Forever Young

By Alan Dove, Photographs by Jörg Meyer, Illustration by Charlotte De Greling

Anyone over the age of 40 has likely noticed that the human body wasn’t optimized for the long haul. Our vision gets worse, our joints start to ache, and things get harder to remember. And if that’s not enough, our risk for cancer, heart disease, osteoporosis, and many other chronic conditions skyrockets, too.

There’s a simple, but not very reassuring explanation for this: evolution expects us to be dead. “We live much longer than we did 5,000, 50,000, or 500,000 years ago, and in outsmarting nature in that way, we have created another definition of aging, which is what happens when we live longer than we were supposed to live,” says Gerard Karsenty, MD, PhD, the Paul A. Marks, MD, Professor and chair of the Department of Genetics and Development at Columbia.

Addressing this very human problem is the focus of geroscience, which seeks to reveal the causes of our age-related decline and find ways to prolong our healthy lifespans. Columbia has become a major center for this work, with a growing number of VP&S faculty approaching the aging puzzle from diverse angles.

Feeling It in the Bones

Dr. Karsenty has had a longstanding interest in skeletal biology, starting with the observation that changes in bone mass affect such seemingly unrelated body systems as cognition, energy metabolism, and fertility. “A hypothesis that has been a driving engine of the lab is that bone mass, energy metabolism, and reproduction should all be co-regulated, or should have coordinated regulation,” he says. An evolutionary perspective promises clues. “The overarching goal of the work is to define to what extent the appearance of bone changed the physiology of mammalian organisms, and to what extent we can harness this knowledge to propose new treatments for degenerative or age-related diseases,” says Dr. Karsenty, who is also professor of medicine and biomedical engineering.

Indeed, his work has revealed that in addition to its other functions, the skeleton is an endocrine organ with a central role in aging, pumping out hormones that affect other organs. Much of Dr. Karsenty’s recent work has focused on one hormone in particular that co-evolved with bones: osteocalcin, named for its ability to bind calcium ions.

Circulating levels of osteocalcin fall dramatically with age, in lockstep with declines in glucose regulation, muscle function, and male fertility. “Once we made these observations, it was clear that osteocalcin has brought us to aging biology,” says Dr. Karsenty.

He and his colleagues are now looking at other physiological processes that decline with age, along with the clinical manifestations that follow, and asking whether osteocalcin regulates those processes as well. By tracing the signaling pathways to and from osteocalcin, the researchers hope to identify targets for future treatments that can postpone the negative effects of aging, prolonging healthy lifespans.

In addition to his lab work, Dr. Karsenty has been deeply involved in the formation of the Columbia Healthy Aging Initiative, which brings together researchers from across the campus to exchange ideas and build collaborations around aging studies. “There are many, many people working on aging biology at Columbia,” says Dr. Karsenty. “The only problem is that sometimes they don’t know it and/or don’t know each other.” For example, he asserts that scientists studying hematological or neurological diseases are necessarily doing work that intersects with aging. “We need to be unified with a common team and a common goal,” he says.

Linda P. Fried, MD, MPH, dean of Columbia’s Mailman School of Public Health, chairs the Aging Initiative’s steering committee. She and Dr. Karsenty have now been joined by over a dozen other investigators at VP&S, the Robert N. Butler Columbia Aging Center, and the College of Dental Medicine. “We are building on it to forge the community and apply for federal funding as a group so that we are recognized as a medical school deeply involved in the study of aging biology,” says Dr. Karsenty. Besides bringing in new funding streams, the initiative has also organized a graduate course and a seminar series on aging biology, and helped build networks of potential collaborators across the university.

Old School

It’s not the first time Columbia has made a big commitment to aging research, and one of the earlier efforts illustrates how such projects can provide a powerful draw for new talent. Jennifer Manly, PhD, is now a professor of neuropsychology in neurology at the Gertrude H. Sergievsky Center and the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, and a leading figure in Alzheimer’s research. Thirty years ago, though, she was a graduate student looking for someplace to study what she realized was a fundamental blind spot in geroscience.

“Researchers had traditionally recruited people for studies of cognition from memory clinics,” says Dr. Manly. While easier to access, those samples are starkly skewed: overwhelmingly white, and from secure socioeconomic backgrounds that provide them with access to advanced specialty care. “This convenience sampling was getting the opposite of what I wanted to study, which was people in communities of color,” she says. A literature search drew her attention to Columbia’s Washington Heights-Hamilton Heights-Inwood Columbia Aging Project (WHICAP), which has tracked aging in a large cohort of Latinx and African American individuals since the 1980s.

When she came to Columbia as a postdoctoral fellow in 1996, WHICAP had already discovered distinct patterns of aging in these populations. Compared with the memory clinic recruits, Dr. Manly explains, “WHICAP found that African American and Latinx older adults declined more quickly and had a higher risk of dementia over time.” She wanted to know why.

As a neuropsychologist, Dr. Manly investigates how experiences across the life course may affect cognitive aging, Alzheimer’s disease, and other dementias.

“Factors such as schooling and literacy strongly predict the risk of cognitive impairment as people age,” she explains. In the U.S., systemic racism, segregation, and income inequality negatively impacted educational opportunity. Participants in the WHICAP cohort, however, attended schools across the country and around the world. “We had data on early educational opportunity that was very different across race and ethnicity,” she says, “and also really different among people of the same race and ethnicity.” Her work revealed that lower-quality early education was a primary predictor of worse cognitive aging, even within groups. “It’s not genetic,” says Dr. Manly. “It’s not biological.”

In subsequent work, her team has tracked down participants in Project Talent, which administered a battery of achievement and cognitive tests to hundreds of thousands of American high school students in 1960. By retesting these individuals in their old age, Dr. Manly was able to identify specific educational correlates that protect against cognitive decline. “Teacher qualifications and teacher training are a big driver of school quality, and they also predict better cognitive function 58 years later,” says Dr. Manly. “We’re trying to understand the school-age interventions that are the drivers of this relationship.” Her current hypothesis is that better early education leaves people with more cognitive reserve, able to tolerate later neuropathology with more resilience.

Under-Studied Ova Age

Yousin Suh, PhD, director of the Reproductive Aging Program, investigates aging in another chronically under-studied population: women. Besides making up a little more than half of humanity, women also carry a unique model organ for studying aging: the ovary.

“When you talk about aging, you’re usually talking about changes that occur in your sixties and seventies,” says Dr. Suh, who is also the Charles and Marie Robertson Professor of Reproductive Sciences (in obstetrics & gynecology) and professor of genetics & development. The ovaries, however, get a much earlier start on aging than other human organs. “You’re talking about something that hap- pens in your thirties and forties.”

Because ovaries age decades before other organs, Dr. Suh initially wondered whether unique molecular mechanisms drive ovarian aging. “When I first arrived at Columbia to help build the field of reproductive aging, I started with what I do best, namely human genetic and functional genomic studies,” Dr. Suh explains. She and her team obtained autopsy samples from women who had died suddenly and analyzed gene transcription patterns at single-cell resolution in young and older ovaries.

“What’s remarkable is that there’s really nothing special” in ovarian aging, Dr. Suh says. “What’s happening in your liver, in your heart, and in your kidneys during your seventies occurs in the ovary, but much earlier; at the molecular level, it’s a clear example of accelerated aging.”

That dovetailed with an earlier discovery Dr. Suh and others had made, that ovarian aging correlates with overall aging. Women who undergo menopause later are more likely to live longer, healthier lives than those with earlier menopause, and brothers of women with later menopause have a longevity advantage. “In other words, there’s a genetic component of ovarian aging that can be applied not just to women, but to human beings, so we are trying to understand these mechanisms,” says Dr. Suh, who has also studied the genetics of centenarians.

Her body of research points to a regulatory protein called mTOR, which other groups have also identified as a critical controller of aging. Rapamycin, a widely used immunosuppressant drug, targets mTOR activity and has been touted as a potential antiaging treatment. However, it would take decades to verify whether the drug extends healthy lifespans in humans. Dr. Suh and her colleagues realized that ovarian aging could provide a much faster answer.

The Validating Benefits of Rapamycin for Reproductive Aging Treatment (VIBRANT) study, which is now seeking to recruit up to 1,000 women, will look at whether low doses of rapamycin can delay ovarian aging and prolong fertility. It’s the start of what Dr. Suh hopes will be a new approach in geroscience. “Because the ovary undergoes aging so much more rapidly, using the same mechanisms that we see in other organs, we should really use the ovary as a first test system for antiaging drugs.”

Not So Fast

Though well-controlled clinical trials such as VIBRANT are just getting started, tantalizing preclinical results have already spawned a rush to promote and commercialize various interventions. Indeed, the hype has grown so thick around antiaging treatments that it’s become hard to publish data that complicates the story. Emmanuelle Passegué, PhD, Alumni Professor of Genetics and Development and director of the Columbia Stem Cell Initiative, was undeterred.

Dr. Passegué and her colleagues had tested the effects of a battery of different treatments on hematopoetic stem cells in aged mice. These cells give rise to all other blood cells and produce crucial regulators of aging. They found that none of the recently popularized interventions, including calorie restriction, exercise, and transfusion of plasma from younger animals, managed to rejuvenate the blood stem cells. “There is no universal strategy for rejuvenation, and what works in certain cells and organs doesn’t necessarily work in different systems,” says Dr. Passegué, whose findings were eventually published in the Journal of Experimental Medicine in 2021. The paper, she notes, “was a hard sale.”

Nonetheless, the work pointed toward a more nuanced and interesting understanding of how blood ages. “It’s not just the seed, it’s the soil—including changes in the bone marrow microenvironment, which are affecting stem cell activity and circulating factors,” says Dr. Passegué. In recent work, she has found that the marrow niche in aging mice degrades and becomes more pro-inflammatory, which inhibits the blood stem cells’ ability to regenerate. After finding that this inflammatory transition is closely linked to glucose metabolism, Dr. Passegué’s team tried another intervention to rejuvenate aged blood stem cells: 24 hours of fasting followed by 24 hours of refeeding. “We found that fasting by itself doesn’t help,” she says. “What really helps is refeeding, because it resets the metabolism of the stem cells.”

Those results are now converging with another line of work in her lab, looking at emergency myelopoiesis, the process by which bone marrow myeloid cells are produced. While hematopoietic stem cells normally give rise to a balanced assortment of blood cell types, the system can also adapt to boost regeneration of specific cells over others. That adaptation commonly happens during infections and in response to various drugs, but dysregulation of the process can also contribute to the pro-inflammatory bone marrow environment seen in aging. In the summer of 2024, Dr. Passegué received a $7.7 million grant from the National Heart, Lung, and Blood Institute to explore those connections.

Aging affects all tissues in the body and “it is essential that we start understanding all these connections between the stem cells, their differentiated progenies, and their environment in the different organs of the body,” says Dr. Passegué. It is one of the key areas of research for the laboratories of the Columbia Stem Cell Initiative that Dr. Passegué directs that aims at improving the resilience and regeneration of many aging tissues and developing new rejuvenation interventions for healthy aging.

Across the spectrum of aging research, scientists in the field agree that understanding the process is crucial for modern medicine. “Aging is the driver of almost all chronic diseases,” says Dr. Suh. “If we understand the basic biology of aging, we’ll be able to target all chronic diseases simultaneously.”