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Neuronal senescence is a major risk factor for the development of many neurodegenerative disorders. The mechanisms that drive neurons to senescence remain largely elusive; however, dysregulated mitochondrial physiology seems to play a pivotal role in this process. Consequently, strategies aimed to preserve mitochondrial function may hold promise in mitigating neuronal senescence. For example, dietary restriction has shown to reduce senescence, via a mechanism that still remains far from being totally understood, but that could be at least partially mediated by mitochondria. Here, we address the role of mitochondrial inorganic polyphosphate (polyP) in the intersection between neuronal senescence and dietary restriction. PolyP is highly present in mammalian mitochondria; and its regulatory role in mammalian bioenergetics has already been described by us and others. Our data demonstrate that depletion of mitochondrial polyP exacerbates neuronal senescence, independently of whether dietary restriction is present. However, dietary restriction in polyP‐depleted cells activates AMPK, and it restores some components of mitochondrial physiology, even if this is not sufficient to revert increased senescence. The effects of dietary restriction on polyP levels and AMPK activation are conserved in differentiated SH‐SY5Y cells and brain tissue of male mice. Our results identify polyP as an important component in mitochondrial physiology at the intersection of dietary restriction and senescence, and they highlight the importance of the organelle in this intersection. [ABSTRACT FROM AUTHOR]

The LPBN (lateral parabrachial nucleus) plays an important role in feeding control. CGRP (calcitonin gene‐related peptide) LPBN neurons activation mediates the anorectic effects of different gut‐derived peptides, including amylin. Amylin and its long acting analog sCT (salmon calcitonin) exert their anorectic actions primarily by directly activating neurons located in the area postrema (AP). A large proportion of projections from the AP and the adjacent nucleus of the solitary tractNTS to the LPBN, are noradrenergic (NA), and amylin‐activated NAAP neurons are critical in mediating amylin's hypophagic effects. Here, we determine the functional role of NAAP amylin activated neurons to activate CGRP and non‐CGRP LPBN neurons. To this end, NA was specifically depleted in the rat LPBN through a stereotaxic microinfusion of 6‐OHDA, a neurotoxic agent that destroys NA terminals. While amylin (50 μg/kg) and sCT (5 μg/kg) reduced eating in sham‐lesioned rats, no reduction in feeding occurred in NA‐depleted animals. Further, the amylin‐induced c‐Fos response in the LPBN and c‐Fos/CGRP colocalization were reduced in NA‐depleted animals compared to controls. We conclude that AP → LPBN NA signaling, through the activation of LPBN CGRP neurons, mediates part of amylin's hypophagic effect. [ABSTRACT FROM AUTHOR]