Aging and Interferons: Impacts on Inflammation and Viral Disease Outcomes

Abstract

As highlighted by the COVID-19 global pandemic, elderly individuals comprise the majority of cases of severe viral infection outcomes and death. A combined inability to control viral replication and exacerbated inflammatory immune activation in elderly patients causes irreparable immune-mediated tissue pathology in response to infection. Key to these responses are type I, II, and III interferons (IFNs), which are involved in inducing an antiviral response, as well as controlling and suppressing inflammation and immunopathology. IFNs support monocyte/macrophage-stimulated immune responses that clear infection and promote their immunosuppressive functions that prevent excess inflammation and immune-mediated pathology. The timing and magnitude of IFN responses to infection are critical towards their immunoregulatory functions and ability to prevent immunopathology. Aging is associated with multiple defects in the ability of macrophages and dendritic cells to produce IFNs in response to viral infection, leading to a dysregulation of inflammatory immune responses. Understanding the implications of aging on IFN-regulated inflammation will give critical insights on how to treat and prevent severe infection in vulnerable individuals. In this review, we describe the causes of impaired IFN production in aging, and the evidence to suggest that these impairments impact the regulation of the innate and adaptive immune response to infection, thereby causing disease pathology.

SARS-CoV-2, COVID-19 and the aging immune system

“…During SARS-CoV-1 infection, levels of type I IFN signaling proteins downstream of RIG-I are further reduced due to infection-induced mitochondrial dysfunction linking to the viral sensor MAVS 116 . Given basal mitochondrial dysfunction, as well as a reduction in TNF receptor-associated factor (TRAF) adaptor protein and phosphorylated IRF3 levels linked to RIG-I signaling in older adults 115,117 , they are particularly vulnerable to such RIG-I insufficiency. Interestingly, RIG-I can restrain SARS-CoV-2 replication in human lung cells, although the mechanism does not require its type I IFN signaling ability 118 .…”

“…Interestingly, RIG-I can restrain SARS-CoV-2 replication in human lung cells, although the mechanism does not require its type I IFN signaling ability 118 . Older individuals also display reduced total numbers of pDCs at baseline, and their pDCs often show reduced TLR7 expression 117 and have diminished capacity to produce type I IFNs [119][120][121] . While there is a strong overlap of reduced type I IFN responses between older adults and patients with severe COVID-19, additional mechanistic connections between the two require further investigation.…”

Immunopathology and Immunosenescence, the Immunological Key Words of Severe COVID-19. Is There a Role for Stem Cell Transplantation?

“…CD14+ CD16-classical monocyte numbers do not change during aging, whereas CD14+ CD16+ non-classical monocytes tend to increase with age (Ventura et al, 2017;Oh et al, 2019;Feng et al, 2021). Despite these functional changes, monocytes seem to be key determinants of sex associated differences in immunosenescence, with a male superior ability in mounting inflammatory responses.…”

Epithelial Cell Transformation and Senescence as Indicators of Genome Aging: Current Advances and Unanswered Questions

“…Suggestively, the age of the genome can be determined by incorporating complex information about single-cell mutations and functional condition of organs and tissues. Such a multilevel approach may provide a treatment solution for various diseases by helping with drug discovery, immunity [ 7 ], and design for the prevention of infectious [ 8 ] and neurodegenerative diseases [ 9 ]. For this purpose, it is necessary to collect basic information at the single-cell/tissue/organ levels about the actual age of genomic content at normal and pathological conditions.…”