Immune responses in aging adults
Cornelia M. Weyand, Jörg J. Goronzy
Cornelia M. Weyand, Jörg J. Goronzy
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Immune responses in aging adults

Abstract

As a widely distributed network of cells, tissues, and organs, the human immune system is profoundly vulnerable to the effects of aging. Intrinsic and extrinsic stressors progressively erode its structural integrity and functional resilience, weakening core protective responses and increasing susceptibility to infection, malignancy, and tissue degeneration. At the same time, aging heightens the risk of chronic inflammation and autoimmune disease. Hematopoietic stem cells become uniquely compromised as aging intensifies metabolic and replicative stress. Their continuous high-volume turnover results in diminished self-renewal capacity, skewed lineage output, and dominance of expanded clones. These changes undermine innate immune competence and amplify inflammatory activity. Adaptive immune function declines with age through coordinated cellular and molecular programs. T and B lymphocytes exhibit a decline in naive cells, progressive loss of stemness, shortened lifespan, and constrained clonal diversity. Aging lymphocytes reconfigure transcriptional networks, undergo widespread organelle dysfunction, develop maladaptive stress responses, and redistribute into noncanonical tissue niches. Collectively, these alterations reduce antigen specificity and precision, promote innate-like immune behavior, and confer resistance to tolerance. These mechanisms result in concurrent immunodeficiency and autoimmunity, exemplified by two autoimmune diseases disproportionately affecting older adults: rheumatoid arthritis and giant cell arteritis.

Authors

Cornelia M. Weyand, Jörg J. Goronzy

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Figure 3

Signatures of T cell and macrophage aging in RA: organelle stress, metabolic exhaustion, and pro‑inflammatory cell death.

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Signatures of T cell and macrophage aging in RA: organelle stress, metab...
Aging of the immune system predisposes the host not only to impaired protective responses but also to the development of autoimmune disease. RA exemplifies this paradox. CD4+ T cells and synovial macrophages from patients with RA exhibit multiple hallmarks of immune aging, including declining organelle function and loss of coordinated interorganelle communication. In CD4+ T cells, defective mtDNA repair undermines ATP generation and disrupts TCA cycle activity. Compromised mitochondrial fitness places secondary stress on the ER and lysosomes, promoting the accumulation of lipid droplets. In RA, these lipid droplets serve as “killer organelles” by packaging the pore‑forming molecule gasdermin D. Synovial macrophages undergo a distinct form of mitochondrial collapse driven by C1q‑dependent activation of the NADase SARM1. This pathway triggers inflammasome activation and culminates in PANoptotic cell death. Release of cytosolic and nuclear material from dying CD4+ T cells and MerTK+ macrophages amplifies synovial tissue inflammation and perpetuates disease.