Molecular Signaling in the Hypothalamus Modulates the Aging Process

IKK is an enzyme complex that is involved in propagating the cellular response to inflammation. It is part of the upstream NF-kappaB signal transduction cascade. A protein inhibitor of kappaB inactivates the NF-kappaB transcription factor by masking the nuclear localization signals of NF-kappaB proteins and keeping them sequestered in an inactive state in the cytoplasm. IKK then specifically phosphorylates the inhibitory protein. This phosphorylation results in its dissociation from NF-kappaB, which activates NF-kappaB.

Transcription factors of the NF-kappaB family are upregulated in many human cancers. NF-kappaB has roles in all stages of carcinogenesis or cancer progression, including protection from cell death, increase of cell proliferation, cell motility and metastasis, tumor inflammation, and angiogenesis. In addition, tumor cells often acquire resistance to anticancer drugs by upregulating NF-kappaB signaling.

Results of mechanistic studies revealed that IKK-beta and NF-kappaB inhibited gonadotropin-releasing hormone (GnRH) to mediate aging-related hypothalamic GnRH decline. GnRH, also known as Luteinizing-hormone-releasing hormone (LHRH), is a 10 amino acid long peptide hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is synthesized and released from neurons within the hypothalamus.

Experiments in mice with modified NF-kappaB expression in the hypothalamus revealed that blockade of NF-kappaB increased life span by up to 20%, while overexpression of NF-kappaB reduced it by a similar amount.

“We are very excited about this. It supports the idea that aging is more than a passive deterioration of different tissues. It is under control, and can be manipulated,” said senior author Dr. Dongsheng Cai, professor of molecular pharmacology at the Albert Einstein College of Medicine.

“Scientists have long wondered whether aging occurs independently in the body’s various tissues or if it could be actively regulated by an organ in the body,” said Dr. Cai. “It is clear from our study that many aspects of aging are controlled by the hypothalamus. What is exciting is that it is possible—at least in mice—to alter signaling within the hypothalamus to slow down the aging process and increase longevity.”

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Albert Einstein College of Medicine