Hypothalamus: Brain Region May Hold Key to Aging

Hypothalamus: Brain Region May Hold Key to Aging

May 1, 2013 — While the search continues for the Fountain of Youth, researchers may have found the body's "fountain of aging": the brain region known as the hypothalamus. For the first time, scientists at Albert Einstein College of Medicine of Yeshiva University report that the hypothalamus of mice controls aging throughout the body. Their discovery of a specific age-related signaling pathway opens up new strategies for combating diseases of old age and extending lifespan. (Source: sciencedaily.com) 

While the search continues for the Fountain of
 Youth, researchers may have found the body's
 "fountain of aging": the brain region known as the
 hypothalamus. (Credit: © James Steidl / Fotolia)

The paper was published today in the online edition of Nature.

"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 senior author Dongsheng Cai, M.D., Ph.D., professor of molecular pharmacology at Einstein. "It's clear from our study that many aspects of aging 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 aging 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 aging 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 aging, Dr. Cai decided to study hypothalamic inflammation by focusing on a protein complex called NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells). "Inflammation involves hundreds of molecules, and NF-κB 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-κB pathway in the hypothalamus of mice significantly accelerated the development of aging, as shown by various physiological, cognitive, and behavioral 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 aging that shortened the lifespan," he said.

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

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

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The above story is reprinted from materials provided by Albert Einstein College of Medicine.

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Reverse aging: Can science turn back the clock?

Reverse aging: Can science turn back the clock?

Sarah Yang-Berkeley on Friday, February 1, 2013 13:47
Source: futurity.org 

UC BERKELEY (US) — Researchers report they’ve made a major advance in understanding the molecular mechanisms behind aging.

"Studies have already shown that even a single gene mutation can lead to lifespan extension," says Danica Chen. "The question is whether we can understand the process well enough so that we can actually develop a molecular fountain of youth. Can we actually reverse aging? This is something we're hoping to understand and accomplish." (Credit: "youth pill" via Shutterstock)

The team was able to turn back the molecular clock by infusing the blood stem cells of old mice with a longevity gene and rejuvenating the aged stem cells’ regenerative potential.

The biologists found that SIRT3, one among a class of proteins known as sirtuins, plays an important role in helping aged blood stem cells cope with stress. When they infused the blood stem cells of old mice with SIRT3, the treatment boosted the formation of new blood cells, evidence of a reversal in the age-related decline in the old stem cells’ function.

“We already know that sirtuins regulate aging, but our study is really the first one demonstrating that sirtuins can reverse aging-associated degeneration, and I think that’s very exciting,” says study principal investigator Danica Chen, an assistant professor of nutritional science and toxicology at the University of California, Berkeley.

“This opens the door to potential treatments for age-related degenerative diseases.”

Chen notes that over the past 10 to 20 years, there have been breakthroughs in scientists’ understanding of aging. Instead of an uncontrolled, random process, aging is now considered highly regulated as development, opening it up to possible manipulation.

‘Molecular fountain of youth’

“Studies have already shown that even a single gene mutation can lead to lifespan extension,” says Chen. “The question is whether we can understand the process well enough so that we can actually develop a molecular fountain of youth. Can we actually reverse aging? This is something we’re hoping to understand and accomplish.”

Sirtuins have taken the spotlight in this quest as the importance of this family of proteins to the aging process becomes increasingly clear.

Notably, SIRT3 is found in a cell’s mitochondria, a cell compartment that helps control growth and death, and previous studies have shown that the SIRT3 gene is activated during calorie restriction, which has been shown to extend lifespan in various species.

To gauge the effects of aging, the researchers studied the function of adult stem cells. The adult stem cells are responsible for maintaining and repairing tissue, a function that breaks down with age.

They focused on hematopoietic, or blood, stem cells because of their ability to completely reconstitute the blood system, the capability that underlies successful bone marrow transplantation.

The researchers first observed the blood system of mice that had the gene for SIRT3 disabled. Surprisingly, among young mice, the absence of SIRT3 made no difference. It was only when time crept up on the mice that things changed.

By the ripe old age of two, the SIRT3-deficient mice had significantly fewer blood stem cells and decreased ability to regenerate new blood cells compared with regular mice of the same age.

What is behind the age gap? It appears that in young cells, the blood stem cells are functioning well and have relatively low levels of oxidative stress, which is the burden on the body that results from the harmful byproducts of metabolism. At this youthful stage, the body’s normal anti-oxidant defenses can easily deal with the low stress levels, so differences in SIRT3 are less important.

“When we get older, our system doesn’t work as well, and we either generate more oxidative stress or we can’t remove it as well, so levels build up,” says Chen. “Under this condition, our normal anti-oxidative system can’t take care of us, so that’s when we need SIRT3 to kick in to boost the anti-oxidant system. However, SIRT3 levels also drop with age, so over time, the system is overwhelmed.”

Old mice, new blood

To see if boosting SIRT3 levels could make a difference, the researchers increased the levels of SIRT3 in the blood stem cells of aged mice. That experiment rejuvenated the aged blood stem cells, leading to improved production of blood cells.

It remains to be seen whether over-expression of SIRT3 can actually prolong life, but Chen pointed out that extending lifespan is not the only goal for this area of research. “A major goal of the aging field is to utilize knowledge of genetic regulation to treat age-related diseases,” she says.

Study co-lead author Katharine Brown, who conducted the research as a student in Chen’s lab, says SIRT3 has some potential in this regard.

“Other researchers have demonstrated that SIRT3 acts as a tumor suppressor,” says Brown. “This is promising because, ideally, one would want a rejuvenative therapy where you could increase a protein’s expression without increasing the risk of diseases like cancer.”

Researchers from the University of Toronto, Massachusetts General Hospital’s Center for Regenerative Medicine, and the Harvard Stem Cell Institute contributed to study, which is published in the journal Cell Reports.

The Searle Scholars Program, the National Institutes of Health, and the Siebel Stem Cell Institute partially funded the study.

Source: University of California, Berkeley

Straight from the Source

Read the original study

DOI: 10.1016/j.celrep.2013.01.005