Fig 1.
Nonlinear effects of sex on immune aging.
Concept illustrating sex-specific, nonlinear trajectories of immune capacity across the life span. Immune function declines with age in both females (magenta) and males (blue), but differs in timing and slope. In females, immune aging is depicted with a pronounced inflection around menopause, corresponding to abrupt hormonal changes, whereas in males, immune decline is depicted as more gradual, consistent with progressive andropause. Dashed lines represent simplified linear models that fail to capture these sex-by-age dynamics, underscoring the importance of considering nonlinearity in studies of immune aging. This figure was created using BioRender. Baker, C. (2025) https://BioRender.com/ky5yq9h.
Table 1.
Drugs withdrawn or relabeled due to female-biased toxicities.
Fig 2.
Sex differences in clinical pharmacology.
Biological sex influences all phases of clinical pharmacology. During drug absorption, males generally exhibit faster uptake due to lower gastric pH and higher absolute blood flow, whereas females tend to have slower absorption associated with delayed gastric emptying and reduced gut motility. Sex differences also shape drug distribution: males show less inter-drug variability and greater distribution to muscle, kidney, and liver, largely reflecting higher lean muscle mass. By contrast, females exhibit enhanced distribution of lipophilic drugs due to a higher proportion of body fat, but reduced distribution of hydrophilic drugs because of lower total body water. Drug metabolism further diverges by sex, with males displaying faster hepatic metabolism and more consistent enzyme activity, while females have reduced clearance of certain drugs, often in a hormone-dependent manner. Differences in drug excretion compound these effects: males typically have enhanced renal elimination driven by higher glomerular filtration rate (GFR), renal blood flow, and transporter activity, whereas females experience slower elimination and greater drug accumulation due to lower renal filtration and plasma flow. Collectively, these sex-specific differences have important clinical implications. Faster clearance in males often results in reduced drug exposure and efficacy, particularly during chronic dosing, whereas slower clearance in females increases net exposure and the risk of dose-dependent adverse events. This figure was created using BioRender. Baker, C. (2025) https://BioRender.com/uw5c86p.
Fig 3.
Considerations for sex- and age-informed personalized medicine.
Overview of how sex and age can be incorporated across different research stages, from preclinical models through data analysis and clinical studies, to inform precision and personalized medicine. In preclinical studies, inclusion of both sex and age, along with factorial and nonlinear designs improve biological interpretability. Analytical approaches that stratify by sex and age and apply nonlinear and mixed-effects models allow detection of age-dependent and sex-specific patterns. In clinical studies, trial designs powered to detect sex-by-age interactions and systematic recording of reproductive and hormonal histories support more informative outcome and interpretation. Together, these considerations make it easier to translate study findings and make sex- and age-informed care more reproducible and useful. In the “preclinical studies” (left), a mouse, killifish, and a plate of cells are depicted. Following this, the “data analysis” (top middle) is represented through machine learning and “clinical studies” (bottom middle) shows a group of individuals representing both sexes, with different colors used to indicate diverse backgrounds. For “precision medicine,” (right) there is an old male and female, with the young male and female split in half behind them. This figure was created using BioRender. Baker, C. (2025) https://BioRender.com/64fqlw8.