The “epigenetic clock” of immune cells ticks independently of the life span of the organism

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

Scientists from the Children’s Research Hospital St. Jude and the University of Minnesota explored the unique “epigenetic clock” of T cell aging and demonstrated that T cells can outlive the organism for at least four lifetimes. In addition, the researchers showed that the healthy age of T cells was separated from the chronological age of the organism.

They also found that malignant T cells from pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL) appeared to be up to 200 years old. The findings were published in The aging of nature.

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

“The immune system naturally has to initiate a rapid proliferative response to a pathogen or tumor,” said co-correspondent Ben Youngblood, Ph.D., St. Jude Department of Immunology. “And in some environments, such as endemic pathogens or chronic viral infections, this happens over and over again. That’s a lot of proliferation that these T cells undergo during a person’s lifetime.”

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

The answer lies in the unique ability of T cells to resist aging.

Epigenetic markers offer more accurate metrics for age

To study this phenomenon, the researchers used specific biomarkers known as epigenetic markers, which accumulate over time. Like counting the rings on a tree stump in a forest, these “epigenetic clocks” tell a retrospective story about the life cycle of a cell independent of the organism itself. Accumulation of genetic mutations, shortening of telomeres (protective caps on chromosomes) and methylation patterns are currently considered the most accurate ways to investigate the aging process.

The researchers saw this as an ideal way to investigate the curious case of T cell aging. “We started to ask what are the hallmarks of aging, specifically epigenetic marks, and how can they 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.”

The model shows that T cells can survive their original organism

Working with co-correspondent David Masopust, Ph.D., University of Minnesota, the researchers found the perfect model to address their questions. This model used the same T cell lineage over several mouse life cycles.

“Dr. Masopust started this model with the assumption that the cells would eventually fall off, but they didn’t, they just kept going,” explains Youngblood. “This led to his seminal 10-year study in mice, which we then used to address whether epigenetic clocks limit the lifespan of organisms.”

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

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

Cancer T cells appear hundreds of years old

Next, the researchers determined what happened under conditions of rapid and long-term proliferation, such as cancer. The team examined T cells from patients with pediatric T-ALL to investigate what happens to their epigenetic clock.

“If the epigenetic clock was linked to the chronological age of the host, then you would expect T cells from pediatric patients with T-ALL to appear young,” said co-correspondent Caitlin Zebley, MD, Ph.D., St. Jude. Department of Bone Marrow Transplantation and Cell Therapy. “But our clock predicted that these cells are very old.

From experience, T cells from T-ALL patients appeared to be 100 to 200 years old. “We think it had to do with the fact that they were multiplying so quickly,” Zebley concluded. The T-ALL model offered invaluable insight into the aging process of leukemic cells.

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

The survival of T cells is vital to our survival

Because of how active our immune system is, the survival of T cells is vital to our overall survival. “T cells have so many opportunities to become cancerous,” 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 malignant transformation. Through this work, one can begin to think about potential therapies to stop or even reverse age-related disabilities.