In my grandparents’ yard, a teetering grapefruit tree spreads its wings. When I visited them in China this past December, the tree was swollen with fruit. We used a fishing net-like contraption to knock the fruits off the tree—my brother cackling with glee every time he got two in one go. It had been almost six years since the last time I had seen my grandparents, and time had stamped an irreversible mark.
In the house, my grandmother would pare the grapefruits with her rough hands, working a small knife with surprising strength. When she placed a metal bowl full of the fruit in front of me, motioning me to eat, she would rub my back—her touch as comforting as it had been when I was two years old.
Visiting both sets of my grandparents had historically been a time to relax. They took care of us. On this most recent trip, though, I found myself wondering about the number of years I’d have left with them. Our arrival was an inconvenience in the way it disrupted daily routine—a disruption that could lead to fatigue, which could induce blood pressure spikes, which could lead to tachycardia, creating a cascade of conditions where small perturbations could be catastrophic.
With a naïve touch of arrogance, I thought that my three months of medical school would prepare me for these eventualities and help provide answers for what to do during health crises. Instead, I sat in silence and held my grandmother’s wrist in my hand, feeling the steady thumping of a pulse for reassurance.
For so long, I had grasped onto the (obviously) idealistic concept that my grandparents were untouchable. Now, that idealistic concept was a moot point—and I wondered what the future would look like. Would there be a magical cure for age-related diseases? Or more realistically, live-in nannies? Hospice care, maybe? Some sort of senior center?
It all boiled down to one question: What was the best way to preserve my grandparents’ independence, health, and mobility to make the most out of the time they had left?
***
People have funneled epic amounts of money into anti-aging research. Living longer—specifically, living longer without being afflicted by the usual age-related ailments—is an industry peppered with supplements, IV infusions, workout programs, and full body MRI scans. It’s the definition of the term “healthspan,” the number of years a person can live without chronic or disruptive disease. Functionally, “healthspan” is similar to the concept of age reversal, where systems in the body can be “de-aged” to reflect that of a younger counterpart.
Scientists are interested in age reversal and lengthening healthspan, perhaps even more so than the idea of simply extending life itself. “We’re mostly working on aging reversal, since longevity takes too long to do in clinical trials,” said George Church, a geneticist at Harvard Medical School. “In my opinion, it’s much easier to monitor improvement in specific diseases or specific organs.”
Quite a bit of previous work in the field has focused on the Yamanaka factors—four transcription factors that can turn differentiated cells (cells that have turned into their final form, like liver cells) into pluripotent stem cells. It’s akin to hitting a factory reset on the cell, turning it back to its youngest, most flexible state. While the logic of overexpressing the Yamanaka factors (or a subset of them) to de-age cells makes sense, the sheer primitiveness of the undifferentiated cell can lead to potential side effects—chiefly cancer growth.
Recently, Church’s lab has been working on a project that looked for genetic factors in the transcriptome (all the RNA that is expressed within a cell) that might trigger the age reversal process—also known as cellular “rejuvenation.” Rather than going all the way back to a stem cell, the team wanted to reverse cellular age by smaller increments—ultimately preserving the cell’s final identity. Led by postdoctoral fellow Alexandru Plesa, the team started by generating a machine learning model that could measure the extent of a cell’s age purely from its gene expression data.
The team tested the model’s accuracy on samples of donor cells and compared its performance on several publicly available datasets. “We validated on published data, because we wanted to make sure that you could not only predict the age of the donor, but also, see if there are things that make cells younger or older, stress them out, or make them function better,” Plesa said.
After choosing a set of top gene candidates, the scientists overexpressed those candidates in different cell lines, looking for any age-modulating effects by way of their machine learning model. They settled on one factor, SRSF1, which when overexpressed in six different aged cell lines, had an average rejuvenation effect of around 26 years.
To test if this would translate to a full organism, rather than individual cells, they used a wound model in young and old mice to see if injection and overexpression of SRSF1 near the wound site would speed up healing. As it turns out, SRSF1 did help—reducing the total time to wound closure in old mice to almost that of young mice, with healing completed in approximately 13 days rather than 15.
Spurred on by these positive findings, the scientists overexpressed SRSF1 in every cell in a mouse’s body, to see if it might help in body-sized processes like muscle regeneration. One of their collaborating labs, run by Harvard stem cell biology professor Amy Wagers, had previously shown that muscle regeneration declined in older mice. Ultimately, though, overexpressing SRSF1 systemically “didn’t lead to any negative side effects, but we didn’t see any positive ones for muscle regeneration,” said Plesa.
While SRSF1 has promise as an age reversal factor, “I don’t think that it’s going to be the thing solving aging,” said Plesa. He and Church anticipate that gene cocktails, with multiple rejuvenation factors, might be the best bet for true age reversal. It’s complicated, though: Genes can interfere with one another, or have multiple effects, or even synergize. Ultimately, the team hopes to see if any of these factors can tackle age-related diseases, or even to revitalize immune system function that is normally lost with age.
“Our motto is to plan for the worst, and hope for the best,” Church quipped.
***
I’m all too aware of hope—whether it’s hope that my experiments work in the laboratory or hope that I can see my grandparents again soon and swing wildly at the grapefruits in their backyard. One of the most gloriously bittersweet parts of studying medicine is that the more I study, the more I realize I have to learn. Who am I learning for if not for them, and for my future patients?
While fancy gene cocktails to reverse aging are being cooked up in the laboratory, I have learned that the reality of aging in the current day is far quieter—as seen with my grandparents. Reaching the point where the end of life is anticipated means the death of certain future possibilities. For Corey Tapper, a palliative care physician at Johns Hopkins University, reaching that endpoint often requires an honest conversation. “We need to deliver that conversation in a compassionate and honest way,” he said. “It’s heavy, and at the same time very rewarding, when patients can simplify what is really most important to them if they are ever in a scenario when time is short.”
Palliative care is a specialty that focuses on improving quality of life for patients—whether or not they are about to pass. When Tapper was in college, his grandfather was diagnosed with lung cancer. The treatment, pushed by the oncologist, only made him sicker, and he passed away six weeks later. Tapper’s family only managed to get hospice care at the very end.
This experience, along with his grandmother’s death a few years later, spurred him to pursue palliative care training. “I want to be there for my patients when they’re at their most vulnerable to help their quality of life and to help them understand what is going on so that we can match their treatments to what’s most important for them,” he said. “If my grandfather had known that the treatment was only going to make him sicker, I don’t think he would have started it.”
I still wonder what my grandparents’ definition of “healthy aging” is—and if some sort of magical rejuvenating factor were available, whether they would take it. My grandfather can still climb up three sets of stairs every day to air-dry the laundry; my grandmother cannot. Conversations about live-in nurses permeate family discussions. On my way to the airport, my uncle turned to me, saying under his breath, “Come back soon. We don’t know how much longer we will have your grandparents around.”
I realized, though, that fixating on what will eventually be lost detracted from the privilege of having most of my grandparents be alive. These days, they enjoy tending to their grapefruit trees and small backyard garden. My grandfather often takes naps in the living room, sinking quietly into the squashy, sunlit couch. My grandmother enjoys late night scrolling on WeChat, and I’ve learned to send her pictures knowing that she will eventually see them. It remains a complex dance to orchestrate a caretaking situation where my grandparents can retain their general independence while also maintaining necessary care and family support. No perfect solution, something that is always evolving.
But at the end of the day, it is their agency that matters most—I think, at least—to live their lives on the terms they set.
