Hypothalamus may hold key to ageing

While the search continues for the Fountain of Youth, researchers may have found the body's ''fountain of ageing'': the brain region known as the hypothalamus.

Dr Dongsheng Cai, M.D., Ph.D.

For the first time, scientists at Albert Einstein College of Medicine of Yeshiva University report that the hypothalamus of mice controls ageing throughout the body. Their discovery of a specific age-related signalling pathway opens up new strategies for combating diseases of old age and extending lifespan. The paper was published today in the online edition of Nature.

''Scientists have long wondered whether ageing occurs independently in the body's various tissues or if it could be actively regulated by an organ in the body,'' says senior author Dongsheng Cai, MD, PhD, professor of molecular pharmacology at Einstein. ''It's clear from our study that many aspects of ageing are controlled by the hypothalamus. What's exciting is that it's possible - at least in mice - to alter signalling within the hypothalamus to slow down the ageing process and increase longevity.''

The hypothalamus, an almond-sized structure located deep within the brain, is known to have fundamental roles in growth, development, reproduction, and metabolism. Dr. Cai suspected that the hypothalamus might also play a key role in ageing through the influence it exerts throughout the body.

''As people age,'' he said, ''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.'' Over the past several years, Dr. Cai and his research colleagues showed that inflammatory changes in the hypothalamus can give rise to various components of metabolic syndrome (a combination of health problems that can lead to heart disease and diabetes).   

To find out how the hypothalamus might affect ageing, Dr. Cai decided to study hypothalamic inflammation by focusing on a protein complex called NF-?B (nuclear factor kappa-light-chain-enhancer of activated B cells). ''Inflammation involves hundreds of molecules, and NF-?B sits right at the center of that regulatory map,'' he said.

In the current study, Dr. Cai and his team demonstrated that activating the NF-?B pathway in the hypothalamus of mice significantly accelerated the development of ageing, as shown by various physiological, cognitive, and behavioural tests. ''The mice showed a decrease in muscle strength and size, in skin thickness, and in their ability to learn - all indicators of aging. Activating this pathway promoted systemic ageing that shortened the lifespan,'' he said.

Conversely, Dr. Cai and his group found that blocking the NF-?B pathway in the hypothalamus of mouse brains slowed ageing and increased median longevity by about 20 percent, compared to controls.

''It's clear from our study that many aspects of ageing are controlled by the hypothalamus. What's exciting is that it's possible - at least in mice - to alter signaling within the hypothalamus to slow down the ageing process and increase longevity," says Dr Cai.

The researchers also found that activating the NF-?B pathway in the hypothalamus caused declines in levels of gonadotropin-releasing hormone (GnRH), which is synthesised in the hypothalamus.

Release of GnRH into the blood is usually associated with reproduction. Suspecting that reduced release of GnRH from the brain might contribute to whole-body aging, the researchers injected the hormone into a hypothalamic ventricle (chamber) of aged mice and made the striking observation that the hormone injections protected them from the impaired neurogenesis (the creation of new neurons in the brain) associated with aging.

When aged mice received daily GnRH injections for a prolonged period, this therapy exerted benefits that included the slowing of age-related cognitive decline, probably the result of neurogenesis. 

According to Dr. Cai, preventing the hypothalamus from causing inflammation and increasing neurogenesis via GnRH therapy are two potential strategies for increasing lifespan and treating age-related diseases. This technology is available for licensing.