-cell interactions and play a signaling role, prompting research into their potential therapeutic effect.
A new study in rats shows that exosomes appear to protect cells in the retina, the light-sensitive tissue in the back of the eye. Researchers investigated the role of stem cell exosomes on retinal ganglion cells, a type of retinal cell that forms the optic nerve that carries visual information from the eye to the brain. The death of retinal ganglion cells leads to vision loss in glaucoma and other optic neuropathies. Stem cells have been the focus of therapeutic attempts to replace or repair tissues because of their ability to morph into any type of cell in the body. However, from a practical standpoint, using exosomes isolated from stem cells presents some key advantages over transplanting whole stem cells. Exosomes can be purified, stored and precisely dosed in ways that stem cells cannot.
Another important advantage of exosomes is they lack the risks associated with transplanting live stem cells into the eye, which can potentially lead to complications such as immune rejection and unwanted cell growth. In a rat glaucoma model, researchers studied the effects of exosomes isolated from bone marrow stem cells on retinal ganglion cells. Exosomes were injected weekly into the rats' vitreous, the fluid within the center of the eye. Prior to injection, the exosomes were fluorescently labelled allowing the researchers to track the delivery of the exosome cargo into the retinal ganglion cells. Exosome-treated rats lost about a third of their retinal ganglion cells following optic nerve injury, compared with a 90-percent loss among untreated rats. Stem cell exosome-treated retinal ganglion cells also maintained function, according to electroretinography, which measures electrical activity of retinal cells. The researchers determined that the protective effects of exosomes are mediated by microRNA, molecules that interfere with or silence gene expression. Further research is needed to understand more about the specific contents of the exosomes.