Aging of the Innate Immune System: An Update

Abstract

The relationship between advanced age and immunologic deficits is becoming an area of rapidly advancing research. Many of the clinical hurdles in the elderly population result from dysregulation of the immune system leading to the inability of the elderly to swiftly combat infection and to the increased incidence of chronic disease states and autoimmune conditions. Herein, we address the crucial alterations in the innate immune system that occur with advancing age. Specifically, we discuss how the effects of advanced age may lead to functional changes in the neutrophil, macrophage, dendritic cell, natural killer cell, and natural killer T cell populations in human and murine models that translate into aberrant innate immune responses. Furthermore, we elucidate how these changes may contribute to documented deficits in adaptive immunity as well as the pathological conditions and the increased morbidity and mortality seen in the elderly population.

Fig. (1)

Neutrophil defects with advanced age. Arrows (↑, ↓ or ↔) denote increased, decreased or unaltered levels in the aged compared to the young. Abbreviations: fMLP, N-formyl-methionyl-leucyl-phenylalanine; GM-CSF, granulocyte monocyte colony stimulating factor; LPS, lipopolysaccharide; TREM-1, triggering receptor expressed on myeloid cell-1, TLR4, Toll-like receptor 4; MyD88, Myeloid differentiation primary response gene (88); IP3, inositol 1,4,5-triphosphate; DAG, diacyl glycerol; cAMP/PKA, cyclic adenosine monophosphate/protein kinase A; ERK, extracellular signal-regulated protein kinase; MAPK, mitogen activated protein kinase; SHP-1, inhibitor of Src family of tyrosine kinases, SOCs, suppressors of cytokine signaling.

Fig. (2)

Macrophage defects with advanced a ge. Arrows (↑, ↓ or ↔) denote increased, decreased or unaltered levels in the aged compared to the young. Abbreviations: IFN-γ, interferon-gamma; ROS, reactive oxygen species; MHC, major histocompatibility complex; RNS, reactive nitrogen species; iNOS, inducible nitric oxide synthase; LBP, LPS-binding protein; JNK, janus kinase; MAPK, mitogen activated protein kinase; PGE2, prostaglandin E2; I-κB, inhibitor of κB; NF-κB, nuclear factor-kappaB; COX, cyclooxygenase; TNF-α, tumor necrosis factor-alpha; MIP, macrophage inflammatory protein; IL, interleukin.

Fig. (3)

Dendritic cell defects with advanced age. Arrows (↑, ↓ or ↔) denote increased, decreased or unaltered levels in the aged compared to the young. Abbreviations: mDC, myleiod dendritic cell; MDDC, monocyte-derived dendritic cell; pDC, plasmacytoid dendritic cell; LC, Langerhan’s cell; LPS, lipopolysaccharide; PI3K, Phosphoinositide-3 kinase; AKT, serine/threonine kinase; MIP, macrophage inflammatory protein; TNF-α, tumor necrosis factor-alpha; IL, interleukin; ssRNA, single-stranded ribonucleic acid; IFN-γ, interferon-gamma; IRF, interferon regulation factor; HSV, herpes simplex virus.