Systemic regulation of mammalian ageing and longevity by brain sirtuins

Abstract

Sirtuins regulate numerous important biological processes in mammals, including various age-associated pathophysiologies. However, whether sirtuins are critical to control ageing and longevity in mammals has been controversial. Recent studies have demonstrated critical roles of sirtuins in the brain, especially the hypothalamus, in governing multiple physiological functions. These data provide strong evidence that brain sirtuins regulate mammalian ageing and longevity at the organismal level.

Figure 1. Schematic diagrams of brain sections adapted from the mouse brain atlas (Franklin and Paxinos, 1997)

Sections represent the approximate posterior levels to Bregma −0.58 mm (a), −1.70 mm (b), and −2.30 mm (c). The locations of the hypothalamic nuclei are indicated by the following: LH, lateral hypothalamus; PVN, paraventricular nucleus; SCN, suprachiasmatic nucleus; DMH, dorsomedial hypothalamus; VMH, ventromedial hypothalamus; Arc, arcuate nucleus; PH, posterior hypothalamus.

Figure 2. Sirt1/Nkx2-1/Ox2r-mediated signaling in DMH and LH neurons systemically regulates aging/longevity in mammals

In the dorsomedial and lateral hypothalamic nuclei (DMH and LH, respectively), Sirt1 interacts with and deacetylates Nk2 homeobox 1 (Nkx2-1), increases orexin type 2 receptor (Ox2r) transcription, and enhances neural activation. The neural activation of the DMH and LH guides skeletal muscle to maintain mitochondrial morphology and function through sympathetic nervous tones. Sustaining DMH/LH function during the aging process leads to preserved youthful physiology including physical activity, body temperature, oxygen consumption, and quality of sleep. The crosstalk between the hypothalamus and skeletal muscle might be critical to regulate systemic aging, although this possibility is currently under investigation.

Figure 3. NF-κB signaling in the MBH systemically regulates mammalian aging/longevity

In the medial basal hypothalamus (MBH), NF-κB activation in microglial cells enhances the production and secretion of the inflammatory cytokine TNF-α, leading to the activation of NF-κB in gonadotropin-releasing hormone (Gnrh) neurons. Circulating Gnrh influences systemic aging phenotypes including muscle endurance, the size of muscle fiber, and skin thickness as well as cognitive functions. Supplementation of Gnrh into the brain also upregulates neurogenesis. Sirt1 and Sirt2 might function as an inhibitor of NF-κB activity in the neurons and/or microglia of the MBH during the aging process.

Figure 4. GH/IGF-1 signaling in the systemic regulation of mammalian longevity

Growth hormone-releasing hormone (Ghrh) is secreted from neurons in the arcuate nucleus (Arc) and stimulates growth hormone (GH) secretion from somatotropic cells of the anterior pituitary gland. The GH leads to secretion of insulin-like growth factor-1 (IGF-1) from the liver. GH and IGF-1 have a negative feedback to the hypothalamus for the regulation of Ghrh production/secretion. Gonadotropin-releasing hormone (Gnrh) is secreted from neurons in the Arc and stimulates luteinizing hormone (LH) secretion from gonadotroph cells in the anterior pituitary gland. FGF21, a hepatokine that can promote longevity in mice, enters into the brain and acts on the suprachiasmatic nucleus (SCN) neurons to suppress vasopressin (Avp) that enhances Kiss1 expression in the anteroventral periventricular nucleus of the hypothalamus (AVPV). AVPV neurons stimulate Gnrh neurons that regulate gonadotropin secretion in the pituitary, and receive a positive feedback from the circulating estradiol. Sirt1 and Sirt6 might regulate the function of Gnrh and Ghrh neurons, respectively, in the hypothalamus.