The sex chromosome is not only the determining factor for sexual identity in society but has also been found to have a significance on gene expression and lifespan regulation (Tower, 2017). This gender-based disparity in health has a clear impact as diseases which are related to ageing have shown a marked sex bias in which women exhibit a longer life expectancy in comparison to men (Zarulli et al, 2017). Adolescent to middle aged masculine tendencies to violence result in a reduced life-span heavily measured by homicides, suicides and accidents, the latter half of the male lifespan, cardiovascular diseases, cancer, stroke and Parkinson’s disease account for the gender gap (Holden, 1987). There are thought to be many explanations for this variation which will be discussed along with sex-specific gene expression and life span regulation.
Life span is used as a measure of ageing, however ageing is defined by the exponential increase in mortality rate with ageing also known as the Gompertz parameters, this method can be applied to describe the distribution of adult lifespans using a probability density function (Vaupel, 1986). The Gompertzian pattern of increased mortality rate has been explained by evolution as a result of decline in force of natural selection (Laskshminaryanan and Pitchaimani, 2002) which elucidates the increasing population around the world.
Gender gap correlation with Angiotensin receptor
Females have been shown to exhibit lower hypertension in comparison to age-matched males for majority of lifespan however hypertension then increases for women post menopause, exceeding or equalling men (Beery and Zucker, 2011). Sex differences are observed in the Angiotensin II model of hypertension, studies suggest that the Angiotensin II induced vasodilatory effect observed in females is due to Angiotensin type 2 receptor (AT2R). Angiotensin type 1 receptor (AT1R) is expressed through chondrocyte proliferation while AT2R is expressed in the hypertrophic phase (Ichiro et al, 2013). AT2R is located on the X chromosome therefore heterogametic males receive their AT2R from the maternal X chromosome which may explain why females exhibit a more balanced angiotensin type I and type II receptor ratio, resulting in a pathway of reactions leading to vasodilation and reduced blood pressure (Figure 1) (Ji and Sandberg, 2008).
Uniparental mitochondrial inheritance
Maternal mitochondrial inheritance of genetic material could be a cause of increased male mortality (Clamus et al, 2012). The transmission of mitochondrial genes has been thought to have resulted in superior female control over mitochondria, therefore a longer life span and increased resistance to stress with respect to males. It has been shown that gene expression is altered during the lifespan, this is consistent with maintenance failure of mitochondria as this triggers inflammation, oxidative stress and proteotoxicity response (Tower, 2017). There is a clear evolutionary effect where males inherit deleterious mitochondrial gene mutations directly from their mother also commonly known as the Frank and Hurst Hypothesis or the ‘mothers curse’ (Frank, 2012).This has been proven with over 290 years of evidence in the human population, (Milot et al, 2017) studied a mutation leading to a male biased disease, Leber’s Hereditary optical neuropathy which has been hypothesised to be a result of the mothers curse. Male carrier exhibited lower fitness relative to non-carriers and females, results concluded the mother’s curse contributes to the reduction of male life-span due to a defect in fitness associated with a mitochondrial variant (Milot et al, 2017).
Multiple viable hypotheses explain why uniparental mitochondrial transmission is selectively advantageous; the spread of deleterious mitochondrial genes and cytoplasmic parasites are limited via horizontal transmission, genetic conflicts within mitochondrial alleles within zygote are avoided, damage to mitochondrial genome is prevented which may have affected metabolically operating sperm, additionally evolution of sexes is enabled (Tower, 2014). A study with drosophila is consistent with the theme of mitochondrial genome mutations causing greater disease in male than females where results have confirmed that a sex-specific selectivity in the mitochondrial genome evolution is a clear factor to sexual dimorphism in ageing (Camus, Clancy and Dowling, 2012).
It can be suggested that males may have developed dominant nuclear DNA to compensate for the for their reduced mitochondrial gene function, however these male optimised nuclear genes would then be inherited to the next female generation only further promoting female-specific gene selection (Tower, 2017). This could potentially be a method of promoting evolution (Tower, 2006), extended research would answer the question if and how males do indeed compensate for impaired mitochondrial genes, and if that is susceptible to manipulation to benefit male health.
Sex gene dosing
Females display a mosaicism of the X chromosome which provides protection from X-linked genetic disorders (Sandberg and Ji 2008). Males are heterogametic and so express X-linked recessive mutant phenotype as they do not carry a second X chromosome to contribute a wild-type copy of the gene like females which is thought to be a significant factor in the gender difference in lifespan (Maklakov and Lummaa, 2013). Research has shown that X-linked genes escape from X chromosome inactivation which results in incomplete dosage compensation, being more prevalent in females due to their homogameticity (Tower 2017). This escape is significant in mental disorders and sex-biased cancers, a study has shown that females are susceptible to hyper-mutation in cancers due to replication stress and late S-phase replication in proliferating cells (Jager et al, 2013). However the escape has also been shown to have some beneficial traits to females as G6PD and XIAP mediate increased stress resistance relative to males, CD40LG and OGT are immune regulatory genes which enable higher susceptibility of females to autoimmune disease (Tower, 2017). The extra X chromosome clearly has significant impact on overall health for females which could be explanatory for the gender gap.
Gene expression changes during ageing
Ageing is characterised by a progressive reduction of cellular integrity, resulted from deleterious nuclear gene alleles, females have greater control over mitochondrial functions and are able to adapt to hydrogen peroxide stress (Morrow and Tanguay, 2015), in regards to survival adaptation is key and therefore the sex better susceptible to adaptation will likely survive longer. There have been found to be four common themes for gene expression changes during ageing as studies indicate that patterns of gene expression change through ageing, they are consistent with failure of mitochondrial maintenance which highlights a clear correlation (Tower, 2017). The themes are; down regulation of genes encoding the components of mitochondria, upregulation of innate immune responses, oxidative stress responses and proteotoxicity response (Tower, 2017). The proteotoxicity response is evidenced by decreased ATP production by abnormal DNA leading to decreased protein production and as a result damage-prone proteins remain to exert increased production of reactive oxygen species (ROS) (Morrow and Tanguay, 2015).
Upregulation of immune response genes and down regulation of mitochondrial metabolism genes is a common feature of ageing across brain regions, experiment results have shown mouse transcriptome responded to age and gender in regionally distinctive regions of the brain (Xu et al, 2007). Increased ROS and accumulation of impaired mitochondria is consistent with downregulation of mitochondrial turnover through ageing (Tower, 2017). ROS is known to promote cell differentiation and so it is plausible that increased ROS correlated with increased cell death and thus the ageing process (Seo et al, 2010) Genes involved in protein degradation and oxidative stress resistance are expressed at increased levels in females relative to males, supporting the concept of female control over mitochondrial function, maintenance and superior ability of neurones in females able to resist age-related metabolic and oxidative stress (Xu et al, 2007).
Sex-specific life span interventions and the next steps
Hormone signalling between the sexes can reduce life span as results show that steroid hormones in particular can limit life span across species through a combination of reproductive metabolism, mitochondrial maintenance and somatic maintenance (Tower, 2015). However a study has shown that ageing is slowed when insulin-like signalling is decreased resulting in 50% extended life expectancy in drosophila melanogaster(Hwangbo, 2004). Life-span has also been extended in drosophila where the gene chico encodes insulin receptor substrate, therefore functioning as an insulin-like growth factor signalling pathway regulating increased life span in females (Clancy et al, 2001). However ideally heat stress hormesis and inhibition of the anti-apoptotic mitochondrial protein dTSPO has shown to increase lifespan in male drosophila (Lin et al, 2014).
Growing evidence continues to support that male life span reduction can be due to mitochondrial maintenance failure and so is limited by chronic stress such as inflammatory, oxidative and proteotoxic stress associate with the failure of mitochondrial maintenance (Tower, 2017). Females have a clear genetic advantage due to their second X chromosome which has enabled a more balanced AT1R and AT2R ratio resulting in reduced hypertension, protection against the mothers curse and therefore many genetic diseases, as well as increased stress resistance. Further research in mammalian biological process remain in need of investigation to fulfil the aim of improving overall quality of life and also to facilitate sex-specific ageing and health interventions.
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Global Health Challenges 