Scientists isolated immune cells of seven of the world's oldest people to see how they differed.
Supercentenarians, people who live to be 110 years old or more, may offer a tantalizing glimpse into the ability to fight off disease through their immune cells.
Researchers at RIKEN Center for Integrative Medical Sciences and Keio University in Japan recently studied a small group of the world’s oldest people and found clues about their longevity in the behavior of their T-cells, the “workhorses” of the immune system.
There are an estimated 300 to 450 supercentenarians worldwide, according to the Gerontology Research Group, a U.S. nonprofit that works to validate such claims. Japan, a generally long-lived society, had 146 supercentenarians in 2015, according to Japanese census data cited in the research.
“The supercentenarians live so long because they are healthy and do not get any disease for most of their lives,” Piero Carninci, an author of the study, published Nov. 12 in the Proceedings of the National Academy of Sciences, wrote in an email. “To be very healthy, we thought that their immune systems...must be special.”
Carninci and his colleagues set out to get a look at supercentenarians’ immune systems, resulting in a first-of-its-kind scientific inquiry into what might make them special. The study’s sample size was small but illuminating: Seven supercentenarians in the experimental group and five controls who were decades younger, aged 50s to 80s. The researchers performed transcriptome profiling of peripheral blood mononuclear cells using single-cell RNA sequencing technology.
T-cells are critical to mounting an immune response and attacking infected cells, according to the National Cancer Institute.
Researchers found a much higher proportion of a subset of CD4 T-cells in the age 110 and over group (25% of total T-cells) compared with the younger group (2.8%) .These CD4 T-cells, which typically have “helper” status, had cytotoxic features in the supercentenarians, meaning they killed invaders.
“These [CD4 CTL] cells are important to protect us from viruses/cancer,” Carninci wrote. “Perhaps they have expanded during aging of the patients while fighting viruses/cancer. Perhaps this expansion was instrumental for their survival (but we cannot say for sure, because correlation does not mean causation). More studies in the intermediate stages of aging [are] needed as further steps.”
“We hope that these studies pave the way to understanding [the] response in healthy aging to cancer and infections. Ideally, one would study these cells and in the future learn how to produce many more,” Carninci added.
“Our study reveals that supercentenarians have unique characteristics in their circulating lymphocytes, which may represent an essential adaptation to achieve exceptional longevity by sustaining immune responses to infections and diseases,” the authors wrote in the paper.
Future research priorities include understanding the molecular mechanisms of how the cells increased in supercentenarians and characterizing their functions such as antigen specificity and cytokine production, lead author Kosuke Hashimoto wrote in an email.
Therapeutic Potential
The research ranks high in terms of scientific interest, said Dr. Ron Gress, chief of the experimental transplantation and immunotherapy branch in the National Cancer Institute’s Center for Cancer Research in Bethesda, Md.
“In terms of therapeutic potential, it’s an unknown yet,” Gress said. “We don’t know the specificity of these [CD4 CTLs.] We don’t know their biological role.”
“We need to understand better the cytotoxic or killing potential of these cells,” he said. “We need to understand what’s driving them. I’m supposing it’s most likely IL- [Interleukin]15 that’s driving them, but I don’t know that.”
“In order to have that kind of [cellular] expansion, a person needs to have a supporting cytokine. That, in other T-cells, is generally IL-15,” Gress said.
“What’s different about this paper is apparently after 100 we expand CD4 cytotoxic cells, which otherwise stay at relatively low frequency in the T-cell population. It means there’s something about the homeostasis of these cells that changes when we go over 100” or at another point in the aging process, which is still unclear, he said.
With immunotherapy in cancer treatment, for example, it’s now possible to genetically modify T- cells to kill targets such as tumors, Gress pointed out. Such personalized T-cell engineering is still relatively new and can be used in CAR.T-cell therapy, or chimeric antigen receptor T-cell therapy. CAR T-cell therapy is FDA-approved for the treatment of some leukemias and lymphomas and is available through clinical trials.
Excitement and Practical Questions
The research “provides a rare snapshot into the circulating immune systems” of supercentenarians, Dr. Dan Winer, associate professor at the Buck Institute for Research on Aging, wrote in an email.
“This work is exciting in that it highlights CD4 CTLs [cytotoxic T lymphocytes] as protective immune cells that potentially facilitate healthy aging and increased lifespan,” he wrote.
“Our understanding of how these cells work to accomplish these important goals is still in its infancy, and more work is needed to determine if these cells actively participate in this process,” Winer wrote. “It is possible that these cells act as sentinels against chronic or repeat viral infections with age (such as cytomegalovirus as one example), or that they act to eliminate age-related senescent cells or cancer cells.”
“Future work will be aimed at determining exactly what CD4 CTLs recognize in the body, and how these cells could be harnessed to fight off age-related disease to promote healthspan.”
Research like this prompts thinking about quality of life and not just quantity of years, said John M. “Johnny” Adams, executive director of the Gerontology Research Group, a nonprofit group that aims to slow and ultimately reverse age-related decline, based In Newport Beach, Ca.
“The first thing that comes to mind is how can we turn this information into a solution that would help people stay younger and healthier and avoid the misery that comes with old age?” he said. “To me the most important thing is remaining healthy throughout whatever time we’re allotted here.”
Assuming the scientific questions can be answered, practical matters may soon follow, Adams suggested.
“How do we cultivate CD4 CTLs in those of us where they do not occur naturally? Is this a downstream effect of something else that’s going on?” he said. “Where do [we[ go for a lab test for a measure of our CD4 CTLs to know how we’re doing to monitor our health as we grow older?”
