Why the ageing brain loses metabolic resilience when sex hormones fall, and why that loss is not the same in women and men.
Hormonal decline is not a uniform event. It unfolds gradually in men and abruptly in women across the menopause transition, and the organ that absorbs it is the most metabolically demanding one in the body. Both sex and gonadal hormone deficiency are strongly associated with neurodegeneration (McGovern et al., 2024), yet the biology linking the two is still described mostly in outline. We work on the part of that biology we consider decisive, which is what happens to brain energy metabolism once hormonal support is withdrawn.
Mitochondria are not only the site of energy production. They buffer calcium, set the balance of oxidative stress, and determine whether a cell survives or dies. Estrogens and androgens act on all of this, regulating mitochondrial biogenesis, dynamics, respiration and stress response. When hormonal signalling recedes, the question is not whether mitochondria are affected. It is what fails first, and in which cells.
We work mainly in astrocytes. They manage the metabolic environment neurons depend on, they express estrogen receptors, and they are among the first cells to meet metabolic and inflammatory challenge. We measure respiration and glycolytic function directly, we track mitochondrial integrity and dynamics under hormonal manipulation, and we test compounds with clinical relevance, including estradiol and tibolone, alongside receptor-selective approaches with particular attention to estrogen receptor beta.
Tibolone, a compound already in clinical use for menopausal symptoms, is one of the routes we use to test whether hormonal support can be restored at the level of mitochondrial function.
Hormone therapy and metabolic reprogramming.
Tibolone exerts neuroprotective actions mediated by estrogen receptors (Del Río et al., 2020).
We do not study hormonal loss on its own. The ageing brain faces lipotoxic and inflammatory pressure at the same time that hormonal support declines. Saturated fats such as palmitic acid accumulate in cells that were never built to store them, and the stress that follows interacts with the hormonal environment rather than running beside it. Our work indicates that male and female astrocytes absorb that combined pressure differently. This is why biological sex is a primary design variable in our experiments and never a subanalysis.
Sex differences in human astrocytes exposed to palmitic acid.
Population studies can show that the menopause transition marks a shift in brain health trajectory. They cannot show why. This is where causality is established, and it is what allows the rest of our programme to speak about mechanism rather than association.
