AFFORDABLE ~ GLOBAL UNIVERSAL HEALTHCARE
Healthcare will be one of the most consequential and hotly contested issues debated during the 2020 presidential election cycle. The issue directly affects everyone in the country and represents close to ¼ of the entire US economy. The Congressional Budget Office recently announced 28.9 million individuals are currently uninsured. A recent Gallup poll disclosed 65 million adults incurred health related bills they could not afford to pay. This same survey also showed Americans borrowed $88 billion last year to pay for healthcare expenses not covered by their insurance(24). The Kaiser family foundation has data that indicates an average family with combined earnings of $75,000 will spend $10,000 to cover healthcare expenses each year(25). The current cost of Medicare represents 16% of our national debt.
The following article provides a viable path to achieving a healthy future within the economic constraints’ individuals, businesses and governments must survive within. A viable path forward to provide Medicare or Healthcare for all, requires a dramatic reduction in the total systemic cost. Dramatically reducing the incidence of disease in an aging population would realize that goal. Without realizing it, scientist unlocked the innate ability of youthful individuals to prevent disease almost 30 years ago. That discovery and the revolutionary scientific discoveries emanating from it, unlocks a direct path to dramatically reduce cost, enabling the expansion of healthcare and dramatically improving quality of life as we age.
Institutional approaches to teaching medicine have been changing since science began to reveal that much of the established medical fact, was in fact, wrong. This realization prompted a famous quote by Dr. Charles Sidney Burwell, the dean of the Harvard School of medicine from 1935 to 1949. “By the time students finish medical school, half of what they learn is no longer true,” Burwell said. “This troubles me, but what troubles me more is I don’t know which half it is.” If you find that revelation surprising, the following information will shock you.
From a large and growing body of scientific research, a case can now be made that almost all the current medical information is colored by a huge misconception; that aging isn’t a treatable disease. New evidence now points to the inescapable conclusion that you can effectively treat aging, and in doing so you can forestall virtually all age-associated diseases, delaying them to the end of a healthy, productive and very long life. Diseases associated with aging are dramatically delayed or prevented when the underlaying molecular cause of aging is targeted and blocked. The significance of this last statement, enabling an increase in our quality of life and a dramatic reduction of the total cost of healthcare is incalculable.
Except for infectious diseases, many of which are now preventable utilizing vaccines, no broad-spectrum attempts have been mounted to preemptively prevent the diseases associated with aging. Growing old gracefully, within this current state of medical bias is impossible. Our goal should be to live disease-free, for as long as possible, and then die in a healthy body at an age much older than today’s actuarial tables for life expectancy would predict. A positive variation of; live hard, (don’t) die young and leave behind a beautiful corpse. This goal; to die young as late as possible, now appears attainable and not in some distant future. Several drugs in development and one available for the last 30 years hold this promise.
Consider the excitement represented by the following titles from articles recently published in prestigious peer reviewed scientific journals and respected news organizations: Journal of Molecular Cell Biology: “The Cure for all that Ails(1)” • Cell Metabolism: “The Grand ConducTOR of Metabolism and Aging(2)” • Journals of Gerontology: “An InhibiTOR of Aging Emerges From the Soil of Easter Island(3)” • MIT: “Is This the Anti-Aging Pill We’ve All Been Waiting For?(4)” • Science Translational Medicine: “TORC1 inhibition enhances immune function and reduces infections in the elderly(5)” • Oncotarget: “Rejuvenating immunity: “anti-aging drug today(6)” • Science Immunology:“Harnessing TORC to boost the horsepower of aging immune systems(7)” • Bloomberg News: “Does a Real Anti-Aging Pill Already Exist?(8)”
All Scientific and Medical Advancements Prolong Life
Today we assume we will die of some disease as our age advances, not from a tiger eating us or becoming a slashing victim as invading hordes overrun our village. Almost all our ancestor’s deaths were caused by injuries due to accidents. Something as small as a splinter and escalating to severe wounds encountered in everything from farming accidents to armed conflicts, all dramatically increased your risk of death prior to antibiotics. Additionally, our understandings of the importance of nutrition and sanitation have improved health and lifespan significantly. Penicillin, discovered in 1928, marked a turning point in our medical history. With the advent of effective antibiotics, antifungals, antivirals, and vaccines, we are now living long enough to experience the most detrimental effects of aging. The chart below (Figure-1) demonstrates the benefits this steady and continuing stream of medical advancements has had on our dramatic increase in longevity. Prior to the 1900s the average human lifespan was around 40 years. In the last hundred years, life expectancy has doubled. It now appears inevitable that this upper limit will again double, not in the next hundred years, but in the next few years.
Association Between Aging and Disease
Aging was always assumed to be in the same category as death and taxes, i.e., inevitable. According to Wikipedia, aging is the process of becoming older. Scientist for the last decade have defined aging as the cumulative damage caused by oxidative stress and glycosylation to our body’s cells. The body then attempts to repair this damage through multiple molecular tools. Eventually, the repair tools also get damaged, reducing the rate and accuracy of these repairs. This process has been identified as the misrepair-accumulation theory. Nobel Prize-winning biologist Peter Medawar called it the “wearing out” theory of aging. This is the belief that aging is caused by entropy, the accumulated effects of recurrent stress. Paraphrasing Dr. Burwell, all this may be half wrong. Aging is not inevitable, it is not becoming older or wearing out. It may not even be exclusively or even primarily the accumulated damage caused by oxidative stress. Although aging is a complex multifactorial process leading to loss of function and disease, it now appears to be an addressable cellular process — run amuck.
The primary risk factor for the most common diseases associated with aging, is advancing age, whatever the cause, and the age-related decline in immune system function associated with it. All the diseases listed in (Table 1, below) have as their primary risk factor, advancing age. It should be noted here that some diseases, even some normally associated with aging can result from genetic defects, developmental abnormalities, environmental factors or infectious agents.
Alzheimer’s, atherosclerosis, arthritis, benign prostatic hyperplasia in men, broken hips and bones, cancer, cardiovascular disease, cataract, dementia, heart fibrillation, hypertension, insulin-resistance and type II diabetes, macular degeneration, menopause in women, myocardial infarction, obesity, osteoporosis, Parkinson, renal and other organ failure, retinopathy and stroke. [ Table 1: Diseases with age as a primary risk factor. ]
Diseases, not aging, are the primary causes of morbidity. Morbidity is the medical term describing the debilitating, direct and indirect effects each disease can cause. The loss of function and mobility caused by the aches, pains, nausea and fevers, are the direct result of immune system activation and disruption all chronic diseases cause. Cytokines, the immune systems chemical messengers are the primary culprits responsible for these negative effects as they become expressed, or as is often the case, over expressed by the immune system, in an attempt to rev up the immunological response to disease.
Affliction with any age-related disease increases the chance you will acquire another disease because this immune system activation disrupts your body’s ability to deal effectively with a second infection or disease process. The older you become the more likely this scenario becomes. The cumulative effect of these diseases and the resulting morbidities are the primary cause of mortality.
Large global studies have been conducted which confirm this link between advancing age and disease(s). The most recent and comprehensive was a review study published in September 2017, titled: “Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016”(9) This review of multiple aging studies provides a clear conclusion. There is a direct correlation between an individual’s age and the likelihood or inevitability of acquiring an age-related disease.
If you could prevent or hold off the diseases often encountered as your age progresses, the secondary health issues that cause death would also be delayed. In other words, you get diseases because you are aging, but you die of the effects of the diseases that an advancing age enables. Slowing, preventing or reversing aging will prevent or at least delay you from getting the diseases associated with aging and this will extend your life. Not indefinitely, but definitely. Many drugs are currently recognized to have the ability to delay or prevent specific diseases. Aspirin delays the occurrence of cancer, strokes, cardiovascular disease and heart attacks. Statins accomplish the same thing by utilizing a completely different mechanism of action. There are many other examples. Each can be considered a disease-specific intervention that delays death, i.e., a disease preventive intervention that results in a longer life. Currently, state of the art medical practice addresses the vast majority of age-related disease after, and only after you begin to present overt symptoms.
All these diseases have one thing in common; you are not likely to acquire any of them if you are young. Youth represents a broad-spectrum, prophylactic, vaccine-like effect against most diseases. The glaring question this last statement raises is; why?
The Primary Connection between Aging and Disease is mTOR.
As your body grows from a single fertilized egg into a complex multicellular organism, a key cellular component, mTOR determines and coordinates multiple processes that control the growth and viability in every one of the resulting cells. mTOR is instrumental in recognizing the status of many cellular receptors including nutrient sensing; (amino acids); energy; (glucose/insulin); oxygen, growth factors and stress. Stress is determined from the ratio of all the input signals and/or critically low levels of any one of them.
After evaluating these input signals, mTOR then sends signals downstream that direct many critically important functions. (Figure 2, above) It controls the actual size each cell obtains. It controls translation (protein synthesis) and transcription (gene expression). mTOR is also a critically important immune regulator, providing a link between cellular metabolism and immune function; directing both the innate and adaptive immune responses with the ability to promote differentiation, activation, and function in T cells, B cells, and antigen presenting cells based on the detection of environmental dangers(18). From the perspective of aging, mTOR’s most important directive is to control the rate at which cells grow (replication and division).
This brief description illustrates mTOR is a multifaceted regulator of many cellular processes. Even this complex description has been greatly simplified. It actually consists of more than 700 molecular receptors, sensors and links within its input/output signaling pathway. (See Figure 3, below) This number is from a 2010 article titled “A comprehensive map of the mTOR signaling network(10).”
As described above, mTOR is involved in many critical decisions that literally keeps us alive, but one of its primary decisions eventually kills almost all of us. mTOR is a contradiction and a continuum, because its primary directive is to drive growth from conception to developmental maturity. The contradiction is there is no off switch. When the growth protocol is completed, having fulfilled the genetic blueprint embedded within our DNA, mTOR continues to attempt to fulfill its primary directive, i.e., to drive growth at the fastest rate possible, driven by available resources and cellular signals. mTOR appears unique because all other known biological processes have signaling feedback loops to terminate specific biological or immunological protocols once they are completed. This growth control brake mechanism is missing within the mTOR signaling pathway.
There is a growing body of evidence this paradox; driving growth after the organism has reached maturity, has long-term, deleterious effects on individual cells and the entire host we can now identify as aging.
If the mTOR complex is the biological target that is the primary cause of aging, then the next question becomes is there a biological response modifier, a drug, that can turn down or turn off that molecular complex without causing serious side effects or death?
Short History of a 30-Year-Old Drug: Rapamycin
A little more than fifty years ago, between 1964 and 1965, a soil sample was collected on Easter Island by a University of Montreal microbiologist; Georges Nógrády. Georges was a member of a scientific expedition sent to Easter Island by the World Health Organization and the Canadian Government. Its purpose was to study the relative roles of environment and heredity on one of the worlds most isolated populations before an international airport was completed there in 1967. Scientiest also wanted to discover why these islanders rarely if ever became infected with tetanus. One of the soil samples they returned with, seemed to hold that answer. It contained the bacterium; Streptomyces hygroscopicus, that expressed a unique compound. The first scientist to isolate that compound was Surendra Nath Sehgal(13). In 1975, he initially identified it as an anti-fungal. This classification led to it’s name. Rapa for the island the original soil sample was isolated from and mycin as an identifying classification of antifungal agents. Rapamycin can be thought of as the opposite of penicillin. Penicillin was discovered in a fungal culture with the ability to inhibit the growth of bacteria. Rapamycin is expressed by bacteria with the ability to inhibit the growth of fungus. Suren worked on and off to develop it for the next 30 years from within an evolving string of closing and merging pharmaceuticals. It was not until the 1990s that the drugs mechanistic target, (mTOR) was identified, finally beginning the scientific track that enables us to understand the disease prevention and antiaging benefits the drug unlocks.
Rapamycin is an enigma because it was initially identified as an antifungal. Its first approval was granted by the FDA in 1999 to prevent organ rejection by suppressing transplant recipient’s immune systems. Ironically both designations completely miss the most important biological benefit of this drug and probably any drug. Rapamycin and its analogs have demonstrated they are biological response modifiers able to down-regulate mTOR, the cellular, bio-sensing, molecular signaling complex that controls many of the cell’s biological directives. Of all the important biological processes it controls, easily the most important is the ability to down-regulate the growth directive of mTOR, resulting in the drugs’ ability to hold off or delay the diseases associated with aging, thereby delaying death.
Why was the ability to prevent disease and extend life, the most dramatic effect ever seen in a drug missed? No one was asking because no one though it was even remotely possible that this drug or any drug could prevent disease or extend life.
As animal studies begin to demonstrate that administering rapamycin was extending the lives of the respective test species, the specter of addressing, what was then a very inprobable question began to emerge. When researchers became daring enough to actually apply for funding to begin actually address the aging questions raised by these observations, they were laughed at. In case you miss the implication, when research grants are laughed at, they don’t receive funding.
Mikhail V Blagosklonny PhD, MD., is a pioneer in the biology of aging and disease prevention. He is extensively published and a faculty member of the Roswell Park Comprehensive Cancer Center. His current area of research is the prevention of cancer by inhibiting organism aging — in other words, “preventing cancer by staying young.” His initial scientific papers on the association of aging and mTOR were rejected out of hand due to entrenched attitudes that aging was not a pharmacologically targetable, biological process. Many reviewers went further by adding snide, caustic and demeaning insults to his initial reviews. Dr. Jonas Salk, the first person to bring therapeutic vaccines into the clinic and widespread human use, including influenza and polio, experienced the same scientific prejudice. His analogy to me was; first they will laugh at you and then they will tell you that you’re wrong. When the research finally proves them wrong and you right, they will maintain your position was their position all along. Brazenly, some will even go on to maintain the idea they had been vocally criticizing was in fact, their own.
The Growth, Aging, Disease, Death Continuum Examined
MTOR has now been identified as the driver of growth and that driving force as the primary cause of aging. That identifies aging as a biological process. All biological processes can be genetically or pharmacologically targeted. To put this in a slightly more dramatic tone, aging is now and always has been a treatable disease like process. This last statement contradicts the convention wisdom of all mankind, for all time, until today.
It also completely redefines the healthcare debate.
These profound statements about the relationship between growth and aging can easily be examined and validated utilizing historical, epidemiological data. If it is statistically unlikely that we get sick from age-related diseases during our youth, while we are physically growing, and if the disease/death rates significantly increase at the point in time that we stop growing, then a strong cause and effect correlation can be established between the growth protocol period controlled by mTOR and the continuum of aging, disease and death.
The scientific consensus is; growth is complete in virtually all humans between the ages of around; 18 in women, and 20 in men. This is not to say that cellular changes do not take place later in life. They do, but the changes occurring after growth stops, are predominately caused by the growth protocol attempting to continue driving growth after it has been completed, i.e., aging.
Less than 5% of all humans die during the first 20 years of the developmental, growth period, even though this same span of time represents 25% of an individual’s current expected lifespan. Even this low number is misleading because more than 75% of all deaths in individuals approaching 20 years of age are classified as external causes, most being accidental deaths. Alcohol, drugs, guns, automobiles, skiing, skateboarding and all manner of fun, illegal and / or dangerous activities contribute to this when we are around the age of immortality, i.e. too young and too dumb to know better. This is identified in the chart below as a shaded green background. The first two years of life are significantly more perilous to infants because the immune system is still developing. After age 2 these development processes are sufficiently complete to enable survival rates to continually increase as the individual lives past this neonatal age. As a group, the individuals between birth and 20 years of age have an adjusted death rate, minus external causes, of around 0.5%. In the absence of bad luck, violence, war or stupidity, the vast majority of younger individuals simply do not die during the first 20 years of the growth phase of life.
What happens when we stop growing? As the chart below (Figure 4) demonstrates, the rate at which deaths occur rapidly accelerates beyond the point where the maturation/growth phase of the individuals stops. (First gold* vertical line in chart.) Beyond this point there is an almost exponential increase in the rate of deaths, which dramatically accelerates (100–1000 fold) between the ages of 35 and 85 years. During this same time period accidental deaths decrease at approximately the same rate.
Relentlessly driving growth provides a survival benefit as it gets the organism to sexual maturity at the soonest possible opportunity, fostering the continuation of the species. This imperative completely disregards the negative effects of aging in a post-reproductive lifespan. After sexual maturity and hopefully reproduction, mTOR considers your continued existence a moot point.
The chart below (Figure 4) represents data from the Center for Disease Control(11)and the Social Security Administration(12). The same data was utilized to color the background of the chart indicating both Health-Span versus the Onset of Disease and the incidence of accidents.
The chart above (Figure 5) demonstrates the potential outcome of selectively blocking the mTOR pathway with low dose, pulsed rapalogs, initiated at the point where growth phase ceases and aging begins. In this theoretical projection, the period where the individual is dealing with debilitating diseases becomes compressed into a relatively short period just prior to death. It also indicates that death may be delayed until long after the current US projected life expectancy of 79.25 years. Finally, the rate of deaths in the general population would move to a more gradual, lineal process. Because this experiment has not and is not being conducted the chart above is a fairytale. There is no data to support the low disease rates and long lives it plots. But there is a great deal of emerging information in multiple animal models and humans that point to these results being obtainable in the near future. What would society look like today if the full therapeutic spectrum of rapamycine was known 30 years ago? I believe it would be closely reflected by the chart above. This may well turn out to be a conservative projection.
Is it Possible You're Actually 20 Years Younger than you think you are?
If mTOR is the cellular program or protocol controlling growth and once growth is complete it continues running, to the determent of the host causing aging, then aging as we know it does not begin until around the age of 20. Prior to that age we are growing, not aging. To put this another way; from conception to age 20 your chronological age increments in a normal manner, but your physiological age does not increase until you stop growing. Once you reach age 21, your cells physiological age are just now becoming (1) one-year-old. This seemingly impossible abstraction is simply because the cells in your body are just now experiencing the first effects of aging because the growth protocol has completed, but the directive driving growth continues unabated, initiating the aging process.
This insight as well as the two charts above inform us of one other important point. The optimal time is to start taking an mTOR inhibitor is in all probability as soon as your body reaches physical maturity. On your 21st birthday, have your first alcoholic drink, (you did wait until you were 21, right) and a low dose of rapamycin. Stop drinking immediately and for all time (of course), but keep taking your weekly low dose of rapamycin until you die somewhere long past 120. Currently the most effective dose of any rapalog to act as an aging or disease preventative is unknown. The current estimate is somewhere below 6 mg once a week. Future human studies will answer this question definitively.
Compelling Evidence of the Disease Prevenative, Ant-aging Effects of Rapamycin
When scientists first pose the question; does a new drug candidate have therapeutic benefit to man, they first study it in animals’ models. Often this research starts in lower life forms including yeast, flies and worms. This moves on to more developed animal models as the research progresses. If the drug works in some, but not all these models you are probably not looking at a drug target, evolutionary conserved, through all species and as such is not critical to life in all species. This point is important when trying to determine if the animal research is going to translate accurately to humans. There are no guarantees or exacting rules extrapolating animal models to humans, but if every animal model you examine has a uniform response to a new drug, with no species dropping out or becoming an exception to the results, it becomes more likely that this same drug will have a similar response in humans.
Consider this abstract; “From rapalogs to anti-aging formula,” by Mikhail V. Blagosklonny and published in Oncotarget in May 30th 2017(14). Clinically available inhibitors of mTOR; rapalogs, including rapamycin; Sirolimus, Temsirolimus and Everolimus, are gerosuppressants (age suppressants), which suppress cellular senescence. Rapamycin slows aging and extends life span in various species from worm to mammals.
mTOR has been studied in increasingly more complex animal models since 1975, progressing through yeast, worms, fruit flies, mice, dogs, monkeys and humans. These studies revealed many remarkable attributes on the functionality of mTOR, but one stark effect has startled every researcher. Every animal, in every study, that received rapamycin, lived longer than untreated matched controls. (Figure 6, above)
Therapeutic Range of Rapamycin: Disease Treatment; Disease Prevention and Antiaging
A growing body of evidence supports the premise that; If a drug is extending the life span of every species it is tested in, then it is also delaying the emergence of disease as well. An obvious question then becomes; If this same drug has the ability to delay all diseases of aging, does it also have a therapeutic effect on each of these diseases, separately? PubMed is a database funded by the US National Library of Medicine, a division of the National Institutes of Health(15). It is a repository of all published medical and scientific research conducted and reported in peer review, scientific and medical research journals. In Table 2, you can see that researchers have studied, and continue to study, rapamycin as a therapeutic agent for the vast majority of the diseases associated with aging. Over thirty-six thousand scientific studies in total, for mechanistic, therapeutic and anti-aging effects have been conducted and reported. The research has been ongoing for several decades with the first article published in 1975, far right green column under (First Published Article). Note also that in every one of these diseases, the research continues today with the date of the (Most Recent Article) indicated in the second, red column. Finally, between these two dates we provide the total number of scientific research articles published for each disease during this span of time, (Total Articles) in the third column.
These targeted PubMed searches indicate, rapamycin has varying degrees of impact on every disease associated with aging. Having found a universal pathway involved in every disease associated with aging can we now make a connection between the mTOR signaling pathway and the same preventative or prophylactic effects associated with youth? Can we further extrapolate this benefit to an anti-aging effect based on eliminating the morbidity these diseases would have caused? The answer in both cases would appear to be yes.
Prior intervention, treatment before acquiring any disease, is more effective than treating diseases after they have disrupted the host’s immune system. Fire prevention is easier, safer, less expensive and more effective than trying to put a fire out. Cancer is an excellent example. The World Health Organization just reported there will be 18.1 million new cases and 9.6 million deaths from cancer in 2018(16). Trials with rapalogs have been conducted in almost every type of cancer, but have meet with varying levels of success. Currently there are three approved rapalogs; Temsirolimus, Sirolimus and Everolimus, and each has been in clinical trials for various types of cancer with both Temsirolimus and Everolimus gaining approval for some forms of cancer with the FDA and the European Medicines Agency (EMEA). This includes renal cell carcinoma (kidney cancer) and neuroendocrine tumors of gastrointestinal or lung origin.
A growing body of emerging information supports the premise that prophylactic use of these drugs are far more effective at preventing cancer than treating any form of cancer after the fact with any oncological or therapeutic drugs including rapalogs.
Kidney transplant recipients who received Rapamycin all had a greatly reduced incidence of any cancers, in spite of the fact that they were taking toxic, immune suppressive levels of rapamycin.
Ironically Suren Sehgal, the discoverer of rapamycin, self-administered rapamycin during his fight with metastatic cancer starting in 1998. His cancer remained in remission for the next five years until his decision to stop taking rapamycin to determine if it was indeed the reason his cancer remained in remission. He died a few months later(8).
As the inevitability of Aging Dies, Antiaging Research Explodes
PubMed allows you to accomplish targeted searches within any specified field. The fellowing search was for “rapamycin and aging” within the title or abstract fields, and during specific time frames. These searches demonstrate the dramatic explosion in scientific research focused on rapamycin in the field of delaying aging. Between 1975 and 2005, 13 papers were published that met the search criteria; between 2005 and 2010, 99 papers were published and between 2010 and 2018, 762 papers were published(15). From this exponential increase in published peer revied papers, it is evident that the scientific community is aware that rapamycin is both an important tool in researching its mechanistic target and that this target has the potential to reduce disease, extend healthspan and lifespan. Many of these papers are now reporting the results of human clinical trials conducted with rapamycin or analogs of rapamycin. Currently Clinical Trial.gov(16)has listings for 324 ongoing, or recently concluded trials for various age related diseases. One of the most compelling aging related studies was in an older human population and it’s goal was to determine if a rapalog (RAD001, Everolimus) increased the immune function of 218 test volunteers who were all older than 65 years of age(5). It did and not by a little bit, but by 20%. This in a patient population who are universally thought to be in a state of immunosenescence (declining immune function during aging).
The Safety and Relative Risk of Taking Rapamycin
You may have heard of rapamycin and just assumed it is toxic and dangerous. Certainly, no one who is not severely ill would ever consider taking it. The drug has a hazardous reputation because “immune suppression,” is the exact opposite of any attribute we associate with a safe drug that improves quality of life, prevents disease or extends life. This black cloud exists because the drugs target and mechanism of action was misunderstood and because it has been given at high, sustained levels, to achieve an immune suppressive effect. The majority of all drugs are toxic and immune suppressive at high, sustained doses. Few individuals or for that matter physicians are aware that rapamycin has a broad therapeutic profile that ranges from immune suppression at high and sustained doses to immune restoration, disease preventive and anti-aging effects at low, pulsed doses(18). Side effects also appear to be dose dependent as well. It is also proving to be an effective treatment for many individually targeted diseases and cancers when administered in a variety of doses and schedules. Rapamycin has one side effect that should be closely monitored in anyone who decides to start taking it. Rapamycin can decrease insulin production. This diminished response to glucose has the potential to cause an increase in insulin resistance. This may raise the risk of developing diabetes. Taking metformin, an inexpensive pre-diabetic drug approved in 1994 appears to mitigate this risk. Metformin reduces the glucose production of the liver and has an insulin-sensitizing effect. There also appears to be synergistic antiaging benefit of combining these two drugs. No one should take rapamycin without first consulting with their physician. Anyone dealing with any pre-existing level of immune suppression should not take rapamycin without consulting with their physician and being carefully monitored. While it is true that high doses of rapamycin can have negative side effects including immune suppression and delayed wound healing, these are greatly diminished at the relatively low, pulsed doses used to prevent disease and extend longevity. Both animal and human studies indicate that even mild adverse events are rare and resolve completely when the drug is withdrawn.
Dr. Blagosklonny, described his evaluation of the level of risk as: “Some people ask me, is it dangerous to take rapamycin? It’s more dangerous to not take rapamycin than to overeat, smoke, and drive without seat belts, taken together.” A pioneer in anti-aging medicine and one of the first practitioners to prescribe rapamycin to his patients for the expressed purpose of delaying the development of diseases and anti-aging is, Dr. Alan Green. He has equated the level of risk of taking less than 6 mg of rapamycin weekly as about the same as taking aspirin. The final paragraph of a study reported in Experimental Gerontology; Dec 2017, on a human study of 25 individuals randomized to rapamycin or placebo, reported the following safety conclusion. Importantly, rapa had no unanticipated detrimental effects in this cohort, therefore trials of longer duration and larger sample size with emphasis on specific parameters that demonstrated improvement in animal models should be feasible in older persons and will be necessary to better understand the potential to modulate aging related outcomes by mTOR inhibitors(5).
The United States Preventative Services Task Force (USPSTF) has described rapamycin as remaining the most promising drug with the potential to alter the preventative medicine landscape(21).
Pharmaceutical strategies to optimize the profitability of unpatentable or off patent drugs.
Rapamycin was not patentable in its original form because it was expressed by a bacterium found in nature and was considered a naturally existing molecule. Producing an identical chemical structure from a synthetic chemical synthesis or a new purification process does allow for the resulting product to be patented. Rapamycin, its preparation and its antibiotic activity were described in U.S. Pat. №3,929,992, and issued Dec. 30, 1975 to Surendra Sehgal et al. Extending the profitable mantel of patent protection is commonly accomplished by making small changes to the chemical structure of the drug. Reguardless of how small these changes are, any difference allows for new patents to be applied for. Obviously the goal of these small changes are two fold. First is to provide patent protections insuring a moat around the products future sales. This also insures the price can be determined by the pharmaceuticals sales, marketing and management teams, not the market place. The second goal is an attempt to improve on the previous drug. The term “improvement,” here is subjective as the pharmacology of the original drug, like half-life, clearance and metabolites, as well as its molecular target, binding kinetics and a hundred other variables can make this second goal a broad target.
Is Rapamycin, the Best Candidate to address Disease Prevention?
Current analogs of Rapamycin (rapalogs) all have the exact same binding site in common. This simply means these drugs all work in the same way on the same target. What differentiates the new crop of patent protected mTOR inhibitors is something called solubility. In drug development terms solubility determines a drugs oral bioavailability. In this specific case the original drug, rapamycine was hydrophobic; it did not dissolve well in water. Drugs that do not dissolve well in water are also more likely to be poorly or more slowly absorbed. These derivatively developed analogs dissolved better in water making them more orally bioavailable. This means these drugs get into the bloodstream through the gut faster, but it also means they don’t stay in the blood stream nearly as long. Rapamycine (Sirolimeus) has a half-life of between 57 and 62 hours. The Everolimus derivative of rapamycin stays in the blood stream for 30 hours. Another new company, Rapamycin holdings, has taken a novel approach to reformulating the old drug, sirolimus, in a process called encapsulated microzonation. The drug is embedded into a matrix that releases the drug after it passes through the highly acidic environment of the stomach. The combination of these formulation enhancements enable the eRAPA version of the drug to produce approximately 30% more drug than an equivalent amount of Sirolimus. A study of eRAPA was just initiated in early stage prostate cancer.
Remember that all these drugs bind the same catalytic cleft within the same molecular target of mTOR (Figure 7). The only differences are the respective ability of each drug to cross the gut and the duration they stay in the blood stream. Even the newest kid on the block, eRAPA is just rapamycin in a new and improved delivery system. Starting their new drug design initiative with a blank sheet of paper, the scientist at Rapamycin Holdings could have produced their own rapalog or chosen any of the “improved,” rapalogs already approved by the FDA. The fact that they chose to utilize the original, natural molecule implies it was the best candidate.
These engineered changes are improvements from the perspective of the companies that developed them because it extends the patent protection window and makes them more profitable over drugs that are off patent and have generic competitors. The analog drugs may be more efficacious in select cancer disease indications. In the context of which drug is the best mTOR antagonist to tackle aging and the reduction of age associated diseases, the older and less expensive drug may be the best one. That’s because effectively inhibiting mTOR to produce the optimal anti-aging effect is target, dose and duration dependent. The optimal antiaging dose has yet to be determined, but there is acuminating evidence you want to suppress only one of the two mTOR molecular complexes that make up what we have been generically referring to as mTOR. mTORc1 appears to up-regulate immunity by blocking the nutritional/growth signaling pathway. That results in the organism believing it is in a calorie restriction mode. mTORc2 appears to trigger the molecule’s ability to down-regulate the immune system. The goal here is to transiently and completely suppress mTORc1, but not mTORc2 or leave mTORc2 as undisturbed or as briefly disturbed as possible. It is already known that Unlike mTORC1, mTORC2 is resistant to direct inhibition by rapamycin. It is unknown what prevents the interaction between rapamycin and FRB on mTORC2(21), but there obviously is some structural or conformational difference imparting this disparity (Figure 7, above).
Selective inhibition of mTORc1 and not mTORc2 is accomplished by administering low does of rapamycin, less than 6 milligrams and administering it intermittently, usually only once a week. The longer half life of the older, off patent drug, “Sirolimus,” may actually be the best current drug available to accomplish these two distinct, disparate goals, given its selective binding kinetics and relative long half-life. To drive this point home, transplant recipients who require immune suppression to prevent organ rejections are given relative high doses of rapamycin daily to produce study state levels of the drug in their blood streams to overcome this selective and reduced binding kinetics of the immune suppressive mTORc2 target.
So the question becomes is an old, off patent drug, available in generic form, just as good or better than the new drugs that are or will be much more expensive. Hopefully this question will get answered in the near future as we learn more regarding the optimal dose and duration to selectively inhibit mTORc1, leaving mTORc2 alone.
Why No Large Government Sponsored Studies?
From extensive animal research and the now emerging human data there is no longer a question of the potential to prevent the diseases of aging and thereby delay death. These developments underscore that rapamycin represents one of the most important medical discoveries in the history of mankind. With this statement becoming more evident by the day; why is the government not taking the lead in quickly conducting human clinical studies. The importance of these studies can’t be overstated. Determining if rapamycin could dramatically impact our ability to delay all diseases of aging has the potential to reduce healthcare cost and human suffering in an incalculable way. The two bullet points below are from a recent article published by the International Longevity center in the United Kingdom(21). The take home point from this study is longer lives improve a countries’ economy, they do not put a strain on it.
• Overall, our analysis suggests that there may well be a longevity dividend, whereby improvements to health result in wider economic and productivity gains in developed countries.
• Improving health and raising life expectancy must therefore remain a key goal not only for a nation’s health and well being, but also for the wider economy.
Politically a clinical trial addressing aging would be a popular decision. From the pharmaceutical’s perspective it potentially represents a financial apocalyptic disaster. Therein may lie the initial and primary roadblock on the road to all of us easily accessing anti-aging drugs that are already approved for other indications. It may provide some insight into why there is, a not so subtle campaign to block the publication of anti-aging research papers. The fellowing editorial “Librarians against scientists: Oncotarget’s lesson by Mikhail V. Blagosklonny, indicates this may actually be occurring (22). On it’s face this appears to be a simple conflict between those advocating fee access to all research and companies that bundle various peer research publications, requiring everyone to pay for accessing them. Free access would appear a realistic and obvious policy when the vast majority of that research is partially or completely funded by government research grants. What appears unusual is the primary target of this conflict is limited to one publication, Oncotarget. Oncotarget is the most visible proponent and publisher of anti-aging research.
Healthcare as a market segment, including; Insurance, pharmaceutical and healthcare industries took in over 5.3 trillion dollars last year. As a comparison, the gross domestic product (GDP) of the entire US economy was 19.39 trillion in 2017. The longer the pharmaceutical industry forestalls the acceptance of antiaging drugs, the more profitable they will remain. The approximately one thousand five hundred drugs currently approved by the FDA, targeting each individual specific disease and maladies the aging population of the world currently suffers from, are now and will always be much more profitable than any single pill. This become an exponential effect when one drug potentially reduces the need for all the others. The global profits of all pharmaceutical companies for 2017 exceeded one trillion dollars. Currently the pharmaceutical industry employees 1,332 lobbyist and collectively invested close to four billion dollars(24)on their lobbying efforts to promote and protect their business interest in just the last year.
Go back to the list of diseases (Table 1) associated with aging and ask yourself how much money would pharmaceutical companies lose annually if the drugs addressing all those diseases were suddenly unnecessary or only necessary in a much smaller population for a greatly truncated period of time? How many television commercials do we get exposed to on a daily basis extolling the virtues of newly approved medications targeting some disease on this list? Also, keep in mind the disclaimers at the end of every one of these ads. Because the act of advertising dramatically increases liability exposure, every conceivable possible side effect must be described. This long list of the possible dire consequences of taking these drug requires every person who might benefit to go through a risk benefit analysis to determine if the new drugs side effects outweighs the morbidity of the disease. The grand finale of this litany of possible side effects is almost always the possibility of death. The side effects described are always much more dire than the effects associated with low dose rapamycin. Antiaging research is a clear and emerging danger to the astonishing profits the pharmaceutical industry currently generates. In a capitalistic society the war between these powerful forces and our ability to access a single pill that threatens a significant percentage of these profits, will quickly become a capitalistic cataclysmic conflict.
Getting the Answer
There will always be claims that proving the antiageing effect of rapamycin would take decades and be prohibitively expensive. There is a running joke about submitting antiaging drug proposals to the FDA. It goes like this. Submit your trial design to us and come back in 70 or 80 years when your data supports a survival benefit to those in the treatment group.
The joke becomes irrelevant when the drug also prevents diseases. At this point the entire body of antiaging research supports that effective drugs in this arena also reduce the incidence of new diseases.
A simple, relatively fast and inexpensive trial can be devised recruiting individuals with the highest likelihood of acquiring a new disease associated with advancing age. These individuals would be between the ages of 65 and 85 with no current ongoing disease process.
Statisticians would obviously be required to power this study, but I would estimate it can be accomplished with 1000 individuals, divided into four groups. Three groups would get randomized to 2, 4 or 6 mg., of rapamycin administered weekly for two years. The final group would be randomized to a placebo. All groups would be prohibited from taking metformin or rapamycine or any rapamycine analogs outside of the study. An exception would be allowed for any individual who experienced an increase in glucose levels over a normal threshold. Additionally, randomly matched controls could also be generated through any health maintenance groups patient population electronic medical database. This simple and inexpensive addition to the study would dramatically increase the statistical significance of the final study. Doubling or tripling the size of your control group dramatically increases the statistical significance of the final analysis.
The reason I believe this study can be conducted in a relatively fast and inexpensive manner is after intake, the only two factors that will need to be monitored in all groups are safety and incidence of acquiring new diseases.
With the benefits identified from the current literature, it would be reasonable to see dramatically fewer diseases associated with age. The literature also supports improvements in all the fellowing health parameters: immune function, cognitive impairment (memory and concentration); kidney function; liver function; blood pressure, cardiac health and function (improvements in both diastolic and systolic, fractional shortening, and ejection fraction), arthritis, dermatological, gastrointestinal, activities of daily living and quality of life. It would also not be unexpected to see improvements in all individuals sensory perceptions including: hearing; sight; smell; taste; and sense of touch. This can be attributed to the improved health of the micro-capillary vascular system. The resulting improved nutrient delivery has the potential to revive the neurons in each of these sensory systems. Finally, with these improvements as an assumption, the quality of sleep is likely to improve. Improved quality of sleep has a high correlation with improved immune functioning, memory and mood. These improvements should also have a positive impact on the emotional state of the individual including reducing the incidence and depth of depression episodes. Monitoring any or all these parameters would add significantly to the cost of any clinical trial, but all could reasonable be expected to improve in light of the literature. Subsets of each protocol arm could be tested for these parameters to reduce the total trial cost.
Let’s make the assumption that this trial would cost 7 million dollars over the 48 months it would run. 36 months of trial duration staggered as recruitment occurs and 8 to 12 months of data analysis. That would be the cost/risk to the sponsor. The potential benefits would be limitless.
One potential sponsor of this study is Kaiser Permanente. I am one of the 12,200,000 patients well served by Kaiser. The benefit of this study could be a dramatic reduction in healthcare cost to both the patient and the provider. The potential benefit to an HMO would be a reduction in total operating cost of between 30 and 50 percent in the near term and 50 to 80% in the long term. This would include reduction in patient care visits and medical cost associated with new diseases acquired by Kaisers patients. A dramatic reduction in the incidence of disease in the entire Kaiser patient/member population would allow for a reduction in the staffing requirements. Kaiser currently employees 211,000 individuals, 22,000 of which are physicians and 57,000 nurses. With a total current operating revenue $72.7 billion and a current clinical trial budget of self-funded research at $63.5 million dollars the study described above would be insignificant compared to the potential benefits that could derive from it. Any calculation of savings to Kaiser would be hypothetical, but could easily be significant in terms of both financial savings and reducing human suffering. Pfizer can well afford to provide the trial drug and placebo for free or at cost. Pfizer’s total income for 2017 was 55.5 billion dollars.
Conclusion
There is now an explosive increase in research that underpins a dramatic and imminent shift in our global approach to healthcare, including disease prevention, aging and delaying death. This revolution will profoundly change our lives and attitudes regarding every aspect of our own health and longevity. It will also have dramatic and far-reaching implications for every segment of the healthcare industry including: Social Security; Medicare; Pharmaceutical and Biotech companies; Health Maintenance Organizations; and all private and governmental health agencies. The ramifications of this research are just now emerging into the mainstream press and physicians are just beginning to be challenged by their own patients for access to antiaging drugs and supplements. Their old perceptions regarding the risks associated with this drug still outweighs the potential benefits for most of them. Expect this to change over the next two years.
This level of disruption to any one industry, much less a significant portion of our entire economy is bound to be met with significant resistance by the entrenched business interest it threatens. Politically this becomes a crucial issue as the emerging realization that one pill can dramatically impact the mind-numbing profits of a healthcare system that prioritizes profits at least as highly as it does compassionate access to healthcare.
Scientists all over the world are discovering additional pathways and emerging molecular targets that also impact aging. Many of these targets are in clinical and pre-clinical development by multiple research labs, biotech’s and pharmaceutical companies. mTOR is emerging as the master biological clock directing nutritional management, growth, cellular functions, immunity, and aging. Combining multiple approaches to prevent diseases and aging will almost certainly prove to be additive and in all probability synergistic in dramatically reducing diseases associated with aging and lengthening the healthspans and lifespans of everyone. The vested Economic interest that will staunchly oppose this dramatic transformation of the entire healthcare industry must be meet with an equally stong, unified and informed opposition.
Living longer is a natural instinct and innate goal of almost every human. A much more important goal to society and government is our emerging ability to prevent almost all disease between the ages of 40 and 80. This will create huge benefits for society by slashing the cost of all medical care throughout the spectrum of the medical establishment. Global Universal health care for all will no longer be a utopian dream, but an economically viable reality within the lifetimes of most of us.
• ••••••••••••••••••••• References ••••••••••••••••••• •
1) Rapamycin: The Cure for all that Ails Journal of Molecular Cell Biology (2010), 2, 17–19 Department of Molecular Medicine/Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, 15355 Lambda Drive,San Antonio, TX 78245–3207, USA
2) The Mechanistic Target of Rapamycin:The Grand ConducTOR of Metabolism and Aging Brian K. Kennedy1 and Dudley W. Lamming, Cell Metabolism 23, June 14, 2016 ª 2016 Elsevier Inc.
3) Rapamycin: An InhibiTOR of Aging Emerges From the Soil of Easter Island Sebastian I. Arriola Apelo and Dudley W. Lamming Journals of Gerontology: Biological Sciencescite as: J Gerontol A Biol Sci Med Sci, 2016, Vol. 71, №7, 841–849doi:10.1093/gerona/glw090
4) Is This the Anti-Aging Pill We’ve All Been Waiting For? (Link) Antonio Regalado MIT Technology Review March 28, 2017
5) TORC1 inhibition enhances immune function and reduces infections in the elderly Joan B. Mannick1,*,†, Melody Morris1, Hans-Ulrich P. Hockey2, Guglielmo Roma3, Martin Beibel3, Kenneth Kulmatycki1, Mollie Watkins1, Tea Shavlakadze1, Weihua Zhou1, Dean Quinn4, David J. Glass1 and Lloyd B. Klickstein1,* Science Translational Medicine 11 Jul 2018:
Vol. 10, Issue 449, eaaq1564
6)Rejuvenating immunity: “anti-aging drug today” eight years Mikhail V. BlagosklonnyOncotarget, Vol. 6, №23 Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USACorrespondence to: Mikhail V. Blagosklonny, email: mikhail.blagosklonny@roswellpark.orgKeywords: mTOR, TOR, February 16, 2015 Accepted: March 28, 2015 Published: March 31, 2015
7) Harnessing TORC to boost the horsepower of aging immune systems Rachael A. Clark Science Immunology Vol. 3, Issue 26, eaau8704 03 Aug 2018:
8)Does a Real Anti-Aging Pill Already Exist? (Link) Bloomberg News By Bill Gifford February 12, 2015, 5:00 AM PST Updated on February 13, 2015, 2:36 PM PST
9) Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016 www.thelancet.com Vol 390 September 16, 2017 Funding Bill & Melinda Gates Foundation. Institute for Health Metrics and Evaluation, Seattle, WA 98121, USA Correspondence to: Prof Christopher J L Murray, cjlm@uw.edu
10) A comprehensive map of the mTOR signaling network Molecular Systems Biology 6; Article number 453; doi:10.1038/msb.2010.108 Etienne Caron1,2, Samik Ghosh3, Yukiko Matsuoka3,4, Dariel Ashton-Beaucage1, Marc Therrien1,5, Se ́bastien Lemieux1,9, Claude Perreault1,2, Philippe P Roux1,5,* and Hiroaki Kitano3,6,7,8,*
11) Centers for Disease Control and Prevention Underlying cause of death https://wonder.cdc.gov/controller/datarequest/D76
12) Social Security Actuarial Life Table https://www.ssa.gov/OACT/STATS/table4c6.html
13) Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. Vezina C, Kudelski A, Sehgal SN. J Antibiot (Tokyo) 1975; 28:721–6.
14) From rapalogs to anti-aging formula By Mikhail V. Blagosklonny Oncotarget, 2017, Vol. 8, (№22), pp: 35492–35507 1 Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA Published: May 22, 2017
15) PubMed; US National Library of Medicine; National Institutes of Health https://www.ncbi.nlm.nih.gov/pubmed/
16) Latest global cancer data: Cancer burden rises to 18.1 million new cases and 9.6 million cancer deaths in 2018 World Health Organization; The International Agency for Research on Cancer (IARC) IARC, 150 Cours Albert Thomas https://www.iarc.fr/en/media-centre/pr/2018/pdfs/pr263_E.pdf
17) Clinical Trials (dot) gov. https://clinicaltrials.gov
18) Immunoregulatory Functions of mTOR Inhibition (Link) Angus W. Thomson, *‡ Hēth R. Turnquist, * and Giorgio Raimondi* Nat Rev Immunol. 2009 May; 9(5): 324–337.
19) Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition. Blagosklonny MV. (Link) Cell Cycle 2006; 5: 2087–2102.
20) Rapamycin in Mice (Link) William R. Swindell Aging 2017, Vol. 9, №9
21) TOWARDS A LONGEVITY DIVIDEND: LIFE TOWARDS A LONGEVITY DIVIDEND: LIFE EXPECTANCY AND PRODUCTIVITY ACROSS DEVELOPED COUNTRIES (Link) Ben Franklin August 2018 International Longevity Centre — UK (Link)
22) Librarians against scientists: Oncotarget’s lesson (Link) Mikhail V. Blagosklonny Oncotarget, 2018, Vol. 9, (№5), pp: 5515–5516
23) Center for Responsive Politics; Open Secrets (dot) com (Link) Influence & Lobbying / Lobbying / Top Industries Washington, DC 20005–5635 info@crp.org • webmaster@crp.org
24) The U.S. Healthcare Cost Crisis: Public Perceptions of the U.S. Healthcare System Gallup, Inc. https://news.gallup.com/poll/248081/westhealth-gallup-us-healthcare-cost-crisis.aspx
25) The Henry J. Kaiser Family Foundation Household Health Spending Calculator https://www.healthsystemtracker.org/household-health-spending-calculator/?_sft_hhsc_insurance=average&_sft_hhsc_size=average&_sft_hhsc_income=average&_sft_hhsc_health=worse-health
••••••••••••••••••••••••••••••••••••••••••••••••••••••••
Publications utilized for background information in this article:
TOR-centric view on insulin resistance and diabetic complications: perspective forendocrinologists and gerontologists. Blagosklonny MV.Cell Death Dis 2013; 4: e964.
Regulation of immune responses by mTOR. Annu Rev Immunol. 2012;30:39–68. doi: 10.1146/annurev-immunol-020711–075024. Epub 2011 Nov 29. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. poweljo@jhmi.edu Author: Powell JD,
A randomized control trial to establish the feasibility and safety of ‘ll) rapamycin treatment in an older human cohort: Immunological, physical c^rperformance, and cognitive effects Ellen Kraiga,b’*, Leslie A. Linehan1’, Hanyu Lianga, Terry Q. Romo1’8, Qianqian Liuc, Yubo Wu ,Adriana D. Benavidesd, Tyler J. Curiela,e, Martin A. Javorsa,f, Nicolas Musi3’6,8, Laura Chiodo8,Wouter Koekb,f, Jonathan A.L. Gelfonda,c, Dean L. Kellogg Jr 0531–5565/ © 2018 Elsevier Inc. All rights reserved.
Aging interventions get human Brian K. Kennedy and Juniper K. Pennypacker Oncotarget, Vol. 6, No.
mTOR is a key modulator of aging and age-related disease Simon C. Johnson1, Peter S. Rabinovitch1 & Matt Kaeberlein Article in Nature · January 2013 DOI: 10.1038/nature11861
Longevity, aging and rapamycin Dan Ehninger, Frauke Neff, Kan XieCell. Mol. Life Sci. (2014) 71:4325–4346 DOI 10.1007/s00018–014–1677–1
Rapamycin and aging: When, for how long, and how much? Matt Kaeberlein* J Genet Genomics. 2014 September 20; 41(9): 459–463. doi:10.1016/j.jgg.2014.06.009.
Rapamycin’s secrets unearthed https://cen.acs.org/articles/94/i29/Rapamycins-Secrets-Unearthed.html
Chemical and Engineering News Volume 94 Issue 29 By Bethany Halford
Rapamycin https://www.acs.org/content/acs/en/molecule-of-the-week/archive/r/rapamycin.html
American Chemical Society July 25, 2016
PodCast interview by Peter Attia M.D. of David Sabatini, M.D., Ph.D.: Dr. Sabatini is the discover of mTOR and many of the associated signaling molecules both upstream and downstream of mTOR including mTORc1 and mTORc2.
Growth and Aging: a Common Molecular MechanismAGING, March 2009, Vol. 1 №4 www.impactaging.com Mikhail V. Blagosklonny1and Michael N. Hall2 1 Roswell Park Cancer Institute, Buffalo, NY 14263, USA 2 Biozentrum, University of Basel, CH4056 Basel, Switzerland
Statistical Analysis of Human Growth and Development Chapman and Hall/ CRC Biostatistics Series 2014 by Taylor & Francis Group Yin Bun Cheung
mTOR signaling at a glance Journal of Cell Science, 2009 Mathieu Laplante1,2 and David M. Sabatini1,2,3,*
