Aging Biotech: Moving Beyond the Hallmarks

The goal of scientists researching the biology of aging is often misunderstood to be extending lifespan at all costs, even if that means living longer in a decrepit and frail state. The reality is that no one, especially those of us studying aging, desires this. Who would want to live like that? The goal of aging research is exactly the same as that of modern medicine: keep us as healthy as possible for as long as possible. The key difference is the means by which this is achieved. Modern medicine is almost entirely reactive: diseases are tackled only once symptoms arise, often after the disease has progressed so much that reversing it is difficult or impossible. Frequently, symptoms aren’t even evident: think of all the cancers, clogged arteries, and dying neurons that progress over years and decades without detection at all. I don’t know about you, but I would rather not get these diseases in the first place! Can’t something be done to prevent them? To prevent the progressive decline of every single part of our bodies? To avoid the need for chemotherapy, triple bypass surgery, and weekly dialysis?

This is precisely why aging researchers study aging. We recognize that there are underlying biological mechanisms at play that progressively change our biochemistry — how our cells, tissues, and organs function and interact with each other. These mechanisms are the root of nearly all the diseases we are likely to experience in our lives, those we are likely to suffer from for years and often decades: heart disease, cancer, diabetes, Alzheimer’s. Arguably worse are the often unseen changes — arthritis, incontinence, and the many chronic aches and pains those of us still young cannot possibly appreciate.

If we understood the underlying causes — the underlying biology of aging — shouldn’t it be possible to prevent these maladies from emerging in the first place? Scientists have been trying for decades to unravel it (and individuals have searched for a solution over the millennia), but the biology of aging is extremely complex. Halting or reversing the molecular process of aging is perhaps the most daunting challenge ever attempted. But isn’t that all the more reason to try? We may not need to “cure aging” entirely to elicit profound good. Even incremental progress could have profound implications — literally, every person in the world could benefit. If you’re not old enough to have overtly experienced aging yourself, you certainly know someone who has.

So what progress has been made? What have aging researchers actually accomplished, and what is left to be done? Well, most progress is in model organisms — nonhuman species used for biomedical research — often yeast, worms, fruit flies, and mice. We know much more about how these organisms age than humans do, because unlike with humans, we can study these organisms in controlled settings, with genetic tools, using invasive assays to understand vital, internal organs. Overall, there is far more unknown about aging than is known, although we do have a solid grasp of the major categories of what goes wrong: the hallmarks of aging. This includes things like damage to DNA, the dysfunction of mitochondria that convert nutrients to fuel for our cells, and alterations to communication between cells. But what is not often depicted is the extremely complex web of interactions between these hallmarks, making cause and effect nearly impossible to disentangle. Which hallmarks arise first? In which part of the body? In which cells? If you fix one hallmark, will others improve? Or do you need to fix several simultaneously? Many, but not all, of these processes also occur in humans, or they occur but in different ways. And humans also exhibit more unique aging characteristics not always evident in other species: menopause, Alzheimer’s, and atherosclerosis come to mind, to name a few.

Reassuringly, scientists have actually made substantial progress getting model organisms to live longer, despite this incomplete picture. We’ve made yeast and worms live several-fold longer than normal, and though lifespan is much harder to increase the closer (evolutionarily) you get to humans, dozens of methods (drugs, treatments, genetic models) have extended mouse lifespan anywhere from 5% to 50% (non-genetic methods like drugs are more often less than 10%, if that). Unfortunately, we have no evidence that any of these work to extend lifespan in humans (yet!). The age-old advice of eat well and exercise is about as good as it gets, though the emergence of diabetes drugs like semaglutide (Wegovy/Ozempic) — with expanded applications for weight loss and heart disease — could have profound societal implications for healthspan (the concept of increasing the healthy years of life — often, but not always, this goes hand in hand with increased lifespan). And many researchers would argue that we should immediately start clinical trials based on a particular set of results seen across all of the model organisms listed above: the extension of both lifespan and healthspan by dampening a molecular signaling cascade known as the nutrient-sensing pathway.

The nutrient-sensing pathway is an example of a conserved pathway. That is, it is so fundamental to cellular functioning that it is found across nearly all eukaryotes (animals, plants, fungi). Though there are specific differences resulting from evolution, yeast, and the cells of worms, flies, mice, and humans all use this pathway to detect the presence of nutrients and respond appropriately. When nutrients are abundant, cells grow and divide. When scarce, cells go into protection mode, recycling their own components to provide the energy needed to survive until nutrients are present again. This recycling, or “self-eating”, is called autophagy, and is especially useful because it promotes the degradation of damaged and dysfunctional cellular components. This recycling is thought to be a core mechanism behind the benefits of caloric restriction and fasting. Dampen that signaling, stress your cells a bit (but not too much: see hormesis), and the end result is so beneficial that your body remains healthier for significantly longer.

Known to increase lifespan for over half a century, nutrient sensing has been perhaps the single largest topic within aging research. As this molecular pathway has been elucidated over the years, more and more therapies and drugs have been developed that attempt to manipulate it at various stages to improve health. In relatively recent history, a drug called rapamycin was shown to increase the lifespan of mice even if not started until old age. This was a monumental breakthrough in aging research because prior to that, it was largely believed that to increase lifespan, one must intervene in the aging process early. Since this time, rapamycin has grown to become the single most robust method of increasing longevity across organisms, with some members of the research community arguing it should be put into large-scale clinical trials right away (it is already FDA-approved at high doses as an immunosuppressant and cancer treatment). In this vein, academic labs and companies like Aeovian Pharmaceuticals, Beiwe Health, and Tornado Therapeutics, continue to work on rapamycin, rapalogs (variants of rapamycin), and other molecules with similar molecular targets. Others, like Trivium Vet and the Dog Aging Project, are taking this treatment to our pets, hoping that it can act as a stepping stone toward applications for humans.

But nutrient sensing is far from the only aging hallmark under investigation. In the last decade, senescent cell elimination has gained traction. A senescent cell is one that has ceased dividing after undergoing damage, typically DNA damage that could make the cell cancerous. This is a good thing, and cellular senescence is critical to preventing cancer (it may also aid wound repair, and it is essential for proper embryogenesis). The problem with senescence arises when senescent cells persist. Instead of being cleared by the immune system, they stick around, spewing pro-inflammatory cytokines and matrix-degrading enzymes into the surrounding tissue. With age, more and more senescent cells accumulate, and early efforts focused on dampening the secretion of these deleterious factors. But, once studies in mice genetically engineered to eliminate these cells showed longer lifespans, the race to develop senolytics — drugs that specifically kill senescent cells but leave healthy cells untouched — was on. One of the earlier players was Unity Biotechnology, which has advanced several candidates to the clinic, but now over a dozen companies are pursuing senescent cell elimination, either using drugs or, like Arda Therapeutics, by taking advantage of the immune system.

The remaining aging hallmarks are similarly under investigation, as the aging biotech space has exploded over the last decade. Now, over 200 companies directly state that they work on aging or longevity, and hundreds more are working on relevant tools, pathways, or indications. The field expanded so quickly from just a handful of companies that several individuals have compiled databases to keep track, including the Longevity Biotech Landscape, the Longevity Industry Database, and AgingBiotech.info. The hallmarks are wonderful for understanding the categories of problems that emerge with age, but they were never meant to comprehensively capture all features of aging, and notably, more and more biotechs are not targeting any hallmark per se. Some are starting from first principles, aiming to uncover new aspects of aging or new interventions that increase lifespan (you would be hard-pressed to find an intervention that increases lifespan without also increasing healthspan, by the way). The newly formed Ora Biomedical plans to screen one million compounds in worms to see which extend lifespan the most, and a similar approach was taken by Longevica in mice a decade ago. EPITERNA is screening approved compounds for lifespan and healthspan effects in yeast, worms, flies, fish, and mice. Gordian Biotechnology has a sophisticated discovery platform that, instead of using cells (or worms, etc.) in a dish for screening, they use cells in a live mouse, using genetic tools to test hundreds of interventions simultaneously in a diseased organ in its natural setting.

Other companies are similarly thinking outside the aging hallmarks box, developing technologies that reverse multiple characteristics of aging simultaneously. One of these approaches is partial reprogramming, a method that turns cells back toward a more stem cell-like state, without actually converting them back to stem cells. The breakthrough methods for reprogramming were published less than 20 years ago, and those results spurred a new era not only for aging research but for all biomedical sciences. Next time, we’ll delve into this revolution and what it means for aging, and then we’ll visit the concept of “replacement” — the idea of removing old cells, tissues, and organs, and replacing them with young ones. Though this sounds like science fiction, the technology has developed more than you may think, and many scientists believe this may be our best chance to really move the needle toward adding a significant number of healthy years to our lives.

Prime Movers Lab invests in breakthrough scientific startups founded by Prime Movers, the inventors who transform billions of lives. We invest in companies reinventing energy, transportation, infrastructure, manufacturing, human augmentation, and agriculture.

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