Abstract
Aging represents one of the most complicated and highly integrated somatic processes. Healthy aging is suggested to rely upon the coherent regulation of hormonal and neuronal communication between the central nervous system and peripheral tissues. The hypothalamus is one of the main structures in the body responsible for sustaining an efficient interaction between energy balance and neurological activity and therefore likely coordinates multiple systems in the aging process. We previously identified, in hypothalamic and peripheral tissues, the G protein-coupled receptor kinase interacting protein 2 (GIT2) as a stress response and aging regulator. As metabolic status profoundly affects aging trajectories, we investigated the role of GIT2 in regulating metabolic activity. We found that genomic deletion of GIT2 alters hypothalamic transcriptomic signatures related to diabetes and metabolic pathways. Deletion of GIT2 reduced whole animal respiratory exchange ratios away from those related to primary glucose usage for energy homeostasis. GIT2 knockout (GIT2KO) mice demonstrated lower insulin secretion levels, disruption of pancreatic islet beta cell mass, elevated plasma glucose, and insulin resistance. High-dimensionality transcriptomic signatures from islets isolated from GIT2KO mice indicated a disruption of beta cell development. Additionally, GIT2 expression was prematurely elevated in pancreatic and hypothalamic tissues from diabetic-state mice (db/db), compared to age-matched wild type (WT) controls, further supporting the role of GIT2 in metabolic regulation and aging. We also found that the physical interaction of pancreatic GIT2 with the insulin receptor and insulin receptor substrate 2 was diminished in db/db mice compared to WT mice. Therefore, GIT2 appears to exert a multidimensional “keystone” role in regulating the aging process by coordinating somatic responses to energy deficits.
Highlights
The natural aging process is associated with an accumulation of molecular perturbations affecting almost all cells, tissues and organs of the body
Compared to wild type (WT) mice, over the 48-h Comprehensive Lab Animal Monitoring System (CLAMS)-assessment period, we found that male GIT2 knockout (GIT2KO) mice demonstrated significantly lower levels of VO2, VCO2, and RER (Respiratory Exchange Ratio) (Figures 1A–C)
Performing such an analysis with primary proteinbased data, extracted from different aged samples of an endocrine organ thought to house the regulatory machinery of aging, i.e., the hypothalamus [24], we identified the G protein-coupled receptor (GPCR)-interacting protein G protein-coupled receptor kinase interacting protein 2 (GIT2) as a “keystone” of the aging process
Summary
The natural aging process is associated with an accumulation of molecular perturbations affecting almost all cells, tissues and organs of the body. The importance of the efficiency in glucose metabolism in the aging process is underscored by the demonstration that multiple glucose-regulatory factors in nematode worms were major age-regulating genes, e.g., daf-2 [insulin receptor analog [9]] and age-1 [phosphoinositide 3-kinase analog – a primary downstream factor of insulin receptor functions [10]]. Translation of these fundamental insulin/ glucose-mediated life span alterations from nematodes to higher organisms has proven problematical: a situation likely due to the increased functional diversity of insulin/insulin-related ligands in more complex, higher organisms. Experimental paradigms in rhesus macaques that attenuate age-related glycemic disruption and increase insulin sensitivity (i.e., caloric restriction) can significantly reduce the incidence of age-dependent pathologies [12]
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