When does the youthfulness of the female brain emerge?

Goyal et al. (1) report in PNAS that the female adult brain has a persistently lower metabolic brain age compared with the male brain at the same chronological age. In interpreting this remarkable finding, the authors propose that sex-related differences in brain development may, in part, play a role in “setting” the female brain at a younger initial brain age at puberty, allowing them to maintain a younger brain throughout adulthood. We argue that this may not be the case and provide evidence to show that, in fact, the opposite may be true during childhood and adolescence.

First, according to figure 2A of ref. 1, surprisingly, the predicted age between 35 and 50 y was underestimated for both males and females. It is unclear if the bias in this age range could have affected the overall findings or played a role in only the result from training on males and testing on females surviving a two-sided t test. Moreover, it is unclear which age range was determinative of the significant difference between predicted and chronological age.

Second, we used cortical thickness, which (i) has been validated as a reliable biomarker for brain age (2, 3) and (ii) has shown strong association with sex hormones during puberty maturation (4, 5) from 265 healthy children and youth (118 boys, 147 girls) between the ages of 5 and 18 y from the NIH MRI Study of Normal Brain Development (6, 7) and estimated the difference between brain age and actual chronological age. Similar to Goyal et al. (1), we first trained the machine learning algorithm (support vector regression with default parameters, implemented using the LIBSVM toolbox) on the male cohort only and then tested it on the female cohort, and vice versa. We found that while cortical thickness-based brain age correlated strongly with actual chronological age in both cohorts (training on boys and testing on girls: r = 0.75, P < 0.001; training on girls and testing on boys: r = 0.71, P < 0.001; Fig. 1A), the mean cortical thickness brain age was, on average, 0.42 y older for girls compared with boys (P = 0.02, two-sided t test; Fig. 1B) when the male data were used as the training set and 0.47 y younger for boys compared with girls (P = 0.03, two-sided t test; Fig. 1B) when the female data were used as the training set. In other words, whereas per Goyal et al.’s investigation, adult females may have a younger brain compared to adult males during development, this pattern is not the same and in fact seems to be in the opposite direction during puberty.

Fig. 1.

Brains of girls are older than brains of boys of the same age. (A) The relationship between brain ages predicted by machine learning and by chronological age. Each dot represents an individual, and lines represent best fits. Predicted brain age for both groups significantly correlated with their chronological age. (B) The difference between predicted and actual ages was higher for girls compared with boys (mean difference, girls versus boys, 0.42 y, P = 0.02, t test) and lower for boys compared with girls (mean difference, boys versus girls, −0.47 y, P = 0.03, t test). The boxplot hinges represent the mean and the first and third quartiles.

While cortical thinning as a biomarker for aging may reflect a different aspect of aging than what metabolic changes may reflect, given that they are both strongly predictive of chronological age, it is likely that they may also be correlated. Therefore, given our finding, we propose that the mechanisms that are involved in keeping the female brain younger in adulthood may get engaged at a later point in life and not during puberty.

Data used in the preparation of this article were obtained from the NIH Pediatric MRI Data Repository created by the NIH MRI Study of Normal Brain Development (7, 8). See NIMH Data Archive DOI:10.15154/1503840 (9).