The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 16 No. 9 • October 2013

Mechanism of Systemic Aging
Controlled by the Hypothalamus

A new paper1 reports the important discovery that activation of innate immunity in the hypothalamus plays a key role in aging. The researchers found that “through activating or inhibiting immune pathway IKK-beta and NF-kappaB in the hypothalamus of mice, we were able to accelerate or decelerate the ageing process, leading to shortened or increased lifespan.”

The researchers found that there was a direct link between IKK-beta and NF-kappaB activation and gonadotropin-releasing hormone (GnRH) decline. GnRH regulates the release of sex hormones and, hence, controls reproduction. The researchers found that GnRH release decreased in GT1-7 cells, a cell line of GnRH neurons, after IKK-beta and NFkappaB activation, but increased after IKK-beta and NFkappaB inhibition. Focusing on the effect of GnRH on aging, the scientists found that delivering the hormone into the third ventricle of the hypothalamus of old mice caused increased adult neurogenesis, whereas neurogenesis normally declines with age. In fact, administration of GnRH via peripheral injections (that is, outside of the brain) ameliorated age-related cognitive decline. (The authors note that certain areas of the brain that are sensitive to GnRH are actually located outside of the blood-brain barrier, thus permitting GnRH to reach the brain from the periphery. The mechanism for the peripheral anti-aging effects of GnRH requires additional study.)

The scientists found, further, that reduced hypothalamic release of GnRH also contributed to other aspects of aging, including declining muscle strength, skin atrophy, bone loss, memory impairment, in addition to (as noted above) adult neurogenesis.

The researchers discovered that while NFkappaB signaling increased in many regions of the brain in aging mice, this increase was greatest in the hypothalamus. Part of their earlier work that led up to this latest discovery revealed that “infection-unrelated inflammatory changes in the mediobasal hypothalamus contribute to the development of various metabolic syndrome components, and the molecular basis is mediated crucially by NF-kappaB and its upstream IKK-beta.”1

Earlier work has also reported NFkappaB involvement in aging processes. For example, another recent paper2 found that the mechanism by which DNA damage drives aging is due in part to NFkappaB activation. A recent review3 reported that transcriptional activation of NFkappaB is increased in a variety of tissues with aging and associated with age-related degenerative diseases such as Alzheimer’s disease, diabetes, and osteoporosis. The review also reports that inhibition of NFkappaB in mouse models has been shown to delay onset of age-related symptoms and pathologies.

Moreover, NFkappaB has been implicated in aging in much earlier work. One paper from 19974 reported that “NFkappaB … exists in a constitutively activated state in cells obtained from the major lymphoid organs of aged animals.” One earlier paper5 found that overnutrition activated hypothalamic IKKbeta/NF-kappaB at least in part by elevated endoplasmic reticulum stress, a mechanism that has also been identified in diabetes. Yet another paper6 reports that depressive-like behaviors in mice subjected to chronic unpredictable stress are mediated by NFkappaB signaling in the adult hippocampus.

Hydrogen Modulation of NF-KappaB Reported In Three Papers

Research on the mechanisms of hydrogen therapy is in early stages, but three papers have reported it to modulate NF-kappaB activation. In one paper,7 hydrogen-rich saline was tested as a treatment in a rat model of amyloid-beta-induced Alzheimer’s disease. Amyloid beta has been found to induce neuronal cell death via ROS (reactive oxygen species) mediated by NF-kappaB activation. In this study,7 NF-kappaB activation in the hippocampus was inhibited by the hydrogen-rich saline. In another paper,8 hydrogen-rich saline prevented neointima (atherosclerotic plaque) formation that followed carotid balloon injury by suppressing ROS and the TNF-alpha/NF-kappaB pathway. In another paper,9 NF-kappaB activation increased early and transiently in response to ventilator-induced lung injury in mice, providing protection against apoptosis and inflammation. This is an example of how timing can be a key factor in determining the effect of a powerful molecule such as NF-kappaB. As the authors comment, “[t]he function of NF-kappaB activation during VILI [ventilator-induced lung injury] has not been fully elucidated and conflicting roles for NF-kappaB, protective and injurious, have been proposed.”9 On the one hand, NF-kappaB triggers upregulation of genes involved in inflammation, infection, and stress responses and, on the other hand, it mediates a cellular survival mechanism against apoptotic cell death. Hence, an early transient increased activation of NF-kappaB might provide a protective effect against the early stages of induced cell death and, if not prolonged, not increase inflammatory and stress responses. Further research is required to unravel the complex timing process.

Finally, a new paper10 reported that treatment of TNF-alpha-induced cell injury in neonatal rat osteoblasts (bone forming cells) with hydrogen dissolved in vehicle inhibited the TNF-alpha-induced activation of the NF-kappaB pathway. This resulted in reduced oxidative stress, preservation of mitochondrial function, suppression of inflammation, and enhancement of nitric oxide availability. The authors note that circulating NO level is reduced and correlated with osteoporosis in aged rats and ovariectomized rats, suggesting (they propose) that hydrogen might be a useful way to treat osteoporosis.

Natural Products That Inhibit IkappaB Kinase (IKKbeta)

Other natural products have been reported to inhibit IKKbeta and/or NFkappaB. For example, the anti-inflammatory parthenolide, a major component of the medicinal herb Feverfew has been reported to directly bind to and inhibit IKKbeta11 and that this results in the inactivation of NFkappaB.

As NFkappaB is involved in many functions, including importantly beneficial activities (such as cellular pro-survival pathways), the key to the use of NFkappaB suppression for optimal anti-aging is to target it to reduce its activity in areas such as the hypothalamus, where overactivity links it to aging-induced changes. Hydrogen easily passes the blood-brain barrier to enter the hypothalamus.

Toll-Like Receptors Play a Crucial Role in the Signaling Pathways Which Lead to Nf-Kappab Activation

Toll-like receptors are molecules that, as part of the innate immune system, recognize structures of microbes (such as LPS, lipopolysaccharide, a component of Gram-negative bacterial cell walls, viral or bacterial nucleic acids, and proteins unique to microbes), thereby activating immune system response. Importantly, “Toll-like receptors (TLRs) play a crucial role in the signaling pathways which lead to NFkappaB activation. TLR4 is considered the lipopolysaccharide (LPS) receptor.”12 A new paper12 ­reports that molecules that activate the mu opioid receptor (such as morphine) decreases TLR4 in mouse macrophages, thus acting as a powerful immunesuppressive agent. In fact, the paper12 reports, “[a] series of studies have demonstrated that MOR [mu opioid receptor] activation is responsible for most of the immunosuppressive effects of opioids.”

We report this interesting and important link between toll-like receptors, opioids, and NF-kappaB, but do not propose that mu opioid agonists (such as morphine) be used to reduce the activation of TLRs for the purpose of decreasing NF-kappaB signaling and reducing immune system inflammation. The risk there is, aside from opioid addiction, that too much suppression of TLRs could increase the risk of infection. As the authors12 note, excessive immunosuppression is a risk when using opioids such as morphine for pain control. We think that the use of hydrogen therapy or other natural products that modulate the effects of NF-kappaB, such as parthenolide (from the herb feverfew),13 offer a safer approach to decreasing excessive activation of NF-kappaB.


  1. Zhang et al. Hypothalamic programming of systemic ageing involving IKK-beta, NF-kappaB and GnRH. Nature. 497:211-6 (2013).
  2. Tilstra et al. NFkappaB inhibition delays DNA damage-induced senescence and aging in mice. J Clin Invest. 122(7):2601-12 (2012).
  3. Tilstra et al. NF-kappaB in aging and disease. Aging Dis. 2(6):449-65 (2011).
  4. Spencer et al. Constitutive activation of NF-kappaB in an animal model of aging. Int Immunol. 9(10):1581-8 (1997).
  5. Koo et al. Nuclear factor-kappaB is a critical mediator of stress-impaired neurogenesis and depressive behavior. Proc Natl Acad Sci USA. 107(6):2669-74 (2010).
  6. Zhang et al. Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell. 135:61-73 (2008).
  7. Wang et al. Hydrogen-rich saline reduces oxidative stress and inflammation by inhibit of JNK and NF-kappaB activation in a rat model of amyloid-beta-induced Alzheimer’s disease. Neurosci Lett. 491:127-132 (2011).
  8. Qin et al. Hydrogen-rich saline prevents neointima formation after carotid balloon injury by suppressing ROS and the TNF-alpha/NF-kappaB pathway. Atherosclerosis. 220:343-50 (2012).
  9. Huang et al. Hydrogen inhalation reduced epithelial apoptosis in ventilator-induced lung injury via a mechanism involving nuclear factor-kappa B activation. Biochem Biophys Res Commun. 408:253-8 (2011).
  10. Cai et al. Treatment with hydrogen molecule alleviates TNF-alpha-induced cell injury in osteoblast. Mol Cell Biochem. 373:1-9 (2013).
  11. Kwok et al. The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IkappaB kinase. Chem Biol. 8:759-66 (2001).
  12. Franchi et al. Mu opioid receptor activation modulates Toll like receptor 4 in murine macrophages. Brain Behav Immun. 26:480-8 (2012).
  13. Dai et al. The NF-kappaB inhibitor parthenolide interacts with histone deacetylase to induce MKK7/JNK1-dependent apoptosis in human acute myeloid leukaemia cells. Br J Haematol. 151(1):70-83 (2010).

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