The biology of aging

By 2034, for the first time in U.S. history, people over the age of 65 will outnumber those under age 18, posing an unprecedented challenge to the American health care system. Understanding the role of aging in disease and infirmity is an urgent priority for mitigating the impact of this major demographic shift.

While growing older can benefit both individuals and society, aging itself is the biggest risk factor for nearly every chronic disease, including heart disease, cancer, Alzheimer’s disease, and chronic kidney disease. All these conditions can significantly lower one’s quality of life—but learning how to prevent each of them separately is like playing a frustrating game of whack-a-mole. “If you cured cancer tomorrow, the average life expectancy would probably go up only by a couple of years,” says Albert Higgins-Chen, MD, PhD, assistant professor of psychiatry.

The gain in life expectancy is limited because even if clinicians successfully prevent cancer in a given individual, slow deterioration across organ systems will continue if left unaddressed, so that patient is likely to end up battling a different chronic disease. “If you’re trying to put out an increasing number of forest fires one by one as they pop up, you’re fighting a losing battle if you aren’t addressing the climate change that’s driving the increased fires,” says Higgins-Chen.

Now, the burgeoning field of geroscience is exploring the processes underlying aging itself with the goal of simultaneously preventing many chronic diseases before their onset. New technologies enable scientists to better assess a person’s risk of developing disease and identify appropriate interventions for future clinical trials. Researchers are learning more about how such devastating chronic diseases as cancer develop, as well as how natural physiological processes like pregnancy affect the way in which someone ages. The new field’s ultimate goal is not only to help ensure that people live longer, but also to maintain their health and vitality in their final decades.

“If we maintain the same rate of age-specific disability that we have now, we will be facing a tsunami of health care needs that we will not be able to meet,” says Luigi Ferrucci, MD, PhD, scientific director of the NIH’s National Institute on Aging and Yale School of Medicine’s first visiting director of geroscience. “[Studying aging] is not only important, but the only hope we have.”

We’re all familiar with the concept of chronological age—our age in years (and months) from the date of our birth. Biological age, on the other hand, refers to where our cells are in the aging process; in some individuals the pace can be faster or slower than chronological aging. Over time, our cells, tissues, and organs can accumulate molecular damage that may accelerate biological age relative to chronological age. In contrast, other people may experience lower levels of molecular damage compared to those of their peers, thus slowing biological aging. This distinction explains why there may be considerable variation in how “old” different men and women look across a group of 60-year-olds, for example.

We know that lifestyle choices affect biological aging. When a person smokes, they inhale carcinogens that directly damage lung cell DNA. Smoking also triggers immune system reactions that alter the composition of immune cells. Both of these processes drive up a person’s biological age.

Some evidence suggests that exercise, on the other hand, might help slow down a person’s biological aging processes. Research shows that individuals who engage in endurance training, for example, have a risk of dying that is three to five times lower than those of the same age who do not. Other research suggests that people who exercise regularly have epigenetic signatures associated with lower levels of biological aging; however, the epigenetic effects of exercise on aging are still poorly understood, and more longitudinal studies—in which researchers follow subjects for a number of years—are needed.

Researchers are investigating the drivers of biological age to uncover novel aging biomarkers, or biological signals of processes, in humans. This research involves utilizing blood samples from large cohorts, often numbering in the thousands, of patients spanning a range of ages. Then, a range of “omics”-based technologies enable the scientists to characterize and quantify the presence of various biological molecules. These fields of study include epigenomics, which measures such modifications of DNA as methylation—a chemical change in which structures called methyl groups attach to or detach from DNA and turn genes on or off. Other -omics include proteomics (the measurement of proteins expressed by an organism’s genome) and transcriptomics (the study of the sum of an organism’s RNA transcripts).

Researchers follow the health trajectories of their patients after the initial blood draw. Follow-up includes tracking which of the patients died, their cause of death, the diseases they developed, and any declines in physical or cognitive functioning. The researchers can then train artificial intelligence to build models based on different biomarkers that predict lifespan or risk of disease/decline in function. An epigenetic clock, for example, uses algorithms based on DNA methylation to measure an individual’s biological age.

In Higgins-Chen’s lab, his team is continuing the work initiated by his former mentor, Morgan Levine, PhD, assistant professor adjunct in pathology, to take it a step further by studying the biological aging process across multiple physiological systems. “Instead of trying to train a general predictor of all-cause mortality, we’re trying to capture signals from, for example, cardiovascular aging, brain aging, or kidney aging, so we can develop a metric for each of those,” he says. A model based on blood biomarkers, for example, could estimate the time it takes to develop leukemia, while separate models based on biomarkers from other physiological systems might predict time to heart disease or cognitive decline. “We’re trying to develop a much richer tapestry of the biological aging process.”

Furthermore, Higgins-Chen’s team is studying how various interventions influence these biomarkers. In one ongoing study, the researchers are compiling a large number of DNA methylation datasets to see how various treatments like rapamycin (an immunosuppressive drug) or metformin (an antidiabetic medication), as well as such lifestyle factors as diet and exercise may mitigate the aging process. They are also studying how such factors as stress, chemotherapy, or radiation accelerate the aging process by comparing biomarkers before and after these events.

Intriguingly, the researchers have found that smoking cessation lowers heart and lung age; gastric bypass for weight loss lowers metabolic age; and metformin reduces inflammation as well as lowering metabolic and kidney age. But the team saw almost no effects in more general biomarkers that do not involve physiology, suggesting system-specific biomarkers of aging may be critical for detecting these effects.

These studies set the stage for future clinical trials on aging, in which researchers will compare the differences in the development of age-related conditions over a period of years among patients on a particular intervention and those given a placebo. Having measurable biomarkers that assess the rate of aging will be essential to understanding whether these interventions are effective. “A lot of prep work needs to be done to even identify what the most appropriate aging biomarkers are for different interventions before someone can actually go do the real test in humans,” says Higgins-Chen.

Researchers are also examining how biological aging contributes to the onset of such chronic diseases as cancer. In 2022, a team led by Jeffrey Townsend, PhD, Elihu Professor of Biostatistics and professor of ecology and evolutionary biology, published the first study to examine tumor genomes across a large cohort of patients to learn which mutational processes contributed directly to cancer development. His team studied the extent to which the cancer was driven by mutations associated with aging, compared to mutations related to exposure to carcinogens like tobacco or ultraviolet light.

The study revealed that the role aging plays in cancer development compared to exposure to mutagens varies according to the type of cancer. Lung cancer, for example, was more likely to be caused by such exposures as smoking or viral infection. Glioblastoma, on the other hand, is driven almost entirely by mutations related to aging. “This wasn’t surprising in a sense, because glioblastomas most of the time occur in people of advanced age, whereas lung cancer can occur at younger ages,” says Townsend. “So it makes sense that it takes a certain amount of aging mutations to lead to cancers like glioblastoma.”

Over the past several decades, the rates of early-onset cancers, in which the disease appears in people under the age of 50, have been on the rise worldwide. Younger adults are facing an increased risk of cancer, including breast, lung, prostate, endometrial, colorectal, and cervical cancers. Townsend hopes to apply the method he has developed to future studies—to examine early-onset tumors and better understand what types of mutations are driving this disturbing trend.

Drivers of biological age, including DNA methylation, can also be accelerated by psychosocial stressors. Could a natural physiological stressor like pregnancy also affect biological aging? researchers wondered.

A team led by Kieran O’Donnell, PhD, assistant professor in the Child Study Center and the Department of Obstetrics, Gynecology, and Reproductive Sciences at Yale School of Medicine, in collaboration with researchers at the University of California, Irvine, examined DNA methylation in blood samples collected from women during early, mid-, and late pregnancy, as well as at three months postpartum. “Going into the study, my hypothesis was that pregnancy would be associated with a sustained increase in biological aging,” O’Donnell says.

To his surprise, this was not the case. The study, published in March in Cell Metabolism, found that pregnancy initially increased the biological age of women by about two years. But from late pregnancy to the postpartum period, biological age then markedly decreased by about two to six years, depending on which epigenetic modulations the scientists measured.

Changes in biological age were not uniform across the cohort, however—some women experienced more accelerated aging than others. Intrigued, the researchers next tried to determine the maternal characteristics associated with these patterns. They discovered that higher body mass index (BMI), for example, was linked to higher biological age estimates during the postpartum period. Breastfeeding, on the other hand, seemed to promote a reduction in biological age after birth.

The United States has “shockingly high” rates of maternal morbidity and mortality, says O’Donnell. Studying these variations in biological aging may help researchers understand which women are at greatest risk of adverse outcomes during and after pregnancy. “These measures of biological aging could be a suite of tools with relevance for predicting both short- and long-term maternal outcomes.” Women who experience pregnancy-related complications, for instance, are at a higher risk of developing cardiovascular disease in later life. O’Donnell has recently received funding from the Burroughs Wellcome Fund to investigate biological aging in pregnant women and its long-term impact on maternal cardiovascular health.

Right now, you can’t visit your doctor’s office and ask for a pill to treat aging. But new therapeutics may be on the horizon. Metformin, for example, is a drug that lowers glucose in people with type 2 diabetes. Emerging preliminary research suggests that the medication may also slow aging and extend lifespans. Ongoing clinical trials including the Albert Einstein College of Medicine-led MILES (Metformin in Longevity Study) and the American Federation for Aging Research’s TAME (Targeting Aging with Metformin) are investigating its antiaging effects in humans.

In the laboratory of Gerald Shulman, MD, PhD, George R. Cowgill Professor of Medicine (Endocrinology) and professor of cellular and molecular physiology, his team is striving to understand the molecular basis of insulin resistance. This work may also have implications for improved treatment of many diseases associated with aging, Shulman says. As we age, we become more prone to developing insulin resistance. “Insulin resistance is a major factor in the pathogenesis of type 2 diabetes, but it’s also a major factor in almost everything cardiometabolic,” says Shulman. “

It drives heart disease, fatty liver disease, obesity-associated cancers, and even Alzheimer’s disease.”

Shulman’s team discovered in 2004 that insulin resistance associated with aging was linked to reduced mitochondrial activity. When our mitochondria slow down, lipids begin to accumulate in our muscle cells, which in turn triggers insulin resistance resulting in the development of type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD), and age-related cardiometabolic diseases. “So our lab is focused on ways of revving up the mitochondria to metabolize the intracellular fat,” Shulman says.

To achieve this, the researchers are developing drugs that promote a process known as mitochondrial uncoupling—which make the mitochondria less efficient so that they have to metabolize more fat to generate the same amount of adenosine triphosphate (ATP), a nucleotide that carries and transfers chemical energy in cells. Mitochondrial uncoupling allows calories to flow out of a leaky mitochondrial membrane as heat rather than turn into ATP or be stored as fat, thus increasing the overall amount of calories burned. OrsoBio, a biotechnology company that Shulman helped co-found, has recently demonstrated the safety and efficacy of a novel liver-targeting mitochondrial uncoupling agent called TLC-6740 in Phase 1B clinical studies to safely promote whole-body energy expenditure in humans.

Many studies of therapeutics for aging are still in their early phases. Future aging research will focus on clinical trials in humans that test the efficacy of antiaging therapeutics—either repurposed drugs or novel compounds, says Higgins-Chen. While doctors may not be writing many antiaging prescriptions any time soon, the next decades will see the introduction of novel treatments that will help adults enjoy better health in their old age. “Progress is going to start off slowly, and then it’s going to accelerate,” he says. “We might not find very much in the next 10 years. But for the next 50 years, I have very, very high hopes.”