Growth Differentiation Factor 15 Connects Stress and Ageing in a UK Biobank Cohort

BackgroundThe brain-body energy-conservation model proposes that signals from metabolically active senescent cells, including growth differentiation factor 15 (GDF15), prompt the brain to downregulate systemic energy expenditure, leading to functional decline. However, large-scale human studies testing this hypothesis are lacking. We examined whether circulating GDF15 is associated with physiological and cognitive ageing phenotypes and whether it mediates the relationship between psychological stress and muscle strength. MethodsWe analyzed data from the UK Biobank, a prospective cohort of over 500,000 adults. Circulating GDF15 concentrations were measured using Olink proteomics. Outcomes included insulin resistance (TG/HDL-C ratio), maximum heart rate during fitness testing, hand grip strength, C-reactive protein, telomere length, fluid intelligence, and physical activity. Psychological stress was assessed via self-report. Associations were evaluated using multivariate linear regression adjusting for age and sex. Mediation analysis tested whether GDF15 mediated the association between stress and grip strength. ResultsHigher GDF15 was significantly associated with reduced grip strength ({beta} = -0.180, p < 0.001), higher insulin resistance, lower maximum heart rate, higher C-reactive protein, shorter telomere length, diminished fluid intelligence, and reduced physical activity (all p < 0.001). Mediation analysis demonstrated that GDF15 partially mediated the association between psychological stress and grip strength (indirect effect = -0.053, 95% CI -0.074 to -0.033). ConclusionThese findings support the brain-body energy-conservation model, suggesting that GDF15 serves as a systemic signal linking psychological and cellular stress to declines in physiological and cognitive function. Targeting GDF15 pathways may represent a novel strategy to mitigate stress-related ageing processes. Graphical Abstract CaptionChronic psychological stress increases circulating GDF15, which signals the brain and contributes to systemic ageing phenotypes including reduced muscle strength, lower maximum heart rate, shorter telomere length, higher insulin resistance, and decreased physical activity. Mediation analysis in the UK Biobank (N = 500,000) demonstrated that GDF15 partially mediates the association between stress and reduced muscle strength, supporting the brain-body energy-conservation model. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/25330886v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1294813org.highwire.dtl.DTLVardef@13aef95org.highwire.dtl.DTLVardef@473fa1org.highwire.dtl.DTLVardef@1a27edd_HPS_FORMAT_FIGEXP M_FIG C_FIG