The coronavirus disease 2019 (COVID-19) pandemic is a global health threat with particular risk for severe disease and death in older adults and in adults with age-related metabolic and cardiovascular disease. Recent advances in the science of aging have highlighted how aging pathways control not only lifespan but also healthspan -the healthy years of life. Here, we discuss the aging immune system and its ability to respond to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We specifically focus on the intersect of severe COVID-19 and immunosenescence to highlight pathways that may be determinant for the risk of complications and death following infection with SARS-CoV-2. New or adapted therapeutics that target agingassociated pathways may be important tools to reduce the burden of death and long-term disability caused by this pandemic. Proposed interventions aimed at immunosenescence could enhance immune function not only in older adults but in susceptible younger individuals as well, ultimately improving complications of severe COVID-19 for all ages.

Immune responses are governed by signals from the tissue microenvironment, and in addition to biochemical signals, mechanical cues and forces arising from the tissue, its extracellular matrix and its constituent cells shape immune cell function. Indeed, changes in biophysical properties of tissue alter the mechanical signals experienced by cells in many disease conditions, in inflammatory states and in the context of ageing. These mechanical cues are converted into biochemical signals through the process of mechanotransduction, and multiple pathways of mechanotransduction have been identified in immune cells. Such pathways impact important cellular functions including cell activation, cytokine production, metabolism, proliferation and trafficking. Changes in tissue mechanics may also represent a new form of ‘danger signal’ that alerts the innate and adaptive immune systems to the possibility of injury or infection. Tissue mechanics can change temporally during an infection or inflammatory response, offering a novel layer of dynamic immune regulation. Here, we review the emerging field of mechanoimmunology, focusing on how mechanical cues at the scale of the tissue environment regulate immune cell behaviours to initiate, propagate and resolve the immune response.

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T follicular helper (Tfh) cells are critical in adaptive immune responses to pathogens and vaccines; however, what drives initiation of their developmental program remains unclear. Studies suggest a T cell antigen receptor (TCR)-dependent mechanism may be responsible for the earliest Tfh-fate decision, but a critical aspect of the TCR has been overlooked: tonic TCR signaling. We hypothesized tonic signaling influences early Tfh cell development. Here, two murine TCR-transgenic CD4 + T cells, LLO56 and LLO118, that recognize the same antigenic-pMHC but experience disparate strengths of tonic signaling, revealed low tonic signaling promotes Tfh cell differentiation. Polyclonal T cells paralleled these findings, with naive Nur77 expression distinguishing Tfh potential. Two mouse lines were also generated to both increase and decrease tonic signaling strength, directly establishing an inverse relationship between tonic signaling strength and Tfh development. Our findings elucidate a central role for tonic TCR signaling in early Tfh-lineage decisions.

Hydropersulfide and polysulfide species have recently been shown to elicit a wide variety of biological and physiological responses. In this study, we examine the effects of cysteine trisulfide (Cys-SSS-Cys; also known as thiocystine) treatment on E. coli. Previous studies in mammalian cells have shown that Cys-SSS-Cys treatment results in protection from the electrophiles. Here, we show that the protective effect of Cys-SSS-Cys treatment against electrophile-induced cell death is conserved in E. coli. This protection correlates with the rapid generation of cysteine hydropersulfide (Cys-SSH) in the culture media. We go on to demonstrate that an exogenous phosphatase expressed in E. coli, containing only a single catalytic cysteine, is protected from electrophile-induced inactivation in the presence of hydropersulfides. These data together demonstrate that E. coli can utilize Cys-SSS-Cys to generate Cys-SSH and that the Cys-SSH can protect cellular thiols from reactivity with the electrophiles.