In the target article, self-protection as an adaptive female strategy (Benenson et al., Reference Benenson, Webb and Wranghamthis issue), the authors extend the staying alive theory (SAT; Campbell, Reference Campbell1999) to be a global theory explaining sex differences in physiology and genetics, and gender differences in culture, without describing mechanisms for how each of these could have evolved under the SAT, nor whether these observations are also consistent with other theories. In particular, we take issue with the supposition that sex differences in immune function are explained by the SAT. In contrast, the pregnancy compensation hypothesis (Natri, Garcia, Buetow, Trumble, & Wilson, Reference Natri, Garcia, Buetow, Trumble and Wilson2019) provides mechanistic explanations for the evolution of sex differences in immune function and differences in industrialized and non-industrialized nations. We explain our critiques below.

First, sex differences in immune function are rampant in industrialized populations, with approximately 80% of autoimmune diseases occurring in women. In general, women are nine times more likely than men to develop autoimmune diseases (Ngo, Reference Ngo2014). For example, women have a higher rate than men for rheumatoid arthritis with a 7:1 female to male ratio (National Institute of Arthritis and Musculoskeletal and Skin Disease, 2019) and Alzheimer's disease with a 2.3:1 female to male ratio (Mouton et al., Reference Mouton, Blanc, Gros, Manera, Fabre, Sauleau and David2018). While there are autoimmune diseases in which men have a higher incidence rate than women (e.g., ankylosing spondylitis; Jørgensen, Pedersen, Nielsen, Jacobsen, & Frisch, Reference Jørgensen, Pedersen, Nielsen, Jacobsen and Frisch2012), these are less common in the population. Thus, there are many more autoimmune diseases with a higher incidence in women and there are many more women affected by these diseases than men.

Importantly, the sex difference in autoimmune disease has not been observed in non-industrialized populations, which are more likely to represent an ancestral disease condition. In fact, autoimmune diseases, in general, are less prevalent in non-industrialized countries (Adebajo, Reference Adebajo1997; Clark, Al-Yaman, Cowden, & Rockett, Reference Clark, Al-Yaman, Cowden and Rockett1996; Strachan, Reference Strachan1989). The SAT cannot explain why autoimmune diseases are present (and show a female bias) in industrialized populations but not non-industrialized populations. Unlike the SAT, the pregnancy compensation hypothesis (Natri et al., Reference Natri, Garcia, Buetow, Trumble and Wilson2019) can explain the differences in the incidence of autoimmune diseases for women in industrial versus non-industrialized nations. The pregnancy compensation hypothesis (Natri et al., Reference Natri, Garcia, Buetow, Trumble and Wilson2019) suggests that differences in the prevalence of autoimmune diseases between industrialized and non-industrialized populations are because of ancestral women's immune system evolving to expect to frequently, and shortly after puberty, host a genetically distinct placenta and fetus during pregnancy without rejecting it, while simultaneously protecting the mother from pathogens and parasites. In the absence of frequent pregnancy, or by postponing pregnancy well beyond puberty, women's immune systems are proposed to experience dysregulation, with the resources that would be directed at tolerating a placenta and fetus redirected such that the immune system attacks healthy tissue.

Ancestral women were more likely to give birth closer to the onset of puberty than women are today, but even today women in industrialized nations have a longer delay between menarche and first pregnancy than women in non-industrialized nations. In 2019, the adolescent fertility rate in the United States and the United Kingdom was 17 and 12 per 1,000 women, respectively (United Nations Population Division, 2021), whereas it was 155 per 1,000 in Chad, 180 in Niger, and 165 in Mali (The World Bank, 2022), three of the least developed countries in the world (United Nations Conference on Trade and Development, 2022). Further, in the United States, the average age of a women's first pregnancy in 2014 was 26 years old, up from 21 years old in 1972 (Mathews & Hamilton, Reference Mathews and Hamilton2016), which is older than women in non-industrialized nations, like Bangladesh (Bongaarts & Blanc, Reference Bongaarts and Blanc2015), and Niger (Pariona, Reference Pariona2017) where the average age of first pregnancy is about 18 years old, and among the Tsimane Amerindians of Bolivia, where the average age of first pregnancy is 18 (Gurven, Reference Gurven2012).

Second, counter to the SAT, in industrialized populations where there is evidence of a higher immune response in women than men, autoimmune disease results in significantly higher morbidity in women with autoimmune diseases, and even higher mortality in women than men (as in the case of Alzheimer's disease). The authors argue that heightened risk for autoimmune disorders observed among women is consistent with SAT, in that this is one expression of women's heightened reaction to physical threats. This argument is aligned with the health-survival paradox, also described in the paper, which states that the greater incidence of illness and severity of physical symptoms is offset by the survival enhancing benefits of a strengthened (if overly active) immune response. However, the argument that a greater prevalence of autoimmune disorders supports greater reproductive fitness among women rests on the assumption that autoimmune disorders do not reduce women's fertility. Yet, it is widely acknowledged that autoimmune disorders are associated with an increased risk for miscarriage (Gleicher, Weghofer, & Barad, Reference Gleicher, Weghofer and Barad2012), and there is also evidence to suggest that autoimmune disorders reduce fecundity among women, two outcomes that would reduce reproductive fitness. Moreover, autoimmunity is associated with elevated risk for numerous infertility-linked disorders, including endometriosis, premature ovarian failure, and polycystic ovary syndrome, among other conditions (as reviewed by Haller-Kikkatalo, Salumets, & Uibo, Reference Haller-Kikkatalo, Salumets and Uibo2012). Thus, while it may be true that enhanced survival after reproductive age could increase reproductive fitness by providing opportunities for caregiving investments to be made in older adulthood, reductions in reproductive fitness owing to increased susceptibility to autoimmune disorders would likely outweigh these benefits.

In sum, if the SAT was an evolved process for women, as explained and extended in the target article, it would not differentially impact women based on whether they are in an industrialized versus non-industrialized nation and it would not negatively impact the reproductive success of women through the increased incidence of autoimmune diseases. The sex differences in immune function, the significant increase in autoimmune diseases in women in industrialized populations, and the unique evolution of the sex chromosomes, instead, can all be explained by the pregnancy compensation hypothesis (Natri et al., Reference Natri, Garcia, Buetow, Trumble and Wilson2019).