Yihui Zhang

Age with grace: a reflection on aging research and investing

March 24, 2021

One of the most memorable and recurrent dreams I had in my childhood is dying in a variety of fashions. Die from falling from the sky, die from escaping prison in the middle of an ocean, die from a refrigerator falling from the sky, examples abound.

I later realized the reason those dreams left a lasting impression on me is that I donʼt experience time as finite when Iʼm awake. We all accept that mortality is bearing down on us, but one of our innate mental tricks that makes it possible for us to exist as mortal beings without going completely insane is we don’t really think about an end date. We wake up every morning assuming we’ll also wake up the next morning, until one morning we donʼt – and on that morning, we don’t know it. Because we are dead. So if we accept that the world we live in is a subjective construct built from our perceptions, weʼre all immortal – we live forever within the context of reality weʼve created for ourselves, because when we die, so does that reality. Doesn’t that make all of us not think about death?

No, it does not. Talk to any diagnosed cancer patient. Youʼll be reminded that while death can be an intellectual concept, and even with the evolutionary mental byproduct that we have, it becomes real when you know you are sick. Because human aging is associated with high susceptibility to sickness, humans since historic times have tried to find ways to live forever. Longevity myths have fascinated people since recorded text. From China, where cultural legend like Fuxi was said to live for 197 years, to ancient Greece, when Tiresias, the blind seer of Thebes, was believed to live for over 600 years, the extent to which we would go to live longer is well documented, all the way to todayʼs scientific outburst of anti-aging research. Woody Allen sums it up neatly: “I don’t want to achieve immortality through my work; I want to achieve immortality through not dying”.

Even with the ever-growing interest, however, many Americans seem to be hesitant about potential life-extending technologies. In a 2016 Pew survey, many expressed concerns about inequity. A majority of Americans surveyed believe that those who obtain the techniques of longevity would “feel superior” to those who don’t. In addition, 73 percent of respondents worry that [new technology] will increase inequality because they will “only be able to be obtained by the wealthy.” Despite raising valid concerns, most people still underestimate just how complex societal implications of lifespan extension research can be. In an imperfect world of shrinking scientific funding that’s driven by financial agenda, we need to first understand different types of longevity research. Specifically, we need to make a clear distinction between extending healthspan and extending lifespan. Simply put, healthspan is the healthy years of life; lifespan is the biological limit of how long a species can live. And as we have learned in recent years, the idea of extending our lifespan at all costs will lead to negative byproducts.

Tech investors are great at avoiding buzzword traps in software startups but have not been great at catching phrases like “measuring 128 different tests through a single drop of blood” or “young blood rejuvenates the body’s organs”. In the show Silicon Valley, Galvin Belson received a blood transfusion from a young “blood boy” while listening to the Pied Piper pitch. But that’s how itʼs supposed to work. The original research, instead, involves parabiosis which requires stitching together two bodies to share not just blood circulation but also organ functions. The research hadn’t even gone through the proper animal study, barely demonstrating efficacy in mice. And yet, companies like Ambrosia have started offering plasma transfusion reservation and earned constant press mentions, so much so that original authors had to warn about the obvious danger in a subsequent paper where they found that: “The inhibitory effects of old blood are more pronounced than the benefits of young, and that peripheral tissue injury compounds the negative effects.”

Physical dangers aside, the fact that people were willing to write, fund, and even pay for a clinically unproven method thatʼs explicitly opposed by the FDA shows our blindness to the fundamental premise in biological aging research. Beyond the biological side effects of rushing pre-clinical research into treatment, the societal imbalance may exacerbate. The argument for living till 150 is obvious. And the argument for lifespan extension being used by the rich is also obvious: they can afford it and the poor can’t. This reminds me of the story of the French queen Marie Antoinette, who in 1789 was faced with an angry crowd. When she asked what was going on, she was told that these people were starving because there was no bread. She replied, amazed, “Well, why don’t they eat cake then?” With regard to lifespan extension, we are not dealing with treatments yet. Related, however, is the desirability of research and development, and, as a result, of financial investments that will not slow down inequalities in life expectancy, or, even worse, may increase them. As a society, we need to consider the moral implications of a world where the lifespans of the rich and poor are dramatically different.

The problem is made more vexing by not just inequalities, but the human inability to dance around with a whole lot of second or third-degree consequences in their mind. The unknown unknowns. There’s a difference between a catastrophe and individual tragedies: a catastrophe affects everyone, admittedly with different intensities, but everyone. Neither money nor power protects you against Covid before a vaccine. For a lack of better words, we simply have no idea what could happen if we add 100 years to our existing life span. Some have speculated a population implosion due to less reproduction, others have argued a potential shift in deleterious mutations in the distant future generations from later to earlier stages of life. Similarly, it is at least theoretically possible that other interventions could increase lifespan without increasing health span to a proportional or greater extent, which is something we clearly do not want.

The goal of investing in aging research and new technology should be, therefore, compression of morbidity. We should prioritize increasing healthy years of life in our lifespan over simply living longer. The current human maximum lifespan is 122 years. It’s a long time. Investing blindly to extend lifespan over 122, in principle, is meaningful, but we should put our dollars into getting more of us to 122 first. Scientifically, this means identifying and repairing the known forms of cell and tissue damage that arise as a result of normal aging. Focusing on health span is simply a better strategy. The best analogy I believe is rust in a complex metal structure; rust is very simple, but the progression of decay as the structure falls apart will be much more complicated. Aging has simple causes, it is exactly an accumulation of damage, but it appears complex in its progression because cellular biology and its reactions to damage are complex. Without understanding how to make us healthier in the process of rusting, it would be incredibly difficult to eliminate rust, or aging, to begin with.

This approach not only makes sense in the scope of scientific agenda but also for the economic agenda. No single treatment alone can make us live longer. It has to be a coordinated effort of the entire health care system. I’m grateful for the opportunity for the past two years to work on expanding the highest-ranked private elderly care and rehab hospital in China. And the reason for its success, a 95.6% percent rate to regain independent living ability for rehab patients, is our focus on health, not cure. Living healthier and longer. Living with dignity. Living without placing undue burdens on the eldercare infrastructure. The current life expectancy gap between America’s richest 1 percent and its poorest 1 percent is over 14 years, but with the goal of extending healthy years of life, aging research can become an equalizer, not a divider.

Thankfully, the research communities have made strides to both increase healthspan and reduce the risk of suffering age-related conditions in later life. There is much more to living a longer life in good shape than simply looking after your health here and now.  One of the key scientific advancements is understanding the role of insulin in aging. In the late 20th century, scientists began to understand that aging is a regulated process. Factors from the environment and the gene both influence how long we live. Almost 30 years ago, by sequencing and comparing genes between worms, a group of scientists led by Cynthia Kenyon found that the loss of the daf-2 gene, a gene responsible for encoding insulin receptors, made some worms live twice as long. How it works is like a mini dominoes game. The mutation of the insulin pathway triggers a cascade of signaling events that ultimately inhibit the functions of protein families (such as FoxO) that regulate aging. Dwarf mice, for example, often have growth hormone deficiency that reduces insulin and makes it live longer. Significantly, this mutation turned out not to be an idiosyncrasy in the tiny worms; it was found in flies, mice, and even human centenarians.

It’s worth mentioning that many drugs on the market today have unexpected positive effects on aging with regard to Insulin. Metformin, for example, contains molecules that act as an insulin sensitizer and exerts its metabolic action on the liver. Worms treated with metformin have shown improved health span. Future approaches with different protocols and experimental designs will be crucial to understanding how insulin works at a molecular level and how it affects throughout phylogeny, especially in humans.

Another important way to study longevity is to study what accelerates aging in the first place and to see if removing those bad actors works. One of agingʼs known characteristics is chronic inflammation. As we start to understand that the key driver of age-dependent inflammation probably lies at the cellular and molecular levels, cellular senescent is singled out. Those are cells that won’t quit signaling to the immune system even when they stop dividing. Now, scientists had ignored senescent cells for decades, dismissing them as waste products trapped in a long- term state of cell cycle arrest with little significance inside living organisms. But in recent years, researchers have established senescence as an important physiological process that appears to play seemingly opposing roles in vivo. On the one hand, senescent cells are thought to mediate tissue development and promote wound repair in later life. Yet as these zombie cells accumulate with age, they can ooze inflammatory proteins believed to cause tissue dysfunction and to push neighboring cells into senescence.

In 2008, it was found that the naked mole-rat, the longest living rodent, shows little to none senescence over the majority of their long lifespan. And in 2011, a group of Mayo scientists found that mice get healthier in old age (in the form of delayed tissue dysfunction) when they clear out some senescent cells. Other useful strategies for inflammation-related targets include ROS and cellular debris and even the ‘Mediterranean dietʼ (with more omega3 fatty acids). Future research must elucidate pathways on which cellular senescence acts to identify actionable targets that may be used for the treatment and prevention of aging. Aging research is at an inflection point. While I discussed just two areas in aging research, we are getting closer to mapping out mechanisms that underlie the aging process at all levels, from the molecular to the organismal. Ranging from protein and caloric restriction, parabiosis, to multi-tissue stem cell, metabolism, and reproductive system, I’m excited for the possibility for therapeutic interventions leading to increased control of age- associated disease and ultimately to healthier aging.

You are the youngest you’ll ever be, you are the oldest of you’ve ever been. As I reflect on the relationship between time and experience, slowing down aging feels like magic. While respecting the principle of physicians primum non nocere, and by understanding the mechanisms of normal aging and the development of interventions to delay aging’s onset and progression, I believe we are on track to extend the healthy years of life for everyone.



















































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