Research Signal – Source date 2024-04-15
Aging can make the immune system less responsive to unfamiliar threats while leaving the body with more persistent inflammatory activity. That apparent contradiction matters in atherosclerosis, the buildup of fatty, inflamed plaques inside artery walls. The plaques are not simply deposits of cholesterol. They develop in an environment where blood-vessel cells, immune cells and modified lipids interact over time.
An April 15, 2024 review, Adaptive immunity and atherosclerosis: aging at its crossroads, brings together findings about how T cells and B cells change with age and how those changes may affect plaque biology. Its central message is not that immunity rises or falls as one overall quantity. Aging changes which immune cells are available, what they remember, where they gather and what signals they release. Some of those changes may intensify artery inflammation, while others may weaken forms of protection.
Why weaker immune responses can coexist with chronic inflammation
Atherosclerosis begins when low-density lipoprotein, or LDL, enters the inner layer of an artery through areas where the vessel lining has become more permeable. Modified LDL, including oxidized LDL, can encourage immune-cell recruitment. Monocytes enter the vessel wall and can become cholesterol-filled foam cells, contributing to plaque growth and formation of a necrotic core containing dead cells.
T cells and B cells then help shape the response to material in and around the plaque. T cells recognize specific molecular patterns and release signals or coordinate other cells. B cells can mature into antibody-producing cells. Their effects depend on the cell population, the target and the surrounding tissue, so “more immunity” is too blunt an explanation for what happens with age.
One part of immunosenescence is a reduced ability to respond broadly to new antigens. Antigens are molecular features that immune cells can recognize. Inexperienced, or naïve, T and B cells have not yet been trained by contact with a particular target. Memory cells are descendants of earlier responses that remain prepared to respond again. With age, the supply of naïve cells declines while central memory cells become more prominent. The remaining T-cell repertoire can also become more narrowly shaped by repeated exposure to persistent viruses or by self-directed immune responses.
At the same time, older immune cells can adopt a more inflammatory secretory profile. Senescent cells may release a mixture of inflammatory factors known as the senescence-associated secretory phenotype, or SASP. The result is not a stronger, better-coordinated response to every new threat. It can instead be a less flexible immune system alongside a background of chronic inflammatory signaling. That combination offers one explanation for how declining responsiveness and worsening inflammatory conditions can coexist.
Blood production and the shrinking supply of new T cells
The aging process changes the starting material from which immune cells are made. In older mice, blood-forming stem cells shift away from lymphoid production, which supplies many adaptive immune cells, and toward myeloid production. Human observations have also supported this age-related myeloid skewing. Hypercholesterolemia and hyperglycemia can further promote myeloid production in ways linked in the reviewed research to faster atherosclerosis and poorer resolution of inflammation.
T cells face an additional bottleneck. Their early precursors travel to the thymus, where they develop into competent naïve T cells that can respond to unfamiliar targets without attacking the body. The thymus shrinks with age and becomes more fatty, reducing its output. Fewer new T cells enter circulation, and the pool that remains is increasingly composed of cells shaped by past encounters.
This population change is different from saying that every older immune cell is biologically senescent. A narrower supply of naïve cells, a different balance of memory and effector cells, and cellular senescence are related but separate ideas. The first describes who is present and in what proportions. The last refers to a state of cellular change that cannot be identified reliably from age alone.
The review describes several ways this altered population can matter in plaque disease. Human plaques from people who had experienced myocardial infarction or unstable angina contained autoreactive CD4+ T cells lacking the CD28 marker. Expansion of these cells has been associated with greater cytotoxic activity toward endothelial cells during acute coronary syndromes. That observation connects a particular T-cell population with diseased tissue; it does not by itself show that the cells caused a cardiovascular event.
In aged atherosclerosis-prone mice, researchers have also found more inflammatory T cells producing interferon-gamma, along with an increase in CD8+ T cells that produce granzyme K. Granzyme K-producing cells were reported in human carotid plaques as well, where they showed plaque-specific clonal expansion. The review notes that it remains unresolved whether those human cells recognize established atherosclerosis-related self-antigens or whether they directly cause cardiovascular disease.
Protection and harm do not belong to one cell type
The functional comparison becomes clearer when antibody responses are included. Some T-cell populations, such as Th1 cells, can promote plaque inflammation, while regulatory T cells can restrain immune activity in some settings. In aged mice with atherosclerosis, regulatory T cells and markers associated with their activity were increased in the aorta. Human plaques also contained expanded regulatory T-cell populations. Yet the review emphasizes that the ability of these cells to suppress inflammation inside an aged atherosclerotic environment remains unresolved. A regulatory signature identifies a state or program of gene activity; it does not settle what a cell is doing in every tissue.
B cells are similarly mixed in their effects. Conventional follicular B cells can support antibody responses that contribute to plaque progression, while B1 cells and regulatory B cells may be protective in particular contexts. B1 cells can produce IgM antibodies that recognize molecular features of oxidized self-material, known as oxidation-specific epitopes. These antibodies may help bind material associated with plaque biology.
In human studies summarized by the review, lower levels of B1 cells and of IgM directed against oxidized LDL or related targets were associated with higher cardiovascular risk. Older people generally had fewer B1 cells and less circulating oxLDL-specific IgM than younger people, with still lower levels reported among age-matched people with coronary artery disease. These findings make the antibody response biologically interesting, but an association with risk is not proof that restoring the antibody would prevent a heart attack or stroke.
Aging changes the places where immune cells coordinate
Adaptive immunity depends on organization as well as cell identity. In lymph nodes and the spleen, naïve T cells encounter presented material and can develop into follicular helper T cells, or Tfh cells. These cells move toward the boundary between T-cell and B-cell areas, where signals help B cells mature. Inside germinal centers, Tfh cells support antibody refinement, including the processes that alter antibody binding and change antibody class.
Age changes the tissue architecture that makes this exchange possible. Secondary lymphoid organs become smaller and less structurally complex. Fibroblastic reticular cells, which form part of the internal scaffolding, decline, disrupting the routes used by T cells and affecting the placement of IL-7, a signal important for maintaining naïve T cells. Within germinal centers, the light-zone area and its follicular dendritic-cell population also decline, potentially impairing immune-cell coordination.
These changes could lead to poorly coordinated germinal-center responses, but their specific cardiovascular consequences remain understudied. The balance between harmful and protective antibody responses may depend partly on where cells meet and which signals they receive. In aged atherosclerotic mice, artery-associated tertiary lymphoid organs have also been described near chronic inflammation. They contain T-cell areas, B-cell follicles and germinal centers, suggesting that advanced plaques may develop their own local immune organization. How this organization affects protective or pathogenic antibody responses is not yet clear, particularly when translating the mouse findings to older adults.
What the evidence can and cannot identify
The review’s therapeutic implications depend on identifying the relevant cells accurately. That is difficult because no single commonly used marker proves that a cell is senescent. Researchers often use markers such as p16, senescence-associated beta-galactosidase, p53, p21 or signs of DNA damage, but each can also appear in other cellular states. In atherosclerotic tissue, macrophages may express some of the same markers during differentiation or inflammatory activation. A marker-positive cell is therefore not automatically an old, harmful cell that should be removed.
The same caution applies to immune-cell programs. A T cell expressing regulatory markers may be suppressive in one setting and less effective in another. Increased regulatory markers in an aged plaque do not resolve whether local immune control is working. Human blood or plaque measurements can reveal relationships with disease, but they do not establish which cells initiate plaque growth, destabilize a plaque or protect against an event.
Mouse experiments add another interpretive layer. Standard laboratory mice live in controlled environments and often have less varied exposure to pathogens than people do. That history shapes immune development. The review points to “wildling” mice, whose immune systems more closely resemble those of mice exposed to natural environments, as one way researchers are testing the limits of conventional models. Whether such models improve the study of age-related atherosclerosis remains an open question, but the underlying point is practical: age, diet and disease status are not the only variables that shape an immune result.
Removing senescent cells is a targeting problem
Senolytics are drugs intended to remove senescent cells. In atherosclerosis-prone mice, the review describes experiments in which quercetin or navitoclax reduced lesion size and circulating inflammatory factors. Those findings make the idea of targeting harmful age-associated cells plausible enough to investigate, but they do not show that removing such cells prevents cardiovascular events in older adults.
The difficulty is selectivity. The same survival pathways targeted by these drugs can matter in healthy cells, and the reviewed approaches were associated with serious blood-cell toxicities, including thrombocytopenia and neutropenia. A treatment that removes a harmful immune population but also weakens useful blood or immune functions could create a different medical problem. More selective approaches are being explored, but the review presents this as an unresolved translation challenge rather than an established cardiovascular treatment.
A safer strategy would require more than finding cells that look old or inflammatory. Researchers would need to identify the populations that are causally involved in plaque disease, distinguish them from cells performing useful immune work, and show that intervention changes cardiovascular outcomes in humans without unacceptable harm.
What targeted immune treatment could change for older adults
The longer-term possibility is more precise cardiovascular care for older adults. Immune features associated with aging could eventually help clinicians match treatment to a harmful immune response, with the aim of reducing plaque-related disease while preserving useful protection against infection and other threats. That would be a clinical capability, not simply a new way to measure biological age.
Reaching it depends on several conditions: the relevant immune populations must be identified, their role in disease must be shown to be causal, and an intervention must prove safe and effective in humans. Risk assessment may help identify people who need closer attention, but the review does not establish a validated prediction tool, a treatment threshold or a numerical cardiovascular benefit. Its contribution is to show why age-related immunity deserves a more discriminating approach: the same aging process can remove flexibility from immune defenses, reorganize the cells that remain and intensify inflammation in the artery wall.
Key Sources
- Primary source: Adaptive immunity and atherosclerosis: aging at its crossroads.
DOI or Journal Page · Review or Meta-Analysis · 2024-04-15
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