Age is just a number: the ‘epigenetic clock’ of immune cells ticks independently of the lifespan of the organism

While most cell types experience functional decline after years of proliferation and replication, T cells can proliferate seemingly indefinitely and without damage.

Scientists from St. Jude Children’s Research Hospital and the University of Minnesota examined the unique “epigenetic clock” of T-cell aging, showing that T cells can survive an organism for at least four lifetimes. Furthermore, the researchers showed that healthy T cell age was independent of the chronological age of the organism.

Furthermore, they found that malignant T cells from pediatric patients with T-cell acute lymphocytic leukemia (T-ALL) appeared to be up to 200 years old. The findings were published in Nature aging.

As researchers investigate the process of cellular aging through repeated replicative growth cycles, some peculiar patterns have emerged involving T cells.

“The immune system must naturally mount a rapid proliferative response to a pathogen or tumor,” says co-corresponding author Ben Youngblood, Ph.D., St. Jude Department of Immunology. “And in some environments, such as with endemic pathogens or chronic viral infections, this happens over and over again. That’s a lot of proliferation that these T cells undergo over the lifespan of a human.”

This raised the question of why, despite this accelerated proliferation, this immune response does not trigger the development of cancer.

The answer lies in a T cell’s unique ability to defy aging.

Epigenetic markers provide more accurate measures of age

To study this phenomenon, the researchers used specific biomarkers, known as epigenetic markers, that accumulate over time. Like counting the rings on a tree stump in a forest, this ‘epigenetic clock’ tells a retrospective story about the life cycle of a cell, independent of the organism itself. The accumulation of genetic mutations, shortening of telomeres (the protective caps on chromosomes) and methylation patterns are currently seen as the most accurate ways to interrogate the aging process.

The researchers saw this as an ideal way to investigate the curious case of T cell aging. “We started asking questions about what the hallmarks of aging are, specifically the epigenetic marks, and how these might be applied to long-lived T cells,” he said. “One of the big questions we had was whether these epigenetic clocks are tied to the lifespan of the organism or not.”

Model shows that T cells can survive their original organism

Through a collaboration with co-corresponding author David Masopust, Ph.D., University of Minnesota, the researchers found the perfect model to answer their questions. This model used the same line of T cells across different life cycles of mice.

“Dr. Masopust started this model thinking that the cells would eventually decline, but that didn’t happen, they just kept going,” Youngblood explains. “This led to his fundamental 10-year mouse study that we then used to determine whether organisms’ lifespan limits limit epigenetic clocks.”

Using this model and an epigenetic clock they developed for T cells, the researchers examined the DNA methylation patterns of T cell lineages. They discovered that age is just a number and that death is not the end.

“People don’t live forever. But in this case we could test that concept on T cells,” Youngblood said. “Is there an end to an epigenetic clock? Is there a plateau? And it didn’t happen for four lifetimes, it just kept counting, which was incredible. These cells are not bound by the reasonable limits of an organism’s lifespan.”

Cancerous T cells appear hundreds of years old

The researchers then determined what happened under conditions of rapid and prolonged proliferation, such as in cancer. The team interrogated the T cells of patients with pediatric T-ALL to investigate what happens to their epigenetic clock.

“If epigenetic clocks were linked to the chronological age of the host, you would expect the T cells of pediatric T-ALL patients to appear young,” says co-corresponding author Caitlin Zebley, MD, Ph.D. , St Jude. Department of Bone Marrow Transplantation and Cellular Therapy. “But our clock predicted that these cells were very old.”

From an experience perspective, the T cells of T-ALL patients appeared to be between 100 and 200 years old. “We think this was related to the fact that they spread so quickly,” Zebley concluded. The T-ALL model provided invaluable insight into the aging process of leukemia cells.

“We were able to use this as a subtraction model from all other programs in the leukemia field to identify programs that are associated with normal aging and proliferation, versus programs that are distinct from leukemia,” Youngblood said. “We’ve gotten a better idea of ​​which epigenetic programs are associated with leukemia and which are just normal hyperproliferation and aging.”

Survival of T cells is essential for our survival

Given how active our immune system is, T cell survival is essential to our overall survival. “T cells have so much potential to become cancer,” Youngblood said, “but they can’t, or humanity wouldn’t exist.”

Youngblood, Zebley and Masopust continue to study the checks and balances that prevent T cells from undergoing malignant transformation. This work will allow consideration of potential therapies that halt or even reverse age-related disability.