Hormones in Ageing and Longevity by Suresh Rattan & Ramesh Sharma

Author:Suresh Rattan & Ramesh Sharma
Language: eng
Format: epub
Publisher: Springer International Publishing, Cham

9.2.4 Autophagy and Proteostasis Impairment

Autophagy is a conserved cellular turnover process that degrades unwanted cytoplasmic material within lysosomes and is impaired with age. A role for autophagy in hypothalamic agouti-related peptide (AgRP) neurons in the regulation of food intake and energy balance was reported. AgRP is a potent appetite stimulator. Starvation-induced hypothalamic autophagy mobilized neuron-intrinsic lipids to generate endogenous free fatty acids, which in turn up-regulated fasting-induced AgRP levels. Inhibiting autophagy resulted in failure to upregulate AgRP in response to starvation and in constitutive increases in hypothalamic levels of anorexigenic pro-opiomelanocortin and its cleavage product α-melanocyte-stimulating hormone that typically contribute to a lean phenotype (Kaushik et al. 2011; Singh 2011).

Loss of autophagy in hypothalamic pro-opiomelanocortin (POMC: precursor polypeptide to adenocorticotropic hormone ACTH, α-MSH and opioid) neurons decreased α-melanocyte-stimulating hormone (α-MSH) levels, promoted adiposity, impaired lipolysis and altered glucose homeostasis. A reduction with age in POMC hypothalamic autophagy, lipolysis and α-MSH levels was revealed (Kaushik et al. 2012).

Neuropeptide Y (NPY), a neurotransmitter produced in the AgRP neurons, stimulated autophagy in mice hypothalamic neurons and was associated with the concerted activation of the PI3 K, MEK/ERK, and PKA signaling pathways. NPY levels decreased with age (Aveleira et al. 2015a). Since both hypothalamic autophagy and NPY levels decreased with age, modulation of NPY levels could help to ameliorate age-related dysfunctions (Aveleira et al. 2015b).

Cold-induced activation of autophagy in pro-opiomelanocortin (POMC) neurons activated lipophagy and cytosolic lipases in a complementary manner to mediate lipolysis in brown adipose tissue (BAT) and liver in mice (Martinez-Lopez et al. 2016).

Growth hormone (GH) secretion decreased spontaneously during lifespan , and the resulting GH deficiency participates in aging-related morbidity. This deficiency does not involve a defect in the numbers, distribution or activity of hypothalamic GH-releasing hormone (GHRH) neurons but due to an abnormal enlargement of GHRH-positive axons, suggesting neuropeptide accumulation leading to failure of hormone secretion from GHRH neurons. Upon closer examination, ultrastructural changes were detected such as selective impairment of secretory vesicle trafficking in aging GHRH nerve terminals, electron dense precipitates preferentially associated with typical secretory vesicles (100–120 nm in diameter) present in large number within axonal profiles and autophagic vacuoles of various sizes. This appears to be the mechanism most likely to account for the hypothalamic dysfunction of the GH/IGF-1 axis during aging (Alonso et al. 2007). In fact, reduced secretion of GHRH in humans may be the cause of GH secretion decline with age (degli Uberti et al. 1997). The effects of gender, aging, sleep, exercise, glucose levels, nutritional status and negative feedback on GH secretion by the hypothalamus were explored early on (Lim et al. 2000).

The somatotropic axis consists of hormonal signaling pathway from the hypothalamus to the somatotrophs of the anterior pituitary gland resulting in the release of growth hormone (GH), which in turn stimulates the production of insulin-like growth factor-1 (IGF-1) in the liver. Previously, it was believed to only regulate directly proliferation, growth, and the counterregulatory effects on glucose metabolism, but in recent years it has been shown to influence aging-related processes, age-related disease, and ultimately longevity.

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