Adjusting Mouse Longevity via the Hypothalamus

NF-κB shows up in a number of places in longevity research, and it's associated with mechanisms known to mediate the relationship between metabolism and the pace of aging. In particular it is associated with the processes of inflammation, which regular readers will know are significant in the aging process. The immune system falls into a malfunctioning state of worsening chronic inflammation in later life, and this contributes to further degenerative aging to some degree.

Selective inhibition of NF-κB has been shown to extend life span in flies, as well as revert some aspects of skin and blood vessel aging in mice. This might have something to do with diminished inflammation, or it may work through other mechanisms, such as alterations to insulin signaling - which is a whole other collection of genes and biochemistry that often appears in aging research.

Nothing happens in isolation in biology. Many of these longevity-associated genes are involved in low-level processes like transcription that influence all of our biochemistry in some way or another, or take part in so many different mechanisms that it's hard to pin down their effects to some simple, clear, single outcome.

In any case, my attention was directed today to a new study in which researchers manipulate NF-κB in the brain to modestly extend life in mice. Interestingly, this also adds to the short list of interventions that can be used to move life span in either direction. Less NF-κB activity means a longer life, and more of it shortens life. In addition, the authors claim that NF-κB inhibition has a positive influence on neurogenesis in the brain, not just on the state of the immune system. The paper isn't open access, unfortunately, so you might start with this article from the science press by way of an overview:

It's all in the brain! Scientists slow down ageing in mice

The researchers said they have speeded up and slowed down the rate of ageing in laboratory mice by manipulating chemical messengers that affect the hypothalamus, which is known to play a fundamental role in growth, development, reproduction and metabolism. The [study] focused on a molecule known to be central to the many biochemical reactions involved in the process of inflammation, which is important in many age-related conditions. "As people age, you can detect inflammatory changes in various tissues. Inflammation is also involved in various age-related diseases, such as metabolic syndrome, cardiovascular disease, neurological disease and many types of cancer."

By manipulating the levels of the molecule, known as NF-κB, within the hypothalamus, the researchers were able to slow down the rate of ageing and increase longevity of mice by up to 20 per cent. The team also found that they could slow the rate of cognitive decline by up to 50 per cent, which they could measure by how easy the mice remember how to find their way out of a maze.

And here's a link to the paper:

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

Here we show that the hypothalamus is important for the development of whole-body ageing in mice, and that the underlying basis involves hypothalamic immunity mediated by IκB kinase-β (IKK-β), nuclear factor κB (NF-κB) and related microglia-neuron immune crosstalk.

Several interventional models were developed showing that ageing retardation and lifespan extension are achieved in mice by preventing ageing-related hypothalamic or brain IKK-β and NF-κB activation. Mechanistic studies further revealed that IKK-β and NF-κB inhibit gonadotropin-releasing hormone (GnRH) to mediate ageing-related hypothalamic GnRH decline, and GnRH treatment amends ageing-impaired neurogenesis and decelerates ageing.

In conclusion, the hypothalamus has a programmatic role in ageing development via immune-neuroendocrine integration, and immune inhibition or GnRH restoration in the hypothalamus/brain represent two potential strategies for optimizing lifespan and combating ageing-related health problems.

Comments

Perhaps this is one reason for the apparent health benefits of various flavonoids, polyphenols and anthocyanins - e.g.,

"Dietary Polyphenols as Modulators of Brain Functions: Biological Actions and Molecular Mechanisms Underpinning Their Beneficial Effects"
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3372091/

"Neuroprotective Effect of Kaempferol Glycosides against Brain Injury and Neuroinflammation by Inhibiting the Activation of NF-κB and STAT3 in Transient Focal Stroke"
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0055839

Posted by: Lou Pagnucco at May 2nd, 2013 12:41 PM

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