April 15, 2025 | The “bioenergetic capacity” of individuals, as marked by the level of certain cognition-associated molecules in the blood, could potentially be predictive of the risk of developing Alzheimer’s and other age-related diseases. A simulated clinical trial suggests that turning back the wheels on that biological clock could be just as effective at slowing cognitive decline as the latest drug to be approved for that purpose by the U.S. Food and Drug Administration (FDA), reports Jan Krumsiek, Ph.D., associate professor of physiology and biophysics at Weill Cornell Medicine.
The association between how efficiently cells generate energy and cognitive decline is a new addition to the evidence base (Nature Communications, DOI: 10.1038/s41467-025-57032-0). As with other biological clocks, being molecularly older than the time elapsed since birth means “something’s awry,” Krumsiek says.
Importantly, he adds, bioenergetic age could be readily measured using an old technology: dried blood spot testing. The test is currently used for newborn screening for various rare but serious conditions affecting a baby's health or survival and involves applying a few drops of blood taken from the heel to a special filter paper card.
The same sort of assay could be performed in adults to collect a set of acylcarnitines, couriers of fatty acids across the mitochondrial membrane that allow them to be used for energy, says Krumsiek. In the latest study, he and his colleagues showed that higher bioenergetic age is linked to acylcarnitine levels in the blood, worsened Alzheimer’s pathology, cognitive decline, and brain atrophy.
Moreover, Alzheimer’s patients who were declining more slowly had lower concentrations of acylcarnitines in their blood to begin with—and the protective effect was on par with those taking FDA-approved lecanemab over an 18-month observation period. Acylcarnitines are a class of 10 to 15 metabolites and “for some of them higher is worse and for some of them lower is worse... but we have worked out which way is which,” he explains.
The classical genetic risks for Alzheimer’s disease, mostly dominated by the APOE4 allele, did not influence the bioenergetic signals detected in the blood, says Krumsiek. However, researchers did call out a genotype in a subgroup of people where “beneficial genetics” conferred a lower biological age based on small enzymic changes of the mitochondria.
The health effects of differing biological and chronological ages have been well established with an assortment of biological (most popularly, epigenetic) clocks; only the set of measurements here is new, says Krumsiek. For wellness purposes, they’re being used to assess overall health as well as offer specific information about organs such as the liver, gut, and lungs.
Certain diseases, as well as lifestyles, are known to influence biological measures of health. It is likely, though yet to be proven, that this will also apply to bioenergetic mechanisms. Mitochondria are at the center of exercise and dietary (e.g., ketogenic) interventions as well as metformin used to lower blood sugar levels, Krumsiek says.
Acylcarnitine is the transport form of carnitine that tags fat for burning by mitochondria, says Krumsiek. Although mitochondria exist in the cytoplasm of cells, acylcarnitines found in the bloodstream reflect the concentrations inside of the mitochondria for reasons that are not fully understood.
That’s why newborns can be tested for enzymatic inborn errors based on concentrations of the same metabolites, he points out. “Nature did us the favor of showing us what is going into the energy factories of cells through the blood.”
Some of the defects in mitochondrial metabolism that can appear later in life are the same ones implicated in genetic disorders in newborns, he notes. “If they change [early on] it is usually very dramatic, but we might see a mild version [of those defects] in aging people,” perhaps because the cell “loses its wiring as we age.” Mechanistic research on mitochondria is needed to test that hypothesis.
Aging joins other risk factors (e.g., hypertension, high cholesterol, and obesity) that cross diseases such as diabetes, stroke, and Alzheimer’s. “Being in a healthy state and thereby maybe slowing down your aging will help with all these risks,” continues Krumsiek. “It is all intertwined... making it very likely that our [bioenergetic] clock would also be predicting [multiple] diseases.”
Alzheimer’s is a particularly devastating experience for both patients and their family members, Krumsiek says, due both to the inevitable cognitive decline and the fact that it is a long-haul disease. It is thought to start years, if not decades, before the “infamous symptoms” become apparent.
By the time people start forgetting words and names, they could already be two decades into the disease, says Krumsiek. This makes Alzheimer’s incredibly hard to research, which may help to explain the paucity of medications for treating it. Some of the prominent FDA approvals in the recent past have triggered debate about whether they are even going after the right target.
Early detection is considered the holy grail since it would allow for potential interventions and improved management of the disease to “significantly stretch out” patients’ quality of life, he says. “Our proposal is if you twist your biological age, you don’t just live with, but you do something... to get into a better state with a better future.” The required first step is to “see that the disease is happening.”
The intention is to see measures of bioenergetic capacity used to motivate healthy lifestyle changes. A potential complication is that most of what is helpful—e.g., exercise and eating more whole grains and greens—is “surprisingly boring” and inciting those behaviors could be challenging for healthcare providers based purely on a new warning sign of problems, says Krumsiek. But specific interventions could emerge to reprogram one’s bioenergetics rather than try to hammer home the same old advice.
Immediate next steps for Krumsiek and his team may include rolling out the bioenergetic age test in a “non-perfect research cohort” inside a doctor’s office or in a home setting, he adds. Assuming this is feasible, they would next attempt to influence the bioenergetic capacity of people, possibly with some sort of dietary intervention.
But “right now and right here,” it is possible to read the molecular clues of one’s health trajectory, says Krumsiek. “Biological age is not the age your driver’s license says, [and] it is not just one number. It affects different systems and one of them is how your body generates energy... [which is] very closely related to Alzheimer’s disease.”