Proteomic basis of mortality resilience mediated by FOXO3 longevity genotype
FOXO3 is a ubiquitous transcription factor expressed in response to cellular stress caused by nutrient deprivation, inflammatory cytokines, reactive oxygen species, radiation, hypoxia, and other factors. We showed previously that the association of inherited FOXO3 variants with longevity was the res...
Saved in:
Published in | GeroScience Vol. 45; no. 4; pp. 2303 - 2324 |
---|---|
Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Cham
Springer International Publishing
01.08.2023
Springer Nature B.V |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | FOXO3 is a ubiquitous transcription factor expressed in response to cellular stress caused by nutrient deprivation, inflammatory cytokines, reactive oxygen species, radiation, hypoxia, and other factors. We showed previously that the association of inherited
FOXO3
variants with longevity was the result of partial protection against mortality risk posed by aging-related life-long stressors, particularly cardiometabolic disease. We then referred to the longevity-associated genotypes as conferring “mortality resilience.” Serum proteins whose levels change with aging and are associated with mortality risk may be considered as “stress proteins.” They may serve as indirect measures of life-long stress. Our aims were to (1) identify stress proteins that increase with aging and are associated with an increased risk of mortality, and (2) to determine if
FOXO3
longevity/resilience genotype dampens the expected increase in mortality risk they pose. A total of 4500 serum protein aptamers were quantified using the Somalogic SomaScan proteomics platform in the current study of 975 men aged 71–83 years. Stress proteins associated with mortality were identified. We then used age-adjusted multivariable Cox models to investigate the interaction of stress protein with
FOXO3
longevity-associated
rs12212067
genotypes. For all the analyses, the
p
values were corrected for multiple comparisons by false discovery rate. This led to the identification of 44 stress proteins influencing the association of
FOXO3
genotype with reduced mortality. Biological pathways were identified for these proteins. Our results suggest that the
FOXO3
resilience genotype functions by reducing mortality in pathways related to innate immunity, bone morphogenetic protein signaling, leukocyte migration, and growth factor response. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2509-2723 2509-2715 2509-2723 |
DOI: | 10.1007/s11357-023-00740-6 |