Age and sex modify the association between plasma Sestrin2 and bone mineral density: a cross-sectional study

Sestrin2 is a stress-inducible protein that plays a significant role in maintaining antioxidant balance and metabolic homeostasis via the AMPK/mTOR pathways. Animal models suggested that Sestrin2 deficiency may be associated with high bone mass; however, how this may translate into humans, especially in aging and stress conditions, is unknown. We performed a cross-sectional analysis of 910 adults recruited from the Qatar Biobank cohort. Participants were stratified into 3 groups: younger than 40 yr, 40-55 yr, and older than 55 yr. We investigated the relationship between plasma Sestrin2 and FN BMD T-score in adults using multiple linear regression, controlling for age, sex, BMI, diabetes, and estimated glomerular filtration rate. We observed a significant interaction between Sestrin2 and age (p < .001). In younger and middle-aged adults, Sestrin2 was not correlated with BMD. However, in adults aged >55 yr, Sestrin2 was strongly and positively correlated with FN T-scores (β = .131, 95% CI: 0.062-0.201, p < .001). This association remained significant after adjustment for all possible confounders, with an effect size reduction of only 7.7%. Further analysis showed that this association is more pronounced in males (β = .155, p < .001) but is not significant in females (β = -.008, p = .935). Our study indicates that Sestrin2 and BMD are significantly correlated but only in aged adults. In contrast to animal models, we showed that Sestrin2 in aged adults is positively correlated with bone density. This suggests that Sestrin2 may serve as a biomarker of resilience against aging-induced stress and osteosenescence. Furthermore, this resilience mechanism appears to be sex-specific, offering protective effects primarily in aging males, likely due to differences in hormonal preservation.