NRF1-mediated innate immune response drives inflammaging.

Area of Science:

• Immunology
• Cellular Biology
• Aging Research

Background:

• Aberrant innate immune responses are linked to cellular senescence.
• The specific mechanisms connecting innate immunity and senescence are not fully understood.

Purpose of the Study:

• To investigate the role of nuclear respiratory factor 1 (NRF1) in regulating innate immunity and cellular senescence.
• To explore NRF1's impact on the senescence-associated secretory phenotype (SASP) and age-related decline.

Main Methods:

• Studied NRF1's role in senescence induction and SASP regulation.
• Investigated the NRF1-TBK1/IRF3 pathway and its connection to type I interferon signaling.
• Utilized NRF1 knockdown in aged mice to assess therapeutic potential.

Main Results:

• NRF1 deficiency delayed cellular senescence and ameliorated age-related deterioration.
• NRF1 enhances SASP by regulating TBK1 and IRF3, key innate immunity components.
• DNA damage-induced ATM kinase phosphorylation of NRF1 exacerbates senescence via the type I interferon axis.
• NRF1 knockdown mitigated aging phenotypes and extended lifespan in aged mice.

Conclusions:

• The ATM-NRF1-TBK1/IRF3-type I interferon axis is crucial for DNA damage-induced senescence.
• Targeting NRF1 presents a promising therapeutic avenue for combating inflammaging and age-related diseases.