Fight Aging! Newsletter, April 30th 2018

Most products provided to people, which may impact their safety one way or another, undergo some form of regulatory review and approval before they are allowed on the market. Medications and devices undergo a very extensive development, review and approval process, as they can have a significant short term and very long term impact on a patient's safety and quality of life. The regulatory bodies, including the FDA and analogous regulatory authorities in other parts of the world, are not perfect. The premise of regulation in medical development however is good and very necessary: to ensure that people are safe and that therapies work. These regulatory agencies focus on consumer protection and aim to prevent serious harm such as that which came to patients when medical research was not done properly, such as the thalidomide disaster which caused countless women to give birth to babies with extremely deformed limbs and other birth defects. Treatments also have to have the effect they promise, as patients pay for them and tolerate the side effects that often come with the treatments. The overall risk-benefit balance needs to be known and acceptable.

The execution of the regulatory development path can be flawed in all the usual ways present in any structure built by fallible human beings, however. I would imagine everyone who has spent significant time working with regulators has a list of items they'd like to change or improve upon. That said, the regulatory systems available are the only viable way to put safe, new treatments into the clinic, and make them ultimately available to large numbers of people. Once we realize and embrace this, we can engage with the regulatory agencies in an informed and purposeful manner and work towards the best common path forward across different parts of the globe.

I have just recently engaged with the rejuvenation research community and it seems that it has been firmly focused, and rightly so, on the early stage research portion of progress, but it may have had comparatively little experience with later stage clinical development of agents for this new frontier. This is the natural progression of a new and exciting frontier in clinical development. I understand the existence of a certain amount of regulatory phobia, as the first view of the enormous cost and complexity of the path of clinical trials for a new therapy is very intimidating. Having been engaged in many clinical trials developing potential treatments for life-threatening diseases such as pediatric brain tumors, I also understand the enormous frustration and the need for access to new potential solutions. But as long as drug candidates are under clinical study, there is still a real inherent risk that one does more harm than good (which is exactly what the trials are intended to find out) and thus the regulations are designed to protect the trial participants first and foremost. In too many cases potential treatments have turned out ultimately harmful or have a much more modest effect impacting the risk-benefit balance negatively. Thus engaging the current regulatory systems is the road we have to travel in order to get treatment options in the hands of medical professionals and patients.

Not all study drugs in development make it; in fact most drugs turn out to be toxic or do not have an acceptable risk-benefit balance. I have been lucky enough to be part of a few innovative drug development projects which dramatically improved the medical outlook for some serious diseases (Remicade, the very first anti-TNF monoclonal antibody was the first successful drug development project I became deeply involved in). It is very gratifying to know that so many patients with Rheumatoid Arthritis, Crohn's Disease and other serious ailments are benefitting from treatment with biologicals, far beyond the reach of any single doctor's direct patient focused capabilities.

For drug development, there are ways to de-risk the complex development path. The development pathway is broken up in separate pieces, which makes the phases more manageable and the development risks (and safety risk for the trial participants) are decreased along the way. Doing this translational step from science to the clinic poorly however, often results in very promising technologies 'dying on the vine' and therefore deprives us all of potential worthwhile solutions. One of the reasons I joined Ichor Therapeutics is to help build this development bridge for the team across its varied projects, to build on and validate the scientific focus by constructing a robust infrastructure for the clinical development of innovative new options to treat aging and its conditions.

A Pharmaceutical Developer's Initial Considerations

As a company founder and pharmaceutical developer, with a specific implementation of new technology in mind, what should one be thinking about? An important initial step is to build a living model of the path ahead, and the first and most important consideration is which indication or indications to pursue. An indication is the reason to use the treatment under development, meaning the specific medical condition and class of patients that will be treated to produce the intended benefits. For example, a therapy that enhances muscle growth might be applied, depending on the technical details, to muscular dystrophy, frailty syndrome, sarcopenia, cancer cachexia, and so forth. Selecting the best initial indication can be based on different departing points: the indication with the best regulatory approval pathway versus an indication which reaches the most patients in a common disease, for instance. Choosing an indication also depends on the initial funding available and timeline constraints. There are almost always far more choices than can reasonably be tackled in the near future by any one company, and understanding the development ramifications of each top contender is key.

Interactions with regulators over the initial development years of any drug candidate will be focused on preparing for, building, and conducting a series of experiments - clinical trials - to rigorously prove that the therapy is safe and effective for the selected indication. This will involve a sizable amount of time and effort; the following costs are middle of the road estimates for indications with a high medical need and a modest sample size studying a chemical drug and might be halved or doubled for any specific company and therapy. Much will depend on the cost of manufacturing the therapeutic, implementing the pre-clinical programs, the regulatory filings, the type of disease and therapy, the medical assessments needed to prove safety and efficacy, the required length of follow up for patients, the geographical location of the trials and so forth.

a) Getting ready for the pre-trial engagement with regulators: design the overall development plan, rigorously develop the manufacturing process and implement the animal studies for initial safety assessment and other scientific building blocks such as mechanism of action and drug exposure. The doses in the animal models are much higher and exposure much larger than will be given to people and thus provide a safety margin. Costs depend on many factors, including whether the drug in development is a chemical or biological drug, the duration of intended treatment and number of patients dosed for instance. This initial work can easily cost 4-6 million, of which about half goes to the manufacturing.

b) Phase I trials: the purpose is to establish safety in a limited number of people (first in man and thus limited exposure of number of individuals) and obtain a baseline set of mainly safety data across escalating doses. Expect at least 2.5-4 million for the trial alone, and then an additional 2.5-3 million for ongoing support and all of the other work necessary to run the development team and activities in a company.

c) Phase II trials: the purpose of phase II is to 1) expand the safety database on recipients of the study drug and to start understanding how the trial endpoints are changed due to exposure to the study drug, meaning the specific measurements of the disease needed to prove safety and effectiveness, and 2) obtain information on the optimal dosage. It takes often at least 300 patients to obtain a rigorous set of data for these items. Much depends on the magnitude of the difference in an endpoint between treated and control participants. This builds the necessary data to design a Phase III. Often multiple Phase II studies are needed. This will cost 10-15 million for a single Phase II trial, and expect the average pharmaceutical company to spend another 10-15 million on ongoing operations and related costs.

d) Phase III trials: the purpose of Phase III is to determine the treatment benefit to a specific population. It also provides most of the safety data. Two such trials are typically needed, and these are the big, expensive, high-publicity projects. The cost will often run 25-50 million for the trial alone.

e) Often other specialized Phase II trials are needed to study the effects on the heart, metabolic breakdown of the study drug, and interactions with other drugs already on the market, for instance, adding to the cost. Also not included are the ongoing manufacturing costs for the study drug needed for the trials, which for each Phase grows in size of number of patients included in the trial, as well as all the regulatory costs (for instance safety reporting). Later stage trials also often require expanded pre-clinical safety work.

The overall development costs vary per study drug and indication and often run in the hundreds of millions or more. Once a drug is approved for one indication, one can build on the existing file to develop follow-on indications, saving significantly on additional development costs.

A full Gantt chart for the end to end process of all the development tasks might take 3 months to assemble and be 3 meters long when printed out. Given that, and the escalating costs during the development timeline, the more that can be done early on to consider and design the best path ahead, the better off one is. No-one wants to have to raise the funding to repeat a later stage trial which came up short, but this happens! In many cases, better planning and choices made far earlier could have avoided such costly outcomes.

An Initial Model of Indications

Many therapies will have multiple possible indications, which can be developed in interactions with regulators. Some will be better than others from the perspective of establishing a foothold in the clinic, and some will be better than others from the point of view of helping more patients (suffering from a disease which affects more people). It is usually the case that these two concerns are opposed as far as size of the required dataset for approval: the intent of the regulator is to protect the public, and applications for approval that lead to the most widespread use will generally require more evidence, time, and funding to reach a sufficient standard of proof of safety and efficacy.

Thus the preferred strategy (if possible) for clinical development professionals is to put forward an initial application for a narrow, critical usage that solves a focused, high medical need problem, one that can be evaluated and proven more easily. Then, once this is well underway, the company can expand their work with regulators to cover other, larger uses of the therapy. This sort of incremental approach to development also allows for applying what one has learned along the way, letting it be more readily incorporated into the ongoing development of the product. A second regulatory application will usually be able to build on the manufacturing and pre-clinical dataset developed for the first indication.

When looking over possible indications, one should consider the following:

a) The medical need - the greater the better. Are patients suffering severe disease effects? Is there no existing therapy? This goes a long way towards determining the degree to which all involved (patients, professionals, doctors, and regulators) will work with you and proactively support your application through the process.

b) The patient population size. This is important in several ways. Firstly, a small population size can lead to an orphan designation, which can offer a number of advantages to development, though maybe now less so than used to be the case. On the other hand, a population that is too small will require more time to enroll the number of patients needed and will render the company unable to produce data that is rigorous enough to pass muster in a reasonable timeframe. A very large population is good as enrollment may be much easier and it supports the ultimate goal of a company to help more people, but as noted above it will lead to greater demands for stringent proof of safety from the regulators - it is often not the optimal first step, but better attempted as an expansion of an indication with a smaller patient population, once the study drug manufacturing is accepted and the drug is proven to be safe in at least one indication. Larger disease indications also may have more competing treatments under development and thus also compete for patient enrollment in these studies.

c) The disease severity. A more severe disease makes it easier to obtain strong data, because the size and speed of onset of the intended benefit resulting from a successful therapy is proportionally larger. It is much easier and less costly to prove effectiveness given large and relatively rapid changes in patient health than it is for more subtle effects which appear over time. Large and rapid beneficial changes are generally only possible to achieve in severe disease conditions.

d) Plausible endpoints that can be measured, and the cost of measuring them. Mortality is a definitive and good endpoint because it is less expensive to assess, but a hard to reach endpoint because patients will have to be followed for many years, unless the disease is rapidly fatal and amenable to intervention. Endpoints based on simple biomedical assays or measurements that can run soon after a therapy is administered, such as presence of a persistent virus, or blood pressure, or blood lipid levels, are much more cost effective where they have been well established in the field and are already accepted by regulators for an indication. Where they have not been established, be aware that the process of introducing a new surrogate endpoint is a long and expensive struggle. Further, some endpoints, such as imaging endpoints, can increase the cost of a trial significantly.

e) The duration of a trial. The cost of a trial is as much determined by its duration as by the number of patients enrolled. Diseases for which there is much competition to enroll patients can be also hard, as all companies and academic groups are looking for the same patients. Some indications will be ruled out for a company at earlier stages simply because there is no practical way to raise sufficient funding given a very long timeline for trials to lead to concrete results.

In most cases, the best approach will either stand out, or be the one left standing after others are eliminated. Here, eliminated can mean "put off for later" as all companies will try to expand their indications as they move forward with more successful data and proven confidence in their approach.

Orphan Indications

Orphan designation can be obtained for an indication that has a has a small population size and great medical need. The intent on the part of regulators is to incentivize companies to work on therapies for what would otherwise be financially impossible diseases. This is achieved through a combination of fast-tracking, vouchers to speed later development, and a greater willingness on the part of regulators to work with companies to smooth the passage of a therapy for an orphan indication. Success in an initial orphan indication has in the past been a more reliable road to initial approval for many companies, even though on the whole it doesn't make the process significantly less expensive. As a consequence, a complex structure and industry has sprung up around the orphan designation, which has arguably veered into attempts to game the system.

On this topic, it is important to realize that the system is not just the rules as written. It is the intent of the regulators, the interpretation of the regulations, and the relationship built with regulators. I have sat in numerous meetings over the years listening to people engage with the regulators to try to design short cuts, where in the end they would have been far better off trying to work within the regulations while building the relationship with regulators in different jurisdictions around the world. Regulators are people just like the rest of us, and being open, earnest, and intent on producing a good outcome for patients receiving the treatment goes a lot further than aggressively trying to cut corners and rules-lawyering. The degree to which the regulatory teams you interact with are engaged with you can be an important determinant of the pace of the regulatory progress. For instance, once I have been happily surprised to receive a phone call from an FDA doctor overseeing the complex important trial I was running, asking how the agency could help us to increase the difficult enrollment and help getting the trial finished.

On starting with an orphan indication, consider, for example, that most gene therapies will be applicable to some form of genetic disorder. If a gene or protein is being manipulated, then there is probably a population of patients who have loss of function mutations in that gene resulting in an inherited disorder. But what if there are only ten such patients ever recorded, all of whom die young, and none presently known? It simply isn't practical to try to address this super rare condition at the outset of development as an orphan indication. Even if a patient is found in the next few years, the results from one intervention are not rigorous enough to proceed with. I'm aware of a trial for a rare condition that lasted for more than 25 years in order to find 90 or so patients, for example, and that is far beyond any timeline a startup company should be considering.

Further, is a proposed orphan designation biologically defensible? For example, one could look at the very large HIV patient population and try to designate a small orphan population of individuals who show adverse reactions to the common antiretroviral drugs, and thus cannot find effective treatment without bothersome side effects. But is that designation of a biological population, and the measures or metrics used, widely accepted by the research community and by regulators, or does it look more like an entirely novel slicing and dicing of the patient population to enable the aforementioned gaming of the system to try to gain advantage? If the end goal is to treat all HIV patients, then the regulators will see that and treat the application accordingly.

At the end of the day, the final safety database resulting from the clinical trial work available for submission should provide sufficient protection to the population of patients who will receive the treatment in the real world. And if that population would be much larger than the one studied, side effects that are less common (and thus not likely observed in the smaller population) will impact the larger population and only be found after exposure of many more individuals. It is because of this that regulators are stringently doing their reviews. Consider work on an orphan indication, but don't take it as a mandatory step and plan to build a safety database commensurate with the intended patient exposure.

Off-Label Usage

Off-label usage interacts with orphan indications and other incremental approaches to providing a therapy to an ever-large patient population over time, and can be viewed through a similar set of lenses. In principal, any approved medical technology can be prescribed for off-label use - for use with another, different medical condition, unrelated to the approved indication. The manufacturer cannot advertise that use, but physicians and patients can follow their own judgment. In practice, consider that the intent of the regulator is firstly to minimize possible harm to patients, and secondly for all use to be tested and proven to accepted and sufficiently high standards. Small amounts of off-label use will typically fly under the radar, as regulators have limited resources. If off-label use expands greatly for any particular therapy, then regulators are bound to intervene and with good reason.

Thus it isn't wise to adopt a restricted or orphan indication and expect off-label use to take the therapy to the broader patient population. Ethically one should be going through the formal and full regulatory process to bring a therapy to that larger population in order to do no harm (primum non nocere, as the first principle). Doing things the right way in the end also works far more effectively than trying to find loopholes and does justice to the risk taken by the study participants and the recipients of the drug when on the market.

There is another factor to consider, as well. A common joke in the development community is that "it is easy to obtain approval, but hard to obtain reimbursement." It is of course not at all easy to obtain approval, which is where the humor lies. In recent years, the payer institutions, such as insurance companies and government medical entitlement programs, have become a gatekeeper and very important factor in the drug development planning of pharma/biotechnology companies. It used to be the case that one could largely put this off as a concern in the earlier stages of company development, but now it has become the case that one can have a therapy approved, but find that no insurance company or other payer will pay for it. Thus in addition to proving worthiness to regulators, when planning trials one must also take into account the evidence that payers will require in order to accept the treatment in their plans. This also serves to suppress any significant off-label use.

Aiming to be a Worldwide Company

It is a good strategy, and well established in practice, to work on application for approval of an indication with multiple regulatory bodies. The goal is to make a successful therapy available to patients globally and a larger eventual market also provides a more realistic scenario to recoup the significant developmental costs and eventually may provide profits for corporate growth, return of investment for early (high risk) investors and further development of additional drug and indications. For example, the US FDA and the European EMA and others, have a solid set of guidelines for harmonized submissions under the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). In the course of talking to both the US and EU, one can craft a plan for trials that will satisfy both agencies, at a similar cost to just one filing. The trials are designed to have the standard components and answer all specific questions for each party, are run once, and provide data for multiple applications, in order to gain approval to access two or more large markets.

My experience is largely with the FDA and EMA. I prefer Europe, as in my experience the Netherlands and Belgium are the best and the fastest locations for the initiation of the initial Phase I study. In general, studies can be conducted at a lower cost and the regulations are more accommodating in Europe. Currency exchange rates can influence these cost differences dramatically, of course.

If Europe is cheaper and faster, then why submit to the FDA early on? A counterpoint is that the US has deep clinical research experience for many diseases in its academic centers and hospitals, and a very sophisticated disease tracking system. This helps in designing clinical trial protocols and predicting enrollment. It also has an extremely large patient population. Compared to Europe, one does not have to deal with quite so many language barriers in the execution of clinical trials. So each continent has its own advantages and certainly the indication should be driven by the geography: certain diseases are not found in the highly developed countries for instance and others are predominantly found there due to lifestyle issues. Certain diseases can only be found in certain geographies or populations.

In summary, the regulators will accept clinical trial data that is developed under ICH guidelines from many parts of the world as long as the clinical trials are implemented appropriately and it is worthwhile to engage with multiple regulatory agencies once one enters later stage trials. As the regulations and local issues constantly change, it is important to keep up to speed or receive the latest information from professionals in the field.

Developing for Quality is Vital

As I mentioned, one of the important parts of the early work in a company that leads up to engagement with regulators is to develop a highly robust development plan and manufacturing and toxicity assessment process. This is the item that surprises many founders, both in terms of the stringency required by regulators, and in terms of the cost of achieving this goal.

It is comparatively easy to produce research grade products on an ad hoc basis, with a moderately wide variation in quality of the output. The core demonstration in cells or mice in any gene therapy paper can be recreated in a laboratory for 100,000 or less, and much of that cost lies in setting up the protocols, not actually running them or assessing the mice. That is far from good enough for a study drug entering the clinic, however. It does in fact cost a few million to assemble a suitable infrastructure to narrow down the product quality to a level suitable for medicine. Appropriately manufactured drug product needs to be used in the definitive pre-clinical toxicity tests as well (non-GLP experiments can provide early stage guidance to select drug candidates and inform the toxicity models).

The focus on developing the overall development plan and required infrastructure and embracing its necessity from the start is one of the distinguishing marks between successful and likely-to-fail startup companies. Smaller startups are able to make enormous advances with relatively little initial funding nowadays, often stimulated with local seed investments. The next phase during the "valley of death" selects the ones which will continue to grow, as they are able to obtain follow-on funding for the more financially challenging phases of the development path. In order to obtain such follow-on funding, a solid and living development plan and meticulous execution of the steps (and if needed, adjustments to the plan!) are key. It pays to be data driven. So is making sure one always has a little extra financial buffer before the next round of funding is thought to be needed, as milestones are always harder to meet and may take a little bit longer. Having to go back for more money before a value inflection milestone is a hit will cost dearly.

Regulation is Complex, and Guidance is Necessary

I would not advocate start up founders attempting to navigate the drug development pathway and regulatory system by themselves. While founders as a category are obviously capable of rapid self-education, in the case in which they are not yet trained and have access to expertise, this isn't in the same category of difficulty as, say, raising the first round with a lead investor (and we all know how difficult that is). It is a much more complex, living, constantly dynamic system that changes in its nuances year to year, and is as much about actual practice (interpretation of regulations), good people, and knowledgeable resources, as it is about the regulations as written.

Find a guide who understands drug development and the regulatory systems you intend to work with very early in the life of the company, soon after founding, and preferably before even starting on the development work - as that work will be strongly shaped by the nature of the indications you choose. Talk to several such people to obtain different views of the development path and regulatory field, and engage one as a consultant and truly integral part of your team. Use smart outsourcing for those activities, which are much better done in specialized (large scale) vendors, and use their highly specialized expertise in a true team like fashion. Never lose oversight though, and manage for success with your associated expert partners as extended team members.

In summary, drug development is a challenging road - don't let anyone tell you differently. The reward at the end is building an extended team with highly specialized complex expertise, now successfully applied, and resulting in the ability to meaningfully improve the lives of patients. Once the core engine is built and running, many projects can be taken through the pipeline and new medical frontiers can be forever changed.

A recently released study indicates that dementia's impact might be compressing a bit. That is, people might be developing dementia later and living with it for a shorter period of time. In data from four different time periods over a period of 30 years, the mean age at dementia onset increased, while the length of time living with dementia decreased. Is it because prevention and care of stroke today is superior compared to decades ago? Stroke is a major risk factor for dementia.

"Prevention of stroke and reduced impact of stroke are great advances, but neither completely explains the trend we are seeing. We are looking at other causes, such as lower burden of multiple infections because of vaccination, and possibly lower levels of lead or other pollutants in the atmosphere. Early education and nutrition might also play a role. Stroke risk has decreased because of greater control of blood pressure. In the past, if you had a stroke you were at 90 percent greater risk to develop dementia. Today, you have a 40 percent greater risk."

A total of 5,205 participants from the Framingham Original and Offspring cohorts were studied. Four epochs were considered from 1977-1984 to 2004-2008. Gender and education adjusted 5-year mortality risks were estimated using delayed entry Cox models with the earliest epoch as reference category. Stratified analyses by sex, education, and age were undertaken. A nested case control study of 317 dementia cases and 317 controls matched on age, gender and epoch was initiated.

In the whole sample, 5-year mortality risk has decreased with time, it was 33% lower in the last epoch compared to the earliest. In the 317 persons who developed dementia, age at onset increased (1.5 years/epoch), and years alive with dementia decreased (1 year/epoch) over time. We observed however, a decreased adjusted relative mortality risk (by 18%) in persons with dementia in 1986-1991 compared to 1977-1983 and no significant change from then to the latest epoch. The nested case control study suggested in matched controls that 5-year mortality relative risk had increased by 60% in the last epoch compared to Epoch 1.

In conclusion, in the Framingham Heart Study population, in the last 30 years, disease duration in persons with dementia has decreased. However, age-adjusted mortality risk has slightly decreased after 1977-1983. Consequences of such trends on dementia prevalence should be investigated.

Autophagy is a major catabolic route in cells responsible for the clearance of proteins and organelles. Pathological levels of autophagy are associated with muscle wasting, but physiological levels are important for cellular recycling. In the present study, indicators of autophagy and unfolded protein response (UPR), which is another system for maintaining cellular homeostasis, were investigated from the muscle biopsies after a single bout of resistance exercise and after 21 weeks of resistance training in previously untrained young and older men.

Aging may blunt some of the positive effects of resistance training when it comes to improvement in muscle quality, but the researchers reported that UPR that is induced by the accumulation of misfolded proteins in endoplasmic reticulum (ER) was activated by a bout of unaccustomed resistance exercise regardless of age. Skeletal muscle appears to adapt to resistance exercise similarly in young and older people in many ways.

Becoming more physically active after a heart attack reduces the risk of death. A study that followed more than 22,000 patients found that those who became more physically active after a heart attack halved the risk of death within four years. Levels of physical activity were reported 6-10 weeks and 12 months after the heart attack. The difference between answers was considered a change in physical activity over the year following the heart attack.

On both occasions, patients were asked how many times they had exercised for 30 minutes or longer during the previous seven days. Patients were categorised as constantly inactive, reduced activity, increased activity, or constantly active. A total of 1,087 patients died during an average follow-up of 4.2 years. The researchers analysed the association between the four categories of physical activity and death, after adjusting for age, sex, smoking, and clinical factors. Compared to patients who were constantly inactive, the risk of death was 37%, 51%, and 59% lower in patients in the categories of reduced activity, increased activity, or constantly active, respectively. "Our study shows that this advice applies to all heart attack patients. Exercise reduced the risk of death in patients with large and small myocardial infarctions, and for smokers and non-smokers, for example."

Researchers recruited 35 people ages 45 to 75 and asked about their physical activity levels and the average number of hours per day they spent sitting over the previous week. Each person had a high-resolution MRI scan, which provides a detailed look at the medial temporal lobe, or MTL, a brain region involved in the formation of new memories. The researchers found that sedentary behavior is a significant predictor of thinning of the MTL and that physical activity, even at high levels, is insufficient to offset the harmful effects of sitting for extended periods.

This study does not prove that too much sitting causes thinner brain structures, but instead that more hours spent sitting are associated with thinner regions, researchers said. In addition, the researchers focused on the hours spent sitting, but did not ask participants if they took breaks during this time. The researchers next hope to follow a group of people for a longer duration to determine if sitting causes the thinning and what role gender, race, and weight might play in brain health related to sitting.

"Frailty progresses with aging, but older women who engage in a high level of daily physical activity can reverse certain characteristics related to aging, such as slow walking and decreased function. But for women over the age of 75, muscle strength and endurance declines. Starting resistance exercise when they are young and continuing it is important so that when they reach a very advanced age they have already built up their strength and endurance reserves."

The study looked at 46 women across two different age ranges, 60-74 and 75-90, to learn how physical activity affects frailty differently in the two groups. Researchers found that there was a larger difference between the two groups in terms of muscle strength and endurance among those who were very physically active. With mobility - as measured by the length of a person's step - and basic functional ability, there was a gap between the two age groups among women who engaged in minimal physical activity. However, that gap disappeared if they did a high level of physical activities. "Their main physical activities consisted of light gardening, light housework and stretching. Is this because they are still working and don't have time for exercise, or do they think they are healthy and don't need to? It appears that committing to regular exercise is not yet a standard part of older women's lifestyles and is instead a reactive behavior to, for example, falls or illness."

Cellular senescence is involved in the development of age-related diseases and the loss of tissue functionality with age. Senescent cells accumulate in vivo and their selective elimination increases the healthspan of mice. While transiently present senescent cells have beneficial functions in wound healing, their chronic persistence and accumulation with age negatively affects the surrounding tissue by the senescence-associated secretory phenotype (SASP). This consists of pro-inflammatory cytokines and chemokines, extracellular matrix (ECM) remodelling proteases and growth factors and results in a vicious cycle of progressive functional loss in tissues and organs.

Negative effects of cellular senescence can be counteracted by: (i) delaying the loss of cell type specific functionality mediated by senescence-associated de- or trans-differentiation, (ii) interfering with the negative effects of SASP or by (iii) selectively eliminating senescent cells. Indeed, several clinically approved drugs including glucocorticoids, metformin, rapamycin, and JAK inhibitors attenuate the SASP. In addition, senolytic substances have been identified including quercetin, dasatinib, navitoclax, piperlongumine, fisetin, A1331852, A1155463 and FOXO4 inhibiting peptides.

Solidago virgaurea, also known as goldenrod, is traditionally used as an anti-inflammatory herbal medicine. A recent study identified 3,4,5-tri-O-caffeoylquinic acid as the constituent with the highest reduction of tumour necrosis factor-alpha and interleuin (IL)-1β concentrations. However, the effect of extracts from S. virgaurea on cellular senescence and fibroblast subpopulations have not been studied so far. Here we report an alcoholic extract of Solidago alpestris (1201) with the ability to block negative effects of senescence in human skin fibroblasts including the SASP in vitro. We screened seven different plant extracts. 1201 showed the clearest effects in terms of changing cell morphology and of reducing SA-β-galactosidase activity and was therefore selected for further studies.

The extract 1201 exhibited weak senolytic activity and delayed the acquisition of a senescent phenotype. When administered to stress-induced premature senescent fibroblasts, this extract changed their global mRNA expression profile and particularly reduced the expression of various SASP components, thereby ameliorating the negative influence on nearby cells. The caffeoylquinic acids with their anti-inflammatory property are likely to be candidates for the SASP-attenuating property of 1201, whereas the three derivatives of quercetin, one of the three naturally occurring senolytics reported so far, could be the driving force behind the slow selective elimination of senescent cells. Thus, the investigated plant extract represents a promising possibility to block age-related loss of tissue functionality.

Once upon a time, the planet was tyrannized by a giant dragon. The dragon stood taller than the largest cathedral, and it was covered with thick black scales. Its red eyes glowed with hate, and from its terrible jaws flowed an incessant stream of evil-smelling yellowish-green slime. It demanded from humankind a blood-curdling tribute: to satisfy its enormous appetite, ten thousand men and women had to be delivered every evening at the onset of dark to the foot of the mountain where the dragon-tyrant lived. Sometimes the dragon would devour these unfortunate souls upon arrival; sometimes again it would lock them up in the mountain where they would wither away for months or years before eventually being consumed...

Stories about aging have traditionally focused on the need for graceful accommodation. The recommended solution to diminishing vigor and impending death was resignation coupled with an effort to achieve closure in practical affairs and personal relationships. Given that nothing could be done to prevent or retard aging, this focus made sense. Rather than fretting about the inevitable, one could aim for peace of mind. Today we face a different situation. While we still lack effective and acceptable means for slowing the aging process, we can identify research directions that might lead to the development of such means in the foreseeable future. "Deathist" stories and ideologies, which counsel passive acceptance, are no longer harmless sources of consolation. They are fatal barriers to urgently needed action.

Senolytic drugs hold the perspective to specifically target senescent cells and thereby to rejuvenate tissues or organisms. Several compounds have been suggested to possess senolytic effects, including navitoclax (ABT-263), quercetin, danazol, and nicotinamide riboside. ABT-263 inhibits BCL-2 protein family members, which are crucial regulators of the apoptosis pathway. ABT-263 was shown to deplete senescent cells of human umbilical vein epithelial cells (HUVECs), IMR90 human lung fibroblasts, and murine embryonic fibroblasts, but not human primary pre-adipocytes. Danazol is a synthetic androgen with telomere elongating capacity, which has been used to target accelerated telomere attrition - a hallmark of aging and senescence. Quercetin is a proteasome activator with anti-oxidant properties that triggers apoptosis via the BCL-2 pathway. Nicotinamide riboside increases levels of nicotinamide adenine dinucleotide (NAD+). Aged mice supplemented with nicotinamide riboside revealed increased lifespan and rejuvenated muscle stem cells.

Primary cells undergo a limited number of divisions before entering the state of replicative senescence. The process of senescence induces changes in morphology, metabolism, secretory phenotype, and differentiation potential of cells, thereby having a significant impact on experimental outcomes and affecting their therapeutic potential. This applies particularly to mesenchymal stromal cells (MSCs), which raise high hopes in tissue engineering and are concurrently tested in a multitude of clinical trials. MSCs comprise a multipotent subset of cells, capable of differentiation towards osteogenic, chondrogenic, and adipogenic lineages. The selective removal of senescent MSCs from cultures might improve standardization and effectiveness of cell preparations for cell therapeutics in regenerative medicine. We have therefore directly compared the senolytic capacity of ABT-263, quercetin, danazol, and nicotinamide riboside in human MSCs during long-term culture.

The effects of these compounds were analysed during long-term expansion of MSCs, until replicative senescence. Furthermore, we determined the effect on molecular markers for replicative senescence, such as senescence-associated beta-galactosidase staining (SA-β-gal), telomere attrition, and senescence-associated DNA methylation changes. Experiments revealed that ABT-263 had a significant but moderate senolytic effect. This was in line with reduced SA-β-gal staining in senescent MSCs upon treatment with ABT-263. However, none of the drugs had significant effects on the maximum number of population doublings, telomere length, or epigenetic senescence predictions. Of the four tested drugs, only ABT-263 revealed a senolytic effect in human MSCs - and even treatment with this compound did not rejuvenate MSCs with regard to telomere length or epigenetic senescence signature. It will be important to identify more potent senolytic drugs to meet the high hopes for regenerative medicine.

DNA demethylation is an important process that maintains transcriptional activity of genes. An increase in methylation in the promoter region of a gene diminishes the promoter activity and gene transcription. Numerous studies showed that DNA methylation is increased with age. Coincidently, the prevalence of arterial stiffness and hypertension also increases with age. Arterial stiffening is an independent predictor of cardiovascular outcomes, such as hypertension, myocardial infarction, cognitive decline in aging, stroke, and kidney diseases. However, the relationship of DNA methylation and aging-related arterial stiffening is unclear. Whether increased methylation led to arterial stiffening has never been determined. Physiologically, an appropriate methylation level is maintained by the balanced methyltransferase and demethylase activity. In this study, we assessed if activation of the demethylase affects arterial stiffening and hypertension in aged mice.

The Klotho gene was originally identified as a putative aging-suppressor gene in mice that extended lifespan when overexpressed and caused multiple premature aging phenotypes when disrupted. The Klotho level decreases with age, while the prevalence of arterial stiffness and hypertension increases with age. At age 70 years, the serum level of Klotho is only about one half of what it was at age 40 years. Moreover, the serum Klotho level is significantly decreased in patients with arterial stiffness in chronic kidney diseases. Our recent study showed that haplodeficiency of Klotho gene caused arterial stiffness. We found, in cultured renal tubule cells, that a small compound (compound H) may be a potential inducer of Klotho gene expression. Whether compound H promotes Klotho expression and release in vivo has never been determined. In this study, we investigated whether compound H increases Klotho levels and attenuates aging-associated arterial stiffening and hypertension.

Our results demonstrated that aging-related arterial stiffening and hypertension are attributed, at least in part, to the increased DNA methylation. Compound H activates demethylases and attenuates arterial stiffening and hypertension in aged mice likely via increasing the Klotho levels. Aging-related arterial stiffness was associated with accumulation of stiffer collagen and degradation of elastin. These changes were effectively attenuated by compound H, suggesting rejuvenation of aged arteries.

One of the most vexing problems with spinal cord injuries is that the human body does not rebuild nerves once they have been damaged. Other animals, on the other hand, seem to have no problem repairing broken neurons. Researchers have studied an amphibian known as the axolotl or Mexican salamander. Captive-bred axolotls are frequently used in biological research, both to learn from the animal's remarkable ability to regenerate body parts and to help inform conservation efforts.

When an axolotl suffers a spinal cord injury, nearby cells called glial cells kick into high gear, proliferating rapidly and repositioning themselves to rebuild the connections between nerves and reconnect the injured spinal cord. By contrast, when a human suffers a spinal cord injury, the glial cells form scar tissue, which blocks nerves from ever reconnecting with each other.

Researchers traced the molecular mechanisms at work in each case. They found a particular protein called c-Fos, which affects gene expression, is essential to the processes axolotls use to repair injured nerves. While humans also have c-Fos, in humans the protein functions in concert with other proteins, in the JUN family, that cause cells to undergo reactive gliosis, which leads to scar formation. In axolotls, this molecular circuitry is carefully regulated to direct axolotl glial cells toward a regenerative response instead.

"Our approach allows us to identify not just the mechanisms necessary to drive regeneration in salamanders but what is happening differently in humans in reposes to injury. In addition to spinal cord regeneration, our work also focuses on other forms of regeneration including scar-free wound healing and limb regeneration."

One of the major goals of geroscience research is to define "biomarkers of aging", which can be thought of as individual-level measures of aging that capture inter-individual differences in the timing of disease onset, functional decline, and death over the life course. While chronological age is arguably the strongest risk factor for aging-related death and disease, it is important to distinguish chronological time from biological aging. Individuals of the same chronological age may exhibit greatly different susceptibilities to age-related diseases and death, which is likely reflective of differences in their underlying biological aging processes. Such biomarkers of aging will be crucial to enable evaluation of interventions aimed at promoting healthier aging, by providing a measurable outcome, which unlike incidence of death and/or disease, does not require extremely long follow-up observation.

One potential biomarker that has gained significant interest in recent years is DNA methylation (DNAm). Chronological time has been shown to elicit predictable hypo- and hyper-methylation changes at many regions across the genome, and as a result, the first generation of DNAm based biomarkers of aging were developed to predict chronological age. The blood-based algorithm by Hannum and the multi-tissue algorithm by Horvath produce age estimates (DNAm age) that correlate with chronological age for full age range samples. Nevertheless, while the current epigenetic age estimators exhibit statistically significant associations with many age-related diseases and conditions, the effect sizes are typically small to moderate. One explanation is that using chronological age as the reference, by definition, may exclude CpG sites whose methylation patterns don't display strong time-dependent changes, but instead signal the departure of biological age from chronological age. Thus, it is important to not only capture CpG sites that display changes with chronological time, but also those that account for differences in risk and physiological status among individuals of the same chronological age.

Previous work by us and others have shown that "phenotypic aging measures", derived from clinical biomarkers, strongly predict differences in the risk of all-cause mortality, cause-specific mortality, physical functioning, cognitive performance measures, and facial aging among same-aged individuals. What's more, in representative population data, some of these measures have been shown to be better indicators of remaining life expectancy than chronological age, suggesting that they may be approximating individual-level differences in biological aging rates. As a result, we hypothesize that a more powerful epigenetic biomarker of aging could be developed by replacing prediction of chronological age with prediction of a surrogate measure of "phenotypic age" that, in and of itself, differentiates morbidity and mortality risk among same-age individuals.

Using a novel two-step method, we were successful in developing a DNAm based biomarker of aging that is highly predictive of nearly every morbidity and mortality outcome we tested. Training an epigenetic predictor of phenotypic age instead of chronological age led to substantial improvement in mortality/healthspan predictions over the first generation of DNAm based biomarkers of chronological age. In doing so, this is the first study to conclusively demonstrate that DNAm biomarkers of aging are highly predictive of cardiovascular disease and coronary heart disease. The new measure, DNAm PhenoAge, also tracks chronological age and relates to disease risk in samples other than whole blood. Finally, we find that an individual's DNAm PhenoAge, relative to his/her chronological age, is moderately heritable and is associated with activation of pro-inflammatory, interferon, DNA damage repair, transcriptional/translational signaling, and various markers of immunosenescence: a decline of naïve T cells and shortened leukocyte telomere length.

The adult human heart cannot regenerate itself after injury, and the death of cardiac muscle cells, known as cardiomyocytes, irreversibly weakens the heart and limits its ability to pump blood. Researchers have turned their focus to stem cell transplantation for cardiomyocyte replacement and recovery of heart function, but studies have shown that implanted stem cells have difficulty surviving and differentiating into cardiomyocytes to repair the damaged muscle. When stem cells were differentiated into cardiomyocytes before implantation, heart function improved, but with a complication: the implanted cardiomyocytes did not contract synchronously with the heart, thus causing potentially lethal arrhythmias (abnormal heart rhythm).

A team of researchres has designed a creative new approach to help injured hearts regenerate by applying extracellular vesicles secreted by cardiomyocytes rather than implanting the cells. Cell-secreted microvesicles are easy to isolate and can be frozen and stored over long periods of time. Such an "off-the-shelf" product has several major advantages over cell therapy-1) it can be used immediately in an acute-care setting, unlike cells that can take months to isolate and grow; 2) it does not cause arrhythmia (which often occurs when cells are transplanted); and 3) the regulatory path towards clinical application is much simpler than for a cell-based therapy.

It is well known from numerous clinical studies that most of the implanted stem cells are washed away within hours of the treatment, but there still are beneficial effects. This has led to the informal "hit-and-run" hypothesis, meaning that the cells deliver their cargo of regulatory molecules before leaving the site of injury. "Consistent with this hypothesis, we postulated that the benefits of cell therapy of the heart could be coming from the secreted bioactive molecules (such as microRNAs), rather than the cells themselves. So we explored whether the benefits of cell therapy of the injured heart could be achieved without using the cells. This way, we would largely simplify the translation into the clinic, and avoid the burden of arrhythmia associated with implantation of contractile cells."

The team derived cardiomyocytes from adult human stem cells and cultured these cells to allow them to secrete extracellular vesicles. The vesicles secreted by undiffereniated stem cells were used for comparison. The researchers then used next-generation sequencing to read their messages and instructions. They found that the extracellular vesicles from cardiomyocytes - but not from stem cells - contained cardiogenic and vasculogenic microRNAs that are very powerful regulatory molecules. The team encapsulated the vesicles in a collagen-based patch that slowly released them over the course of four weeks when implanted onto the injured heart in rat models of myocardial infarction. "We were really excited to find that not only did the hearts treated with cardiomyocyte extracellular vesicles experienced much fewer arrhythmias, but they also recovered cardiac function most effectively and most completely. In fact, by four weeks after treatment, the hearts treated with extracellular vesicles had similar cardiac function as those that were never injured."

In the late 2000s, researchers found that leukemia cells highly expressed a gene encoding CD47, a surface molecule known for its role on normal, healthy cells as a "don't eat me" signal to phagocytosing macrophages. Researchers demonstrated in cell culture experiments that macrophages only engulfed leukemia cells that did not display CD47 on their surface, and since then have found CD47 on every type of cancer they've been able to get their hands on. "It was shocking. We knew that we were on the track of a potential therapeutic." At least three biomedical companies have raised and invested tens of millions to test drugs that block CD47.

But back in 2008, when the researchers first tried to publish work on how macrophages engulfed leukemia cells lacking CD47, reviewers didn't buy it. Since the 1980s, cancer researchers have linked macrophages and macrophage-stimulating genes to tumor growth and poor outcomes for cancer patients, and the cells had been pegged as nothing but bad news when it came to cancer. In 1996, for example, researchers reported that women whose breast cancer biopsies contained a high density of macrophages were much more likely to succumb to the disease over the subsequent five years than those with low densities. The same correlation was later confirmed in a dozen other types of cancer. These cells earned the name tumor-associated macrophages, or TAMs, and research focused on where they came from and how to block or deplete them. The data suggesting that macrophages could help defeat cancer just didn't fit.

TAMs, which can make up as much as 50 percent of a tumor's mass, had been found to repress other immune cell activity, encourage blood and lymph vessel development to support growing tumors, and help cancer cells metastasize to new sites in the body. But over the past decade, some research has surfaced to support the conclusion that TAMs may have an upside. "Several years ago, the idea was, 'Let's deplete these cells because they are bad.' I think now we are back to saying, 'Maybe it's just very complex.'"

Even as therapies that block TAM activity or prevent macrophage recruitment to tumors reach clinical trials, many researchers are not ready to give up on what macrophages may have to offer in the fight against cancer. There's no question that macrophages can participate in antitumor responses, "it's just that the tumors develop a way of polarizing or educating those macrophages to help the tumors rather than destroy them." Many researchers are now taking advantage of macrophages' plasticity to re-educate the cells to work for the patient. One way to switch TAMs from what's known as the M2 phenotype, which promotes cancer growth, to the immune-boosting M1 phenotype is to provide the cells with proinflammatory stimuli, such as interferons or ligands for Toll-like receptors. Alternatively, researchers can directly target molecular switch proteins responsible for driving M2 characteristics, such as PI3-kinase and the transcription factor STAT3. In animal models, drugs that inhibit these molecules have successfully skewed TAMs toward M1 phenotypes and shrunk tumors.

In a new study performed in mice, researchers uncovered one explanation for why exercise might be beneficial: It stimulates the heart to make new muscle cells, both under normal conditions and after a heart attack. The human heart has a relatively low capacity to regenerate itself. Young adults can renew around 1 percent of their heart muscle cells every year, and that rate decreases with age. Losing those cells is linked to heart failure, so interventions that increase cell formation have the potential to help prevent it.

"We wanted to know whether there is a natural way to enhance the regenerative capacity of heart muscle cells. So we decided to test the one intervention we already know to be safe and inexpensive: exercise." To test its effects, the researchers gave one group of healthy mice voluntary access to a treadmill. When left to their own devices, the mice ran about 5 kilometers each day. The other healthy group had no such gym privileges, and remained sedentary.

To measure heart regeneration in the mouse groups, the researchers administered a labeled chemical that was incorporated into newly made DNA as cells prepared to divide. By following the labeled DNA in the heart muscle, the researchers could see where cells were being produced. They found that the exercising mice made more than 4.5 times the number of new heart muscle cells as did the mice without treadmill access. After experiencing heart attacks, mice with treadmill access still ran 5 kilometers a day, voluntarily. Compared with their sedentary counterparts, the exercising mice showed an increase in the area of heart tissue where new muscle cells are made. The researchers now plan to pinpoint which biological mechanisms link exercise with increased regenerative activity in the heart.

The rate at which the protein amyloid-β accumulates into the sticky plaques associated with Alzheimer's disease (AD) is already slowing by the time a patient would be considered to have preclinical AD, according to a longitudinal study of healthy adults. The research suggests that anti-amyloid therapies would be most effective before individuals reach the threshold for preclinical AD, long before the first signs of memory issues. Determining how early to intervene is a central challenge in slowing the progression of AD. Clinical trials of drugs for lowering amyloid levels typically involve individuals who do not yet have symptoms but are considered "amyloid positive" and at risk for developing AD. These trials have been largely unsuccessful, perhaps because they begin too late.

To untangle the relationship between amyloid-β, the AD-associated protein tau, and memory impairment over time, researchers studied healthy men and women between the ages of 61 and 88 over a five-year period. Brain scans revealed that even trace amounts of amyloid-β predicted future levels of tau, and both preceded memory decline. The researchers found that greater baseline levels of amyloid-β were associated with a faster rate of accumulation, but only to a point, after which higher amyloid-β levels were associated with slower accumulation. "It appears rates of amyloid accumulation already begin to slow in preclinical AD, suggesting it is a relatively late stage of AD progression. Thus, it is crucial to examine older adults early, before amyloid levels have saturated, to intervene to slow disease progression."

Research suggests that "inflammaging" plays a key role in aging; many publications also suggest that of the various sources of this chronic age-related inflammation, senescent cell accumulation and the senescence-associated secretory phenotype it produces is the primary culprit. What might we expect to see if therapies to remove these problem cells are used in people?

I have a different view from the majority. I was one of the big fans of senescent cells, and I was 100% inspired by the idea of finding them, eradicating them, and using that for rejuvenation. However, after we spent several years very focused on an extensive study of senescent cells in vivo, we realized that for a major portion of the mouse lifespan, we simply cannot find these cells. This is not because they don't exist; I think they appear pretty frequently during our lives and mice's lives, but they are being very efficiently eradicated by the immune system.

Whether the changes in inflammation in vivo with age are due to the activity of senescent cells is a big question, because when we tried to find these cells in, for example, an irradiated organism, most of the cells that people thought were senescent before the existence of conventional biomarkers appeared to be just parts of the immune system, which is malfunctioning in aging and created the appearance of senescent cells. Macrophages frequently become positive for biomarkers of senescent cells, and people using these biomarkers without looking carefully call them senescent. You might say that does not matter because the whole concept did not change that much; who cares what you name these cells? If certain cells with certain properties accumulate with life and if they secrete something bad, the concept is still intact, and I agree with that.

However, knowing the nature of these cells, we can choose the right weapon against them, and as long as we try to kill the cells that we can make senescent in culture and think we are killing the same cells in vivo, I think that we are on the wrong path. This is my first problem; my second problem is that the accumulation of senescent cells means a malfunction of the immune system because the normal immune system gets rid of them very efficiently. If you kill a cell that cannot be removed by the immune system, you are not getting rid of this potential garbage; you turn it into a different type of garbage. Because to eradicate a senescent cell, something needs to find it and eat it, swallow it, such as a macrophage.

If this function is not working very well and you simply help the immune system by killing these cells, they still remain in the same place where they were; they're just dead. Maybe this is good or not; maybe this will indeed help another branch of the immune system to clean up. I think, in general, that this is not obvious; first, it's not obvious to me that senescent cells are unique in creating the "smell" of garbage that leads to inflammation or if it's only one of many types of cells that become damaged and accumulate with age. I'm not sure that killing them physically really helps to improve the situation, because you are creating a wave of remains that has to be taken care of, too.

I personally chose an approach to invest in the immune system and repair its function so that it can do its job better, instead of us thinking that we can substitute it. So far, in medicine, substitution of lost function has only worked well in orthopedics but not in other areas. Therefore, I think that we need to either invest in a mechanism that blocks the appearance of senescent cells or invest into the mechanism of natural eradication to make the immune system work better. For example, if the part of the immune system that is responsible for clearing senescent cells gets exhausted, you can always try to redirect adaptive immunity against them by vaccination; I would see that as a more appealing thing.

There have been few cancer treatments with such a promising future as using the patient's own immune system. Known as chimeric antigen receptor T-cell therapy, or CAR-T, this treatment uses re-engineered killer T-cells to attack cancer cells, but it also causes potentially deadly side effects. Now, research is opening doors to making such therapy safer and more effective. The researchers see the current CAR-T system as having three major flaws: target specificity; strength of response; and lack of adaptive capability, which is essentially the issue of relapse. "Our system has the ability to address those three problems."

Traditional CAR-T is a treatment engineered for one specific patient to treat one specific type of cancer cell. The new refined system - called split, universal and programmable (SUPRA) CAR-T - can be continuously altered to target different types of cancer cells, turned on and off, and overall offers a significantly more finely tuned treatment than the current therapies. "Instead of thinking about CAR-T as engineering cells that kill cancer, the way I think about it is as an antibody that drags a killer T-cell with it. What's amazing about it is that once the CAR T-cell binds and activates, it will recruit more T-cells and make copies of itself. Drugs don't do that."

This overwhelming immune response is also what causes the severe side effects. And there have been advances in drug therapy to mitigate these side effects by blocking unnecessary portions of the immune response while still allowing the CAR-T to attack the cancer cells. And the greater number of cancer cells means a stronger immune response. But the SUPRA CAR-T system would let doctors deactivate the entire treatment in case the side effects became too severe. The normal immune system requires T-cells to sense two targets coming from an invader cell before it attacks it and SUPRA CAR-T works in the same way. Before SUPRA CAR-T attacks cancer cells, it needs to sense that both targets are present on the cell. If only one is present, the system isn't activated.

SUPRA CAR-T also splits the T-cell from the target-sensing portion of the system. The target on cancer cells is called an antigen and whichever antigen is chosen is sought out by an antibody on the CAR T-cells. The new system breaks apart the T-cell from the antibody and allows for the ability to switch targets. The ability to switch targets is what can prevent relapse in patients. Cancer cells are smart and will mutate to no longer display the target when they sense the T-cells attacking after attaching to it. The SUPRA CAR-T system allows the T-cells to attack a new target by simply injecting the patient with a new batch of antibodies rather than having to re-engineer the T-cells, which is the most expensive portion of the treatment.

The third feature this split system produces is the ability to finely tune how active the T-cell response, which helps mitigate the dangerous side effects of previous CAR-T systems. By introducing a third component that can block the bonding of the T-cell and the antibody, the SUPRA CAR-T system can be deactivated. The level of deactivation can be tuned by choosing the strength to which this third component binds to the antibody.