St. Jude researchers have used an epigenetic clock, DNA methylation, and a mouse model to show that T cell proliferation can continue beyond the lifespan of an organism. They have also found that T cells from acute lymphoblastic leukemia appear to be hundreds of years old. This is a significant discovery, as most cell types experience a decline in function after years of proliferation and replication, but T cells seem to be able to proliferate indefinitely.Researchers at St. Jude Children’s Research Hospital and the University of Minnesota have studied the ‘epigenetic clock’ of T-cell aging and found that T cells can live through at least four lifetimes. They also discovered that the age of healthy T cells is not necessarily linked to the age of the organism they belong to. Additionally, the researchers determined that T cells from pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL) could appear to be up to 200 years old. These findings were published in Nature Aging. This research contributes to our understanding of cellular aging.As T cells go through repetitive growth cycles, some interesting patterns have been observed. Ben Youngblood, PhD, co-corresponding author from St. Jude Department of Immunology, explains that the immune system needs to quickly increase in response to an infection or tumor. In some cases, like with chronic viral infections, this rapid growth happens repeatedly. This means that T cells undergo a lot of growth in a person’s lifetime. The question arises as to why this constant proliferation of T cells does not lead to cancer development. The answer can be found in the T cell’s ability to regulate its growth.Article title: Epigenetic markers and the study of aging
Epigenetic markers offer more accurate metrics for age
To investigate this, scientists used specific biomarkers called epigenetic markers that build up over time. Similar to counting the rings on a tree stump in a forest, this ‘epigenetic clock’ provides a retrospective narrative about the life cycle of a cell regardless of the organism itself. The accumulation of genetic mutations, the shortening of telomeres (the protective caps on chromosomes), and methylation patterns are currently considered the most precise methods to examine the aging process.
The r rnrnResearchers saw this as an ideal way to investigate the interesting case of T-cell aging. “We started asking questions about what the hallmarks of aging are, specifically the epigenetic hallmarks, and how these can be applied to long-lived T cells,” he said. “One of the big questions we had was whether these epigenetic clocks are bound by the lifespan of the organism or not.”
Model shows T cells can outlive their origin organism
Through a collaboration with co-corresponding author David Masopust, PhD, University of Minnesota, the researchers found the perfect model to address theirquestions. This model used the same line of T cells through several mouse life cycles. “Dr. Masopust started this model assuming the cells would eventually decline, but they didn’t, they just kept going,” explains Youngblood. “This led to his foundational 10-year mouse study which we subsequently used to address whether organismal lifespan limits constrain epigenetic clocks.”
Using this model and an epigenetic clock they developed for T cells, the researchers explored the DNA methylation patterns of T-cell lineage. They found that age is just a number, and death is not the end. “Humans don’t live forever. But in this case, we could test whether the limits of organismal lifespan constrain epigenetic clocks.”
“We found that concept fascinating for T cells,” Youngblood stated. “Is there a point where the epigenetic clock stops? Does it reach a plateau? And we discovered that for up to four lifetimes, it just kept ticking, which was remarkable. These cells are not restricted by the typical limits of an organism’s lifespan.”
T cells affected by cancer appear to be hundreds of years old
Next, the team investigated what occurs under conditions of rapid and prolonged proliferation, such as in cancer. The researchers examined the T cells of patients with pediatric T-ALL to understand what happens to their epigenetic clock. “If epigenetic clocks were associated with the individual’s chronological age, thThe T cells from pediatric T-ALL patients were expected to appear youthful,” explained co-corresponding author Caitlin Zebley, MD, PhD, from the St. Jude Department of Bone Marrow Transplantation & Cellular Therapy. “However, our analysis indicated that these cells were actually quite old.”
From a practical standpoint, the T cells of T-ALL patients seemed to be aged between 100 and 200 years. “We believe this was due to their rapid proliferation,” Zebley concluded. The T-ALL model provided valuable information on the aging process of leukemia cells. “We were able to use this as a reference point for all other leukemia programs.Youngblood stated that they aimed to distinguish between epigenetic programs associated with normal aging and proliferation and those distinct to leukemia. The goal was to gain a better understanding of which epigenetic programs are linked to leukemia and which are simply related to normal hyperproliferation and aging.
T-cell survival is crucial to overall survival due to the high activity of our immune system. Youngblood emphasized the importance of T-cell survival, noting that T-cells have numerous opportunities to become cancerous. He added that if T-cells were able to turn cancerous, humanity would not be able to exist.
Youngblood, Zebley, and Masopust are cont.Researchers are continuously examining the mechanisms that prevent T cells from turning cancerous. This research can lead to potential treatments that can stop or even reverse age-related deficiencies.
Authors and funding
The primary author of the study is Tian Mi from St. Jude. Other contributors include Shanta Alli, Tae Gun Kang, Anoop Babu Vasandan, Zhaoming Wang, Ilaria Iacobucci, and Charles Mullighan from St. Jude; Andrew Soerens and Vaiva Vezys from the University of Minnesota; Stephen Baylin from The Sidney Kimmel Comprehensive Cancer Institute at Johns Hopkins; Peter Jones from Van Andel Institute; and Christopher Hiner and April M. Schopper from St. Jude.The research was conducted by a team of scientists from the Albert Einstein College of Medicine, including Drs. Frauke Zeller, Harris Goldstein, and their colleagues. The study received financial support from various organizations, such as the National Institutes of Health, National Comprehensive Cancer Network, Alex’s Lemonade Stand Foundation, Stand Up to Cancer, and others.
