Genetic and Epigenetic Sexual Dimorphism of Brain Cells during Aging

Abstract

In recent years, much of the attention paid to theoretical and applied biomedicine, as well as neurobiology, has been drawn to various aspects of sexual dimorphism due to the differences that male and female brain cells demonstrate during aging: (a) a dimorphic pattern of response to therapy for neurodegenerative disorders, (b) different age of onset and different degrees of the prevalence of such disorders, and (c) differences in their symptomatic manifestations in men and women. The purpose of this review is to outline the genetic and epigenetic differences in brain cells during aging in males and females. As a result, we hereby show that the presence of brain aging patterns in males and females is due to a complex of factors associated with the effects of sex chromosomes, which subsequently entails a change in signal cascades in somatic cells.

Keywords: aging; brain; epigenetic; genetic; sexual dimorphism.

Figure 1

Sex differences in the incidence of diseases in men and women. The font size on a gray background correlates with the % of the incidence of the disease in a given sex [3]. Neurodegenerative or psychiatric diseases are shown in red font, autoimmune diseases are shown in blue font, and pain and social disabling disorders are shown in black font. An underlined font (e.g., male: Sjogren’s syndrome) corresponds to 5%, and the largest font (e.g., male: Myasthenia gravis) corresponds to 25%.

Figure 2

Sex-dependent molecular pathways associated with brain aging. During aging in males, genes associated with synapses, neurons, and dendrites are changed; however, in females, there are transcriptional changes in genes linked with microglia and astrocytes. Moreover, GIT2 gene expression changes in young age switch hypothalamus metabolic pathways that make females more resistant to metabolic changes in old age. Decreased activity through the mTor signaling pathway allows increasing lifespan more among females than males. In comparison to females in males, it is better to increase the male lifespan by decreasing the expression of RIIβ and increasing SIRT6 gene expression. However, some changes that are effective for prolongation of the lifespan in males are ineffective for females, for example, increased expression of the IGF-1 gene in females causes obesity, elevated IL-6 levels, and constant astrogliosis and resistance, whereas in males the same changes in IGF-1 gene expression cause an increase in GluA2 receptors and a decrease of astrogliosis and IL-6 levels with a constant value of choline. Created with BioRender.com.

Figure 3

Sex-dependent differences in structure and function of microglia during normal development. During age, phagocytic activity changes: in females, phagocytic activity appears earlier than in males and unspecific phagocytosis increases with age significantly. However, in males, only pathogen-associated phagocytosis increased with age. At young ages among males, microglial cells participate in the elimination of dendritic spines containing D1 receptors, and in adult age in nociceptive transmission in the spinal cord, whereas in females microglia do not participate in such processes. Metabolic calcium activity of microglia is also different among males and females. In adult males there is an increase in the number of active cells; however, the total number of cells remains constant with age. On the other hand, among females, the ratio of active microglial cells remains constant up to old age, it is increased at this period of development. In female microglia, there are gene expression changes associated with ubiquitination, ionic magnesium transport, and GABAergic and glutamate activity in comparison to males. However, in males, the level of expression of genes of insulin receptors and pathogen-specific response is much higher in comparison to females.

Figure 4

General scheme of production and effects of sex hormones and IGF-1 on the brain (LH—luteinizing hormone; FSH—follicle-stimulating hormone; GH—growth hormone; IGF-1—insulin-like growth factor 1; E1—estrone; E2—estradiol; E3—estriol; T—testosterone; DGT—dihydrotestosterone). Created with BioRender.com.