Iron status as a confounder in the gender gap in survival under extreme conditions

Zarulli et al. (1) report on male–female survival differences in populations of slaves and populations exposed to severe famines and epidemics. Although the facts are clear and convincing, attention should be paid to the role of iron as a confounder in explaining the gender-based mortality differences. Because iron is scanty in the biosphere, human populations in Europe and Africa have been selected based on iron conservation (2). In particular, Celtic, Viking, and Bantu populations have undergone an iron-driven genetic selection (2, 3). On the other hand, iron conservation makes populations more prone to siderophilic infections and vitamin C deficiency (4–6). Among famine victims, scurvy is a common cause of death (4). As women generally have smaller body iron stores compared with men, they are less prone to develop scurvy or infections with siderophilic microorganisms under extreme situations like those described in the Zarulli et al. (1) study (famines and epidemics). It is striking that all but one of the seven populations selected by Zarulli et al. are characterized by high allele frequencies of iron-conserving mutations [Q248H ferroportin and hemoglobin S (Liberia, Trinidad), HFE C282Y (Ireland, Iceland, and Sweden)] or suffering from siderophilic infections (dysenteria). In the case of Liberia, a high prevalence of hemoglobin S carriers (a condition associated with iron overload) is present, exceeding those of the neighboring countries (7). During the Irish famine, scurvy was a major cause of death, which has been linked to the extremely high HFE C282Y allele frequency in Ireland (4).

Except for the slave population of Trinidad, in all of the other cases described by Zarulli et al. (1), starvation, dysentery, and diarrhea are likely to have been major causes of death. Hereby, it is noteworthy to state that Shigella, enteropathogenic Escherichia coli, and Entamoeba histolytica (the main microorganisms involved in dysentery) are siderophilic microorganisms (8–10). Exposure of bacteria to members of the stress-associated catecholamine hormones, principally norepinephrine, has been demonstrated to increase both growth and production of virulence-related factors. Mutation of genes for enterobactin synthesis and uptake revealed an absolute requirement for enterobactin in norepinephrine-stimulated growth of E. coli O157:H7. In conditions of extreme stress, like the ones described by Zarulli et al. (1), the stress hormone norepinephrine promotes iron shuttling between transferrin molecules, thereby enabling the bacterial siderophore enterobactin to more readily acquire iron for growth (10). The stress-associated hormonal output may affect enterohemorrhagic E. coli pathogenicity (10).

The gender gap in life expectancy coincides with the gender gap in iron status and reduces after menopause, which further supports the role of iron in this respect. Next to social factors, genetic particularities affecting iron metabolism of populations at risk also might contribute to the explanation of the gender gap in survival.