Senescent Factors Suppress Innate Antiviral Immunity in Aged Mice via Two Distinct Mechanisms
Xu Zhang1, Qi Zhang1, Li Wang1
1Department of Infectious Diseases, Medial Research Institute, Zhongnan Hospital of Wuhan University, State Key Laboratory of Virology and Biosafety, Taikang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China.
Abstract:
The accumulation of senescent cells contributes to age-related inflammation and heightened susceptibility to viral infection. The mechanisms by which cellular senescence and aging exacerbate virus-associated diseases remain poorly understood. Here we show that innate antiviral immunity is progressively impaired with aging in mice, in parallel with systemic accumulation of senescent cells. Mechanistically, senescent cells suppress innate antiviral response mostly via four senescence-associated secretory phenotype (SASP) factors. GDF15 and IGF1 trigger AKT-MEK-mediated inactivation of GSK3β, leading to suppression of the TBK1-IRF3 axis. IL1α and IL6 induce expression of p52 and RelB to suppress transcription of antiviral genes. Consistently, combined blocking of GDF15, IGF1, IL1α, and IL6 promotes innate antiviral immunity in aged mice. These findings reveal that SASP factors antagonize innate antiviral immunity through distinct pathways and suggest a potential strategy to restore immune competence to defend viral infection in aged individuals by targeting the four SASP factors.
Insights
Aging impairs innate antiviral immunity due to senescent cells. Blocking four key senescence-associated secretory phenotype (SASP) factors restores immune function in aged mice, offering a strategy against viral infections.
Area of Science:
- Immunology
- Gerontology
- Virology
Background:
- Cellular senescence and aging are linked to increased inflammation and susceptibility to viral infections.
- The precise mechanisms by which aging and senescence worsen viral diseases are not well understood.
- Innate antiviral immunity declines with age, correlating with senescent cell accumulation.
Purpose of the Study:
- To investigate how cellular senescence and aging impair innate antiviral immunity.
- To identify specific senescence-associated secretory phenotype (SASP) factors involved in immune suppression.
- To explore therapeutic strategies for restoring antiviral immunity in aged individuals.
Main Methods:
- Aging mouse models were used to study the decline in innate antiviral immunity.
- Senescence-associated secretory phenotype (SASP) factors were analyzed for their role in immune suppression.
- Specific molecular pathways (AKT-MEK-GSK3β-TBK1-IRF3 and p52-RelB) were investigated.
- The effect of blocking key SASP factors on antiviral responses in aged mice was evaluated.
Main Results:
- Innate antiviral immunity is progressively impaired in aged mice with accumulating senescent cells.
- Four SASP factors (GDF15, IGF1, IL1α, and IL6) were identified as key suppressors of innate antiviral responses.
- GDF15 and IGF1 inhibit the TBK1-IRF3 pathway via AKT-MEK-GSK3β.
- IL1α and IL6 suppress antiviral gene transcription through p52 and RelB.
- Simultaneous blockade of these four SASP factors enhanced innate antiviral immunity in aged mice.
Conclusions:
- Senescence-associated secretory phenotype (SASP) factors antagonize innate antiviral immunity through distinct molecular pathways.
- Targeting GDF15, IGF1, IL1α, and IL6 presents a potential strategy to restore immune competence against viral infections in the elderly.
- Understanding these mechanisms can lead to novel therapeutic interventions for age-related vulnerability to viruses.
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