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The carotid body (CB) is a neuroepithelial tissue consisting of O 2 -sensitive glomus cells that constantly scan the arterial blood for O 2 and generate a discharge as an inverse function of O 2 content. Aging is a cumulative result of decreased O 2 supply paralleled by a decreased O 2 tissue demand and oxidative damage to cells derived from aerobic metabolism. Here we studied how CB affects the aging process. This is a study of CB ultrastructural morphometry and immunohistochemical expression of proteins underlying CB responsiveness. The study was based on human CBs obtained from cadavers of people who died due to traumatic events in young and old age. The study was supplemented by investigations of CBs obtained from young and old rats subjected to chronic normoxic and hypoxic conditions. We found changes in the old normoxic CBs akin to the effects of chronic hypoxia such as enhanced extracellular matrix, reduced synaptic contacts between glomus cells, fewer glomus cells, secretory vesicles, and mitochondria. These changes were accompanied by enhanced expressions of hypoxia-inducible factor one-alpha (HIF-1α), vascular endothelial growth factor (VEGF), and nitric oxide synthase (NOS2). We conclude that hypoxia and aging share a common background consisting of deficient O 2 tissue supply, mitochondrial dysfunction, and a limited ability to deal with increased cellular oxidative stress. Aging leads to adaptative reductions in CB responsiveness to hypoxia shifting the chemosensory setpoint upward. We submit that the attenuated CB sensitivity at old age may be tantamount to "physiological denervation" leading to a gradual loss of the chemosensing role in the prevention of tissue hypoxia by increasing lung ventilation., Competing Interests: Conflicts of Interest The authors declare no conflict of interest concerning this article., (Copyright © 2023 Elsevier B.V. All rights reserved.)

We present a proteomic analysis of the rat carotid body (CB) preparation by comparison between normoxia and hypoxia. Proteomic investigation would be helpful to identify the stress-induced protein during hypoxia and to know what O(2) species are being sensed by CB cells. Adult Wistar rats were used, one group was kept in room air (21% O(2)) as control, and the other was kept in a Plexiglas chamber for 12 days in chronic hypoxia (10-11% inspired oxygen). A total protein extract for each lysated tissue was separated using a broad pH range no-linear IPG strip (3-10) and the second dimension was performed on a 9-16% polyacrylamide gel. Exposure to hypoxia for 12 days produced significant changes in protein expression, providing an initial insight into the mechanism underlying differences in susceptibility to hypoxia. Further investigation is needed to have an overview of the specific set of proteins present in the CB and the functions of such proteins in signal transduction and adaptation during hypoxia.

Hypoxia transiently increases transcription of the gene encoding heme oxygenase-1 (HO-1) and potently activates production of endothelin-1 (ET-1), the latter of which plays a central role in cellular adaptation to hypoxia. The ventilatory response to hypoxia attenuates with aging, and decreased responsiveness to hypoxia is seen in the aged vs. young rats, suggesting that the functionality of the oxygen-sensitive mechanism is age-dependent. In the present study, we examined the effects of aging on the expression of HO-1 and ET-1 in the carotid body, which is a small cluster of chemoreceptors and supporting cells that measure changes in the composition of arterial blood flowing through it. Our results revealed that HO-1 and ET-1 were expressed in carotid bodies of both young and old rats, although less so in the old ones. Exposure to chronic intermittent hypoxia significantly increased both HO-1 and ET-1 immunoreactivity in both young and old carotid body tissues, with the persisting age-dependent inequality to the disadvantage of old age. Considering that ET-1 is capable of enhancing intermittent hypoxia-induced chemosensory responses by the carotid body, our results suggest that decreased induction of ET-1 and HO-1 during aging could form the basis for age-related reductions in chemosensory discharge.

Aging is characterized by a lower homeostatic capacity and the carotid body (CB) plays an important role during aging. Here, we sought to elucidate whether the aging effects on the oxygen-sensitive mechanisms in CB cells occur through a reduction of the contact surfaces in the synaptic junctions. The hypothesis was that the CB would undergo a "physiological denervation" in old age. Two groups of male Wistar rats, young (2-3 months old) and senescent (22 months old) were used. CBs were rapidly dissected and the specimens were subjected to a routine transmission electron microscopic procedure. Expressions of HIF-1 proportional, variant, VEGF and NOS-1 were evaluated by immunohistochemical analysis. Our results show that in the old CB, HIF-1 proportional, variant, VEGF and NOS-1 expressions decrease. The cell volume, the number of mitochondria and that of dense-cored vesicles were reduced, and the nucleus shrank. There also was an accumulation of lipofuscin and a proliferation of extracellular matrix. Most importantly, there were fewer synaptic connections between chemoreceptor cells. The total number of synapses observed in all electronograms decreased from 125 in the young to 28 in the old CB. These results suggest the aging CB undergoes a "physiological denervation" leading to a reduction in homeostatic capacity. The age-related reduction of synaptic junctions may be a self-protective mechanism through which cells buffer themselves against reactive oxygen species accumulation during aging.

Neuroglobin (Ngb) is a member of the vertebrate globin family expressed particularly in the brain and in the retina. Ngb is concentrated in the mitochondria-containing areas of neurons, and its distribution is correlated with oxygen consumption rates. Previously we have shown that Ngb is expressed in carotid body (CB) tissues. Considering that hypoxia and aging may be linked through a series of adaptive and protective mechanisms (e.g. reduction in mitochondrial numbers), we investigate the role of Ngb during aging and hypoxia. Two groups of six rats (age-matched 3 and 24 months old) were kept in room air as a control groups, the others two groups were kept in a Plexiglas chamber for 12 days in chronic hypoxia (10-12% inspired oxygen). The presence of Ngb in the CB tissue was detected by immunohistochemistry using a polyclonal antibody. Ngb immunoreactivity was significantly higher in CB tissues from young rats exposed to chronic intermittent hypoxia, whereas CB tissues from old rats did not show any significant increase in Ngb levels after hypoxia. Similar to hemoglobin, Ngb may act as a respiratory protein by reversibly binding gaseous ligands NO and O(2) and could act as a NO scavenger and participate in detoxification of Reactive Oxygen Species (ROS) generated under hypoxic conditions.