The study, published in EMBO Molecular Medicine, was led by Dr. Benjamin Hunter and Associate Professor Sean Lal from the School of Medical Sciences. The team examined donated human heart tissue from patients receiving heart transplants in Sydney, comparing it with tissue from healthy donors. Their analysis revealed that diabetes drives specific molecular changes inside heart cells and alters the physical makeup of heart muscle. These effects were most pronounced in patients with ischemia cardiomyopathy, which is the leading cause of heart failure.

“We’ve long seen a correlation between heart disease and type 2 diabetes,” said Dr. Hunter, “but this is the first research to jointly look at diabetes and ischemia heart disease and uncover a unique molecular profile in people with both conditions.

“Our findings show that diabetes alters how the heart produces energy, maintains its structure under stress, and contracts to pump blood. Using advanced microscopy techniques, we were able to see direct changes to the heart muscle as a result of this, in the form of a build-up of fibrous tissue.”

Heart disease remains the leading cause of death in Australia, and more than 1.2 million Australians are living with type 2 diabetes.

Associate Professor Lal said: “Our research links heart disease and diabetes in ways that have never been demonstrated in humans, offering new insights into potential treatment strategies that could one day benefit millions of people in Australia and globally.”

Looking Inside Diseased Human Hearts

To better understand how diabetes affects the heart, the researchers studied heart tissue from both transplant recipients and healthy individuals. This direct examination allowed them to see how diabetes influences heart biology in real human patients rather than relying solely on animal models.

The results showed that diabetes is more than a co-morbidity for heart disease. It actively accelerates heart failure by interfering with essential biological processes and reshaping heart muscle at the microscopic level.

“The metabolic effect of diabetes in the heart is not fully understood in humans,” said Dr. Hunter.

How Diabetes Disrupts the Heart’s Energy Supply

In healthy hearts, energy is mainly generated from fats, with glucose and ketones also contributing. Previous research has shown that glucose use increases during heart failure. However, diabetes interferes with this process by reducing how sensitive heart cells are to insulin.

“Under healthy conditions, the heart primarily uses fats but also glucose and ketones as fuel for energy. It has previously been described that glucose uptake is increased in heart failure, however, diabetes reduces the insulin sensitivity of glucose transporters — proteins that move glucose in and out of cells — in heart muscle cells.

“We observed that diabetes worsens the molecular characteristics of heart failure in patients with advanced heart disease and increases the stress on mitochondria — the powerhouse of the cell which produces energy.”

Structural Damage and Fibrosis in the Heart Muscle

Beyond energy production, the researchers found that diabetes affects the proteins responsible for heart muscle contraction and calcium regulation. In patients with both diabetes and ischemic heart disease, these proteins were produced at lower levels. At the same time, excess fibrous tissue accumulated within the heart, making the muscle stiffer and less able to pump blood efficiently.

“RNA sequencing confirmed that many of these protein changes were also reflected at the gene transcription level, particularly in pathways related to energy metabolism and tissue structure, which reinforces our other observations,” said Dr. Hunter.

“And once we had these clues at the molecular level, we were able to confirm these structural changes using confocal microscopy.”

Implications for Future Treatment and Care

Associate Professor Lal said identifying mitochondrial dysfunction and fibrosis-related pathways opens the door to new treatment approaches.

“Now that we’ve linked diabetes and heart disease at the molecular level and observed how it changes energy production in the heart while also changing its structure, we can begin to explore new treatment avenues,” he said.

“Our findings could also be used to inform diagnosis criteria and disease management strategies across cardiology and endocrinology, improving care for millions of patients.”

Scientists at Cold Spring Harbor Laboratory (CSHL) have now identified a promising way to jump-start intestinal repair. Their strategy relies on CAR T-cell therapy, a powerful form of immunotherapy best known for treating certain cancers. By applying this approach to the gut, the researchers hope to open the door to future clinical trials aimed at improving intestinal health, particularly in people affected by age-related decline.

Targeting Aging Cells That Refuse to Die

This work builds on earlier research led by CSHL Assistant Professor Corina Amor Vegas, whose laboratory studies cellular senescence. As the body ages, it accumulates senescent cells, which no longer divide but also do not die off. These lingering cells have been linked to many age-related conditions, including diabetes and dementia. In earlier studies, Amor Vegas and her team engineered immune cells known as anti-uPAR CAR T cells that selectively remove senescent cells in mice, leading to major improvements in the animals’ metabolism.

The researchers next asked whether removing senescent cells could help restore the intestine’s ability to heal. Amor Vegas partnered with CSHL Assistant Professor Semir Beyaz and graduate student Onur Eskiocak to investigate. They delivered CAR T cells directly to the intestines of both younger and older mice. According to Amor Vegas, the results were striking. “In both cases, we see really significant improvements,” she says. “They’re able to absorb nutrients better. They have much less inflammation. When irritated or injured, their epithelial lining is able to regenerate and heal much faster.”

Protection Against Radiation-Induced Gut Damage

Leaky gut syndrome is particularly common among cancer patients who receive pelvic or abdominal radiation therapy. To model this, the team exposed mice to radiation that damaged their intestinal epithelial cells. Mice treated with CAR T cells recovered far more effectively than those that did not receive the therapy. Notably, a single dose of CAR T-cell treatment continued to support healthier gut function for at least one year.

The researchers also found compelling evidence that anti-uPAR CAR T cells encourage regeneration in human intestinal and colorectal cells, Eskiocak notes. While the precise biological mechanisms behind this effect are still being explored, the findings point to strong therapeutic potential. Beyaz emphasizes the broader significance of the work. “This is one good step toward a long journey in understanding how we can better heal the elderly,” he said.

By analyzing metabolic signals tied to health and diet, the scientists were able to reconstruct details about ancient climates and landscapes, including temperature, soil conditions, rainfall, and vegetation. The results, published in Nature, point to environments that were significantly warmer and wetter than those found in the same regions today.

Studying metabolites — the molecules produced and used in digestion and other chemical processes in the body — can reveal information about disease, nutrition, and environmental exposure. While metabolomics has become a powerful tool in modern medical research, it has rarely been applied to fossils. Instead, most studies of ancient remains rely on DNA, which mainly helps establish genetic relationships rather than day-to-day biology.

“I’ve always had an interest in metabolism, including the metabolic rate of bone, and wanted to know if it would be possible to apply metabolomics to fossils to study early life. It turns out that bone, including fossilized bone, is filled with metabolites,” said Timothy Bromage, professor of molecular pathobiology at NYU College of Dentistry and affiliated professor in NYU’s Department of Anthropology, who led the international research team.

Why Fossil Bones Can Preserve Chemistry

In recent years, scientists discovered that collagen — the protein that provides structure to bones, skin, and connective tissues — can survive in ancient bones, including dinosaur fossils.

“I thought, if collagen is preserved in a fossil bone, then maybe other biomolecules are protected in the bone microenvironment as well,” said Bromage, who directs the Hard Tissue Research Unit at NYU College of Dentistry.

Bone surfaces are porous and filled with tiny blood vessel networks that exchange oxygen and nutrients with the bloodstream. Bromage proposed that during bone growth, metabolites circulating in blood could become trapped inside microscopic spaces within the bone, where they might remain protected for millions of years.

To test this idea, the team used mass spectrometry, a technique that converts molecules into charged particles for identification. Tests on modern mouse bones revealed nearly 2,200 metabolites. The same approach also allowed researchers to detect collagen proteins in some samples.

Testing Fossils From Early Human Landscapes

The researchers then applied this method to fossilized animal bones dating from 1.3 million to 3 million years ago. These samples came from earlier excavations in Tanzania, Malawi, and South Africa, regions known for early human activity.

The fossils belonged to animals with modern relatives still living near those sites today. The team analyzed bones from rodents (mouse, ground squirrel, gerbil) as well as larger animals, including an antelope, a pig, and an elephant. Thousands of metabolites were identified, many of which closely matched those found in living species.

Health Diet and Disease Written in Bone

Many of the detected metabolites reflected normal biological processes, such as the breakdown of amino acids, carbohydrates, vitamins, and minerals. Some chemical markers were linked to estrogen-related genes, indicating that certain fossilized animals were female.

Other molecules revealed signs of illness. In one striking case, a ground squirrel bone from Olduvai Gorge in Tanzania, dated to about 1.8 million years ago, showed evidence of infection by the parasite that causes sleeping sickness in humans. The disease is caused by Trypanosoma brucei and spread by tsetse flies.

“What we discovered in the bone of the squirrel is a metabolite that is unique to the biology of that parasite, which releases the metabolite into the bloodstream of its host. We also saw the squirrel’s metabolomic anti-inflammatory response, presumably due to the parasite,” said Bromage.

Tracing Ancient Diets and Environments

The chemical evidence also revealed what plants the animals consumed. Although plant metabolite databases are far less complete than those for animals, the researchers identified compounds linked to regional plants such as aloe and asparagus.

“What that means is that, in the case of the squirrel, it nibbled on aloe and took those metabolites into its own bloodstream,” explained Bromage. “Because the environmental conditions of aloe are very specific, we now know more about the temperature, rainfall, soil conditions, and tree canopy, essentially reconstructing the squirrel’s environment. We can build a story around each of the animals.”

These reconstructed habitats align with previous geological and ecological research. For example, Olduvai Gorge Bed in Tanzania has been described as freshwater woodland and grassland, while the Upper Bed reflects drier woodlands and marshy areas. Across all studied locations, the fossil evidence consistently points to climates that were wetter and warmer than today.

“Using metabolic analyses to study fossils may enable us to reconstruct the environment of the prehistoric world with a new level of detail, as though we were field ecologists in a natural environment today,” said Bromage.

Research Team and Support

Additional study authors include Bin Hu, Sher Poudel, Sasan Rabieh, and Shoshana Yakar of NYU College of Dentistry; Thomas Neubert, Christopher Lawrence de Jesus, and Hediye Erdjument-Bromage of NYU Grossman School of Medicine; along with collaborators from institutions in France, Germany, Canada, and the United States. The research was supported by The Leakey Foundation, with additional support for the scanning electron microscope provided by the National Institutes of Health (S10 OD023659 and S10 RR027990).