Collaborative research provides clues to immunity, longer life

by Michael Howell

Feeling old and especially vulnerable in the face of the many variations of Flu and RSVP viruses going around? There is good reason to be concerned. Recent research has shown that aging is associated with a reduced ability to generate immune responses against novel infections. Research into mortality from SARS-CoV2, for instance, shows that even after the rollout of effective vaccines, older Americans have remained the hardest hit by the virus. In 2023, people over the age of 65 made up more than half of all Covid-associated hospitalizations and 90% of in-hospital Covid deaths in the U.S. (Robert Verity, et al in The Lancet Infectious Diseases June 2020). 

Although previous chronic health diseases are a significant factor, aging itself also plays a major role. One theory is that it all starts in the bone marrow, where a primitive reserve of stem cells replenishes the ranks of blood and immune cells to the tune of about 500 billion new cells every day. Some of these hematopoietic stem cells, or HSCs, are more likely to become long-lived stewards of immune memory like B cells and T cells; others are more likely to give rise to blood cells and front-line immune defenders. They all work in concert to get the balance right. As people age, though, one lineage of HSCs starts to dominate, throwing the equilibrium off-kilter and leaving them not only more vulnerable to infection, but also less able to respond to vaccines.

But older people need not despair. Recent research by a team of scientists led by Dr. Kim Hasenkrug, Scientist Emeritus at National Institute of Allergy and Infectious Diseases (NIAID) Rocky Mountain Laboratory in Hamilton, in collaboration with a team from Stanford University led by Dr. Irving Weissman, suggests that an aging immune system can be rejuvenated. (Ross, J.B., Myers, L.M., Noh, J.J. et al. Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity. Nature (2024). https://doi.org/10.1038/s41586-024-07238-x)

Their latest experiments have shown that immune systems of aged laboratory mice can be made more youthful and effective at fighting disease by depleting a subset of hematopoietic stem cells (HSCs). The researchers think the method they developed may have potential for rejuvenating immunity in elderly people and are pursuing further study.

Dr. Hasenkrug has been working on problems with the immune system since 1978, primarily in relation to HIV. He said he became especially interested in the AIDS immune response during the Covid Pandemic when so many people were dying. They noticed that the vaccines were not working that well in the elderly.

“As you get old the immune response gets old just like the rest of you,” said Hasenkrug. He said the immune response dominates with memory cells. Those are cells that have already seen a virus, or bacteria and they are able to respond very quickly if they see that bacteria again. That’s how immunity works with vaccines. As you age, he said, you have fewer cells that can respond to new infections.

“If you think about how evolution occurred,” said Dr. Hasenkrug, “people were located in isolated communities where you weren’t exposed to things like Ebola Virus from Africa if you were in Europe. So you developed immunity to all the types of infections that were in your locale and as you aged it wasn’t so important to respond to new infections because you had pretty much already seen everything, so you had a lot of memory cells that protected you, but you couldn’t respond very well to brand new infections. But more recently with planes, trains and automobiles, we are exposed to a lot of novel pathogens, things we have not seen in our past that arise in locales far away. Things like this are prone to causing pandemics.” 

He said it was his colleague at Stanford University, Dr. Irving Weissman, who discovered the hematopoietic stem cell (HSC). That’s the stem cell that gives rise to all of your blood cells and all of your immune cells. Our immune systems, according to Hasenkrug, have two sets of defenses against would-be invaders. 

There are the innate immunity forces, patrolling cells that can distinguish between friend and foe and attack any foreign microorganisms they come across. All of these kinds of cells are descended from “myeloid” HSCs. They release signaling molecules that trigger inflammation, but the attack is not very specific. “They can dampen infections, but they can’t kill it,” he said. 

But they also marshal the forces of the adaptive immune system. These are the camps of B cells that reside in lymph nodes and produce pathogen-specific antibodies and T cells, the body’s special forces units that are each programmed to fight only one specific microbe. These cells make up the “lymphoid” lineage of HSCs.

“The innate immune response and the adaptive immune response work together and you need both,” he said, “but as you age, you have fewer lymphocytes that have not seen the infection yet. They are just waiting to identify something to respond to. Once they do, they will start dividing and making lots of cells with the exact specificity needed.

“As you age, however, you get fewer and fewer of those naïve cells and that in turn may limit your response and you become more and more dominated by myeloid lineage stem cells.  Those stem cells can then present problems such as too much inflammation,” said Hasenkrug, “They can also become cancerous. So the more you age the more you become susceptible to myeloid lineage cancers.” It can aggravate other diseases that are inflammation related as well including a lot of brain cancers that have an inflammatory component.

According to Hasenkrug, it was the Stanford group that came up with the idea that if you just killed off a bunch of these stem cells that were myeloid biased, maybe the balanced stem cells would then take over and you would have a more youthful looking immune system. 

Jason Ross, a postdoctoral researcher in Weissman’s lab, began the work by sifting through massive datasets of proteins expressed on the surface of different mouse HSCs and identifying three that were uniquely expressed on myeloid-biased HSCs. Through genetic profiling his team identified proteins on the surface of these two types of stem cells that were different and followed up by developing antibodies to proteins on the cells’ surface and injected them into mice and found that antibodies did bind to those myeloid cells and kill them. 

To test their hypothesis, they identified my-HSC-specific genes in laboratory mice and then developed three methods using antibodies to deplete the targeted my-HSC gene products. Within a week the team began observing a “rebalancing” of the immune system, with increases in lymphoid cells and decreases in myeloid cells. Markers of inflammation and “immune exhaustion” associated with age also were decreased. Even after 16 weeks, a single treatment remained effective in the aged mice.

“The question then became ‘what is the effect on the immune system?’ and ‘does it really impact how you are able to fight disease?’ That’s where the RML group stepped in and tested for functionality of the immune response by challenging aged animals with mouse retroviruses,” said Hasenkrug.

“I just supervised the work,” he said. “I think it’s important to say Lara Myers did the bulk of the work. She’s the one that did the mouse work, spending hours and hours working with the mice and she did an incredible job. It’s a tough job.”

He said the team observed increased virus-specific T-cell development in treated mice compared to aged untreated controls, reduced pathology, and significantly increased virus control, with four of nine treated mice completely clearing the infection, proving that if you infected mice with these antibodies and replenished their balanced stem cells you were then able to induce vaccine immune responses and fight off infection.

The scientists also found that the my-HSC-specific antigens targeted for depletion in mice are also present in human my-HSC, suggesting that similar protocols could be used in humans.

“These experiments represent the first steps towards identifying therapeutic targets to deplete human my-HSCs and to rejuvenate the aged immune system using this strategy,” it states in their report published last week in Nature.

Stem cell biologist Robert Signer of UC San Diego’s Stem Cell Discovery Center, an expert in the biology of hematopoiesis who was not involved in the Stanford study, is quoted in Molteni’s article in STAT News, saying  “It’s been mostly assumed or speculated what the consequences are of an increase in these myeloid cells as we age. This paper helps to show that directly, which is an important breakthrough.”

He agreed that the study is very much a first step, one that invites more questions than answers at this point. But they’re questions worth going after, he said, because they open the door to the radical possibility of reversing a diverse set of age-associated conditions with a single intervention.

“Targeting these stem cells offers the opportunity to have an outsized impact,” said Signer. “Not only does it help keep blood function normal but it could also improve immune function as well as lowering inflammation, which has the potential to ameliorate a myriad of chronic diseases.”

Dr. Marshall Bloom, Director for Science Management at RML, said that it was important to note that this was not a “one-off” study but was the result of decades of research and collaboration between scientists at RML under the direction of Dr. Hasenkrug and Stanford University scientists under the direction of Dr. Weissman.

Both men grew up in Great Falls and as young high school students visited the McLaughlin Research Institute for Biomedical Sciences located in Great Falls which sparked their interest in bio-medical research. They both ended up working at the institute and have remained in touch over all these years.

It was in 1992 that Weissman began using his Montana ranch and NIAID’s nearby Rocky Mountain Laboratories (RML) as an ideal setting to foster collaborations between Stanford research groups and NIAID scientists. At the annual “Weissman Retreat,” budding, mid-career and senior scientists gathered annually to share ideas and plan projects, sometimes while fishing on the Bitterroot River adjacent to the ranch, sometimes while hiking the miles of nearby canyon trails, or sometimes during casual discussions at the laboratory campus or the ranch dinner table.

Hasenkrug said, “We sit down, eat, drink – and talk science for hours. Some of those conversations have led to important experiments.” He said over the last few years he has initiated at least four new translational research projects inspired at these events. 

Dr. Hasenkrug  said that the next steps in their current work will be to improve their methods and make sure everything works well in mice and then try it out on primates, because they are more like humans, and then move into clinical trials on humans if everything still looks good. He said any clinical trials are at least 3 to 5 years out.