Biological Aging Clock Forum
While it may seem from the media that the world is constantly in the state of critical collapse, it is not as bad as it seems and the level of welfare is increasing even in the farthest developing countries. Did you know that the average life expectancy in the world, including the countries commonly perceived as less privileged, is 73.2 years? If not, before reading any further, please check out the table on the life expectancy by Wordometers and find your country on the list. The US currently ranks 46 with an average life expectancy of 79.11 between Cuba (79.18) and Panama (79.1). If you are born in Hong Kong today, a city in China (77.47), which ranks first on the list (85.29), you should expect to live on average 6 years, or about 7.5% longer than the average American.
I have Worldometers bookmarked and check it every morning when I wake up to see how many people died of aging while I was asleep to get more motivation to go through the day, think of more ways to generate QALY, and avoid being distracted by less important issues. And it constantly puzzles me why the countries that spend the most on healthcare and research are not there at the top of the list in terms of average life expectancy. And, why are countries not competing on life expectancy while competing on pretty much everything else?
Dr. Alexander Fleming
And I could not think of a better group of people to ask this question than Thomas Seoh and Dr. Alexander Fleming, of Kinexum, who with Stanford Professor Lawrence Steinman, founded the Metabesity conference which brings together some of the most important decision makers in the government, academia, and the industry.
Thomas Seoh
On September 11, 2020, they organized the industry’s first panel on the regulatory considerations for aging biomarkers. It included senior officials from the US Food and Drug Administration (FDA) and the National Institute on Aging (NIA).
Dr. Alex Zhavoronkov: Let’s address the most important question I posed in this article. You recruit senior regulators at Metabesity events. Why don’t we see governments competing on the longevity of their citizens and some of the most developed countries that technically drive progress in science and technology are so far behind?
Dr. Alexander Fleming: First, regulators, medicine, industry and the general population have not historically viewed aging as a disease or condition to be treated or cured, but rather as an unalterable human condition. There is not yet adequate awareness of the abundant evidence that geroscience has amassed that biological aging can be delayed or even reversed. Decision makers do not appreciate that this science can be applied to prevent or delay major chronic diseases and thereby substantially improve health and quality of life and reduce healthcare costs.
Second, when the general public is asked if they want materially longer lives, many tend to picture a dependent nonagenarian in a wheelchair or an ICU bed, instead of a vigorous, healthy, mentally alert senior equivalent to those decades younger. The emphasis of geroscientists is to increase heathspan, the period of life free of chronic disease and not just to increase lifespan.
Third, many people are uncertain about the socioeconomic and cultural implications of extended healthspan, in terms of retirement, new careers, personal finance, and making way for new generations.
Education of policy makers and lawmakers and voters about the promise of advancing science and medicine for extending healthy longevity, the unsustainability of the current trajectory of health care costs and the qualitative and quantitative benefits of “the longevity dividend” is the key.
But to specifically answer your question, Alex, some countries ARE leading the way: UK, Singapore, Switzerland, and others. The UK, has adopted a national goal of extending healthspan by 5 years by 2035, with more equitable access. The US is behind such leaders in even recognizing healthy longevity as a national priority, and we need to spark an enlightened “arms race” to harvest “the healthy longevity dividend”. But first, we have to educate our citizenry that geroscience has shown us that it is now no longer a question of ‘if’, but ‘when’ we can delay or even reverse biological aging. We need widespread understanding that healthy, vital elderly are assets, not liabilities.
Dr. Alex Zhavoronkov: What steps should the government take to accelerate the progress in aging research and translation of aging research into clinical practice?
Dr. Alexander Fleming: A major challenge to Big Pharma and investors entering the field is the lack of clear regulatory pathways and evidence needed for approving both drugs and nutritional products with health span claims. Today, if a company approaches the FDA with a product that reduces the aging process, the agency would probably only give approvals for reducing risk of one chronic disease or another, and that would not reflect the full value of the product. Worse would be the scenario in which the product is not approved even though it results in consistent positive effects across multiple chronic diseases, but none of the effects on the individual diseases is sufficient to support approval of any individual disease indication. The largest uncertainty facing developers of these products is the evidence that would be required to support a health span claim. We need to hear from FDA that it can approve products under the above scenario. This would enable trials of 3-5 years’ duration instead of the decade it might take to show convincing preventive effects in healthy populations on individual diseases…. Investors will not get behind trials that have to be long and large enough to show large effects on delaying each chronic age-related disease. The costs, times and risks of such trials are beyond the ability of an investor to consider. There are creative trial design approaches that can feasibly provide convincing evidence, but FDA’s willingness to accept them is needed. Federal legislation, analogous to the Orphan Drug Act and the 21st Century Cures Act, for encouraging FDA to provide clear guidance and incentivize the development of these products could be game-changing.
By the way, such interventions should not be limited to drugs or biologics but include a range of modalities, including nutritional product supplements and medical devices, including mobile apps and sensors. Other measures, like exercise and social interventions, are also important but do not involve regulations. Additional legislation and public policies could declare healthy longevity a national interest and set a national ‘moonshot’ goal (like the UK’s goar to extend healthspan by 5 years by 2035). Additional studies will further quantitate how much the longevity dividend would, net of increased benefit costs for longer-lived elderly, save on public health care costs and create economic value.
Federal appropriations can also supplement resources in addition to those dedicated to researching individual chronic diseases. Today, there is sort of a ‘whack a mole’ problem: heroic efforts are made to save a patient from heart disease, only for them to die from cancer a few years later; if heroic measures beat back the cancer, the patient succumbs to dementia. While we should certainly continue to invest in research into diabetes and cardiovascular and neurodegenerative diseases and cancer, we should invest a small portion of the billions of dollars going into the War on Diabetes, the War on Obesity, the War on Alzheimer’s, and the War on Cancer, into ways to delay or even reverse biological aging, and thereby prevent or delay all or a number of these chronic diseases.
Dr. Alex Zhavoronkov: What is Metabesity and what is the story behind it?
Dr. Alexander Fleming: I coined the word “Metabesity”, around 2013, to name the constellation of age-related chronic diseases, from diabetes to cardiovascular and neurodegenerative diseases to cancer to the aging process itself, all with shared metabolic roots, which therefore may be targeted together with common solutions. The intent of naming this target was to encourage concerted effort to invest in and achieve solutions to prevent multiple diseases—and not wait to manage them. Metabesity is sometimes confused with metabolic syndrome and obesity, which are drivers of Metabesity but far from being the only drivers. The emerging geroscience convinced me that after the great successes of medicine against acute diseases and conditions the next frontier could be the prevention of chronic age-related diseases and disabilities. This is a passion on which I want to focus the remainder of my professional life. Around 2016, my co-chair, Larry Steinman, co-discoverer of the MS drug Tysabri and multiple other therapies and long-time former head of the Stanford’s immunology program, and I organized a conference on this motivating theme. Our inaugural conference was in London in October, 2017, set across the street from Wembley Stadium in London. Alex, you were there, and made quite a mark, along with other leaders from various disciplines. We held the next conference at the Carnegie Institution for Science in Washington, DC in October 2019, and here we are now, as a virtual conference in October 2020 due to the pandemic. This has been a pro bono labor of love, and the losses have been covered by our strategic regulatory and clinical development advisory firm, Kinexum. This year, we established the not-for-profit Kitalys Institute to take over organization of future Metabesity conferences and support other initiatives aimed at supporting healthy longevity.
Dr. Alex Zhavoronkov: I decided to dedicate my life to aging research and longevity biotechnology almost 20 years ago and back then it was a very barren place. There were only a few scientists to follow, few companies, and definitely less funding. However, during the past decade, the situation seems to have changed dramatically. Even the pharmaceutical companies are looking closely at aging. What do you think was the main catalyst for this acceleration? In your opinion, what are the main discoveries made over the past few years that will help drive the longevity ecosystem?
Thomas Seoh: I’m no historian of geroscience, but certainly important scientific and technological milestones have created a mounting sense of excitement - from the discovery that the lifespans of different species, from yeast to worms to rodents, could be extended by genetic and molecular pathway intervention. Other milestones include the demonstration that an old mouse sharing a circulatory system with a young mouse rejuvenates while the younger mouse ages, the reprogramming of mature cells into young, pluripotent cells utilizing Yamanaka factors, and the discovery of epigenetic biological clocks and other biomarkers of aging. Accelerating advances in molecular, cellular and systems biology, rocket-boosted by Big Data and Artificial Intelligence, your field of expertise, Alex, where you have made substantial contributions, indicate that geroscience discoveries will continue to grow explosively for the foreseeable future. The small town you arrived at 20 years ago is now explosively growing into a megalopolis.
Dr. Alex Zhavoronkov: I attended the recent panel you put together with the FDA and NIH on the regulatory issues around the biological aging clocks. One of the questions was on the barriers for using the deep aging clocks developed using artificial intelligence in clinical trials. And I was very surprised when Dr. Robert Temple of the FDA said that there are fewer barriers than we think and that the introduction of such clocks may not overcomplicate the trial or put it at risk. Can you expand on this issue and on the future of aging clocks in clinical trials?
Thomas Seoh: That discussion between pre-eminent thought leader Bob Temple from the FDA and some of the leading experts in biological clocks and other biomarkers of aging was indeed elucidating, and an important start of a “cultural exchange” between the innovator scientists and the regulators. First, we should explain that biological clocks and other biomarkers of aging measure biochemical and other biometric values to estimate a biological age that may be more indicative of health and the amount of lifespan an individual may have left than her chronological age - we all know people who seem young and well-preserved for their age, or who seem older and frail beyond their years. It’s important to recognize a distinction in what Dr. Temple said: he was fine with, indeed very supportive of, how tools like biological clocks and other biomarkers of aging could be used to inform selection of drug candidates, enrich clinical trial populations, generate hypotheses for testing whether clinical benefits could be demonstrated, etc. But one critical role developers of interventions against biological aging hanker for is biomarkers to be ‘promoted’ into surrogate markers or registrable endpoints that can be the basis for approval of therapies for the market. This is important because in the absence of biomarkers, actual clinical benefit would need to be demonstrated; for a therapy that purports to extend lifespan, a clinical trial would have to demonstrate, for example, that those on the intervention lived longer compared to controls, which could take years for such a trial to complete. And here, Dr. Temple noted that historically, it took decades of emerging scientific and medical consensus to elevate biomarkers such as blood pressure, cholesterol, hemoglobin A1c or viral load to surrogate markers or registrable endpoints deemed sufficiently predictive of heart attack, stroke, diabetes or AIDS to serve as the basis of approval. So he was saying use biological clocks and other biomarkers of aging however they may be deemed useful guidance for product development. But, to gain regulatory approval, sufficiently long and large clinical trials are needed to demonstrate an intervention's clinical benefit (like improved function or longer survival). These outcome trials can be used to validate biomarkers as predictive of such a clinical benefit so that they can become the basis for approval of future interventions.
Dr. Alex Zhavoronkov: In your opinion, why did the resTORbio trial on rapalogs fail? Could they have done better if they were to use aging clocks?
Dr Alexander Fleming: The resTORbio trial did fail on the primary endpoint of the percentage of subjects with clinically symptomatic respiratory illness. However, demonstrating benefits on symptoms is a very high bar, if not an unreasonable one for an initial phase 3 trial for a first in class and indication therapy. The trial actually did show some encouraging results and there is good reason to pursue development in higher risk populations. COVID-19 might provide such an opportunity.
Using a deep aging clock would not have altered the regulatory result, that the trial failed to meet the primary endpoint(s). However, deep aging clock data could well help to generate hypotheses about responsive subgroups or other factors for testing in further trials. Again, the goal of the field, to seek approval if an intervention moved the needle to the requisite extent on the clock, remains distant, according to Bob Temple, until the clock has been ‘validated’ by trials demonstrating the agreed upon and required clinical benefits.
Dr. Alex Zhavoronkov: And my final question. You first invited me to speak at Metabesity London in 2017. And despite the event being rather small, the level of the speakers was staggering. You had Tomas Olssen, the chair of the Nobel Assembly that selects the recipients of the Nobel Prize in Medicine and Physiology, Sir. John Bell, one of the world’s most famous Canadian physician-scientists, top executives from the UK National Health Services, National Institute for Health and Care Excellence, and other government officials, and big pharma executives. How do you manage to get this level of speakers to present at the conference? I assume that you can not simply call them up? What is your secret?
Thomas Seoh: Actually, it is that simple, we ask them, but the secret sauce is the extent and quality of connections of co-chairs Larry Steinman, a member of the National Academy of Sciences, and Zan, with his deep regulatory and clinical connections. Also, a couple of distinctive features of our Metabesity conferences are that (i) like Steven Spielberg is said to have started making movies he wanted to watch, we organize conferences we want to attend; and (ii) we try to avoid it being a parade of lectures from the podium - we try to put together a dinner salon comprised of leaders from various disciplines, rather than put on a music concert. So as one example among many of a session I am really looking forward to at Metabesity 2020, there is a session in the lifestyle track on exercise entitled Why is Exercise Geroprotective? Molecular and Evolutionary Perspectives with geroscientist Tom Rando (a Stanford colleague of Larry Steinman) and evolutionary biologist and cultural anthropologist Dan Lieberman of Harvard (whom I heard at my 25th college reunion), moderated by Judy Foreman, longtime science journalist and author of Exercise is Medicine (recruited by Adriane Berg, Executive Director of the Kitalys Institute, from her own very broad network). I think the word has gotten around that we put on an insightful and important yet fun dinner salon at Metabesity, and a number of speakers want to come chat with other speakers and our sophisticated audience. You know, there are conferences on how human lifespan might be expanded to centuries, and those on how to make money investing in the longevity space; our distinct ‘lane’ is translating emerging science into material, accessible gains in public health. This starts with clinical translation but extends to daunting challenges in the commercial, public policy, healthcare practice, and consumer behavior domains. To come up with practical ways forward requires bringing a large, diverse set of smart committed people together across what are traditionally subject matter or functional silos—and that makes it fresh and exciting for the speakers and the attendees.
Targeting Metabesity 2020: Extending Healthspan will transpire 12-15 of October as a free virtual conference and will bring together many top academics, clinicians, government officials, pharmaceutical companies, and startups.
