Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH

Abstract

SummaryAging is a result of gradual and overall functional deteriorations across the body; however, it is unknown if an individual tissue works to primarily mediate aging progress and lifespan control. Here we found that the hypothalamus is important for the development of whole-body aging in mice, and the underlying basis involves hypothalamic immunity mediated by IKKβ/NF-κB and related microglia-neuron immune crosstalk. Several interventional models were developed showing that aging retardation and lifespan extension are achieved in mice through preventing against aging-related hypothalamic or brain IKKβ/NF-κB activation. Mechanistic studies further revealed that IKKβ/NF-κB inhibits GnRH to mediate aging-related hypothalamic GnRH decline, and GnRH treatment amends aging-impaired neurogenesis and decelerates aging. In conclusion, the hypothalamus has a programmatic role in aging development via immune-neuroendocrine integration, and immune inhibition or GnRH restoration in the hypothalamus/brain represent two potential strategies for optimizing lifespan and combating aging-related health problems.

Growth hormone modulates hypothalamic inflammation in long‐lived pituitary dwarf mice

“…Immunofluorescent staining for GFAP was less intense in the ARH of 18‐month‐old Ames male mice (Fig. 3) compared to littermate control mice ( P  < 0.05), consistent with other work associating long lifespan with lower hypothalamic inflammation (Zhang et al ., 2013). Thus, Ames dwarf mice resemble CL mice in that both mice have lower levels of hypothalamic inflammation.…”

“…Recent evidence has suggested that hypothalamic inflammatory pathways may influence mouse lifespan in either direction (Zhang et al ., 2013). Activation of NF‐kB dependent cytokine production and glial activity increases with age in the hypothalamus, and augmentation of this effect, either genetically or by viral‐mediated gene delivery, can shorten mouse lifespan (Zhang et al ., 2013).…”

“…Activation of NF‐kB dependent cytokine production and glial activity increases with age in the hypothalamus, and augmentation of this effect, either genetically or by viral‐mediated gene delivery, can shorten mouse lifespan (Zhang et al ., 2013). More impressively, blunting hypothalamic inflammatory signals can increase lifespan in mice (Zhang et al ., 2013).…”

“…Activation of NF‐kB dependent cytokine production and glial activity increases with age in the hypothalamus, and augmentation of this effect, either genetically or by viral‐mediated gene delivery, can shorten mouse lifespan (Zhang et al ., 2013). More impressively, blunting hypothalamic inflammatory signals can increase lifespan in mice (Zhang et al ., 2013). Glial activity and production of mRNA for the inflammatory cytokine TNF‐α are diminished in CL mice (Sadagurski et al ., 2015), consistent with the idea that lower hypothalamic inflammation may modulate aging processes and lifespan in mice.…”

Anti‐inflammaging effects of human alpha‐1 antitrypsin

“…DNA damage response and its downstream GATA4, p38MAPK, and mTOR pathways regulate SASP (Rodier et al ., 2009; Freund et al ., 2011; Kang et al ., 2015; Laberge et al ., 2015). All of these pathways converge on NF‐ĸB, the master transcription regulator that controls the expression of immune‐responsive genes (Zhang et al ., 2013; Guo et al ., 2014). A recent study showed SASP gene expression required cGMP‐AMP (cGAMP) synthase (cGAS) in mouse and human senescence model in vitro induced by DNA damage and ionizing radiation (Yang et al ., 2017).…”