The New Age Of Aging

WELCOMETO THE NEW AGE OF AGINGWhere Innovative Treatments and Technologies Prevent the Underlying Causes of Aging-Related Disease Before They Ever Begin.

Globan HealthspanPolicy Institute

Washington, DCwww.healthspanpolicy.org

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© Global Healthspan Policy Institute 2016401 Ninth Street, NW, Suite 640 First published in 2016 by Global Healthspan Policy InstituteWashington, DC 20004healthspanpolicy.org Printed by Global Healthspan Policy InstituteOriginal language: English

CONTENTSWelcome To The New Age of Aging 2By Edwina Rogers, J.D.; CEO, GHPI

Our Mission 3By Joseph Antoun, M.D., M.P.P., M.S.; Chair, GHPI Board of Directors

Why Exactly Do We Think About Treating Sickness In Terms of Individual Diseases? 4By Nir Barzilai, M.D.

Aging: The Biggest Risk Factor For Disease 5By George Martin, M.D.

Economic Meltdown 6By S. Jay Olshansky, Ph.D.

How Can New Treatments and Technologies Have An Impact On Aging-Related Disease? 7By Ilia Stambler, Ph.D.

What We Can Expect: New Growth Sectors In The Medical Technology Development Pipeline 8By Ilia Stambler, Ph.D.

The Breakthroughs 10By Kevin Perrott, President, GHPI Board of Directors

Metformin* 11Senolytics 12Regenerative Medicine 13Gene Therapies 14Parabiosis 15Nanotechnologies 15Rapamycin 16Organ Preservation** 17The Path Forward 18

*Assembly and presentation of Breakthroughs are jointly credited to the GHPI Policy Research Team and Dr. Il ia Stambler.

**GHPI acknowledges the substantial contributions from the Organ Preservation Alliance in this section.

Edwina has been a public policy expert in healthcare for more than twenty years and has worked for two Presidents and four Senators. She was General Counsel of the National Republican Senatorial Committee during the 1994 Republican takeover of the Senate, served on the National Economic Council and in the Department of Commerce, and has been a lobbyist for countries as diverse as South Korea, Taiwan, and India, among others. She was also the founding Executive Director of the Patient Centered Primary Care Collaborative from 2006-2011, a Washington, D.C. trade association responsible for implementing the Patient Centered Medical Home model around the U.S.

WELCOMETO THE NEW AGE OF AGING

2 The New Age Of Aging

Aging is the biggest challenge facing our world today, and our public policies are not yet ready to face it.GHPI works to change this.

We are in the “Age of Aging”. Baby boomers are aging faster than ever before, and our societies are not prepared for it. If the “Silver Tsunami” is not transformed into a wellspring of opportunities through bold and proactive policy leadership, we will face unprecedented socio-economic, healthcare and geopolitical challenges. Indeed, by the year 2050, two billion people will be over 60 and 1.6 billion over 65. The numbers are more staggering in some countries like South Korea, where by this same year 41% of the population will be over the age of 60.

These figures reflect historic and current trends. For instance, in 2000, for the first time in history, there were more people over age 60 than children below age 5. Presently, while Italy has the highest senior population of any country in Europe, Japan has more than 50,000 people aged 100 or more.

GHPI represents a consortium of thought leaders in the field of public policy and research in the field of the underlying causes of aging-related disease, in order to best advance longer, more productive healthspans as peak priorities for governments around the world. Our mission contributes to the

enhancement of the human healthspan by engaging with and shaping public policy and supporting new breakthroughs in the field of healthy aging, with a vision to serve as the global institute of excellence and reference in public policies relevant to aging, longevity & healthspan.

GHPI considers aging to be an opportunity. Seniors are the wisest and most experienced among us, and unfortunately, because of unfavorable lifestyle habits and a healthcare system that focuses predominantly on disease treatment rather than prevention, seniors sometimes find themselves to be unhealthy, unproductive, and unable to serve as the social assets they truly are. To reverse this course, we need to reform public policies to focus on healthspan rather than on sick-care, to invest more into advancing innovative longevity technologies, and to maximize seniors’ contributions within society.

Enhancing healthspan should be a top social priority. Creating a policy environment that fosters research and development in healthy human longevity, clarifies regulatory review processes and ensures access to new healthspan technologies must be a top policy-making agenda. At GHPI, we catalyze the translation of these positions into reforms and actions, to foster a healthier tomorrow - today.

Sincerely,

Joseph Antoun, M.D., M.P.P., M.S.

Chair, GHPI Board of Directors

Dr. Joseph Antoun is the co-Director of the Center for Health Policy at the University of Chicago, Harris School of Public Policy Studies, where he teaches comparative health systems, pharmaceutical policy and leadership & negotiations in healthcare. He is also the CEO of Health System Reform S.A.L., a Professor of Health and Pharmaceutical policy at the Buck Institute for Research on Aging, a visiting fellow at the Department of Social Policy at the London School of Economics and Political Science, and the co-Editor in Chief of the Journal of Health Systems Reform.

“IN THE YEARS AND DECADES TO COME, IT WILL BE NICE TO LOOK BACK ON THIS ERA AND SAY, "WOW, THE MEDICAL COMMUNITY WAS REALLY ON TOP OF THIS. THEY DEVELOPED THESE INTERVENTIONS THAT KEPT EVERYBODY HEALTHY LONGER, PREVENTED THESE DISEASES, LOWERED HEALTHCARE COSTS, AND KEPT THE WORLD ECONOMY GROWING."Brian Kennedy, President and CEO, Buck Institute for Research on Aging and GHPI Fellow

OUR MISSIONBY JOSEPH ANTOUN, M.D., M.P.P., M.S.

The New Age Of Aging 3

The answer is simple. In the 20th century, most of the gains in life expectancy were due to our success in treating infectious diseases like pneumonia, flu, and tuberculosis. Our success led us to create institutions, like the National Institutes of Health, that are divided into “silos” - different labs, working to cure different diseases, separately, and with little collaboration.

In the 21st century, infectious diseases are no longer the greatest threat to life expectancy - aging-related diseases are. Now, as our old institutions turn to face a new challenge, they find that their old tools are not as useful as they once were - and the time it takes to teach an old dog new tricks seems insurmountable.

As a result, we find ourselves as a culture left with a perspective on treating illness and disease that is largely reactionary - and aging Americans are the clearest victim of that vision. In every aspect of the medical research, development, and regulatory oversight wings that seek to find the cures to human suffering the world over, we see that same story repeated over and over again - and until very recently there was no end in sight.

That’s changing.

The scientific community has begun achieving success in identifying, targeting, preventing, and treating the underlying mechanisms of aging-related diseases. Numerous pre-clinical studies have been shown to extend the number of healthy, productive years possible through genetic, environmental, pharmaceutical, and technological interventions. Through new policies and broader thinking, the U.S. government is clearing the way for a new paradigm - one where we can actively treat and address the factors that lead to the diseases of old age right here, right now - and open a new market for preventive treatments and technologies that can reduce our healthcare costs by trillions.

Most might say that the road ahead is a long and

rocky one - but that’s just not true. In actuality, extensive research has already been done - it just needs the support of public and private champions to see it through.

For instance, take the drug Metformin, the world’s drug of choice for treating Type-II diabetes and used for over 30 years. Not only is Metformin generically produced and sold for pennies on the dollar, in intervention-based and observational studies around the world it has been shown to:

reduce the risk for multiple cancers by over 30% [i, ii]

prevent the onset of diabetes by over 30% in obese prediabetics [iii]

decrease deaths from diabetes by over 50% [iv]

Increase the life expectancy rates of unhealthy, obese diabetic patients beyond that of healthy, non-obese persons [v]

Can you imagine a world where the same pill can be delivered to an aging population to treat the effects of aging diseases now - as well as to their grandchildren, to delay and prevent the onset of those very diseases in the future?

Metformin is the first in a new class of next-generation drugs that target the processes of aging-related disease. It will transform our world in the 21st century just as much as the availability of clean water and germ theory did in the last. The potential is vast, and it is coming faster than we think - and right on time.

Nir Barzilai, M.D.

Director, Institute for Aging Research at the Albert Einstein College of Medicine

Director, Paul F. Glenn Center for the Biology of Human Aging Research

Director, National Institutes of Health’s Nathan Shock Centers of Excellence in the Basic Biology of Aging

WHY EXACTLY DO WE THINK ABOUT TREATING SICKNESS IN TERMS OF INDIVIDUAL DISEASES?BY NIR BARZILAI, M.D.

Dr. Barzilai and the team of researchers at the American Federation of Aging Research were recently profiled in the new Ron Howard “Breakthrough” documentary “The Age Of Aging” for

their work in the landmark TAME/Metformin clinical tr ials. For more information, turn to page 11.


There is now widespread recognition of a “silver tsunami” - the unprecedented numbers of those of us who have reached the ripe old age of 85 years or more. Some view such demographic changes with apprehension, especially as regards perceived social and economic implications.

Others, including myself (a few months shy of age 89), regard this as a reason to celebrate the advances in public health, preventive medicine and the basic and clinical biomedical research that made this possible. Moreover, as a pathologist and gerontologist, I am excited about recent advances in my field that have opened the door not only for further increments of lifespan but, more importantly, for meaningful increases of healthspan, providing an opportunity for many more of us to continue to lead productive and rewarding lives well past the age of 85.

Biological aging is by far the major risk factor for virtually all of the major chronic diseases of our society - most cancers, cardiovascular diseases and strokes, Alzheimer’s disease and related dementias, Parkinson’s disease, type 2 diabetes, osteoporosis, osteoarthritis, chronic renal disease, cataracts, age-related macular

degeneration, loss of hearing, etc. In the U.S. alone, nearly 75% of all deaths are linked to only 9 of these aging-related diseases. [vi]

Research that reveals the fundamental mechanisms underlying biological aging, together with advances in understanding individual differences in disease susceptibilities (Precision Medicine) therefore has the potential to greatly delay, ameliorate or, in some cases, to even prevent these diseases. Although

requiring more research, we are encouraged by evidence that the major gains in lifespan exhibited by centenarians can be associated with comparatively less aging-related disease and associated pain and suffering. Finally, social and economic studies (see the following pages) provide evidence that interventions that slow the rate of aging can be cost-effective.

Thanks to the efforts of colleagues at the National Institutes of Health, new collaborations have been formed among the

various NIH institutes to discover common mechanisms of aging that underlie their mandates to investigate the individual disease entities noted above. All these new innovations represent a transformative paradigm shift in research on diseases of aging that I hope to contribute to for many healthy and productive years to come!

George M. Martin, M.D., Professor of Pathology Emeritus (Active), University of Washington

An acclaimed pioneer in the development of genetic approaches to the pathobiology of aging in human subjects, Dr. Martin has received the Pruzanski Award of the American College of Medical Genetics and a World Alzheimer Congress Lifetime Achievement Award. He is a member of the National Academy of Medicine.

AGING: THE BIGGEST RISK FACTOR FOR DISEASEBY GEORGE MARTIN, M.D.

In the U.S. alone, nearly 75% of all deaths are linked to 9 aging-related diseases. The very act of aging itself is the strongest risk factor for developing these diseases.


According to the CDC, by 2030, the number of U.S. adults aged 65 years or older will more than double to about 71 million, and Medicare spending will increase by 25% ($9 billion). In the last 25 years, the growing needs of the aging population has placed unprecedented demands on the entire U.S. healthcare system, resulting in a nine-fold increase in Medicare spending (from $37 billion in

1980 to $336 billion in 2005). [i] In 2014, U.S. health care spending increased 5.3 percent following growth of 2.9 percent in 2013 to reach $3.0 trillion, or $9,523 per person. [vii] In their last year of life, patients suffering from aging-related diseases equal one-third of the entire Medicare budget - that’s a cost of about $15,000 per person. [viii]

In 2004, it was estimated that “75 percent of the $1.9 trillion spent on all health care in the United States stems from preventable

chronic health conditions … but only 1 percent was allocated to protecting health and preventing illness.” [ix]

Due to a lack of treatment for the processes of aging disease, over 80% of older adults have at least one chronic condition (50% have two), resulting in loss of social and/or bodily function for victims. [x]

Persons with neurological disabilities report the lowest levels of mental well-being of all. [x]

Surprisingly, despite experiencing the highest levels of disability [xi], the

oldest members of the aging population report high levels of well-being, when these conditions do not affect personal independence. [xii-xvi]

The strongest determinant of high levels of well-being in all sectors of the aging population around the world is the ability to remain in the workforce and generate income. [xvii]

ECONOMIC MELTDOWNIMPACT TO FEDERAL SPENDING

BY S. JAY OLSHANSKY, PH.D.

IMPACT ON HEALTHCARE PROVIDERS

IMPACT ON EMPLOYERS AND THE PUBLIC

Dr. Olshansky’s research in connecting the dots between aging-related disease and the vast repercussions it has on public health, economics, and quality of li fe have made him the go-to choice for media sources as diverse as 60 Minutes, Fox News, Men’s Health, and Penn and Teller. He was most recently a subject of the recent Ron Howard “Breakthrough” documentary “The Age of Aging”, in his work to support the TAME/Metformin trials.

What are the ambitions of this community of researchers seeking to tackle the underlying causes of aging-related disease? What drives them, and what is their direction, their course?It’s simple, really.The long-term goal that we all have is to extend the period of healthy life. We can see it; we know it's a desirable goal, and we have evidence that it can be done. Now, let’s set it as a goal and pursue it, and pursue it aggressively.We're not trying to make human beings live forever; we're not trying to even have people live significantly longer. What we're trying to do is ensure that the period of healthy, productive years of life is maximized for the greatest number of persons possible, through the most effective and economically-beneficial means possible.The facts speak for themselves. By renewing attention to the processes of aging and redoubling efforts to ameliorate their broader societal effects, we can change our tomorrow, today.Sincerely,S. Jay Olshansky, Ph.D.Professor, University of Illinois at Chicago School of Public Health


HOW CAN NEW TREATMENTS AND TECHNOLOGIES HAVE AN IMPACT ON AGING-RELATED DISEASES?BY ILIA STAMBLER, PH.D.

What do we stand to gain by endorsing the perspective that aging-related diseases can be addressed at their root through incredible new prevention and treatment technologies?

More than we have ever thought possible.

The economic impact alone is enough to class this paradigm shift on par with the widespread availability of clean water and acceptance of germ theory around the world. We now know that the early detection and preventative treatment of aging-related diseases, while currently effective in detecting the presence of new diseases themselves, can also be used to identify and treat the very causes of those diseases [xviii - xx]. The current and potential cost savings for this are immense:

For Alzheimer’s disease, heart disease, cancer, and type 2 diabetes, the cost savings for early detection and preventive intervention per patient are commonly estimated at several thousand dollars for the developed countries ($1,000-

$10,000+ for Alzheimer’s disease [xxi], $1,000-$10,000+ for various forms of cancer [xxii], comparable for heart disease and type 2 diabetes [xxiii]).

But what are these new technologies? What are the industries and markets coming alive around this topic today, and how will they change our world?

In the following pages, we’ll give you a snapshot of just a few of the most promising areas of research, and the impact that they will have on not just your life - but the lives of those to come. We’re not selling snake oil here - what we’re presenting is simply the logical result of decades of promising scientific research and development.

And it’s more than just that, even - it’s the cutting edge of innovation, and it’s arriving faster than you think.

Sincerely,

Ilia Stambler, Ph.D.

Dr. Stambler is a researcher at Bar Ilan University, Israel and former scientif ic writer at the Biophysical Schottenstein Center for the Research and Technology of the Cellome. His research focuses on the historical and social implications of aging and life extension research. He acts as the outreach coordinator and an executive committee member of the International Society on Aging and Disease


A variety of new markets will emerge - and currently are emerging - as a result of this research. As new treatments, drugs, and services can be marketed dually to both aging - and youthful - populations, a general increase in the following sectors can be expected. Here we offer a brief overview of those sectors - and in the following section, the research that will provide for this growth.

Diagnostic Technologies and Devices

The first sector impacted will be the medical technology industry itself - specifically, in these two core areas:

1 BIOMARKERS OF AGING AND AGING-RELATED DISEASESNew cellular, molecular, and biochemical markers and measurements for the onset of biological age will be - and are being - developed. [xxiv] A wide array of additional

biomarkers and clinical end points are also being sought to diagnose degenerative aging and aging-related ill health, and to determine correct “biological age”. [xxv] Clinically applicable and scientifically grounded diagnostic criteria and definitions for aging may also have profound and encouraging implications for the regulation and promotion of research, development, application and distribution of healthspan-extending therapies. [xxvi, xxvii]

Measurements include, but are not limited to: age-related changes in telomere length (telomere measurement)epigenetic screening (methylation markers) advanced glycation endproducts (AGE-Reader)measurements of oxidative stress (amino acids with oxidized side chains)“critical function” protein countsDNA repair capacitiesdecreases in stem cell populationswhole genome sequencing

WHAT WE CAN EXPECT:NEW GROWTH SECTORS IN THE MEDICAL TECHNOLOGY DEVELOPMENT PIPELINE

Industry Spotlight:Sports Medicine and Rapid-Detection Brain Injury DiagnosticsIt should go without saying - the technology we use to ensure the best possible health and performance of our athletes will soon enter the broader consumer marketplace. Take the example of Banyan Biomarkers, Inc.: recently awarded a $500,000 GE/NFL collaborative grant, they’ve developed the first simple point-of-care blood test biomarker kit for rapid detection of mild and and moderate brain trauma in victims. The product is being marketed specifically for the sports medicine community, as an on-the-spot diagnostic tool to detect the need for brain trauma treatment as soon as it occurs - avoiding potential decades of untold volumes of healthcare costs and suffering from degenerative head injuries for athletes and the teams they represent. [xxviii]


New medical technologies in the therapeutic sector are also crucial not only for the evaluation of effectiveness, but also for the actual administration of treatments and interventions against degenerative aging processes.[9] [10].

CURATIVE AND PREVENTIVE MEDICAL TECHNOLOGIES AGAINST AGING-RELATED ILL HEALTHThese technologies are designed to reduce and prevent the effects of aging-related disease, and are for the desirable conditions of healthy and independent longevity [xxxiii, xxxiv].

Drug design and delivery systems for pharmacological treatments (specific drugs, such as rapamycin, metformin, statins, aspirin, etc.)regenerative and cell therapy technologiesphysical therapy and electromagnetic stimulationE-education and computer games to improve cognitive status in the elderlycompliance, prompting and motivation software and devices (i.e. for medical regimens, and for the reduction of risk factors such as smoking, alcohol consumption)calculation and delivery of dietary factors and regiments (i.e. supplements, nutrients, functional foods)

GEROTECHNOLOGIESWhile not specifically therapeutic, curative, or preventive technologies, assistive technologies are designed to address the existing conditions that result from aging-related disease, such as frailty, senility, and the like. The most significant impact these devices have is on increasing the quality of life of aged persons [xxxiii, xxxiv].

robotics for the agedimproving means of accessambient assisted livingsurveillance and early warning deviceswalking, hearing, seeing and other functional aidsassistive devices and personal coaches for physical activity, exercise, rest and sleep.

THERAPEUTIC TECHNOLOGIES

Industry Spotlight:Health Data Systems and the New Quantified Health InitiativeThere is a need for the rapidly growing field of Personal Health Applications/ Quantified Health applications (collecting and analyzing large amounts of personal health data to improve health care) to be employed in the diagnosis of aging-related conditions. [xxix]

Quantified Health systems such as distributed online databases [xxx],, individual wearable devices[xxxi],, health center databases and data collection systems [xxxii], are in need of strong data integration - for the measurement parameters listed above, as well as a vast and growing consortium of new parameters in years to come. The gross economic value of databasing measurements of blood glucose, electromagnetic measurements (ECG, EEG, EMG, etc.), VO2max (maximal oxygen consumption) and many more are not currently known.

What is known? In order to understand the most optimal human functioning for all these markers for a person of any age - the databasing of scores of patient data will be key.

2 FUNCTIONAL ASSESSMENTS AND QUANTIFIED HEALTHFunctional medical measurements are also rapidly becoming the subject of biomedical technology development [xxix], such as measurements of:

muscle strength (manual muscle-testing; dynamometer: hand-grip strength)vascular rarefaction and dysfunction (capillaroscopy; forearm blood flow techniques)gait speed, step-to-step variability, balance, functional mobility, and endurance capacity (VO2 max) nutritional state/intake computer apps and games to train and improve cognitionsocial participation and psychological type profiling in older persons


THE BREAKTHROUGHS

Anyone who has faced a serious health challenge or watched a loved one suffer knows there is nothing more important in life than being able to do the things you love with the ones you love. Other concerns tend to just fall away.

As is the case with many people facing diagnosis of a terminal disease, much of my

time was spent searching for solutions in a sea of information, much of it conflicting. Over time, however, I learned a tremendous amount, not only about the science that could help with my own situation, but the incredible potential of new discoveries that could help millions of others suffering from their own challenges.

My cancer is now “cured” but the sense of urgency I felt to accelerate the development of interventions to maintain, restore, and increase healthy lifespans remains. Millions of people are all suffering from debilitating conditions, and while new science tells us cures are possible, this promise is not being realized as fast as it should.

My understanding as an entrepreneur is that one often needs to roll up one’s sleeves if they want a job done. I realized from my own personal experience that the best way of doing this was through education - by providing timely and relevant information to those motivated to take action. This information is vital not only to patients and caregivers but also to the key decision-makers in government and industry.

In presenting the following eight core areas of research, we understand that medical professionals, public officials, industry specialists, and the terminally ill are all limited in their time and energy. It’s our job to get the most innovative and cogent research out to everyone in a form that doesn’t just make sense - but inspires bold new action for cures, prevention, and treatment, as well.

We’re here, and the science, opportunities, and key players behind the work presented here are only a short phone call away. If you’d like to learn more about any of the topics listed here, don’t hesitate to reach out.

Sincerely,

Kevin Perrott

Board President, GHPI

Kevin Perrott is a serial entrepreneur and philanthropist who has founded multiple non-profits and star t-ups to accelerate the development of cures able to restore function in older individuals. He is currently a researcher at the Buck Institute for Research on Aging.

Core to everything discussed in this publication is on the following pages.Without popular and private support the overall quality of life will continue to improve at only an incremental basis - instead of the exponential and rapid changes that are possible.


I’M A CANCER SURVIVOR BY KEVIN PERROTT

THE SCIENCEA non-profit team of researchers is opening the regulatory pathway for a whole new class of drugs to be developed and brought to market through the landmark TAME/Metformin trials.

On November 28, 2015, the FDA approved the testing of Metformin, a decades-old diabetes medication, as the first drug to treat aging, due to its capacity to reduce by 30% all cancers in users and other morbidities. [5]Metformin:

prevents the onset of diabetes by ~30% [iii]prevents new cardiovascular events in diabetes ~30% [xxxv]decreases onset of cancer by ~30% [i, ii]decreases deaths from diabetes by over 50% [iv]associated with an increase in life expectancy rates of unhealthy, obese diabetic patients beyond that of healthy, non-obese persons [v]is associated with delayed cognitive decline and Alzheimer’s Disease [xxxvi]

THE IMPACT WIth an FDA-approved reduced-cost budget of $64 million, the TAME study will recruit and monitor the health of 3,000 individuals between 65 and 79 years of age at fourteen centers throughout the nation over a six year period. [v]The study will show if Metformin use results in less aging disease for the control group or not. Metformin is a generic drug, and this study does not directly benefit any pharmaceutical company.

The study is intended to “open the door” to the larger pharmaceutical industry, so that a whole new class of drugs can be developed and brought to market. Researchers are working with the FDA to ensure that Metformin can be the case example that changes the current “one drug, one disease” approval process - ensuring that new drugs can be prescribed and reimbursed that have a positive effect on multiple disease at once. Since this is a non-profit project with a direct impact on public health, charity administrator the American Federation for Aging Research is working with congressional appropriators and other government officials to provide for costs.

THE ECONOMICSThough the long-term effect of preventing and delaying the onset of multiple aging-related diseases will be an economic boom in years to come, the direct effect on diabetes in targeted “danger zones” in the U.S. has a similarly substantial, but immediate, impact.

METFORMINDiabetes alone costs the U.S. $245 Billion in 2012 [xxxvii]$176 billion in direct medical costs (medical goods and services) $69 billion in indirect costs from lost workdays, restricted activity, disability, and early deathBy 2050, 1 of every 3 Americans may have diabetesMetformin is the preferred “drug of choice” for the treatment of diabetes - but not in the U.S. states where diabetes and obesity are most prevalent. [xxxviii] It is also not currently prescribable for prediabetics.

Potential Impact in Mississippi Alone:Number of Prediabetic Mississippians 2 Million [xxxix]

Metformin prevents the onset of diabetes by 34% [xxxx]

Number of Mississippians Who Can Avoid Getting Diabetes 680,000


THE SCIENCEMany cells can divide to maintain and repair tissues. When “division-capable” cells experience stresses such as chemotherapy or injury they can become “senescent”. Senescent cells are incapable of division, grow larger, and often secrete pro-inflammatory factors into the surrounding environment, influencing repair. After the repair is complete, senescent cells go away, or at least mostly do, as they begin to show up in tissues suffering from age-related disease and increase in number over time. Amazingly, recent studies demonstrate that removal of these senescent cells in mice can delay the appearance of many age-related diseases and increase healthy lifespan [l]

THE IMPACTThe race is on to identify methods of addressing the negative influence of senescent cells in humans. New start-ups around the world are looking for “senolytic” drugs and other approaches to remove senescent cells found in tissues affected by age-related disorders such as osteoarthritis, COPD, kidney failure, and many others. [l,li] Research shows that these methods may not need to be perfect to be beneficial with the hope being that restoration of function lost to multiple disorders of aging would be possible. Part of the challenge here is that such ‘broad-spectrum’ methods to target multiple conditions at once is not part of the FDA strategy, but GHPI is working on that through its work with getting the TAME study funded.

THE ECONOMICSThe total number of degenerative conditions causally associated with senescent cells is as yet unknown, but what is known is that senescent cells are found in tissues that exhibit age-related pathologies and that when they are removed, the tissues are healthier. If we examine the total cost of some of these degenerative conditions in the U.S., such as arthritis at $121 Billion dollars per year [lii] just as one example, we can see the potential of such senolytic drugs and approaches to decrease the burden of the costs of treatment for these conditions is dramatic.

SENOLYTICS

A new class of drugs has been created that can target and destroy senescent cells that eventually lead to cancer, Alzheimer’s, and other aging-related diseases.


THE SCIENCEGenerally, regenerative medicine, using stem cells of various origins to rebuild, “regenerate” or improve the function of worn out and aging organs and tissues, are promising for combating the degenerative pathologies of aging.[15] Now, even entire “replacement organs and tissues” can be grown outside of the body – using such methods as growing tissues on biodegradable scaffolds, 3D tissue printing, bioreactors or self-organization — to “replace” the worn out and aging body parts. [lv] Very recently an even more promising direction has emerged – the induction of regeneration within the body by pharmacological means (e.g. using inhibitors of prostaglandin breakdown, thus promoting cell proliferation). [lvi]

THE IMPACTOf special importance for regenerative medicine in contending against aging-related degeneration is the ability to regenerate the thymus gland (that produces the immune T-cells that play the crucial role for the immune defense). This importance derives from the fact that such an ability could dramatically improve therapy not only for aging-related non-communicable chronic diseases (such as heart disease and neurodegenerative diseases that are strongly related to altered immune response), but also help combat infectious, communicable diseases (like HIV/AIDS, Herpes and Influenza) thanks to improved immunity. Such regenerative ability for the thymus was shown by genetic engineering interventions (e.g. using over-expression of the FOXO gene) [lvii] and even pharmaceutical treatments (e.g. using the FGF21 hormone).[lviii]

THE ECONOMICSIn terms of the impact to infectious disease alone, the economics are astounding. In the next 10 - 15 years, the global cost of treating and preventing HIV/AIDS is projected at nearly $35 billion, [lix] $2.5 billion for herpes, [lx] and $100 billion for influenza. [lxi] The potential cost offset for other major infectious diseases, such as HPV and others, is also immense. More than 80% of American women will contract at least one strain of genital HPV by the age of 50; these statistics are similar for herpes, and carry recurring economic burdens in lost workdays due to ongoing breakouts. [lx, lxii]

REGENERATIVE MEDICINEThrough pharmaceuticals and stem cell therapy, we can now restore the health of aged organs to previous, youthful standards of health.


THE SCIENCEEpigenetics (acquired or heritable changes in gene function without changes in DNA sequence), has been increasingly investigated and manipulated for its effects on aging and aging-related diseases. Their amelioration, at the level of the entire organism as well as particular tissues, has been demonstrated using demethylating agents, small interfering RNAs (siRNAs) and micronutrients as potential therapeutic agents. [lxiii]

THE IMPACTGene therapy opens the door to a world where future parents can have their genome sequenced in real-time, and then selectively eliminate defective genes in their children. The effect would be a major reduction in genetic

disorders in the coming generations, such as sickle-cell disease, Down syndrome, cystic fibrosis, and a host of others. Further, this technology can currently be used in adults to identify the genes that lead to Alzheimer’s and other diseases, empowering patients with new preventive care options well before old age. The most cutting-edge therapy uses CRISPR technology to insert healthy, working genes in adults and children with genetic disorders, such as hemophilia, to eliminate the effects of the disease in real-time. [lxiv]

THE ECONOMICSIn 2003, the total cost of the human genome project had topped $1 billion, and had taken 12 years to complete. Now, projects of that size can be done in a few days for less than $1,000. The market for direct-to-consumer

genome sequencing can be compared to the explosion of the home computer market through Windows and Apple.

Even though no CRISPR/CAS9 technology has been approved for market in the U.S., it is a booming service in the medical tourism community. In countries like Colombia, the most cutting-edge gene therapies described here (and much, much more) can be performed at a per-patient cost of less than $10,000. While U.S. markets are falling far behind, the most common and rare genetic disorders are being eliminated for patients with access to these clinics.

GENE THERAPIESGene therapies can be used to identify the diseases you are most prone to and then insert new, healthy genes to

prevent and delay their effects.


We now have the first operating medical nanorobots, that can eliminate cancer and other waste cells.Some of the uses of nanomedicine against degenerative aging include nanoparticles, such as Buckminsterfullerene or “bucky-balls” C60 with assumed antiviral, antioxidant, anti-amyloid, immune stimulating and other

therapeutic activities, with some reported healthspan-extending results in animal models.[lxxxii] Moreover, we now have the first operating medical nanorobots. These robots assist in precise drug delivery and act as prototypes of artificial immune cells. [lxxxiii, lxxxiv] These nanodevices are primarily intended to eliminate cancer cells, and can also be used to eliminate other types of cells, e.g. senescent cells. In another area

of development, oxygenated micro-particles seem highly promising, especially in critical conditions, as oxygen deprivation is the main (or even the ultimate) cause of death, as well as one of the primary economic costs of healthcare delivery services and systems the world over. [lxxxv]

NANOTECHNOLOGIES

PARABIOSISBy splicing the circulatory systems of animals (mice) together, via the process of “parabiosis”, blood from young donors has shown to have rejuvenating effects on aged tissues, including the heart, brain, and muscle tissues, including improved strength and cognitive ability.

Some of the implicated rejuvenating substances included: Notch signaling activators, deactivation of the transforming growth factor (TGF)- that blocks cell division, oxytocin, and Growth Differentiation Factor 11 (GDF11). In September 2014, a clinical trial by Alkahest in Menlo Park CA, became the first to start testing the benefits of blood and plasma of youthful donors in older people with Alzheimer’s disease. [lxxxvi] Researchers

and industry specialists have hypothesized that it may be possible, with existing blood and plasma bank, donor, and collection infrastructure and services, to conduct large-scale and cost-effective donation campaigns at college campuses around the world, using either an incentivized or non-incentivized model.


THE SCIENCEThe immunosuppressant drug Rapamycin produces improvements of energy metabolism, extends healthspans, and delays aging in mice. In human studies, it was also effective against particular aging-related diseases, such as Alzheimer’s disease, in studies conducted at UT Health Science Center’s Barshop Institute for Longevity and Aging Studies. [xxxxi]

THE IMPACTDelaying and preventing the onset of senility is a key component in ensuring high quality of life and productivity for the aging population. Recent studies show that persons with neurological disabilities, such as Alzheimer’s, report the lowest levels of mental well-being of all. [xxxxii] Seniors with even more debilitating disorders than Alzheimer’s report high levels of well-being when these conditions do not affect personal independence. [xxxxiii - xxxxvii] Most importantly, the strongest determinant of high levels of well-being in all sectors of the aging population around the world is the ability to remain in the workforce and generate income [xxxxviii] - fully realizable with the support of Rapamycin.

THE ECONOMICSAlzheimer’s disease costs U.S. families and society up to $215 billion a year. Though Cancer and heart disease are bigger killers, Alzheimer’s is the most expensive malady in the U.S., costing families and society $157 billion to $215 billion a year. [xxxxix] The offset of these costs, combined with Medicare exemptions, could put a major dent in healthcare costs, and reduce the costs of the drug.

RAPAMYCINRapamycin can mimic the effects of caloric restriction, the only foolproof method of preserving healthy human lives long into old age.


THE SCIENCENew research is seeking to freeze and store heart, liver, and other organ donations for long-term use in emergency healthcare. [lxv] As of 2015, the Department of Defense now operates three separate, but complementary, cryopreservation grant programs to fund research for 20 or more leading American research teams and support U.S. commercialization of science, while achieving military as well as civilian health goals.

THE IMPACTSince organs cannot be stored, or even transported long distances in many cases, an estimated 21 people die each day awaiting a transplant, equalling 35% of all U.S. deaths [lxvi - lxviii]. Around the world, the situation is even worse, with organ transplants meeting less than 10% of the global need. At present, we discard nearly two thirds of potential donor hearts and one fourth of potential donor kidneys. [lxix, lxx]. If just half of all unused hearts and lungs could be utilized, it is estimated that transplantation waitlists for these organs would disappear in 2-3 years [lxxi].

THE ECONOMICSThe world market for replacement organ therapies alone is estimated at over $350 billion. [lxxii] In addition, the Alliance for Regenerative Medicine’s 2013 annual report states that “potential savings from regenerative medicine treatments – for the U.S. ... have been estimated at approximately $250 billion a year.” The economic cost of treating end-stage renal disease has been estimated at over $1 trillion over the course of a decade [lxxiii]. $34.3 billion of the U.S. Medicare budget was spent on dialysis in 2010 alone [lxxiv]. In addition to the financial burdens, dialysis patients typically experience a poor quality of life compared with transplantation [lxxv]. By eliminating logistical burdens, organ banking can bring down the costs of transplantation, which for some procedures have skyrocketed to more than $1 million [lxxvi]. A number

of important facts underscore the urgent need and economic potential of public/private healthcare infrastructure for organ preservation. Currently, the demand for organ transplants in the U.S. outweighs the supply by a factor of 5 to 1, and the gap continues to grow [lxxvii] The young disproportionately suffer from limb loss - and our economy suffers

in turn from their loss of productivity and mobility. Currently, two million people are living with limb loss in the U.S. alone and 185,000 amputations are conducted each year [lxxviii, lxxix]. Additionally, approximately 1,600 wounded service members sustained

amputations during the wars in Iraq and Afghanistan [lxxx]. Recent world crises and mass casualty events, such as the Paris bombings, could record lower levels of loss of life with effective organ banking medical countermeasures in place.

ORGAN PRESERVATIONThe U.S. has recently granted the first federal funding to end the organ donor shortage through long-term, cold storage organ banking.

“More people die in the U.S. from organ impairment than die from cancer [lxxxi].”


NEW REGULATORY FRAMEWORKS(U.S. - specific)The FDA’s current “one disease, one drug” model is not an agency-exclusive model, but one that is shared across the public and private spectrums, resulting in less cooperation and replicative research. The incentivization of translational research and treatments that seek to positively impact multiple areas of aging-related disease, not just one, can prevent duplicative research and empower more cost-savings and public health benefits.

OPENING REGULATORY PATHWAYS(U.S. - specific)A shortened approval pathway for therapies with high levels of efficacy in preclinical and early clinical trials, as well as terminal cases, can ensure that patients with the most to gain from new treatments have access. Additionally, it will ensure that industries offering new treatments can afford to do so in the U.S., as opposed to creating new economic benefits for other countries through the medical tourism market. Over 22 states have currently passed the “Right To Try” law, allowing for terminal patients to have access to treatments and technologies that have passed FDA phase-1 clinical trials, and the FDA’s Compassionate Use program provides even broader access to all U.S. citizens. Greater public and regulator education is needed to ensure that the research detailed in this publication can directly stimulate new markets in these states.

STRONGER, CLEAR DEFINITIONSThe underlying processes of aging-related disease may be introduced as a part of the International Classification of Diseases (ICD) [lxxxvii] in order to more effectively establish clear biomarkers for the detection, prevention, and delay of aging-related morbidity and mortality. As of 2016, the current ICD10 listings lack clinically applicable and scientifically grounded criteria necessary for proper diagnoses [lxxxviii] . This action is a direct implication of the WHO’s Global Strategy and Action Plan (GSAP) on Aging and Health. [lxxxix]By meeting these challenges, we can continue to create new markets for private and public stakeholders the world over - not to mention revolutionize the way public health and aging are both perceived and addressed. In the years to come, we look forward to an unprecedented time of innovation and opportunity in the new age of aging.

THE PATH FORWARDIn nearly all ways, innovation for research into the underlying causes of aging-related disease represents innovation for the entire community of industries associated with the medical technology development pipeline. At the same time, innovation is always confronted by regulatory challenges that must be met with clear information and strong education:


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Edwina Rogers, J.D.CEO

Madeline SchusselDirector of Policy

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Judith Campisi, Ph.D.Buck Institute for Research on Aging

Nir Barzilai, MDAlbert Einstein College of Medicine

Jay Olshansky, Ph.D.University of Illinois at Chicago

George Martin, Ph.D.Member, National Academy of Medicine

Gordon Lithgow, Ph.D.Buck Institute for Research on Aging

David Sinclair, Ph.D.Harvard Medical School

Gil Atzmon, Ph.DAlbert Einstein College of Medicine

Kyung-Jin Min, Ph.DInha University

Aftab Ahmad, Ph.DNational Academy of Young Scientists

Georg Fuellen, Ph.DIBIMA Director

Antonei Csoka, Ph.DHoward University

Caleb Finch, Ph.D.University of Southern California

Heinrich Jasper, Ph.D.Buck Institute for Research on Aging

Abbe de Vallejo, Ph.D.University of Pittsburgh

Greg Neimeyer, Ph.D.University of Florida

Nadiya Kazachkova, Ph.DUniversty of Azores

João Pedro de Magalhães, Ph.DUniversity of Liverpool

Brian Kennedy, Ph.D.University of Southern California

Veronica Galvan, Ph.D.The Barshop Institute for Longevity Studies

Thomas A. Pyszczynski, Ph.D.UC Colorado Springs

León F. Ferder, MD., Ph.D.University of Puerto Rico

Steven N. Austad, Ph.D.University of Alabama

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The New Age Of Aging