The immune system, like other parts of the human body, falters with age. Beginning as early as age 40, people become more vulnerable to new pathogens and serious infections, don't respond as well to vaccines, and wounds take longer to heal, among other changes.
Bolstering the immune system could enhance overall health among older individuals, and many scientists are investigating the possibilities. But for Columbia University scientist Donna Farber, most of this research is too narrowly focused.
"When we talk about how our immune system changes with age, pretty much everything we know is based on studies of the immune cells and antibodies in blood. But most of our immune system resides in lymphoid organs and barrier sites such as our lungs and guts," says Farber, who is the George H. Humphreys II Professor of Surgical Sciences and professor of microbiology & immunology at Columbia University Vagelos College of Physicians and Surgeons.
"It's the immune cells in our tissues that really protect us from viral infections and other pathogens." But until recently, it had been virtually impossible to measure these wide-ranging stores of immune cells.
Yosuke Sakamoto (left), a postdoctoral fellow in the Farber lab, is a surgeon who obtains human samples for studies of immune cells in tissues. Joshua Gray, another postdoctoral fellow, is looking at an image of lymphocytes from the lungs of a human tissue donor. Photo credit: Farber lab, Columbia University Irving Medical Center
About 15 years ago, Farber created the first tissue bank dedicated to studying the human immune system to paint a more complete picture of the immune system and how it ages. The tissue bank draws on Columbia's status as a leading transplant center, which has enabled the collection of tens of thousands of samples, including lungs, intestines, spleens, bone marrow, and lymphoid organs, from organ donors.
Compared to animal tissue, these samples tell a more accurate story about how immune cells function in people.
Not all immune cells age equally
Farber's most recent studies from the tissue bank are revealing secrets of aging immune cells within our tissues.
Some cells are surprisingly old. Using radiocarbon dating, Farber's team found that memory T cells-which retain the imprint of past infections-survive for up to ten years in the spleen, whereas memory T cells in the blood and the intestines only live for one to two years.
Other cells are surprisingly youthful. Immune cells in the blood that were more frequently stimulated by pathogens bore markers of senescence-indicating they had run out of steam-while others, including those in the spleen, had fewer or none of these markers.
"The way a memory T cell ages depends very much on which tissue it's in," Farber says. "Our findings suggest that vaccines that target sites where immune cells reside may be a more effective strategy than boosters, and that different strategies may be needed depending on which organ you are trying to protect."
Aging macrophages could predict age-related diseases
Looking beyond memory T cells, the researchers found divergent aging patterns in other immune cells as well. Many types of T cells and B cells found in tissues remained mostly unchanged with age. Macrophages, however, had age-related changes that resembled molecular changes found in conditions such as Alzheimer's and cardiovascular disease.
"It's possible that some age-related diseases are due to macrophage aging, which could point to new targets for these diseases," Farber says.
Some age-related changes may be beneficial. For example, lymph nodes in the gut that help combat new pathogens, degrade significantly with age. "We really don't know why that is, but it could be that having a diminished capacity to protect against new viruses comes with the unexpected benefit of having less tissue-damaging inflammation," Farber says. "We don't normally encounter a lot of new pathogens as we age. But controlling inflammation and tissue damage is really something you need in the elderly."
Farber's team is now collaborating with researchers from institutions around the world to establish new tissue banks and study the human immune system.
"When you take a comprehensive look across the entire immune system, which is vast and diverse, you learn new things," Farber says. "Having this information could help us find new ways to boost our response to new pathogens and fight cancer more effectively."
References
Additional information
"Asynchronous aging and turnover of human circulating and tissue-resident memory T cells across sites" was published July 29 online in Immunity.
All authors (from Columbia University unless noted): Nora Lam, J. Carlos Angel, Bruce A. Buchholz (Lawrence Livermore National Laboratory, Livermore, CA), YoonSeung Lee, Stuart P. Weisberg, Brea H. Brown, Julia Davis-Porada, Daniel P. Caron, Isaac J. Jensen, Peter A. Szabo, Basak B. Ural, Steven B. Wells, Masaru Kubota, Rei Matsumoto, Maigan Brusko (University of Florida, Gainesville, FL), Todd M. Brusko (University of Florida), Chao Lu, Andrew Yates, and Donna Farber.
The study was supported by grants from the National Institutes of Health (AI106697, AI50680, R35GM138101, R01CA266978, HL145547, R24GM137748, K08122130, 7K00AG073570, F30AI174785, T32AI106711, K01AG78439), the Helmsley Charitable Trust, and the National Science Foundation. Research samples were obtained from the New York Brain Bank at Columbia University, the Washington Heights-Inwood Columbia Aging Project, and the National Institute on Aging Alzheimer's Disease Family-Based Study.
The authors declare no conflicts of interest.
"Multimodal profiling reveals tissue-directed signatures of human immune cells altered with age," was published online Aug. 13 in Nature Immunology.
All authors: Steven B. Wells (Columbia University, NY), Daniel B. Rainbow (University of Cambridge, UK), Michal Mark (Weizmann Institute, Israel), Peter A. Szabo (Columbia), Can Ergen (University of California Berkeley, CA), Daniel P. Caron, Ana Raquel Maceras (Wellcome Sanger Institute, UK), Elior Rahmani (Berkeley), Eli Benuck (Weizmann Institute), Valeh Valliolah Pour Amiri (Berkeley), David Chen (Columbia), Allon Wagner (Berkeley), Sarah K. Howlett (University of Cambridge), Lorna B. Jarvis (University of Cambridge), Karen L. Ellis (University of Cambridge), Masaru Kubota (Columbia), Rei Matsumoto (Columbia), Krishnaa Mahbubani (University of Cambridge), Kouresh Saeb-Parsy (University of Cambridge), Cecilia Dominguez-Conde (Wellcome Sanger), Laura Richardson (Wellcome Sanger), Chuan Xu (Wellcome Sanger), Shuang Li (Wellcome Sanger), Lira Mamanova, Liam Bolt, Alicja Wilk (Wellcome Sanger), Sara A. Teichmann (Wellcome Sanger), Donna L. Farber (Columbia), Peter A. Sims (Columbia), Joanne L. Jones (University of Cambridge), and Nir Josef (Berkeley and Weizmann Institute).
The study was funded by grants from the National Institutes of Health (AI106697 and AI128949), the Chan-Zuckerberg Initiative Seed Networks for the Human Cell Atlas (CZF2019-002452), the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014), the Wellcome Trust, and the UKRI Medical Research Council. Tissue samples were obtained from the Cambridge Biorepository for Translational medicine and LiveOnNY.
Columbia authors report no conflicts of interest. Additional declarations can be found in the article.
