Abstract
Dr. Joon Yun is the President of Palo Alto Investors, LLC, an investment management firm founded in 1989 with over $2 billion in assets. He joined the firm in 1998 as a healthcare analyst. Concurrently, Dr. Yun served on the clinical faculty at Stanford during 2000–2006 as a board-certified radiologist. Dr. Yun graduated from Harvard College, received his MD from Duke, and completed his residency and fellowship at Stanford. He has served on corporate and nonprofit boards and is a founder of the Palo Alto Institute, a private foundation. Dr. Yun has published numerous patents, peer-reviewed scientific articles, books, and business essays. Dr. Yun is the founder and sponsor of the Palo Alto Longevity Prize, a $1 million life science competition that challenges teams from all over the world to “hack the code” to improve health span.
I had the good fortune as an undergraduate at Harvard to learn evolutionary theory from professors Edward Wilson, Carroll Williams, Stephen Jay Gould, Peter Ellison, and Bert Holldobler. Of the many impressionable topics of the day, the controversy surrounding the proximate and ultimate causes of senescence stood out. The idea that aging might be a trait is—if you will pardon the expression—old, dating at least to August Weismann in the 19th century. In a 1951 lecture, Peter Medawar countered that traits such as senescence, which emerge after the reproductive age, are only weakly reflected in natural selection. Layers of debate followed. 32 In contemplating Medawar's argument, I wondered why nature did not select against senescence in males, who, unlike their female counterparts, retain gene transmission capacity through their dotage. Furthermore, why did nature not select for deferral of the age of female reproductive senescence, since that deferral is a potentially heritable trait?
The subject of reproductive senescence lingered in my mind during subsequent years of medical training. I was particularly struck by the dramatic changes in the rate and causes of mortality after the age of female reproductive senescence, which occurs in a relatively narrow age band across populations during the fifth decade of life. Prior to that age, deaths are mostly attributable to acute external insults such as infection and trauma. After that age, causes of death shift to diseases of aging such as heart attack, stroke, and cancer. It is as if biologic functions are relatively protective against aging until the age of reproductive senescence; then capitulation of those functions ensues, not only passively allowing features of aging, but in some cases—such as chronic inflammation—also accelerating them. An age-old controversial question looms: Are those biologic functions that protect against (or promote) senescence codified, regulated, and reprogrammable?
In this regard, it's worth revisiting a debate that once raged in cell biology. There was once strong philosophical objection to the idea that cell senescence and apoptosis were regulated processes. 33,34 Now, those ideas are widely accepted and the pathways have been established extensively. Moreover, it has become apparent that some cells are capable of reprogramming their own senescence and apoptosis pathways to yield “immortal” cells—a sinister biologic embodiment of the “regulatory capture” concept, otherwise known as cancer. Fortunately, biologists too can play the regulatory capture game and remodel those same pathways in the hopes of developing treatment strategies against cancer. Yet, there may be even bigger lessons to learn from cancer. In addition to studying what cancer is doing “wrong,” what if we also studied what cancer is doing “right”—shedding its senescence and apoptosis programs to reveal how robust life can be. How ironic it would be if cancer, the scourge of human health, could inspire ways for bioscientists to reprogram human aging, an even bigger scourge of humanity.
There is risk in overstating the potential analogy between cellular senescence and organismal senescence, but denial of the potential for fractal patterns could prove even riskier. The assumption that human aging is not encoded—the prevailing wisdom—portends a Whack-A-Mole approach to dealing with human aging, which is exactly what we already have today. Continuation of this approach is unlikely to help us solve aging in our lifetimes. By contrast, the assumption that human senescence (or protection against it) is encoded suggests biologic elegance underlying the apparent complexity of aging and portends potentially elegant solutions that could be envisioned sooner. The assumption also creates a differentiated search space for solutions than where mainstream science is already looking, and searching those roads not taken is of value to the overall effort. Indeed, emerging evidence suggests that reproductive senescence in Caenorhabditis elegans is codified and reprogrammable in the service of health extension and longevity. 35 Thus, the phrase “hack the aging code” is a provocation to the scientific and entrepreneurial community to look for the Occam's razors of senescence and to cultivate the most simple, upstream, and elemental solutions.
After medical school, I began to contemplate biologic functions in the context of homeostatic capacity, the capability of systems to self-stabilize in response to stressors. Think of homeostatic capacity as system resilience, robustness, coping capacity, buffering capacity, dynamic range, or anti-fragility. A simple way to visualize homeostatic capacity is to imagine a Weeble, a popular self-centering toy from the 1970s. For organisms, it is life's foundational trait—itself comprised of a hierarchy and network of traits—endowed by nature and shaped by evolution. Examples include mitochondrial homeostatic capacity, immunologic homeostatic capacity, wound-healing homeostatic capacity, and protein homeostatic capacity.
Health can be understood as the interaction of a person's homeostatic capacity and stressors. Feeling healthy is the feeling of “nothing.” Occasionally, an external stressor such as an infection or a car accident can challenge our homeostatic capacity and make us sick. If our homeostatic capacity helps us recover, deeper layers of homeostatic capacity, such as adaptive immunity and bone healing, protect us even better from repeat insults. A stressor can overwhelm a young person's homeostatic capacity and death ensues. In the pre-modern age, most people died from such insults before reaching the age of reproductive senescence. Health innovations of the first half of the 20th century, such as antibiotics and aseptic surgery, which help restore homeostasis, allowed most youth in developed countries to begin living past the fifth decade of life when aging becomes the predominant cause of mortality.
Because homeostatic capacity is so pervasively effective when we are young, we are made aware of it only by its absence. We particularly appreciate it after we start losing it noticeably during the fifth decade. Recovering from stressors—a late night, hangover, jet lag, or injury—suddenly take far longer than previously. We can't tolerate hot weather, cold weather, high altitude, or diving like we once could. Cartwheels, somersaults, and roller coasters that once left us joyous now leave us discombobulated. Pupils don't accommodate appropriately in darkness.
Consider changes that we can't feel. When we are young, homeostatic capacity returns elevated blood glucose and blood pressure to baseline levels. As homeostatic capacity erodes with age—something about the biology at the age of reproductive senescence appears to catalyze an inflection point—those levels may no longer self-tune. We call these conditions diabetes and hypertension, respectively. Indeed, the panoply of ailments associated with aging may be epiphenomena of eroding homeostatic capacity. If so, could restoring homeostatic capacity reverse aging?
We developed the Palo Alto Prize to focus on restoring the body's homeostatic capacity to the peak levels observed in young adults. We believe healthy longevity will be an outcome of sustained homeostatic capacity. This is not the focus of the current healthcare system, which attempts to restore a body's homeostasis as people age, rather than the body's intrinsic homeostatic capacity. The prevailing paradigm of the extant system is to center out-of-balance biologic functions or—to extend the earlier analogy—to prop up a leaning Weeble. As a consequence, while the current healthcare system helps people live longer lives, it does not solve the fundamental problem of aging. This model of health care has two fatal flaws. First, increasing life span without solving aging leads to pro-cyclical escalation of healthcare costs that threatens to bankrupt the system. Second, aging eventually kills everyone.
We believe aging is a solvable problem and eventually will be solved. However, every week of delay until that happens, another million people will die—the majority from aging-related diseases. That's why we launched the Palo Alto Prize now. It's a race against time.
The Palo Alto Prize initiative will be a series of prizes, the first two of which have been disclosed. The ultimate goal of the series of prizes is to increase health span. Core to our belief is that restoration of homeostatic capacity—which otherwise appears to erode significantly after reproductive senescence—could be the gateway to sustained health. If we can restore homeostatic capacity to that of our peak level and sustain it at that level, our per annual mortality rate could be so low that we would be dying mostly from acute insults such as trauma and infection.
In such a scenario, people could live in a sustained healthy state, and life span could telescope dramatically and be determined by statistics and stochastic events rather than term limits. Because we see restoration of homeostatic capacity as the primary goal and longevity as a related outcome, we launched them as dual, related prizes.
The current “end of aging” Palo Alto Prize is just the beginning. We hope it expands our collective capacity for research and innovation. I will remain dedicated to the cause until it is solved.
A cardiac stress test, which measures heart rate and blood pressure response to changing cardiovascular demand, is an example of a measure of homeostatic capacity. Orthostatic blood pressure is another example. However, both are impractical in their current forms to deploy widely for the purposes of the Prize. Virtually all of the rest of the biomarkers in medical diagnostics today are measures of homeostasis and only weakly reflect homeostatic capacity. Indeed, we envision new frontiers of diagnostics specifically dedicated to measuring homeostatic capacity.
An ideal homeostatic capacity biomarker would be measurable continuously to provide researchers greater temporal resolution to the biodata. Most biomarkers available today, however, can only be sampled as point-in-time data through methods such as blood draws or biospy. Given the temporal elegance of biologic functions—for example, the variation of blood pressure over a circadian cycle—the hallmark flaw of modern biodata is the lack of temporal resolution. Without temporal resolution, most biodata is probably bionoise.
However, it will take years to develop novel continuous biosensors and empirically validate new measures of homeostatic capacity. In the meantime, a million people are dying each week. Therefore, until better measures of homeostatic capacity have been developed—and we are open to suggestions—we elected to start with a measure that is available today, heart rate variability (HRV).
HRV is a surrogate of cardiac autonomic capacity, which itself is a proxy of systemic autonomic capacity. The latter is just one measure of a body's overall homeostatic capacity. As a surrogate of a proxy of a surrogate, HRV has limitations in serving as a marker of overall homeostatic capacity.
Despite its limitations, however, HRV is a serviceable biomarker of homeostatic capacity for the purposes of the Prize. It can be measured non-invasively and inexpensively on a wide variety of devices that already have a global footprint. Esoteric biomarkers that can only be measured by a few laboratories limit the competition to a few groups, whereas biomarkers that can be measured on a wide variety of extant devices, such as HRV, open the aperture of potential competitors to a broader community. For reflecting homeostatic capacity, the temporal resolution provided by real-time, continuous, and dynamic HRV data is potentially more valuable than static, point-in-time biomarkers.
HRV has been studied extensively for half a century. The loss of variability of heart rate as a predictor of mortality has been used clinically in fetal medicine since the 1960s. Lifestyle features such as chronic stress and smoking, which are associated with decreased HRV, are also associated with increased rates of aging-related diseases and mortality. Lifestyle features such as exercise, which augment HRV, are also associated with amelioration of aging-related diseases and mortality. Although such associations do not prove causation, through these initial prizes we are interested in learning if innovations that improve measures of homeostatic capacity will translate to amelioration of diseases and lowered mortality.
Grant funding promotes innovation through a “push” mechanism. Funding supports scientific pursuits, and what happens subsequently is often a result of serendipity. When a canoe is pushed from the back, it can fishtail in directions different than the intended target. In many ways, this is great for science because valuable, unintended discoveries can be made. At the same time, intended questions may remain unanswered.
Incentive prizes promote innovation through a “pull” mechanism. When a canoe is pulled, it travels straight in that direction. Thus, prizes offer an alternative way to solve a very specific problem. We structured this particular aging initiative as a prize in part to introduce homeostatic capacity as a neologism to science and to build a community around it.
I also like prizes because they mimic how evolution works. The combination of niches, diversity, and selection is a powerful driver of innovation in the natural world. Why not apply those Darwinian principles to scientific discovery?
The Prize represents a chance to be part of a community of scientists, industry leaders, and philanthropists who believe that ending aging is one of the grand challenges facing humanity today.
Absolutely. We have been sharing the concepts behind the “end of aging” prize with key figures in the valley for many years before launching the Palo Alto Prize. These conversations helped shape the Prize to become what it is today. The fact that there are many aging initiatives underway now is heartening. When it comes to ending aging, we are all on the same team. The more shots on goal the better. No matter who wins the race, we all win.
Prizes are great ways to “pull” innovations, but more “push” funding is also needed in the aging field. I was surprised to learn that when it comes to private funding for aging research, there is nothing comparable in size to the American Heart Association or American Cancer Society, even though aging is one of the biggest risk factors for heart disease and cancer. Therefore, I agreed to seed fund a public charity that will support aging research.
I am also reaching out to folks from unrelated scientific and technical disciplines to integrate their ideas, frameworks, and innovations into aging research. For instance, in computer science, a network of systems perfectly functional as individual parts can behave in a deranged fashion when not properly integrated as a whole. As a result, systems integration became a big industry. What if the molecular, cellular, and physiologic derangements seen with aging are not the result of failing systems but a result of the disintegration or dys-synchrony (e.g., destruction of clocks or control systems) among otherwise intact systems? Could we ameliorate aging through restoring system synchrony by recalibrating biologic clocks and endocrine functions? Could we ameliorate aging by repairing the body's control systems, such as the autonomic nervous system, which is known to degenerate with age? Indeed, the very systems that sustain health in our youth, such as inflammation, could undermine our health during aging when no longer operating as an integrated system—an instantiation of George William's antagonistic pleiotropy hypothesis. This is just one example of how frameworks in fields seemingly unrelated to biology can help solve some of our most important problems in aging.
Last, I would encourage everyone to aim high in their endeavors. When we aim low, the rewards are small and people fight to divide the pie. When we aim high, the transcendency of the mission nurtures collaboration. Whereas low aims invite incrementalism, high aims force us to try new things, which makes human endeavor far more fun and wondrous. The hunt for the end of aging should have the latter feel.
Let us imagine a world without aging. The end of aging would be the end of healthcare as we know it. The feed-forward relationship between healthcare innovation and increasing future consumption would finally be decoupled. If homeostatic capacity is restored and indefinitely sustained, humans would be able to persist at low annual mortality rates currently enjoyed by young adults. Median life span could telescope to a number of years that might have once seemed unimaginable. Human capacity, thus, would finally be fully unleashed.