Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.
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- Request for Startups in the Rejuvenation Biotechnology Space, 2017 Edition
- Nrf2 Improves Clearance of Damaged Proteins Associated with Neurodegeneration
- A Look at Ascendance Biomedical, Packaging Medical Tourism for Longevity Therapies
- A Conservative View of Senescent Cell Clearance Research and Development
- A Look Back at 2016 in Longevity Science
- Latest Headlines from Fight Aging!
- An Example of Opposition to Living Longer
- Fear of a Grim Future as a Source of Opposition to Longevity Therapies
- An Effort to Equip Macrophages with Bacterial Enzymes to Prevent Atherosclerosis
- Results from the Gensight Biologics Trial of ND4 Allotopic Expression
- More in the Debate Over Whether or Not Aging Should be Called a Disease
- Dopamine D4 Receptor Allele Correlates with Longevity
- Calling for a Closer Examination of Mitochondrial Biochemistry in the Aging Brain
- Chondrocyte Cell Death in Osteoarthritis
- Chimeric Antigen Receptor Therapy Continues to Perform Well in Lymphoma Patients
- Metformin Acts through mTORC1
Request for Startups in the Rejuvenation Biotechnology Space, 2017 Edition
Some lines of rejuvenation research after the SENS model of damage repair, alongside a number of other useful compensatory technologies such as a select few gene therapies, have reached the point at which clinical development can make the leap to for-profit development in startups. There is a sizable amount of money out there on the sidelines waiting for this; investors of all stripes, from biotech veterans and new longevity-science-focused funds to angel communities. The message in this post is primarily intended for entrepreneurs and those out there in the scientific community with relevant work that is approaching the stage at which translational research and development can begin in earnest. We all know how hard it is to raise money for important, transformative research within the world of grants and philanthropic funding. If you have credible work and can put together a credible team, then look to venture funding sooner rather than later. That is my advice in the present environment.
I am interested in seeing the following types of technology emerge into for-profit development in the next few years, to join those like senescent cell clearance that are already well underway. The list is in no particular order of preference. If any of these cover your area of work and you have the ability to build a way to treat aging and its causes, then I want to hear from you. If you are working on anything else that is in the near future rejuvenation therapy list or the SENS portfolio, and is closer to realization than I expected it to be, then I want to hear from you. There is a growing community of investors out there with a considerable interest in seeing this field of research and development prosper.
Better Senescent Cell Assays
Cellular senescence is a cause of aging. Clearing these cells will turn back or slow the progress of many age-related conditions, and should extend healthy life spans at the same time. The current assays used to evaluate the presence of senescent cells in tissue are, shall we say, good enough for getting the job done in a laboratory setting when the goal is research and development. However, they are too manual, time-consuming, and costly for the near future in which near every adult will want to know the state of their cells before and after a clearance procedure, and in which senescent cell levels in specific tissues will become an important diagnostic tool for a range of age-related conditions. The existing assays are also poorly available to patients, where they exist at all in the current laboratory services market. Better, cheaper, faster assays are needed: ultimately, this should be something that is no more costly or challenging or restricted than is a blood sugar test kit that is sold over the counter.
Restoration of the Aged Thymus
There are numerous studies in mice demonstrating the ability to restore some fraction of lost immune function via transplantation or regeneration of the thymus, such as via foxn1 signaling or using forms of cell therapy and tissue engineering. A straight transplantation of a youthful thymus extends life in aged mice. These approaches work by enabling a higher rate of maturation of new T cells, which lessens some of the constraints that act to cause immunosenescence, the age-related decline in the immune system. This work is too promising not to be ushered rapidly towards the clinic, and some of the relevant lines of research are certainly close enough to make the leap.
Safe Ablation of Immune Cells Free from Side-Effects
Removing all or near-all circulating mature immune cells is an approach that has been used to cure multiple sclerosis, an autoimmune condition in which the immune system becomes misconfigured to attack crucial parts of the patient's cellular biochemistry. The immune system repopulates itself with fresh cells after such a comprehensive removal, but without any of the particular problems that produce autoimmunity. This should work equally well against any autoimmunity that doesn't have a strong genetic cause - or at least it would be very surprising to find an acquired autoimmunity that survived such a treatment. Similarly, many aspects of age-related immune dysfunction either involve autoimmunity or some other form of acquired imbalance and malfunction in immune cell populations. Removing all of the cells should help to turn back the clock to some degree, sweeping away that disarray. Unfortunately even the best of the present methods used to ablate immune cells so completely are essentially forms of chemotherapy: they have significant side-effects, and are probably unacceptably risky for older patients. To move ahead, methods of side-effect-free targeted destruction of all forms of immune cell are required: any such technology would immediately be applicable to autoimmunity and immunosenescence in the old.
Packaged and Reviewed Medical Tourism Services
We are on the verge of the clinical availability of worthwhile therapies that either compensate for or treat the causes of aging. This will happen outside the excessively regulated US medical system, in regions where only safety has to be demonstrated. BioViva and Sierra Sciences would like to offer follistatin gene therapies for example, and the first senolytic drugs to clear senescence cells are well categorized enough to be offered by any clinic just as soon as people put their minds to it. The availability of stem cell therapies developed in much the same way following the turn of the century. Despite that history, the medical tourism market is still very immature at the present time. There is a lack of organizations to provide informed reviews of clinics and procedures and to package the various needed portions of the product into one service: flight, stay, therapy, follow-up, and so on. When the flow of patients is small, as is the case for many medical conditions, it might make less sense to enter this market. The new therapies to treat the causes of aging will be beneficial to half of the population presently alive, including all of those presently in good health, however: an enormous market.
Gene Therapy with Reliable, Well-Established High Levels of Cell Coverage
As the initial BioViva data hints at, and as has been demonstrated in animal studies, the challenge for gene therapy is that without sufficient coverage of cells, and especially stem cell populations, the effects are small or transient. The first broadly useful gene therapies in the matter of aging are likely to be the myostatin and follistatin therapies that increase muscle mass, thereby slowing or somewhat compensating for the progression of sarcopenia. The first attempts in humans, either gene therapy or antibody blockade, are nowhere near as impressive as the results in mutant lineages in which all cells have the altered or missing genes, however. In this dawning CRISPR-powered era of gene therapies, there is first and foremost a great need for reliable, high levels of cell coverage. Any significant step towards solving this problem can be applied to the first classes of enhancement gene therapy, and thereby make them far more useful and valuable.
Small Molecule or Enzymatic Glucosepane Cross-Link Breaking
Cross-links in the extracellular matrix are a significant cause of aging, contributing to, for example, the chain of consequences that passes through arterial stiffening, hypertension, and finally cardiovascular disease and death. Also loss of skin elasticity, which most people seem to care about a lot more, somewhat irrationally. Comparatively little work is taking place to produce therapies that can break the dominant type of cross-link in humans, glucosepane, and most of that work is being funded by the SENS Research Foundation. Now that glucosepane has been efficiently synthesized, the door is open, however. Any group with knowledge of this area of biochemistry can put in practical work towards the production of good tissue models, antibodies suitable for glucosepane cross-link assays, and small molecule or enzymatic cross-link breakers. The SENS Research Foundation teams are not the only research groups out there who have expressed interest in this area in the past, and a little competition would be a welcome sign of progress.
Nrf2 Improves Clearance of Damaged Proteins Associated with Neurodegeneration
The protein Nrf2 shows up in a number of places in the study of aging and related aspects of cellular biochemistry. Higher levels of Nrf2 appear to correlate well with longer species lifespan, at least among mammals in the wild, but this is also arguably the case in the various genetically engineered lineages of mice, worms, and flies that exhibit longer lifespans. Until recently the main focus of research into the role of Nrf2 has been the regulation of antioxidants as a response to cellular stress, as occurs due to the metabolic demands of exercise, for example. Of interest here is that Nrf2 levels decline with age, which is probably a phenomenon that we'd be better off without; it is one of many, many candidates for the mechanisms of aging that float somewhere between the root causes and the final consequences in the long chain of cause and effect that produces degenerative aging as we know it.
In the research linked below, the authors expand the bounds of influence for Nrf2, linking it to some of the mechanisms of cellular housekeeping that strive to remove damaged proteins. In particular, it seems influential in the matter of a few proteins associated with neurodegenerative conditions, such as α-synuclein in synucleinopathies like Parkinson's disease. Greater cellular maintenance activity is a common theme in many of the methods that have been demonstrated to modestly slow aging in laboratory species. When cells have less damage at any given moment in time, that damage has less of a chance to cause further downstream harm. There are many researchers who place natural mechanisms of quality control and damage repair at the center of all methods of slowing aging via metabolic and genetic alteration discovered to date, and evidence such as calorie restriction requiring the maintenance processes of autophagy in order to extend healthy life makes this a fairly compelling argument.
If greater levels of Nrf2 indeed produce greater housekeeping efforts in the clearance of damaged proteins, then that new knowledge fits well into this bigger picture given what is known to date. Where is this all going, however? Despite a good many years during which numerous researchers have argued for the importance of increased cellular maintenance, there has been next to no concrete progress towards therapies based on this principle. I was noting calls to action on this topic a decade ago, and I am by now somewhat surprised at the continued lack of motion towards the clinic in this part of the field, despite a growing catalog of research very much like the results presented here.
Single Protein May Hold Secret to Treating Parkinson's Disease and More
At their root, neurodegenerative diseases, such as Parkinson's, Huntington's, Alzheimer's, and amyotrophic lateral sclerosis (ALS), are triggered by misbehaving proteins in the brain. The proteins misfold and accumulate in neurons, inflicting damage and eventually killing the cells. In a new study, researchers used a different protein, Nrf2, to restore levels of the disease-causing proteins to a normal, healthy range, thereby preventing cell death. The researchers tested Nrf2 in two models of Parkinson's disease: cells with mutations in the proteins LRRK2 and α-synuclein. By activating Nrf2, the researchers turned on several "house-cleaning" mechanisms in the cell to remove excess LRRK2 and α-synuclein. "Nrf2 coordinates a whole program of gene expression, but we didn't know how important it was for regulating protein levels until now. Overexpressing Nrf2 in cellular models of Parkinson's disease resulted in a huge effect. In fact, it protects cells against the disease better than anything else we've found."
In the study, the scientists used both rat neurons and human neurons created from induced pluripotent stem cells. They then programmed the neurons to express Nrf2 and either mutant LRRK2 or α-synuclein. The researchers tagged and tracked individual neurons over time to monitor their protein levels and overall health. They took thousands of images of the cells over the course of a week, measuring the development and demise of each one. The scientists discovered that Nrf2 worked in different ways to help remove either mutant LRRK2 or α-synuclein from the cells. For mutant LRRK2, Nrf2 drove the protein to gather into incidental clumps that can remain in the cell without damaging it. For α-synuclein, Nrf2 accelerated the breakdown and clearance of the protein, reducing its levels in the cell. "I am very enthusiastic about this strategy for treating neurodegenerative diseases. We've tested Nrf2 in models of Huntington's disease, Parkinson's disease, and ALS, and it is the most protective thing we've ever found. Based on the magnitude and the breadth of the effect, we really want to understand Nrf2 and its role in protein regulation better."
Nrf2 mitigates LRRK2- and α-synuclein-induced neurodegeneration by modulating proteostasis
The prevailing view of nuclear factor erythroid 2-related factor (Nrf2) function in the central nervous system is that it acts by a cell-nonautonomous mechanism to activate a program of gene expression that mitigates reactive oxygen species and the damage that ensues. Our work significantly expands the biological understanding of Nrf2 by showing that Nrf2 mitigates toxicity induced by α-synuclein and leucine-rich repeat kinase 2 (LRRK2), by potently promoting neuronal protein homeostasis in a cell-autonomous and time-dependent fashion. Nrf2 accelerates the clearance of α-synuclein, shortening its half-life and leading to lower overall levels of α-synuclein. By contrast, Nrf2 promotes the aggregation of LRRK2 into inclusion bodies, leading to a significant reduction in diffuse mutant LRRK2 levels elsewhere in the neuron.
Disruption of protein homeostasis is an emerging theme in Parkinson's disease pathogenesis, making mechanisms to reduce the accumulation of misfolded proteins an attractive therapeutic strategy. By identifying the stress response strategies activated by Nrf2, we also highlight endogenous coping responses that might be therapeutically bolstered to treat Parkinson's disease.
A Look at Ascendance Biomedical, Packaging Medical Tourism for Longevity Therapies
Ascendance Biomedical is a fairly new venture, still in the early stages of formalizing its structure and agenda. It is focused on the twofold path of (a) establishing patient-funded trials of potentially useful therapies in the longevity science space, and (b) packaging participation in trials and later purchase of therapies via medical tourism, bundling all of the complications into a single product. The people involved overlap with the principals of the Global Healthspan Policy Institute, and are fairly well connected in our community. The organization is tackling just a few types of therapy to get started, gaining experience in how best to go about this class of project.
Now, I will be the first to say that their initial and current work on trials and medical tourism is in areas that are not all that interesting to me, in that I don't believe they will have any great impact on aging: an established but not widely adopted cancer therapy and a hormone therapy approach to restoring ovarian function in older women. I'm not singling out Ascendance Biomedical in saying this. A number of similar initiatives are taking place in the aging research community, such as the Ambrosia trial for plasma transfusion, the TAME trial for metformin, and the TRIIM trial for thymus rejuvenation. What these all have in common is that if you think that aging is caused by accumulated molecular damage, then little should be expected to emerge from these efforts: these are hormone treatments, supplements, and existing drugs, or new therapies that seem at best to fall into much the same region as first generation stem cell transplants, in that they alter signaling in old tissues in some way that helps a little. They are not damage repair. I think we can do much better than all of this, via the SENS approaches. In any case, the point is not Ascendance Biomedical today, it is the potential Ascendance Biomedical of a few years from now.Ascendance Biomedical
Ascendance Biomedical is a novel corporation founded with an ambitious goal in mind: We want to make it easier for everyone to gain access to life-saving treatments - without the hassle. We are a team of physicians, scientists and entrepreneurs unified in the mission to save and improve lives. Ascendance Biomedical provides products and services which enable our customers to access the most cutting-edge biomedical technologies and treatments in the world. Working with clinics, physicians and scientists all over the world in all regulatory zones, we help you get the care that you need. We not only provide medical care and treatment, we also assist with flights, accommodation, travel instructions, the processing of medical records, direct connection with medical personnel upon arrival, analysis of your case to get you the best price with local physicians and - most importantly - set you up to receive the required treatments and interventions for your condition. Ascendance Biomedical offers not just products, but all-inclusive healthcare solutions for patients worldwide.
Medical tourism for senolytic treatments to clear senescent cells - one of the SENS programs for the treatment of aging - is on the Ascendance Biomedical agenda for the near future, and this is a very plausible exercise given the present state of the science. All of the existing senolytic drugs are very well characterized, new ones are being discovered among compounds easily ordered from chemical suppliers, and thus the costs to set up trials are reasonable when considered in the grand scheme of things. What is needed is an organization that specializes in rolling out such trials and then managing easy access to the therapies via medical tourism thereafter. Once such an organization exists, and is well connected in our community, then all further SENS therapies will have a much more cost-effective path to initial human trials and the clinic as soon as safety is proved. That will be important, as none of us will want to wait around for the ten years it will take someone with deep pockets to fight their way past an uncaring FDA. As for stem cell therapies, that can happen in parallel with public access to treatments outside the US.
When looking at the near future of rejuvenation biotechnology, you have to look beyond the therapies themselves and see the development of an ecosystem of companies sympathetic to the SENS vision for the medical control of aging. The first therapies are not only important for the treatments themselves, but also for the organizations that are created in the process of development, and which continue onward afterwards to take on new challenges. We need companies like Ichor Therapeutics that come attached to an established laboratory service business. We need companies like Oisin Biotechnologies doing the work of building the therapies. We need startup incubators and incubator-like organizations like the Methuselah Foundation is becoming. We need the angels and venture capitalists who think SENS is a great idea. We need the non-profits that help to push the research into readiness, such as the SENS Research Foundation. And of course, we need efforts like Ascendance Biomedical that focus on building a better, smoother, more efficient bridge to the clinic. All of these components in the ecosystem are emerging, piece by piece, thanks to a great deal of hard work beyond the scenes.
The medical tourism industry has only grown since stem cell therapies first became available, and since the regulatory burden in the US and Europe continues to increase. More regulation means more costly medicine, and worse medicine - the gap between what is possible and what is allowed continues to grow as it takes ever longer for research to be approved by the FDA and other regulatory bodies. Yet in many ways the medical tourism industry is very immature. There is little in the way of service organizations, reviewers, independent assessors and standards bodies. When you choose medical tourism, you must undertake a lot of work yourself, and will probably find yourself wishing that someone just offered simple, sensible packaged products for therapies of interest. This lack of market maturity may be a consequence of the fact that, in the grand scheme of things, very few people actually purchase any given therapy on any given day. The healthy, or at least those not in very dire straits, vastly outnumber the sick and the damaged. The advent of therapies like senescent cell clearance using senolytic drugs changes the whole economic picture here, however. This is a product that can be sold to everyone over the age of 40, once every few years. The pool of potential customers is far, far greater than that for a therapy for any given age-related disease, and the economics mean that yes, we should absolutely see the emergence of a competitive marketplace for packaged services like those offered by Ascendance Biomedical.
A Conservative View of Senescent Cell Clearance Research and Development
Today I thought I'd point out publicity materials for recent research from yet another group involved in the search for senolytic drugs to clear senescent cells from the body. The position taken is conservative - at least in part - but that is the style of the formal scientific community. Excitement in print is not the done thing. Nonetheless, it is becoming something of a challenge to hold a very conservative position on clearance of senescent cells as one of the foundations for rejuvenation therapies at the present point in time. It takes some rigor to stand up and say that this may still all go nowhere, and much more needs to be done to prove utility. The evidence in animal studies is robust and compelling, and growing more so with every passing month: extended life spans in mice, slowed and reversed mechanisms for age-related diseases, and measures of tissue aging turned back in specific organs. Behind the animal studies lies decades of evidence to support the role of senescent cells in aging and age-related disease in humans.
Maintaining a strongly conservative position until the very last moment is very much a part of the culture of science in our era. No-one is crucified quite so extensively as the scientist who makes bold predictions that then prove incorrect, or even just not entirely correct. The entire scientific community is haunted by the spirits of Pons and Fleischmann, now and for a time yet, but that is merely the easiest of many examples to reach for. The scientist who remains exceptionally and overly conservative, on the other hand, to the point of holding back his or her field, is only pilloried decades down the line, far too late to offer any threat to career and livelihood. People can and should do as they will, following inquiry and progress, but where such incentives exist, it is wise to note their existence while listening to the output of the scientific community. The aging research community in particular was until very recently one in which a great deal of informal policing took place, guiding researchers away from work and public pronouncements on the prospects for the treatment of aging as a medical condition. Who knows how much further along we might have been absent the decades of that stifling culture, thankfully now done away with.
In any case, below find a conservative view for the present state of research and development in the cellular senescence field - which is to say nowhere near as conservative as it would have been a few years ago, or were the author not planning to found a company to develop a senolytic treatment. But a little cold water never hurts for those of us who are enthusiastic about the prospects for this line of research in the near future. There is, after all, still work to be done before the public can travel to overseas clinics to obtain the first therapies with the confidence that comes with initial human trials: the dose-response curve in mice and humans needs fleshing out to set expectations; we'd like to see better alternative senolytic drugs, those that are not chemotherapeutics with interesting side-effects at higher doses; a variety of service companies need to mature and collaborate. All of this will take a few years to settle down into a treatment with known outcomes (measured in terms of proportion of senescent cells removed and short-term side-effects), a low enough cost for the public at large, and that is available via medical tourism in at least a few clinics.
Anti-aging therapies targeting senescent cells: Facts and fiction
It's an exciting time to be an elderly mouse. Researchers believe that by removing senescent cells (cells with a persistent damage response), which naturally accumulate with age, senior rodents can regrow hair, run faster, and improve organ function. This strategy may bring us one step closer to the "fountain of youth," but it's important to be cautious and not hype. The removal of senescent cells, first discovered in the 1960s, received renewed interest in the 2010s as a therapeutic option to combat some aspects of aging. Researchers noticed that these permanently arrested cells accumulate in mature tissue and that some of them secrete factors that are harmful to tissue function and impair their neighboring cells. To explain what causes this noise in the system, a new paper proposes a "senescence-stem lock model" in which the chronic secretion of pro-inflammatory factors by these senescent cells keeps neighboring cells in a permanent stem-like state and thereby prevents proper tissue renewal.
There are three milestones for realistic translation of an anti-senescence approach. Firstly, the proof of concept. Several studies have already addressed whether senescence is a cause of aging and whether its elimination stalls this process. By taking out senescent cells, naturally aging mice lived 25% longer, which is evidence that it could be possible. Secondly, the development of safe therapeutics. Anti-senescent drugs are already being tested, but none of them have yet to be deemed safe because they also target pathways expressed by non-senescent cells. It is likely that this marker will be passed in the near future. Thirdly, reversal of aging. Researchers will need to identify whether clearance of senescence can also be applied retrospectively to counteract features of natural aging that have already manifested. Although aging does seem like it can be stalled through therapeutic compounds, it remains unclear whether age-related diseases can be completely deterred.
"When bringing in a defective car for repairs it is insufficient to remove the rust and broken parts; you also want to replace these. A perfect anti-senescence therapy would not only clear senescent cells, but also kick-start tissue rejuvenation by stimulating differentiation of nearby stem cells. This may be complementary with, for instance, the exciting approaches recently made in the field of transient expression of stem cell factors. I would also advise caution for claiming too much, too soon about the benefits of the fast-growing list of therapeutic compounds that are being discovered. That being said, these are clearly very exciting times, and I am confident we will find applicable anti-senescence treatments that can counteract age-related pathologies."
The Fountain of Youth by Targeting Senescent Cells?
The potential to reverse aging has long been a tantalizing thought, but has equally been considered mere utopia. Recently, the spotlights have turned to senescent cells as being a culprit for aging. Can these cells be therapeutically eliminated? When so? And is this even safe? Recent developments in the tool box to study senescence have made it possible to begin addressing these questions. It will be especially relevant to identify how senescence impairs tissue rejuvenation and to prospectively design compounds that can both target senescence and stimulate rejuvenation in a safe manner.
Given the recent high-profile reports on this topic, the idea of fighting the effects of aging by targeting senescence is at least plausible. However, it is surprising that in decades of modern research, and the roughly half a century in which senescence has been known, nobody has discovered compounds that are beneficial to health by influencing senescence. It is therefore important to separate fact from speculation and temper unrealistic expectations. Targeting senescence may simply not lead to the fountain of youth. That being said, with anti-senescence therapies we are the furthest we have ever been on the path to healthspan extension and restoration of the loss of health experienced during aging.
From ongoing research, it will become clear to what extent senescent cells can indeed inflict a permanent lock in the stemlike state of their surrounding cells and whether targeting senescence may influence tissue repair and rejuvenation. Targeting senescence and stimulating rejuvenation might at least potentially counter individual age-related diseases and in doing so, we might be getting closer to achieving the goal of developing a 'therapy' against aging. Coming years will undoubtedly see exciting developments to come.
Abstract 2843: TASC1, a selective anti-senescence therapeutic which potently and selectively counteract resistance to chemo- and radiotherapy
Cellular senescence, induced by chemotherapy and radiotherapy, can drive therapy resistance in vivo. Senescence is a tumor suppressive mechanism, but senescent cells can secrete a range of proteins that ironically promote tumor growth, migration and metastazation and therapy resistance. Recent evidence has shown that genetic removal of senescent cells indeed causes a strong reduction in tumor growth and metastasis formation. Unfortunately however, therapeutic options to remove senescent cells are currently lacking. Here, we show the development and optimization of a biochemical compound, TASC1, that potently and selectively kills senescent cells in vitro and in vivo and lowers organ toxicity in a mouse model employed to address the off-target effects of cancer therapy.
A Look Back at 2016 in Longevity Science
Well, another year passes and here we are again, one step closer to the defeat of aging and age-related disease. Ours is an era of revolutionary progress in biotechnology, and it is starting to show. The past year was characterized by both significant fundraising and significant progress towards the clinical translation of the first complete SENS rejuvenation therapy: clearance of senescent cells from aged tissue. This is hopefully the first of numerous other SENS therapies based on repair of molecular damage to arrive over the next few years. I recently updated my predictions for the near future, looking over the parts of the field that are very close to the making the leap into for-profit startups. These are exciting times.
Regarding senescent cell clearance, I have to open by talking about fundraising. The two topics go hand in hand. Oisin Biotechnologies is the senescent cell clearance company closest to our community of supporters, seed funded back at the end of 2014 by the Methuselah Foundation and SENS Research Foundation, and led by one of the earliest donors to the Methuselah Foundation, someone who has been involved in this community for longer than I have. I've been talking about the need to extend our support for research beyond the laboratory and into startup companies, and in the tradition of doing rather than just talking about doing I participated in one of the funding rounds for Oisin Biotechnologies this year, joined by a number of other supporters. The money is going to good use, but that wasn't the big news in senescent cell clearance funding for 2016, of course. The big news was that UNITY Biotechnology landed one of the largest biotechnology industry funding rounds of recent years: 116 million in order to bring senolytic drugs to the clinic. That and the efforts that led to it will shape this field for years to come.
Over the course of the year, more evidence for the effectiveness of senescent cell clearance rolled in. Teams associated with UNITY Biotechnology showed 25% life extension in normal mice resulting from removal of senescent cells. Other work has shown restoration of function in aged lung tissue, and improved vascular health. New evidence reinforces a role of senescent cells in osteoarthritis, as well as in atherosclerosis, immunosenescence, and diabetic retinopathy. Many other papers have emerged in which researchers link senescent cells in some way to their particular areas of interest in aging. It is safe to say that the broader research community has been well and truly woken up on this topic, and are now engaged in producing a great weight of specific evidence in support of senolytic therapies as a way to delay and reverse numerous processes contributing to age-related disease. The tipping point has passed and things are moving very rapidly now in comparison to past years. How soon before the first senolytic therapies become available via medical tourism, immediately following the first human trials? Not more than a few years, I'd say. A lot of people are running, not walking, to enter this area of development at the moment.
When it comes to fundraising for SENS rejuvenation research, well, there has been a lot of that this year as well. In fact I think the long-standing grassroots of our community is reaching the point of exhaustion on this front. There is only so much water in the well when it comes to charitable support from a single community - and we've certainly given a great deal to the cause. Our community must grow to match the opportunity, but given what is happening for senescent cell clearance, I think this is a very real possibility. In crowdfunding initiatives this year, the Major Mouse Testing Program raised 50,000 for a senescent cell clearance study, and that happened back to back with the SENS Research Foundation raising 70,000 for work on one component of a universal cancer therapy based on blocking telomere lengthening. While that fundraiser was still running, Michael Greve of the Forever Healthy Foundation stepped up to pledge 10 million to SENS research and funding for the startup companies that will emerge from that research. This is the founding donation for the new SENS Project|21 initiative, seeking 50 million to bring significant segments of the SENS portfolio of rejuvenation therapies into readiness for the clinic by 2021. Somehow, in the midst of all of that excitement, the SENS Research Foundation staff found time to once again run the acclaimed Rejuvenation Biotechnology conference in August, bringing together industry and academia to build the necessary bridges for tomorrow's rejuvenation therapies.
Along the way, Ichor Therapeutics raised a funding round to build a therapy from the LysoSENS work of past years: bacterial enzymes turned into drugs to break down specific forms of harmful metabolic waste that contribute to age-related disease. BioViva recieved support from Deep Knowledge Ventures and allied with Sierra Sciences to set up a clinic in their gene therapy efforts. Ambrosia pulled in funds to run a trial of the transfer of young blood plasma to old individuals. The Methuselah Foundation launched their 500,000 research prize for tissue engineering in collaboration with NASA. Further, the founders of CellAge, one of the newer groups to enter the senescent cell clearance space, are currently running a crowdfunding initiative in order to produce better cellular senescence assay and identification technology for the research community.
Last but far from least, the end of year fundraiser for the SENS Research Foundation is coming to a close as I write as well: there is still money left in the various matching funds supplied by Michael Greve, Josh Triplett, Christophe and Dominique Cornuejols, and Fight Aging! This year, we decided to match a year of donations for anyone who signs up as a SENS Patron by pledging monthly donations. This is thinking in the long term, helping to build a steady flow of donations to SENS rejuvenation research, and you'll see more of this initiative in the year ahead.
While the two topics above generate the greatest excitement and attention, there was - of course - way more to the past twelve months in longevity science than senescent cells and fundraising. Gene therapies, for example, are rapidly coming closer to reality, and the first will be available via medical tourism soon enough. Reliable and comprehensive cell coverage remains an important hurdle, though there are promising signs of progress there. The BioViva human study of one reported results for the telomerase gene therapy and, later, the follistatin gene therapy. The only thing stopping you or I from undergoing those same therapies is a matter of knowing who to call and having the necessary funds, but costs will fall rapidly in the years ahead as the number of potential providers rises and data emerges. I'm very enthusiastic about myostatin and follistatin gene therapies, and less so when it comes to telomerase gene therapy. There, I'd like to see results in species other than mice, as their telomere dynamics are significantly different. Many people inside and outside the scientific community are pushing for the development of telomerase therapies to slow aging, however, and at the present adventurous pace we'll see more human data before data in other mammals.
2016 was a big year for the cryonics community, with a great deal of attention from the media, much of surprisingly good, including profiles of supporters and the Russian KrioRus group. Cryonics simply makes sense, and we can hope that more press attention translates into a larger community of supporters making material contributions to the end goal. On that topic, I finally stopped procrastinating and signed up. As it turns out, having a backup plan only works if you actually use it. There are other signs of growth, such as the CryoSuisse initiative, and continued efforts to produce reversible vitrification for the organ transplantation industry. The Brain Preservation Foundation's technology prize was won by a cryonics approach, though not the one currently in widespread use for reasons that have a lot to do with differences in end goal between various interested factions: restoration versus copying and uploading.
Work on the SENS strategy of cross-link breaking is also forging ahead. I wrote up a state of research article early in 2016, and it remains broadly correct for the end of 2016. This research is largely funded by the SENS Research Foundation, and has yet to spread all that far beyond this small number of research groups. In effect it is in much the same position as senescent cell research found itself prior to 2011, looking for the first drug candidate and the first impressive demonstration to gain more interest from outside sources. Fortunately, in this case there is a greater flow of philanthropic funding, so we should see that breakthrough arrive within the next few years. Meanwhile, evidence continues to accumulate for the role played by cross-links in degenerative aging beyond the obvious candidates, including blood vessel stiffening, such as impaired muscle regeneration
On the mitochondrial contribution to aging, this year the SENS Research Foundation in-house team achieved allotopic expression of mitochondrial genes ATP6 and ATP8 - a big advance. The newly public company Gensight Biologics was funded with tens of millions in venture capital on the basis of doing the same for just one gene, ND4. That work too was supported by the SENS Research Foundation in its earliest stages nearly a decade ago. This is a valuable technology. Now three of thirteen mitochondrial genes can be moved to the cell nucleus: only ten to go in order to remove the contribution of mitochondrial damage to aging. Also of note is research that demonstrates a link between mitochondrial DNA deletions and the progression of sarcopenia, age-related loss of muscle mass and strength - but I am glossing over a good dozen very interesting papers on mitochondrial aging from the past twelve months in order to point out that one.
A number of relevant new organizations have arrived on the scene in 2016. Beyond UNITY Biotechnology and CellAge, mentioned above, the Global Healthspan Policy Institute, focused on lobbying, launched early in the year. On the subject of lobbying, the considerable grassroots efforts among researchers to have aging formally defined as a disease continue, alongside similar efforts to put more of an emphasis on the treatment of aging in definitions provided by influential standards bodies. Separately, the Life Extension Advocacy Foundation continues to expand their footprint in the community. There is a lot of new material at their site; worth a look.
Mitochondrially targeted antioxidants as a means to address inflammatory conditions, and maybe modestly slow the progression of aging or specific age-related conditions, have been in the news. The development of the SkQ series of compounds started in Russia, where it is already used in treatments for inflammatory eye conditions, and has now made its way into European clinical development at MitoTech. There are other lines of mitochondrial antioxidant, such as SS-31, but these are not as far along towards the clinic.
The public view of longevity assurance therapies might be coming around to support for the topic, per a survey conducted this year, provided that such therapies produce extended healthy life rather than extended frailty. In the field, it seems there is a still a considerable need for education, however. People tend to exhibit many incoherent and inconsistent positions when it comes to death, aging, and doing something about both of those topics. The comment sections of social news sites are still filled with people decrying longevity science when news comes to their attention. It is still overall a challenge to raise funds, despite our gains in recent years, and despite the growing interest on the part of various deep pockets. I have to think that the people who claim to want to age and die are failing to think critically about their own personal futures.
In Alzheimer's research, a trial of amyloid clearance via immunotherapy in humans finally worked. The field is littered with failures from the past decade, so this is a big deal. Further, there has been progress towards therapies to clear tau protein from the brain as well, including results from an an initial human trial for safety of a potential immunotherapy. On a different topic, an intriguing study appears to show that memories lost to Alzheimer's pathology can be restored via dendrite regrowth, at last in the early stages. A number of other possibilities beyond immunotherapy have emerged to reduce amyloid levels, such as drawing it out from the brain by clearing it elsewhere, or revisiting the possibility of β-secretase inhibitors. Further, the idea that amyloid builds up because physical drainage channels atrophy will get a test soon, via Methuselah Foundation funding of Leucadia Therapeutics. There are many other types of amyloid in aged tissue, however, and all those will need clearance as well. We might watch Pentraxin Therapeutics as one example of progress in this area. Like so much of this work, it proceeds at a crawl, even following a successful trial back in 2015.
Research on regeneration of an aged thymus, thereby restoring some of the decline in the immune system, continues to move forward. A recent study provided confirmation of benefits resulting from transplantation of a young thymus into an old mouse, for example. In addition to ongoing work on FOXN1 signaling as a possible way to regrow thymus tissue, it was discovered that FGF21 may also be a relevant target. Another team demonstrated that thymic decline correlates with lifespan in dog breeds. Meanwhile, tissue engineers continue to work on the production of working thymus tissue and cell therapies, aiming for the same goal of restoration.
DNA methylation patterns are a promising basis for a biomarker of aging, a test that could be used before and after a putative rejuvenation therapy to evaluate its likely long-term performance. The use of DNA methylation patterns is spreading, and evidence for their potential utility accumulates. Researchers have examined changes early in aging, assessed aging in skin tissue, determined that stroke patients are biologically older than their peers, found that people measured as being biologically older have a greater risk of cancer, and showed that known statistical differences between the life expectancies of various communities also show up in DNA methylation.
Immune system clearance and recreation has tremendous potential as therapy for autoimmunity and many aspects of age-related immunosenescence. This year, researchers demonstrated the ability to cure multiple sclerosis via a fairly simple process of destroying mature immune cells, with no need to attack blood stem cells. This is very promising for the near term development of similar therapies. All that is needed is a less harmful method of targeted cell killing, one that can be safely used by older patients. Fortunately there has been some progress in that direction in the past year, and I think we'll see more in the years ahead. Many methods currently under development in the cancer research community might be converted to this use.
Lastly for this year, a number of short essays fell from the pen to the page. Some might even be worth reading again as we look forward to 2017 and further, faster progress towards therapies to treat the causes of aging:
- Do Current Stem Cell Therapies Produce Rejuvenation?
- It is Quite Possible to Create a Senescent Cell Clearance Therapy that is Too Good
- Overfund the Life Insurance Policy that Pays for Your Cryopreservation
- The SENS Rejuvenation Biotechnology Companies
- Developing the Art of Group Buy Medical Tourism: 100 People Traveling to Pay 10-20,000 for a Rejuvenation Therapy
- Thinking About the Pipeline: Getting Therapies into Clinics
- Why Do So Few Wealthy, Sick Individuals Fund Medical Research to Treat Their Conditions?
- If I Were Going to Raise a Venture Fund, I'd Earmark 10% of Capital for Creating Startups By Funding Research that is Close to Completion
- A Short List of Potential Target Genes for Near-Future Gene Therapies Aimed at Slowing Aging or Compensating for Age-Related Damage and Decline
- Effective Therapies to Extend Healthy Life May Well be Widely Available for a Decade or More in Advance of Definitive Proof
- The Next Five Years will be a Critical Time for the Development of Rejuvenation Biotechnology after the SENS Model of Damage Repair
- On the Topic of Senescent Cells: Should We All be Trying to Take Navitoclax?
- How to Go About Using Myostatin Antibodies to Grow Muscle Today
- Request for Startups in the Rejuvenation Biotechnology Space, 2017 Edition
- The Slow Death of the Self that is Produced by the Normal Operation of Human Memory
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An Example of Opposition to Living Longer
When technology provides the choice to live longer in good health, we should not forget that this is in fact a choice for the individual, no different from many other choices about medicine and life that already exist. It is civilized to respect those who decide that further time or improved health isn't their cup of tea, but as the debate over euthanasia illustrates, respect for self-determination really isn't something that comes naturally to those in power. It is one of the great failings of human nature. I point out this article as a catalog of the major categories of mistaken viewpoints and debates over extending human longevity from someone who has listened to the arguments and chosen the other path. Insofar as the end result is a personal choice to live longer or not, then that should be respected. The problems start when people work towards forcing that choice on others, by halting research or blocking availability of new technologies likely to extend life; fortunately we've seen much less of that sort of rhetoric now that scientists are closer to realizing ways to slow aging or produce rejuvenation in the clinic.
For my part, I'd say that the thing that turns people from life isn't time or cynicism, it is the burden of accumulated loss and pain: the friends no longer there, the debility and disease that encroaches year by year. That growing weight produces a great weariness, ultimately turning every simple act into a gray struggle. Even before that point it is unpleasant. This burden will be lifted through the application of better medical technology in the decades ahead; preventing the death of friends; removing the causes of pain and disability; restoring the resilience of youth in mind and body. Regardless of the plausible future, or the availability of specific therapies in any given year, it is still the case that individual choices in this matter should be respected.
At age 74, I have already experienced many of the indignities of aging and before very long will also confront the inevitability of death. Although neither prospect is particularly pleasant, I strongly believe in the normality and necessity of both. Claims that science will soon prevent aging and dramatically prolong life strike me as irresponsible hype and false hope. I am all for efforts to expand our healthspan, but see little value in prolonging our lifespan, and little possibility that we will soon discover a fountain of youth. My grandson, home from college for Christmas break, disagrees with what he regards as my sentimental and regressive attachment to the status quo. He is participating in stem cell and genetics research and believes that it is feasible and desirable to double the human lifespan and make aging just another curable disease. He has no qualms about this research and regards my doubts as technically naive and ethically unnecessary.
I say that the world is already terribly overpopulated and is rapidly becoming even more overpopulated. Malthusian dynamics ensure that providing a longer life for some must be purchased at the high cost of a more brutal life for the many - a life threatened by even more wars, migrations, famines, and epidemics. My grandson says that overpopulation is best solved by reducing birthrates. This has already been done with great success almost everywhere in the world except Africa and the Middle East. It will be a better, more mature, and healthier world if people live longer and have fewer diseases and fewer children. A longer lifespan will make people wiser, more future oriented, and less willing to take foolish risks in the present. This could lead to more rational decisions on how best to preserve our planet as a decent place to live.
I say that curing disease is the primary goal of medical science. But aging is not a disease - it is an entirely expectable wearing down, an expression of biological entropy that cannot be reversed. We should certainly target the diseases that occur in old age in an effort to extend the average human healthspan. Success will improve the well being of the elderly and have a small subsidiary effect on lifespan - e.g. more people living into their 80s, 90s, and 100s. But we should not expect that better treatment for diseases will allow people to live to biblical ages. My grandson says that it is far too early to tell whether aging in humans is more a reversible disease or an inescapable degenerative process. But since aging is caused by biochemical processes, it most likely can be prolonged by biochemical interventions. We can't decide the question based on values and reasoning - only by actually doing the aging research will we learn whether aging is preventable. And sure it may take many decades, but that's precisely why we have to allocate the resources now to get the project off to a fast start.
I say that only the rich will be able to afford new products that prevent aging and promote longevity. The resulting caste system based on lifespan will be even more unfair than our current divisions based on wealth and power. My grandson says that the distribution of benefits that will accrue from aging research is a political, economic, and ethical question, not a scientific one. Given human nature and existing institutional structures, the benefits will almost certainly be enjoyed in a markedly unequal and unfair fashion - greatly favoring the rich and powerful, with only a very slow trickle down to the population at large. This inequity has accompanied every previous technological advance in the long march of human progress and is not specifically disqualifying to progress in slowing aging and death.
I say that there is something arrogant and unseemly about tampering with anything so fundamental to life as aging and death. Their inevitability has always been an essential element governing the ebb and flow of all the species and all the individual organisms that have ever lived on our planet. Why assume that we have the right, or the need, to tamper with such a basic aspect of nature? My grandson says that scientific progress has always challenged conservative values based on a sentimental attachment to the past. He says that I would probably have worked hard to convince the first agriculturalists that they were breaking some sacred and natural code when they chose to settle down in one place rather than continue following the hunt. There is no inevitable, inexorable, over-riding, and natural law defining and governing one correct path of human destiny.
My grandson is much more optimistic than I that we will soon have the technical means to prolong youth and postpone death - and that we should use them. I am more accepting of the limits of life - eager to improve its quality, rather than expecting to extend its duration. My grandson trusts scientists to make scientific decisions. I believe that scientists have conflicts of interest that make them uniquely unqualified to judge the ethical implications of the scientific opportunities open to them. If scientists can do something, they will do it - fairly heedless of unintended consequences. My grandson has the optimism and enthusiasm of the young. I have the pessimism and caution of the old. In a final flourish, My grandson trumped my argument that aging and death are somehow natural to the evolutionary scheme of things with the paradox that evolution has also given us the power to control aging and death and that surely we are programmed to use it. He is probably right. I don't think our debate will be settled on ethical or theoretical grounds. History provides precious few examples of a society voluntarily rejecting the application of a powerful new technology - e.g. China burning its navy in the fifteenth century; Japan banning guns in the seventeenth. But both were closed societies whose conservative decisions were governed by internal political concerns; they were much less responsive than ours to economic and scientific competition and pressure. My guess is that scientists will be given the freedom and the funding to follow every possible path to the fountain of youth and to doubling the lifespan. Although our knowledge base is increasing exponentially, the more we learn about the body, the more we appreciate how difficult it is to translate basic science into clinical application. Our bodies are remarkably complex and carefully balanced machines. Scientists can tinker with them, but I suspect that the basic cycle of life and death will be very hard to change.
Fear of a Grim Future as a Source of Opposition to Longevity Therapies
A great many people believe, despite all of the evidence to the contrary, that humanity is set upon a downward spiral into future far worse than the present. You will see this in any public discussion of rejuvenation therapies or efforts to slow aging: many participants couch their opposition to longevity therapies in terms of wishing to die before the world becomes worse. This sort of histrionic public display doesn't seem to be peculiar to our era. Dystopia has always held a greater fascination than utopia in literature, and heralds of the coming apocalypse have been around in one form or another for about as long as people have recorded their thoughts on the matter. Every story is the story of the Fall, as they say, in which the mythic past was better than the present, and in any given lifetime the combination of human psychology, degenerative aging, and the biochemistry of memory serves to make the past rosy with nostalgia in comparison to the uncertainties and pains of the present. Yet from an examination of the concrete data we are clearly not heading towards the abyss, or even a meaningful decline in the long term. Quality of life, longevity, and wealth has improved, steadily, for centuries. The pace is increasing, not decreasing. The future is golden and wondrous beyond easy measure. It is a fascinating and terrible aspect of the human condition that so many people reject this truth outright to find greater comfort in fear and self-sabotage.
The future looks grim? I would like to point out a few problems in the reasoning of the professional catastrophists who say that life won't be worth living and there's thus no point in extending it anyway. First, we need to take into account that the quality of human life has been improving, not worsening, throughout history. Granted, there still are things that are not optimal, but there used to be many more. Sure, it sucks that your pet-peeve politician has been appointed president of your country (any reference to recent historical events is entirely coincidental), and it sucks that poverty and famine haven't yet been entirely eradicated, but none of these implies that things will get worse. There's a limit to how long a president can be such, and poverty and famine are disappearing all over the world. It takes time for changes to take place, and the fact the world isn't perfect yet doesn't mean it will never be. Especially people who are still chronologically young should appreciate the fact that by the time they're 80 or 90, a long time will have passed, and the world will certainly have changed in the meanwhile. If we decided not to create rejuvenation because right now the world isn't as nice a place as it could be, in 60 years we may well end up as a bunch of sick, decrepit suckers with a foot in the grave, regretting our decision because in the meantime the world has become much better than we had expected.
Also, let's not forget that what we're talking about here is rejuvenation and that life extension is just a trivial consequence of it. Without rejuvenation, your health will eventually go below a critical threshold and the pathologies of old age will start to emerge. Even if the world did become a worse place to live in over the next few decades, frankly I fail to see how being sick and decrepit would make it any better. If death ever became preferable over life on this planet, painless suicide would be a much more humane and efficient option than going through the whole ordeal of old age. Additionally, if we're really so convinced that the world has no hope of being better in the future, then there's little point in making more babies. If we said we don't want to extend our lives because the world is and will forever be too horrible a place to live in, it would be rather contradictory - or even cruel, depending on how you want to see it - to bring more people into it. Either the world is broken beyond repair and we'd better not leave any progeny to live on it, or it can be fixed, in which case we may just as well stick around and start fixing it instead of complaining about how bad the world is.
Yes, we've got a problem with poverty, but it is not as bad as you might think. As a matter of fact, the number of people living below the threshold of absolute poverty has been plummeting over the last two centuries, going from somewhere in between 84% and 94% of the world population to something around 11% in 2013. Regardless of whether or not you think the world is going to be worth living in in the near future, odds are the present situation is better than your average Joe thinks it is. Maybe this is not your case - maybe you're well informed and you check your facts before jumping to conclusions - but you cannot possibly have not noticed the overall pessimism of people about issues like the ones above and the future in general. You don't believe me? Here's an example. In 2013, people in the UK were asked whether they thought extreme world poverty had increased, decreased, or stayed the same in the last 30 years. The correct answer was that, during that time, poverty had decreased faster than ever before in history. A whopping 55% thought that poverty had gone up. Only 12% got it right, and you should keep in mind that the interviewees were people holding university degrees. The US isn't doing any better, really: 66% thought extreme poverty had almost doubled over the course of the previous 20 years, while it had in fact almost halved. Why is this? Why is everyone prone to thinking we're doing so bad and that the future is grim, despite all the evidence indicating that we've improved a lot, we're doing far better than before, and we can expect to do even better?
We tend to see the details, but not the big picture. Most people understand the world by generalizing personal experiences which are very biased. In the media the "news-worthy" events exaggerate the unusual and put the focus on swift changes. Bad news sells. The media tend to magnify bad news over good news. We're more interested in bad news because of the potential danger they could represent for ourselves and our dear ones. Good news is generally less interesting, unless it touches us personally. Since the media live off selling news, they give out more bad news than good news. In that we have a flair for the dramatic. Personally, I think it's quite normal to feel uneasy and worried for the future whenever we hear bad news. Bad news puts us in a bad mood, and in a bad mood it is easier to see everything negatively. Further, when a lot of people all around you nod approvingly at stereotypes about poverty, tragedy, disgrace, all sort of catastrophes, supposed evilness of human race, etc, it is easy to think they're right just because they're many. Breaking from the crowd isn't easy, and a lot of people would rather just agree with the majority than having to go through the trouble of contradicting them. Further still, we tend to disqualify the positive. I wonder how many people, while reading this article, have thought something like: "Well, sure, poverty has diminished, but so what? It's still not zero." We need to appreciate any improvements we achieve.
In short, no, we're not doing badly. We're not doing perfectly, either, but we're doing pretty good. We have been improving for a long time now, and there's every reason to believe we will continue on this positive trend. If you want certainties, I doubt anyone can give you any; but there's sure cause for optimism. The best you can do is stick around with the rest of us and do your part, however small, to help make the world a better place.
An Effort to Equip Macrophages with Bacterial Enzymes to Prevent Atherosclerosis
This research is an example of the LysoSENS methodologies pioneered by the SENS Research Foundation today, and in past years by the Methuselah Foundation. The approach involves mining the bacterial world for enzymes capable of breaking down resistant metabolic waste in human cells, so as to remove the contribution of that waste to degenerative aging. In this case the target is the lipids that build up in blood vessel walls and overwhelm macrophages that arrive to deal with the problem. The macrophages become foam cells and die, which only produces more damage and attracts more macrophages to try to clean it up. Over time this turns a small area of damage and inflammation into a growing plaque of fatty waste and dead cells, narrowing and weakening the blood vessel. If macrophages could be made resistant to this fate, it would remove a major contributing cause of atherosclerosis, a condition that is ultimately fatal when plaques rupture and block or break major blood vessels as a result.
Atherosclerotic cardiovascular disease (CVD) is the leading cause of death in the United States. CVD originates from aberrations in normal lipid metabolism (some genetic, some lifestyle choices) that result in elevated plasma lipoproteins (principally LDLs) and/or low levels of high-density lipoproteins (HDLs). For many people, CVD is an age dependent, progressive disease that is largely undetected or ignored until an event (i.e. myocardial infarction or stroke) occurs in the later stages of disease. Therefore, current therapies focus on preventing a second event (or a primary event in high risk individuals) by reducing the circulating levels of LDLs and/or increasing HDLs.
However, at a biochemical level the inability of macrophages to degrade the cholestane ring of cholesterol is a fundamental component of CVD. If macrophages had the ability to degrade cholesterol, they would not become engorged with cholesterol/cholesterol esters and elicit the maladaptive immune response that leads to the onset and progression of atherosclerosis. Recently, studies of Mycobacteria survival in human macrophages revealed a surprising observation. Mycobacteria feed on cholesterol while contained in the phagosomes of macrophages. Importantly, two enzymes that catalyze cholestane ring opening have been identified. We plan to test the hypothesis that genes encoding enzymes identified in bacteria can be humanized and used to transformation human monocyte derived macrophages, enabling the degradation of phagosome-cholesterol. The main objectives are to: 1) humanize bacterial genes encoding key ring opening enzymes, 2) develop an innovative expressions systems to regulate the expression of these genes in response to changes in cellular levels of cholesterol, and 3) characterize the production and fate of compounds generated following cholestane ring opening. If this paradigm-challenging hypothesis is true, the proposed studies should lead to the development of an entirely new approach for the medical management of CVD.
Results from the Gensight Biologics Trial of ND4 Allotopic Expression
Gensight Biologics is the company that emerged from the first viable line of allotopic expression research, in part supported some years ago by the SENS Research Foundation and the charitable donations of our community. Allotopic expression is the name given to gene therapy to copy mitochondrial genes into the cell nucleus, providing a backup source of proteins. Since mitochondrial DNA damage resulting in loss of function for genes involved in packaging energy store molecules is one of the causes of aging, allotopic expression of all thirteen genes used in this process will remove this contribution to degenerative aging and age-related disease. This is challenging work and still in progress - only three of these genes have had allotopic expression demonstrated to date. Along the way, however, these incremental successes can be used to cure inherited mitochondrial disorders caused by the loss of one specific mitochondrial gene, such as the blindness of Leber's Hereditary Optic Neuropathy. That is the initial goal for the Gensight Biologics staff. They are well funded these days, having gone public earlier this year, and are making good progress, as this latest trial data shows. Their GS010 product is the vector for introducing suitably modified ND4 into the cell nucleus:
GenSight Biologics, a biopharma company that discovers and develops innovative gene therapies for neurodegenerative retinal diseases and diseases of the central nervous system, today reported additional promising results after 78 weeks of follow-up in its Phase I/II clinical trial. These results confirm the favorable safety and tolerability profile of GS010, while demonstrating sustainable visual acuity improvement in patients with Leber's Hereditary Optic Neuropathy (LHON). Each cohort of three patients was administered an increasing dose of GS010 through a single intravitreal injection in the eye most severely affected by the disease. Recruitment was completed in April 2015 and long-term follow-up is ongoing. These patients had an average onset of disease of 6 years at the time of treatment. At baseline, both treated and untreated eyes had an off-chart median visual acuity.
At 78 weeks post-injection, the mean change of visual acuity from baseline in the treated eyes of all patients* was -0.61 LogMAR, equivalent to a mean improvement of +30 ETDRS letters. For all untreated eyes at week 78, the mean change from baseline was -0.31 LogMAR, equivalent to a mean improvement of +15 ETDRS letters. This provides a treatment effect (mean difference between treated worse-seeing and untreated best-seeing eyes) of +15 letters in favor of treated worse-seeing eyes. More interestingly, in patients with an onset of vision loss of less than 2 years at the time of treatment, a mean gain of +32 ETDRS letters (-0.63 LogMAR) was observed in treated eyes, while a mean gain of +12 ETDRS letters (-0.23 LogMAR) was observed in untreated eyes, resulting in a difference of 20 ETDRS letters in favor of treated eyes. The patient group with vision loss for 2 years or less at the time of injection demonstrated a treatment effect in favor of the treated eye of increasing magnitude from week 36 onwards.
More in the Debate Over Whether or Not Aging Should be Called a Disease
Here I'll point out a recent objection to the formal classification of aging as a disease, which seems to merge at the edges with an objection to treating aging at all, or an objection to aiming high, or the belief that significant progress in this field is not plausible. The latter is, sadly, a common position in the field of aging research. At the very least there is a strong separation of the ideas of aging and disease, which doesn't seem to me to be justified. Aging and age-related disease are only made separate in concept, divided by the names we give to various states and processes. At the low level in our cellular biochemistry it is the same forms of damage that give rise to what is called normal aging and what is called an age-related disease. Matters of degree only separate "healthy" (in decline, less than they were) senior individuals from patients diagnosed with specific age-related diseases.
Is aging a disease? Mutaz Musa answers this question in the affirmative. In response to his article, we suggest that, aside from containing fundamental logical flaws, Musa's argument produces a simplistic picture of the complexities of aging, both as a concept and as an actual phenomenon. While the author's opinion appears to be driven by a sincere desire to optimize people's lives, his approach might in fact be counterproductive: by pathologizing aging, he creates more, not less, challenges to ascribe meaning to age-related physical decline. The questions raised in Musa's piece are nonetheless thought-provoking, as he confronts assumptions about what constitutes disease and what causes aging. In particular, Musa asks us - researchers who study the various processes of aging - to consider how we define aging, disease, and the causes and effects that link these phenomena.
There are logical flaws in Musa's opening statements. "No longer considered an inevitability, growing older should be and is being treated like a chronic condition," he writes. This proclamation contains argumentative entanglements that are common in the field of aging research, and which should be considered carefully. Musa's first claim, that "growing older is no longer considered an inevitability," only makes sense if you consider "growing older" not as a descriptive term for the latter stages of the time that passes from birth to death, but as another way of denoting the state of becoming frail, diseased, mentally and physically infirm, and so on. Aging researchers have found that such decline is not an inevitable occurrence associated with aging (backed up and famously articulated in research frameworks such as Successful Aging). But stating that some or all of these effects may be avoided is not the same as saying that "growing older is no longer considered an inevitability."
Another illustrative example of shifts in logic and meaning occurs when Musa writes about age-related changes in the body, arguing that some of these show "that perfectly normal processes that are critical to survival will quite naturally lead to disease. In a biological sense, the mere passage of time is pathological." Here, Musa turns the fact that some routine processes lead to pathology into an argument that these processes are, therefore, pathological. That some processes lead to pathology does not mean that these processes are responsible for disease. Even a process like the production of reactive oxygen species (ROS) through mitochondrial function does not automatically lead to dangerously damaged DNA - it can, but only if there are no antioxidants available, and if DNA repair mechanisms are compromised in some way. We don't define smoking as a disease, we define lung cancer as a disease: smoking is a risk factor, but does not always lead to lung cancer. By collapsing causal risk factors and pathology into one, aging researchers will not become better equipped to deal with the complexity of either part. Nor will anyone benefit from a pathologization of bodily processes that happen in everyone, at all times.
Further, to propose, as Musa does, that if some process over time leads to pathology, then "the mere passage of time" in a biological sense is pathological, is an inductive fallacy. A fallacy that ignores the multiple processes and effects happening in the body over time, all the time, where some have effects most people want, and some do not. Regardless of our abilities to traverse our senior years illness free, we will all, eventually, die. Conflating aging and illness, however, weakens our ability to impart meaning to such inevitability. It seems that while Musa comes to represent an approach to aging that will undoubtedly attract research funding that will help scientists find ways to allow people to live physically healthier lives, it is also an approach that seeks to reduce complex issues to more simple models, thus creating an illusion - or at least the hope - of control and of biotechnological solutions to issues that also have existential and social aspects. This approach overemphasizes the importance of prolonging life at the expense of coming to terms with the possibilities of frailty and various forms of decline - not to mention death - in later life. This will not create less suffering. It will create unrealistic expectations of future scientific mastery of the human condition, telling us that frailty and decline should be avoided at all costs. This is neither a healthy psychological reaction to frailty and decline, nor will it ultimately lead to anything but individual disappointment and a mistrust of a science that promises more than it can deliver.
Dopamine D4 Receptor Allele Correlates with Longevity
The standard way to determine whether a genetic variant is associated with longevity is to look at its prevalence in the population at various ages. If the relative proportion of the variant increases in the surviving population, then that may be because it is having an impact on survival. Only two genes have variants that robustly appear to associate with longevity in multiple study populations, however, APOE and FOXO3A, and even there the size of the effect is small. The picture that has emerged from genetic studies of longevity and aging to date is one of thousands of tiny interdependent influences, interacting with the environment and one another, such that correlations in one study population near always fail to show up in another, even when both studies are carried out in the same part of the world. Still, the studies continue, with researchers now digging deeper into areas of genetic analysis that were previously skipped for technical reasons. Here is a recent example, in which researchers do manage to replicate a finding of association with longevity for a variant of the dopamine D4 receptor:
Age at death in adulthood has a heritability of approximately 25%. According to a recent review of genome-wide association studies (GWAS) APOE and FOXO3A gene variants are associated with longevity. Although association of other genetic polymorphisms did not reach the level of genome wide significance, identified pathways and genetic signatures have been shown to be important in longevity. Inheritance of long life span seems to be rather complex, with modest individual genetic effects, along with significant gene-environment interactions. Based on a study of exceptional longevity, genetic factors seem to be even more important where familial clustering of extreme old age is robust. These individuals might lack some of the risk factors related to various diseases, and at the same time carry protective genetic variations against basic mechanisms of age-related illnesses, also referred to as 'longevity enabling genes'.
It is important to note that due to technical reasons GWAS and SNP studies on longevity have not investigated any variable number of tandem repeat variations (VNTR) in association with longevity. It has been proposed that a specific VNTR variant, the 7 repeat allele of the dopamine D4 receptor gene (DRD4), could be an important factor in extreme longevity, because it plays a major role in the brain's dopaminergic functioning. Surviving participants of a 30-year-old population-based health survey (N = 310, age range 90-109, mean age: 95.2 years) possessed a 66% higher rate of 7 repeat allele carriers as compared to that of an ancestry-matched young population (N = 2902, age range 7-45). In addition, this association was far more pronounced in females (there were 39.3% allele 7 carriers in the old vs 21.9% in the young population) as compared to males (29.7% in the old vs. 21.9 in the young population). There is supporting evidence from animal studies of this gene: DRD4 knock-out mice lived 7-9.7% shorter and showed reduced spontaneous locomotor activity, as compared to those with functional DRD4 genes. Also, while the wild type mice showed clear beneficial effects of an enriched environment on lifespan, the DRD4 knock-out mice did not a show lifespan increase when reared in an enriched environment.
Initial association result of the DRD4 VNTR 7 repeat allele and longevity have not yet been replicated to date, which would be reassuring given recent arguments regarding the critical importance of replication in genetic studies. The major goal of the present study was to test association of the DRD4 VNTR 7 repeat allele and longevity using continuous age groups. We analyzed association of the DRD4 VNTR with longevity. Association analyses of continuous age groups using genotype data from 1801 Caucasian participants from 18 to 97 years of age showed a significant increase of allele 7 carriers with age. Interestingly, from age 18 to 75 ratio of those carrying the 7-repeat allele increased progressively from 29.5% to 46.9% in the tested age groups, however, in the older age groups the proportion of allele 7 carriers dropped intensively (44.4% in those between 76-85 years and 31% in the 86-97 age group). This "drop" might be due to the relatively small sample size of the age groups, but might also point to the fact that relative importance of environmental, genetic and stochastic determinants of survival vary with age. Association of the DRD4 gene variants with longevity fits well with the assumption that inheritance of longevity is complex, with modest individual genetic effects interacting with each other as well as with the environment. We propose that the DRD4 allele 7 could be a "longevity enabling genetic variant," protecting against basic mechanisms of age-related illnesses, but the precise manner in which this is accomplished is unclear at this point.
Calling for a Closer Examination of Mitochondrial Biochemistry in the Aging Brain
Mitochondrial dysfunction is strongly associated with the progression of aging, and forms of damage to mitochondrial DNA are one of the contributing causes of aging. Here, researchers review what is known of the changes that occur in mitochondrial biochemistry in the aging brain, and call for further work in this area to clarify the many specific uncertainties. Despite these uncertainties, there is more than enough evidence to move forward with attempts to repair mitochondrial DNA damage, as this may well remove the mitochondrial contribution to degenerative aging and age-related disease even in the absence of a complete understanding of all of the processes involved. There is a very reasonable expectation of significant gains to result from this work, justifying greater efforts in this area of development.
The mitochondrion is a ubiquitous intracellular organelle instrumental to eukaryotic existence. It is the major intracellular site of oxygen consumption and producer of the high energy molecule adenosine triphosphate (ATP). Mitochondria carry out tasks besides energy production, including cellular homeostasis and signalling, iron processing, haem and steroid synthesis, protein and lipid biosynthesis and apoptosis. These organelles are extremely dynamic and variable, capable of responding to numerous stimuli (including temperature, nutrients, hormones, exercise and hypoxia); they initiate the production of new mitochondria and their selective removal. The brain, per gram, has the highest demand for glucose than any other tissue. Brain function is entirely dependent on glucose and oxygen from the carotid and vertebral circulation. Glucose oxidation followed by oxidative phosphorylation is accountable for the vast majority of ATP generated in the brain. Brain energy metabolism declines with age. Our own group and others have observed this decline to be clinically homogenous in most brain regions. This metabolic change is considered to be a feature of the ageing phenotype as well as age-related neurodegeneration, where there is mounting evidence supporting the role of dysfunctional mitochondria in their progression.
As our understanding of ageing has progressed mitochondrial function has come to the forefront as pivotal to the aged phenotype. Classical theories, including the mitochondrial free radical theory of ageing (MFRTA), have led the field. According to the MFRTA an accumulation of oxidative damage, caused by mitochondrial free radicals, is the driving force behind ageing. However, this theory conflicts with growing evidence from animal models. Species comparison between the long lived naked mole rat and short lived mouse indicates little difference in the production of ROS between species and no age-dependent variation in antioxidant enzyme expression. This suggests that mitochondrial ROS may act as signalling molecules, prolonging maximum lifespan. MFRTA also fails to fully explain the functional brain mitochondrial deficits that occur with age. These deficits include reduced respiration, dynamic changes in shape and size, activation of permeability transition pore and loss of membrane potential. Although functional studies have gone some way to identifying these mitochondrial changes, there is variability found in the direction and extent to which these differences occur. There is even evidence to suggest that oxidative phosphorylation activity may in fact increase with age. There are similar inconsistencies which exist for the role and the activity of mitochondrial antioxidants, fusion and fission dynamics and other mitochondrial proteins with age. Profiling of mitochondrial protein expression in tissues from different ages can add molecular insight, which in conjunction with functional studies can be a powerful approach towards unravelling this complexity.
With evidence pointing toward a pivotal role of mitochondria in neurodegenerative disease and the aged phenotype, an understanding of the changes to the proteome is warranted. Mitochondrial proteomic alteration in brain ageing is clear, however the directionality and extent of these alterations is not. The application of quantitative proteomics to mitochondria is timely to more comprehensively investigate these changes. With the advent of new proteomic technologies, bringing greater reproducibility and accuracy, the field of mitochondrial proteomics is open-ended and improved clarity of the mitochondrial changes that occur in the brain with age is expected in the near future.
Chondrocyte Cell Death in Osteoarthritis
Researchers here review what is known of mechanisms contributing to the death of chondrocyte cells in aged joint cartilage. The loss of cartilage is characteristic of osteoarthritis, and given the prevalence of this condition in old people, there is considerable interest in finding ways to halt this process. Like all things in the biology of aging, it is far from simple and far from completely mapped, however. This paper omits mention of the likely role of cellular senescence in the development of osteoarthritis, something that seems much more relevant now that means of removing senescent cells are emerging, so you might treat this publication as a companion piece to another paper on that topic published earlier in the year.
Osteoarthritis (OA) is the most common chronic joint disease. OA pathophysiology was, for a long time, attributed to biomechanical constraints exerted on weight-bearing articulations (e.g., knees, hips). However, metabolic factors are also well recognized as mediators in the onset of OA. Adipose tissue can act as an endocrine organ, releasing bioactive molecules, such as pro-inflammatory cytokines, of which levels can be significantly and positively correlated with cartilage degradation in OA patients. OA is characterized by a progressive breakdown of articular cartilage, involving the remodeling of all joint tissues (bone, synovium, ligaments) with the appearance of osteophytes, synovial inflammation, subchondral bone thickening, and in fine joint space narrowing. Cartilage degradation constitutes one of the prominent hallmarks of the disease.
Articular cartilage is a conjunctive tissue composed of only one cell type, chondrocytes, enclosed in a self-synthesized extracellular matrix (ECM). These specific cells represent approximately 1% of total cartilage volume and are responsible for matrix composition and integrity, thereby conferring to cartilage its functions of mechanical support and joint lubrication. Histochemistry analyses have demonstrated the formation of chondrocytes clusters, the presence of irregular surfaces, cartilage volume loss, and matrix calcification in OA cartilage compared to normal cartilage. These changes in cartilage structure are linked to the alteration of molecular components of ECM. Distribution of the collagen II network is modified, being uniformly distributed throughout the normal cartilage layers, but at a decreased level in OA-degenerated areas and at an increased level in chondrocytes clusters.
Chondrocytes are quiescent cells that rarely divide under physiological conditions: Adult human cartilage is a post-mitotic tissue displaying virtually no cellular turnover. Moreover, the ECM is not innerved nor vascularizated, thereby avoiding new cell supply to compensate for potential cellular loss. As a consequence, phenotypic stability, anabolic/catabolic balance activity, and survival of chondrocytes are crucial for the maintenance of proper articular cartilage. During the course of OA, all of these criteria are modified. Compelling studies report the presence of empty lacunae and hypocellularity in cartilage with aging and OA progression, suggesting that chondrocyte cell death occurs and participates to OA development. However, the relative contribution of apoptosis per se in OA pathogenesis appears complex to evaluate. Indeed, depending on technical approaches, OA stages, cartilage layers, animal models, as well as in vivo or in vitro experiments, the percentage of apoptosis and cell death types can vary. Although an excess of autophagy can lead to cell death, the current view is that the trigger of autophagy in chondrocytes aims to avoid cell death, especially in the early stages of OA.
Currently, there is no treatment for a full stop of OA progression. Therefore, preventing, limiting, or delaying chondrocyte cell death, in order to maintain cartilage matrix integrity, might constitute a tempting approach. Caspase inhibitors are the most studied among all of the apoptosis regulators in OA. However, a tight control of the delivery site of these anti-apoptotic agent should be required (limited to the cartilage injury site) in order to avoid the risk of systemic malignancies. In addition, studies have shown that chondrocytes shifted towards necrotic cell death, suggesting that cells trying to avoid apoptosis paved the way for another dying process, such as necrosis. Minimizing oxidative stress and preserving mitochondria integrity could constitute an alternative approach. Antioxidants have demonstrated anti-apoptotic and anti-OA effects in rat and mouse models. Promoting autophagy could also indirectly act on removing defective mitochondria and the associated oxidative stress. Moreover, as key autophagic proteins were found to be decreased in aging and OA cartilage, restoring autophagy could be considered to delay OA development. A better molecular delineation of apoptotic and autophagic processes may help in designing new therapeutic options for OA treatment.
Chimeric Antigen Receptor Therapy Continues to Perform Well in Lymphoma Patients
A patient's T cells can be altered with the addition of chimeric antigen receptors so as to make them aggressively target cancer cells. This form of immunotherapy is one of the best attempted to date, and is producing impressive results in a variety of cancers, starting with leukemia and lymphoma. Here is another example of positive results in a form of lymphoma: the treatment eliminates cancer to produce remission (called "complete response" in the paper) for nearly half of the patients in the small study, as opposed to the one in ten achieved through prior therapies. As the list of side-effects in the paper make clear, however, while this is a considerable improvement there is a still a way to go yet in the production of better cancer therapies.
Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL) in the United States, accounting for approximately 30%-40% of all cases of NHL. Studies examining outcomes in patients with relapsed/refractory DLBCL show that the response rates to subsequent therapy varies from 14% to 63%. However, relapsed/refractory DLBCL is broadly defined and consists of a heterogeneous patient population. Outcomes are particularly poor in those patients with truly refractory DLBCL, defined as no response to last line of chemotherapy or relapse within 1 year of autologous stem cell transplant (ASCT). A large patient-level meta-analysis of patients with refractory DLBCL found that outcomes in this homogeneous population are significantly worse, with a complete response (CR) rate of 8%, a partial response (PR) rate of 18%, and median overall survival of 6.6 months, indicating a major unmet need for effective therapies for these patients.
Adoptive cell therapy with T cells genetically engineered to express chimeric antigen receptor (CAR) targeting CD19 is a promising approach for treatment of B cell malignancies. A recent single-institution study demonstrated high response rates with an overall response rate of 73% and a CR rate of 55% with anti-CD19 CAR T cells containing CD3ζ/CD28 signaling domains administered in conjunction with low-dose cyclophosphamide conditioning regimen in patients with relapsed/refractory B cell lymphomas. KTE-C19 is an autologous CD3ζ/CD28-based anti-CD19 CAR T cell product that uses the same CAR construct as in the earlier study but is manufactured in a centralized, closed, and streamlined process of approximately 8 days. ZUMA-1 is the first multicenter study evaluating the safety and efficacy of anti-CD19 CAR T cells in patients with refractory NHL. We report here the safety, efficacy, and correlative studies of apheresis product, KTE-C19, and in vivo effects from the phase 1 portion of ZUMA-1.
As of August 2016, the median follow-up time was 9 months. Nine patients were enrolled in the study. Two patients experienced adverse events due to disease progression, discontinued the study, and never received KTE-C19. Seven patients received conditioning chemotherapy and KTE-C19. Patients ranged from 29 to 69 years of age and had received two to four prior lines of therapy. Three were refractory to second-line or later lines of therapy, and four patients had relapsed post-ASCT within 1 year. Despite the small numbers in this study, the overall and complete response (CR) rates were high and durable relative to historical controls. Durable efficacy of the KTE-C19 regimen was observed in patients with rigorously defined chemotherapy refractory disease who had no viable treatment options. Rapid CRs were demonstrated after only 1 month of follow-up in only those four (57%) patients who relapsed after prior ASCT, and responses are ongoing at 12+ months in three of seven (43%) patients. In these three patients, the duration of response with KTE-C19 markedly exceeded the time to relapse after their prior ASCT. This is remarkable, as the expected CR rate in this chemotherapy refractory patient population is 8%, and median survival is 6.6 months with conventional therapies.
Metformin Acts through mTORC1
The evidence for metformin to do anything meaningful to longevity in animal studies is fairly ragged - similar studies show a range of results, none of them spectacular, and many of them too small to be significant. It is a marginal candidate for a drug to slow aging when compared to, say, rapamycin, which has much more robust results in animal studies. Further, the whole business of trying to slightly slow aging by tinkering with the ongoing operation of metabolism, slowing the pace at which the cell and tissue damage that causes aging accumulates, is itself an expensive exercise in achieving marginal results. I have to imagine that the reason the TAME human study of metformin and measures of aging exists is not to achieve useful results, but as a form of pressure on the FDA to start accepting treatments for aging. Since metformin has been approved and widely used for decades, the options for rejecting the trial were limited, and once any such trial has been accepted, the next will be easier to push through the established resistance to considering aging as a condition to be treated.
There are a limited number of core mechanisms involved in the link between metabolism and natural variations in longevity, but since all aspects of cellular biochemistry are connected to one another there are any number of ways to influence those core mechanisms. The enormous complexity of molecular biology makes it very hard to map these connections. That work is ongoing now and will be for a long time yet. Thus as a general rule we shouldn't be surprised to learn of newly discovered links between any two of the many approaches demonstrated to modestly slow aging in laboratory species. Here researchers connect metformin with mTOR, the target of rapamycin. mTOR forms two complexes, mTORC1 and mTORC2, and most of the interesting and beneficial effects observed involve suppression of mTORC1. That mTORC2 is suppressed as well is the cause of a number of the harmful side-effects. So there has been some interest in finding ways to target only mTORC1. In that context, it is interesting to see evidence for metformin to be acting in that way, but it doesn't change the basic point that this is all a very marginal exercise with little expected utility for human longevity at the end of the day.
Metformin has been used to treat type 2 diabetes (T2D) for nearly 60 years. It also has potential benefit in cancer prevention and treatment. The class of drugs to which metformin belongs, the biguanides, inhibit cellular growth in a variety of cancer cell lines, particularly in melanoma and pancreatic cancer cells. While it is widely accepted that the mitochondrion is a primary target of metformin, exactly how mitochondrial inhibition by metformin is transduced to the drug's other health-promoting effects, including its anticancer properties, remains unclear. Mitochondrial inhibition by metformin causes energetic stress, which results in activation of the energy sensor adenosine monophosphate-activated protein kinase (AMPK). However, multiple lines of evidence indicate that AMPK is dispensable for metformin's beneficial effects, invoking other major metformin effectors downstream of mitochondria.
The protein kinase mechanistic target of rapamycin complex 1 (mTORC1), which also serves as an energy and nutrient sensor, plays a central role in regulating cell growth, proliferation and survival. Inhibition of mTORC1 activity has been reported in cells in culture treated with metformin, suggesting that reduced TOR activity may be important for the metabolic effects of biguanides. In support of this idea, both metformin and canonical mTOR inhibitors have highly similar effects on the transcriptome, selectively decreasing mRNA levels of cell-cycle and growth regulators. Metformin may inhibit mTORC1 via modulation of Rag GTPases, but the mechanism by which this occurs is uncharacterized. It has been suggested that the pathway that leads to metformin-mediated inhibition of mTORC1 could represent a distinct mechanism of mTORC1 regulation, since no signaling pathway has been identified that connects the mitochondrion to mTORC1 without involvement of AMPK. Whether a mitochondrial-mTORC1 signaling relay plays a role in the action of metformin is still unknown.
As in mammals, metformin promotes health and extends lifespan in C. elegans, raising the possibility of conservation of genetic pathways responsible for metformin's beneficial effects. Using unbiased, iterative genetic screens in C. elegans, we identified a single, central genetic pathway by which metformin regulates growth. We report two elements absolutely required for the anti-growth properties of metformin: the nuclear pore complex (NPC), and acyl-CoA dehydrogenase family member 10 (ACAD10). These two metformin response elements were used to illuminate the major, biological pathway through which metformin induces its favorable effects. Remarkably, this ancient pathway unifies mitochondria, the NPC, mTORC1, and ACAD10 into a single signaling relay that mediates metformin's anti-aging effects in C. elegans and inhibits growth in C. elegans and human cancer cells alike.