Epigenetics of the developing and aging brain: Mechanisms that regulate onset and outcomes of brain reorganization

Abstract

Brain development is a life-long process that encompasses several critical periods of transition, during which significant cognitive changes occur. Embryonic development, puberty, and reproductive senescence are all periods of transition that are hypersensitive to environmental factors. Rather than isolated episodes, each transition builds upon the last and is influenced by consequential changes that occur in the transition before it. Epigenetic marks, such as DNA methylation and histone modifications, provide mechanisms by which early events can influence development, cognition, and health outcomes. For example, parental environment influences imprinting patterns in gamete cells, which ultimately impacts gene expression in the embryo which may result in hypersensitivity to poor maternal nutrition during pregnancy, raising the risks for cognitive impairment later in life. This review explores how epigenetics induce and regulate critical periods, and also discusses how early environmental interactions prime a system towards a particular health outcome and influence susceptibility to disease or cognitive impairment throughout life.

Keywords: Aging; Andropause; B-vitamins; DNA methylation; Epigenetics; Estrogen; Histone modification; Menopause; Neurodegeneration; Neurodevelopmental; One-carbon metabolism; Perimenopause; Puberty.

Fig. 1.

One-carbon metabolism utilizes co-factors such as folate, choline, and various other B vitamins (B6, B12, riboflavin), to produce S-adenosylmethionine (SAM), the universal methyl-donor that provides methyl-groups used for DNA, histone, and other protein methylation. Impaired one-carbon metabolism results in loss of SAM production, an accumulation of homocysteine, and can lead to dysregulation of the epigenome.

Fig. 2.

The hypothalamic-pituitary-gonadal axis is activated during puberty by the epigenetic silencing of repressive factors. Kisspeptin expression in the hypothalamus activates GnRH-releasing neurons that signal to the pituitary to synthesize and release LH and FSH. LH and FSH then stimulate estrogen and testosterone production in the ovaries and testes, respectively. During reproductive senescence, pituitary responsiveness to GnRH decreases and LH pulses become desynchronized leading to an impaired sex steroid production and a loss of negative feedback onto the hypothalamus and pituitary. Luteinizing hormone (LH), Follicle stimulating hormone (FSH), Gonadotropin-releasing hormone (GnRH).

Fig. 3.

In humans, menopause is strongly associated with the accelerated epigenetic patterns of aging in blood. Post-menopausal women are “biologically and epigenetically” older than pre-menopausal women of the same chronological age (hypothetically marked along each trajectory as “X”). Epigenetic changes prior to and during the perimenopause transition may provide an explanation for the age-related negative health and cognitive outcomes associated with early menopause.