Year: 2022
Type: article
Abstract: Immune-senescence refers to the aging of the immune system and the resulting deterioration in its ability to fight infections and cancer in older individuals.This phenomenon is reflected in the numerous infectious diseases which show increased severity in the elderly, most recently demonstrated by the COVID-19 pandemic.The trajectory of the COVID-19 pandemic would have differed markedly if the severity of disease in older individuals was similar to healthy young individuals.Therefore, understanding what factors contribute to immune-senescence and how to reverse them is of great importance.While several defects are thought to contribute to immune-senescence, the molecular mechanisms involved remain poorly understood.In recent work we discovered that altered glycosylation in T cells contribute to T cell aging [1].In particular, the level of N-acetylglucosamine (GlcNAc) branching on cellsurface N-glycans was increased in T cells, most prominently in naïve CD4 + T (TN) cells, from old mice and humans.Surprisingly, we found that old females had a greater age-dependent increase in branching than males.Our previous work has demonstrated that Nglycan branching is a critical negative regulator of T cell activation and pro-inflammatory responses [2, 3], with decreased branching leading to hyperactivity, inflammation and autoimmunity.Thus, the elevated branching observed with aging is expected to result in T cell hypoactivity and contribute to T cell aging.Indeed, reversing this elevation in N-glycan branching rejuvenated old CD4 + TN responses in vitro and resulted in reduced disease severity in an in vivo model of salmonella infection in old female mice.Mechanistic studies revealed that the elevated branching was driven by cell-extrinsic factors in old mice, with further investigation identifying that elevated interleukin-7 (IL-7) signaling in old CD4 + TN cells was the major driver of branching in mice.In humans, serum levels of the simple sugar N-acetylglucosamine (GlcNAc), a key N-glycan branching pathway metabolite whose serum deficiency is associated with severity of the autoimmune disease multiple sclerosis and reduced myelination [4, 5], were also elevated in an age dependent manner.Interestingly, although serum GlcNAc was elevated in both sexes, it only associated with TN cell branching in females, suggesting another factor may be involved.Indeed, although supplementa-
Source: Aging
Authors: Haik Mkhikian, Michael Demetriou
Institution: University of California, Irvine
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4291237363