Rewriting Immune Ageing Ageing weakens the immune system, leaving older adults vulnerable to infection, cancer and chronic disease. But what if immune decline is not only a property of ageing cells, but of the tissues that surround them? Professor Noga Ron-Harel of the Technion leads the ERC-funded IMMAGE project to uncover how ageing microenvironments reshape T cell function. T lymphocytes are central players in immune defence. They patrol the body, recognise threats and expand rapidly when danger appears. Beyond fighting infections, they also maintain tissue balance, sensing damage and restoring homeostasis. Yet with age, T cells lose their edge. They proliferate less efficiently, respond poorly to vaccination and display molecular features of dysfunction. This decline contributes not only to infection susceptibility, but also to cancer progression and broader age-related pathologies. For Professor Noga Ron-Harel, Principal Investigator at the Technion – Israel Institute of Technology, ageing has long been more than a research topic - it has been a driving scientific curiosity. Originally trained in biochemistry and neuroimmunology, Ron-Harel pursued postdoctoral research at Harvard Medical School in the emerging field of immunometabolism. “I have always been intrigued by ageing,” she says. “During my postdoc, I realised that if we want to truly understand immune decline, we need to understand the metabolic mechanisms behind it.” This long-standing interest ultimately led her to suspect that another layer of complexity was at play. “Ageing is often described as the accumulation of cellular damage,” she explains. “But immune cells do not live in isolation. They reside within tissues that also age. We asked whether the environment itself might be driving immune dysfunction.” This question became the foundation of the ERC Starting Grant project, IMMAGE – Age-related changes in the microenvironment of T cells.
The spleen is more than a lymphoid organ. It is also responsible for filtering and recycling senescent red blood cells. With age, this recycling system becomes less efficient. Red blood cells accumulate, rupture and release their contents, creating a microenvironment rich in iron, heme and oxidative stress. Proteomic analyses revealed that T cells from aged spleens expressed elevated levels of proteins involved in detoxifying heme and coping with oxidative damage. The cells were not merely failing – they were adapting. Illustrative Summary of Research Findings. Created in BioRender. Lab, R. H. (2026) https://BioRender.com/77y7zsg
The breakthrough The breakthrough came from a simple but unexpected observation. Ron-Harel’s first PhD student, David Ezuz, collected T cells from both the spleen and lymph nodes of naturally aged mice. The mice were approximately two years old – the equivalent of advanced age – and were compared sideby-side with healthy two-month-old controls. No accelerated ageing models were used; the team maintains its own geriatric cohort to study physiological ageing. When the aged T cells were stimulated outside the body, the results were striking. Cells from lymph nodes performed almost as well as young cells. Cells from the spleen, however, were profoundly dysfunctional. “Within the same animal we saw dramatically different functional states,” says Ron-Harel. “That told us something in the local microenvironment was shaping the ageing trajectory of these cells.”
Feed-Forward Loop Between Immune Aging and Host Tissue Aging
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Toxic Adaptation Iron is essential for T cell activation. It supports DNA synthesis, mitochondrial biogenesis and the metabolic reprogramming required for rapid proliferation. However, excess iron in an oxidative environment can trigger a specialised form of cell death known as ferroptosis. Faced with iron overload in the aged spleen, T cells respond defensively. They reduce iron uptake and increase iron storage capacity. This shields them from ferroptosis, improving survival in a hostile niche. But this adaptation comes at a cost. “When these cells are later stimulated – for example during vaccination – they cannot access enough iron to fuel proper activation,” Ron-Harel explains. “They survive better in the toxic environment, but they lose functional capacity.” In experiments published in Nature Aging, the team demonstrated that supplying bioavailable iron at the time of vaccination restored T cell proliferation and antibody production in aged mice. Lifecycle of a T Cell.
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This was a pivotal moment. “For years we tried supplementing metabolites directly to ageing cells and saw minimal effects,” she says. “This was the first intervention that made a significant difference – and it only worked because we understood the environmental context.” Transplant experiments reinforced the concept. Young T cells transferred into aged hosts adopted dysfunctional traits within weeks, thus the microenvironment was not a passive backdrop; it was an active driver. Whether the opposite transplant of aged T cells into a young host will suffice to recover functionality is still under investigation. The immune system plays a central role in maintaining homeostasis and normal function of most organs and tissues. If we find new ways to enhance immunity in the elderly, for example by correcting the ageing microenvironment, we may simultaneously improve vaccination responses, cancer immunity and resilience against multiple agerelated diseases.
cells circulating in peripheral blood. This connection is important. It suggests that the same environmental pressures shaping T cell dysfunction in aged mice may also operate in humans. If CD39 reflects exposure to a toxic, iron-rich microenvironment, it could serve as a measurable blood-based indicator of immune ageing — providing a potential bridge between experimental findings and clinical translation. To further bridge mouse and human biology, Ron-Harel is part of a new Technion initiative establishing an Institute for Healthy Aging (iTechAGE). The planned longitudinal cohort will collect multidimensional data, including blood and serum samples that can facilitate the search for systemic signatures of splenic-derived signals. While spleen tissue is not easily accessible in living humans, circulating immune cells may reflect the imprint of their tissue environments.
“Ageing is often described as the accumulation of cellular damage. But immune cells do not live in isolation...... We asked whether the environment itself might be driving immune dysfunction.” Beyond Ageing
Building a Research Identity
IMMAGE investigates two complementary mechanisms. One focuses on toxic signals within ageing tissues, particularly the hemolytic environment of the spleen. The other explores whether ageing stromal cells fail to provide sufficient metabolic support to T cells during activation – work that is ongoing. The implications extend beyond chronological ageing. Ron-Harel’s group together with Prof. Carina Levin, head of the children hematology unit in Ha’emek Hospital in Israel, is now studying patients with chronic hemolytic diseases such as beta thalassemia and sickle cell anaemia. These individuals experience persistent red blood cell breakdown within the spleen, creating a microenvironment reminiscent of the aged condition. “They are known to exhibit immune dysfunction,” she notes. “We are investigating whether chronic hemolysis induces premature immune ageing through similar mechanisms.” The team identified elevated levels of a surface protein called CD39 on T cells that had been exposed to the aged splenic microenvironment. CD39 is not just any marker; in previous human studies, it has been linked to exhausted or dysfunctional T
The ERC Starting Grant, running from 2023 to 2027, has been instrumental in shaping the lab’s direction. What began as a focus on cellular immunometabolism has evolved into a broader investigation of tissue-immune crosstalk. Today, her laboratory comprises 11 members, whose combined skills span metabolism, immunology and systems biology, enabling the project’s expanding scope. “Writing the ERC proposal forced us to synthesise our findings into a unifying hypothesis,” Ron-Harel reflects. “It helped us define who we are scientifically.” The Nature Aging publication marked a major milestone, but many additional leads uncovered during the project are still being pursued. At its core, IMMAGE reframes immune ageing as a systems-level phenomenon. Rather than viewing T cells as intrinsically worn out, it positions them within ageing ecosystems that can either nurture or impair their function. If we can improve the environment in which immune cells function, by nourishing them and removing damaging signals, we may unlock new ways to restore immune strength in later life. For ageing societies worldwide, that possibility carries profound significance.
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IMMAGE
Age-related changes in the microenvironment of T cells
Project Objectives
As we age, our T lymphocytes become less effective, contributing to organ decline and disease. This project studies how aging tissues affect T cells, focusing on poor metabolic support, and harmful signals in older organs. By understanding and targeting these changes, we aim to restore immune function and improve overall health in aging.
Project Funding
This project has received funding from the European Research Council (ERC) under the Horizon 2020 research and innovation program (IMMAGE # 101077922).Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or European Research Council.
Contact Details
Project Coordinator, Noga Ron Harel, Ph.D Assistant Professor Faculty of Biology iTechAGE - Center for Healthy Aging Technion, Israel T: +972-73-378-1349 E: nogaronharel@technion.ac.il W: https://ronharellab.technion.ac.il/ Reference: https://pubmed.ncbi.nlm.nih.gov/41107597/
David Ezuz Noga Ron-Harel
Noga Ron-Harel is an Assistant Professor at the Technion, specialising in immunometabolism and ageing. Her research explores how metabolic changes drive T cell dysfunction and immune decline across the lifespan. David Ezuz is a postdoctoral fellow at the Technion, studying immune ageing. His research focuses on how microenvironmental stress, particularly iron metabolism, shapes T cell function and decline in ageing.
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