Editors' ChoiceAging

The Source of Youth and Longevity Revealed?

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Science Translational Medicine  05 Jun 2013:
Vol. 5, Issue 188, pp. 188ec93
DOI: 10.1126/scitranslmed.3006620

Who hasn’t wanted to halt the aging process to look and feel younger? Aging of the body is inevitable, and the physiological manifestations range from graying of hair to dementia, diabetes, cardiovascular disease, and ultimately death. Although much is understood about the consequences of aging, very little is known about the underlying causes.

Now, Zhang and colleagues present intriguing new data that implicate the hypothalamus and immune-neuroendocrine mechanisms in the aging process of laboratory mice. Using transgenic mice, viral vectors, and pharmacological manipulations, the authors demonstrate that microglial cells in the mediobasal hypothalamus become increasingly active as animals age. This activation is evidenced by secretion of tumor necrosis factor–α (TNF-α) from these cells, with subsequent increases in the enzyme inhibitor of nuclear factor κB (IκB) kinase-β (IKK-β) and transcription factor nuclear factor κB (NF-κB). By blocking IKK-β, and thereby the activation of hypothalamic NF-κB, the authors were able to extend life and reverse several signs of aging: cognitive dysfunction, muscle weakness, and diminished bone mass. The authors also showed that activation of IKK-β and NF-κB leads to decreased secretion of gonadotropin-releasing hormone (GnRH) by hypothalamic neurons, and that systemic treatment with GnRH decelerates aging in mice that overexpress IKK-β in the hypothalamus.

This work is fundamentally important because it explains how whole-body aging may be controlled by immune-neuroendocrine mechanisms in the hypothalamus. The notion that this system may be targeted therapeutically to combat aging-related conditions is particularly attractive, especially if similar mechanisms are involved in aging of humans.

G. Zhang et al., Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature 497, 211–216 (2013). [Pubmed]

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