Comparative endocrinology of aging and longevity regulation

Abstract

Hormones regulate growth, development, metabolism, and other complex processes in multicellular animals. For many years it has been suggested that hormones may also influence the rate of the aging process. Aging is a multifactorial process that causes biological systems to break down and cease to function in adult organisms as time passes, eventually leading to death. The exact underlying causes of the aging process remain a topic for debate, and clues that may shed light on these causes are eagerly sought after. In the last two decades, gene mutations that result in delayed aging and extended longevity have been discovered, and many of the affected genes have been components of endocrine signaling pathways. In this review we summarize the current knowledge on the roles of endocrine signaling in the regulation of aging and longevity in various animals. We begin by discussing the notion that conserved systems, including endocrine signaling pathways, "regulate" the aging process. Findings from the major model organisms: worms, flies, and rodents, are then outlined. Unique lessons from studies of non-traditional models: bees, salmon, and naked mole rats, are also discussed. Finally, we summarize the endocrinology of aging in humans, including changes in hormone levels with age, and the involvement of hormones in aging-related diseases. The most well studied and widely conserved endocrine pathway that affects aging is the insulin/insulin-like growth factor system. Mutations in genes of this pathway increase the lifespan of worms, flies, and mice. Population genetic evidence also suggests this pathway's involvement in human aging. Other hormones including steroids have been linked to aging only in a subset of the models studied. Because of the value of comparative studies, it is suggested that the aging field could benefit from adoption of additional model organisms.

Keywords: aging; endocrine; hormone; insulin-like growth factor; lifespan; longevity; senescence; signaling.

Figure 1

Endocrine signaling pathways affecting longevity. (A) Role of the conserved IIS signaling pathway in longevity regulation. Insulin-like peptides bind to an insulin/IGF receptor on the plasma membrane. Ligand binding causes dimerization of the receptor, activating the intracellular tyrosine kinase domain. Phosphorylation by the receptor kinase domain activates the PI3 Kinase (PI3K). The signaling activity of PI3K, antagonized by the PTEN phosphatase, activates the Akt kinase. Akt phosphorylates FOXO/DAF-16 which is then sequestered in the cytosol. In the absence of IIS signaling, FOXO translocates to the nucleus and activates transcription of longevity promoting genes. AKT signaling also opposes longevity by activating the TOR pathway, which inhibits autophagy, a pro-longevity process. (B) Endocrine signaling in the C. elegans germline longevity pathway. The germ line stem cells send an unknown signal that allows other tissues to detect that they are present. When the germ line stem cells are ablated, the somatic gonad releases the steroid dafachronic acid that binds to the nuclear hormone receptor DAF-12. It is unclear exactly where DAF-12 acts to receive this signal but the intestine is a possible location. As a result of signaling via DAF-12, DAF-16/FOXO activity increases in the nuclei of intestinal cells. This in turn leads to signaling from the intestine to the other tissues that informs them about status of the DAF-16/FOXO in the intestine. INS-7 promotes IIS signaling which suppresses DAF-16/FOXO activity but DAF-16/FOXO in the intestine can down regulate the expression of INS-7 and this may be one mechanism by which intestinal DAF-16/FOXO controls other tissues. (C) Regulation of longevity by 20-hydroxyecdysone (20E) and juvenile hormone (JH) in insects. JH suppresses reproductive diapause which promotes longevity. JH may also negatively affect longevity in other ways. The receptor(s) to which JH binds is unknown. 20E activates the ecdysone receptor which may reduce longevity. IIS engages in cross talk with both JH and 20E and also reduces longevity via other signaling pathways.