Researchers find link between two aging pathways in mice



About 1,100 people each year die in the UK from lung cancer related to indoor radon, but current government protection policies focus mainly on the small number of homes with high radon levels and neglect the 95% of radon related deaths caused by lower levels of radon, according to a study published on bmj.com. The

Full Post: Lung cancer related to indoor radon could easily be prevented

Two previously identified pathways associated with aging in mice are connected, say researchers at the Stanford University School of Medicine.

The finding reinforces what researchers have recently begun to suspect: that the age-related degeneration of tissues, organs and, yes, even facial skin with which we all struggle is an active, deliberate process rather than a gradual failure of tired cells. Derailing or slowing this molecular betrayal, although still far in the future, may enable us to one day tack years onto our lives - or at least delay the appearance of that next wrinkle.

“There is a genetic process that has to be on, and enforced, in order for aging to happen,” said Howard Chang, MD, PhD, associate professor of dermatology at the school and a member of Stanford’s Cancer Center. “It’s possible that those rare individuals who live beyond 100 years have a less-efficient version of this master pathway, just as children with progeria - a genetic aging disease - may have components of this pathway that are more active.”

The study, which will be published in the Jan. 9 issue of Cell , grew out of a three-year collaboration between Chang and Katrin Chua, MD, PhD, assistant professor of endocrinology, gerontology and metabolism at Stanford and member of the Stanford Cancer Center and the Veterans Affairs Palo Alto Health Care System. Chang and Chua are co-senior authors of the research.

The researchers focused their investigation on two seemingly separate pathways linked to aging. One involved a molecule known as SIRT6 - a member of the sirtuin family of proteins that modulate life span in organisms such as yeast and worms - that Chua’s laboratory has been studying for several years. She and her lab members have previously shown that SIRT6 is involved in genomic stability and the protection of chromosomal ends called telomeres. Telomeres, which grow shorter with each cell division, are thought to function as a kind of internal molecular clock associated with aging. Furthermore, mice lacking SIRT6 are born normally but die within a few weeks because of a rapid, multi-organ degeneration that somewhat resembles premature aging.

“Sirtuin family members have been implicated in aging and age-related diseases,” said Chua, “but very little was known about how SIRT6 worked on a molecular level until recently. Our new study reveals that SIRT6, in addition to its role in genomic stability and telomere protection, also regulates gene expression.”

The other pathway involved a more well-known protein called NF-kappa B, or NF-kB, that binds to and regulates the expression of many genes, including those involved in aging. The expression of many of these genes increases with age, and blocking the activity of NF-kB in the skin cells of elderly mice causes them to look and act like younger cells.

The researchers wondered if NF-kB and SIRT6 somehow work together to help cells age appropriately. They found that, in human and mouse cells, SIRT6 binds to a subunit of NF-kB and modifies components of a nearby DNA packaging center, called histones. This modification makes it more difficult for NF-kB to trigger the expression of the downstream gene - perhaps by causing the DNA to twist in such a way to boot off the protein.

“It seems that an important job of SIRT6 is to restrain NF-kB and limit the expression of genes associated with aging,” said Chang. “We’ve been interested in the activity of regulatory genes such as NF-kB during aging for several years now, and we were quite happy to find this very clear biochemical connection between these two pathways.”

Young mice lacking the SIRT6 protein displayed elevated levels of NF-kB-dependent genes involved in immune response, cell signaling and metabolism - all potentially involved in the uniformly fatal aging-like condition that killed them within four weeks of birth. Tamping down the expression of the gene for NF-kB’s SIRT-binding subunit allowed some of the mice to escape this fate.

“Mice lacking SIRT6 seem to hit some kind of a wall at around four weeks of age,” said Chua, “when their blood sugar drops to a level barely compatible with life. Reducing NF-kB activity somehow allows the mice to get over this critical period and to live much longer. These mice provide a great new tool to study the effect of SIRT6-deficiency in much older animals than was possible before.”

The researchers are now working to understand how NF-kB knows when and to what extent during an organism’s lifetime to initiate the degenerative process and what role SIRT6 may play.

“It’s a very provocative question,” said Chang. “We’ve tied together two previously separate pathways in aging. Now we’d like to better understand what regulates that pathway.”

Chang and Chua’s co-authors on the study include graduate students Tiara Kawahara and Mara Damian; research associate Eriko Michishita, PhD; postdoctoral scholars Adam Adler, PhD, and Ron McCord, PhD; research assistants Elisabeth Berber, PhD, Meihong Lin and Lisa Boxer; and Stanford undergraduate Kristine Ongaigui.

The research was supported by the National Institutes of Health, the Department of Veterans Affairs, the California Breast Cancer Research Program, the American Cancer Society and the Paul B. Beeson Aging Research Program.

http://www.stanford.edu

Link




New evidence may explain why it is that we lose not only our youthful looks, but also our youthful pattern of gene activity with age. A report in the November 26th issue of the journal Cell, a Cell Press publication, reveals that a protein perhaps best known for its role in the life-extending benefits of

Full Post: Researchers provide new evidence that aging can be slowed



French scientists have found a drug they say tricks the body into burning off fat - and it even works on a high-fat diet. Reducing calorie consumption by about 20% has been shown to slow down the aging process, improve endurance and protect against diet-induced obesity and metabolic diseases such as diabetes. Last year researchers

Full Post: New drug tricks the body into burning off fat



Rather than testing for individual marker genes or proteins, researchers at the University of California, San Diego (UC San Diego) and the Moores UCSD Cancer Center have evidence that groups, or networks, of interactive genes may be more reliable in determining the likelihood that a form of leukemia is fast-moving or slow-growing. One of the

Full Post: Networks of interactive genes may predict Leukemia’s development



Few things are as tiresome as house hunting and moving. Unfortunately, metastatic cancer cells have the relocation process down pat. Tripping nimbly from one abode to another, these migrating cancer cells often prove far more deadly than the original tumor. Although little has been known about how these rogue cells choose where to put

Full Post: Researchers gain new insight into cancer metastasis



Like our current financial crisis, the aging process might also be a product excessive deregulation. Researchers have discovered that DNA damage decreases a cell’s ability to regulate which genes are turned on and off in particular settings. This mechanism, which applies both to fungus and to us, might represent a universal culprit for aging. “This

Full Post: Researchers identify a potentially universal mechanism of aging