When does the youthfulness of the female brain emerge?

Goyal et al., report in the February issue of PNAS that the female adult
brain has a persistently lower metabolic brain age compared with the male brain
at the same chronological age (1). 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
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 the Figure 2A in Goyal et al, surprisingly, the predicted
age between 35-50 y were under-estimated 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 from the NIH MRI
Study of Normal Brain Development (6) and estimated the difference between
brain age and actual chronological age. Similar to Goyal et al., we first trained the
ML algorithm (support vector regression with default parameters, implemented
using 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; Figure 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;
Figure 1B) when the male data was used as the training set and 0.47 y younger
for boys compared with girls (p = 0.03, two-sided t-test; Figure 1B) when the
female data was used as the training set. In other words, while per Goyal and
colleagues’ investigation adult females may have a younger brain than adult
males during development, this pattern is not the same and in fact seems to be in
the opposite direction during puberty.
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.