# Sirtuin 1 and Hormonal Regulations in Aging
## 3 SIRT1, Hypothalamus, and Endocrine Regulations
### SIRT1 and the Hypothalamic-Pituitary-Gonadal Axis  
The hypothalamic-pituitary-gonadal (HPG) axis involves a complex interaction of hormones that includes the secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland, and the production of sex steroids from the gonads. SIRT1 influences this axis at multiple levels, highlighting its importance for maintaining reproductive health (Figure 2A). Sex hormones orchestrate multiple processes by binding to specific receptors in many organs. The dramatic changes in sex hormone levels that occur naturally during aging predictably alter the function of various systems. Such an example is the loss of the cardiovascular protective effect of estrogens due to decreased estrogen secretion in the permenopausal period in older women [17]. Age-related changes in estrogen-receptors (ER) expression and estrogen production are associated with a higher risk of hypertension, extreme salt sensitivity, increased vascular smooth muscle contractility, and inflammatory pathologies in the rodent kidney [17]. In postmenopausal women, unlike younger adults, the beta subtype of ER dominates over the alpha-ER subtype. Such an imbalance between receptor variations yields a predisposition for cardiovascular problems [18]. Furthermore, sufficient estrogen levels prevent hypertension in young women by inhibiting the sympathetic vasoconstrticr pathway [19], and their decrease after menopause is another risk factor for cardiovascular disease. Decreased levels of both androgens and estrogens lead to impaired antioxidant capacity and decreased NO production in vascular tissues, resulting in proinflammatory and proapoptotic changes [20; 21]. Normal levels of sex hormones have anti-inflammatory effects on adhesion molecules, cytokines, and immune cells in blood vessels. Therefore, their reduced secretion in elderly men and women promotes pathological conditions such as atherosclerosis [17]. Figure 2: SIRT1 regulations on the hypothalamus–pituitary–gonadal (**A**) and hypothalamus–pituitary– liver axes and on metabolic status (**B**). IGF-1 with down arrow means decreased secretion of liver-derived IGF-1 by SIRT1. Changes in gonadotropin levels induced by menopause reduce the peak of LH secretion immediately before ovulation but increase its pulse secretion and that of FSH. Data show a direct negative influence of higher FSH levels on bone density in female mice [22] and on visceral adipose tissue accumulation in 3-month-old male and female C57 BL/6 mice [23]. In midlife women systolic and diastolic blood pressure, pulse pressure, and mean arterial pressure are consistent with a menopause contribution [24]. During postmenopausal life, most estrogens are produced by peripheral aromatization of androgen hormones (an-drostenedone is converted to estrogen and testosterone to estradiol). Because this reaction occurs predominantly in adipose tissue, obese postmenopausal women typically have higher levels of sex hormones (both estrogen and testosterone) [10]. While estrogen synthesis usually declines during menopause and remains low after it, testosterone produced by the ovarian theca cells maintains pre-menopausal levels. Postmenopausal women with higher plasma testosterone levels are at greater risk of developing coronary heart disease and metabolic syndrome [25]. SIRT1 plays a critical role in regulating reproduction through the hypothalamic-pituitary-gonadal axis (Figure 2A). In SIRT1 KO mouse models, levels of gonadotropinreleasing hormone secreted from the hypothalamus are reduced, and, consequently, decreased levels of LH, FSH, and sex hormones and impaired gametogenesis are observed [26; 27]. Furthermore, deacetylation of SIRT1 appears to be a common response in estrogen and insulin signaling for the hormonal regulation of adipocyte autophagy and adipose tissue storage in females [28].