The orexin neuropeptide system: physical activity and hypothalamic function throughout the aging process

Abstract

There is a rising medical need for novel therapeutic targets of physical activity. Physical activity spans from spontaneous, low intensity movements to voluntary, high-intensity exercise. Regulation of spontaneous and voluntary movement is distributed over many brain areas and neural substrates, but the specific cellular and molecular mechanisms responsible for mediating overall activity levels are not well understood. The hypothalamus plays a central role in the control of physical activity, which is executed through coordination of multiple signaling systems, including the orexin neuropeptides. Orexin producing neurons integrate physiological and metabolic information to coordinate multiple behavioral states and modulate physical activity in response to the environment. This review is organized around three questions: (1) How do orexin peptides modulate physical activity? (2) What are the effects of aging and lifestyle choices on physical activity? (3) What are the effects of aging on hypothalamic function and the orexin peptides? Discussion of these questions will provide a summary of the current state of knowledge regarding hypothalamic orexin regulation of physical activity during aging and provide a platform on which to develop improved clinical outcomes in age-associated obesity and metabolic syndromes.

Translational Science: How experimental research has contributed to the understanding of spontaneous Physical Activity and Energy Homeostasis

“…These changes, associated with the sedentary behavior characteristic of the aging process, make older people more susceptible to chronic diseases 40,41 . There is a clear age-related decrease in SPA 42 and energy expenditure 39 . Additionally, elderly people seem to be especially susceptible to compensation in SPA caused by volitional exercise.…”

“…As an example, mice are considered middle-aged when 40 weeks old and senescent when 72 weeks old 44,45 , making studies on aging much more viable in rodents than in humans. Some advances have already been achieved, such as the role of hypothalamic neuropeptides on the decrease of SPA 42 , as discussed in the next session.…”

“…administration resulted in a significant decrease of SPA and increased food intake 49 . Orexin A (hypocretin), another neuropeptide, has also been shown to be involved in the central regulation of SPA 42 . Orexin neurons are concentrated in the lateral hypothalamus (LH), perifornical area, and dorsomedial hypothalamus 42,50 .…”

“…Orexin A (hypocretin), another neuropeptide, has also been shown to be involved in the central regulation of SPA 42 . Orexin neurons are concentrated in the lateral hypothalamus (LH), perifornical area, and dorsomedial hypothalamus 42,50 . Some studies in rodents suggest the effect of orexin A on SPA is more relevant to energy balance than its role on the control of food intake 51 .…”

“…In another study by Teske et al 52 , it was shown that orexin projections from the LH stimulates orexin and dopamine signaling in the SN and promotes SPA. Importantly, a reduced activity of hypothalamic orexin signaling seems to be related to the decrease in spontaneous physical activity during aging 42 . In relation to hormones, insulin and leptin emerge as potential modulators of SPA.…”