Robert W. Williams, PhD, Co-Authors Paper on Longevity Genetics

UTHSC Researcher Co-Authors Paper on Longevity Genetics Published in Nature

Memphis, Tenn. (May 23, 2013) – How do we age? And why is it some people live twice as long as others? Genetics research is offering a new clue to the
mysteries of aging, thanks to a multidisciplinary team of scientists from Europe and the U.S.A. They have uncovered a new mechanism that contributes to
aging and it’s located in the cell’s mitochondria. Mitochondria are the power generators of all cells in animals, converting glucose into a steady stream
of ATP molecules – molecules that store and transport chemical energy within cells.

Robert W. Williams, PhD, is one of the co-authors of the recent manuscript titled, “Mitonuclear Protein Imbalance as a Conserved Longevity Mechanism.” The
paper appears in the May 23 edition of Nature, the international weekly journal of science. Dr. Williams is the UT-Oak Ridge National Laboratory Professor
in the Department of Anatomy and Neurobiology at the University of Tennessee Health Science Center (UTHSC). To view the paper upon publication, visit:

http://www.nature.com/nature


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While differences in the environment are a crucial element in aging, genetics also plays a role. The international team of researchers uncovered a process
in mitochondria that influences longevity using a combination of powerful methods. By knocking down specific genes, they stretched life span by up to 60
percent in a simple model organism – a worm called C. elegans. The work has not yet been linked directly to aging in humans, but the fundamental
biology of mitochondria and their role in energy production are shared. More intense work is likely to highlight some of the key aging switches in cells.

Mitochondria: Energy Source and a Biological Hourglass

There are hundreds of mitochondria in each cell, driving virtually all facets of life. Remarkably, each mitochondrion comes with its own mini-genome made
up of just 13 genes. This is not enough information to build a mitochondrion, and a thousand other proteins are imported, courtesy of the main nuclear
genome. The balance of activity between mitochondrial genes and nuclear genes is normally maintained very precisely. The team discovered that disrupting
this balance and stressing the mitochondria just the right way can actually extend life span.

The project began using information on the genetic causes of differences in life span in a large family of mice that routinely live from one to nearly
three years. In his work at UTHSC, Dr. Williams was able to pinpoint a small part of the genome that is crucial for some of the inherited differences in
life span. The Memphis team’s work provided a short list of suspect genes – not a smoking gun. Johan Auwerx, Professor and Nestle Chair In Energy
Metabolism at the Ecole Polytechnique Federale de Lausanne (EPFL) in Switzerland, and a Swiss team took these genetic suspects and tested each in C. elegans, a simple animal that has become a linchpin in aging research. The average life span of worms increased from 19 to more than
30 days.

The powerful combination of the mouse genetics and the molecular analysis in worms pointed to a set of mitochondrial ribosomal proteins (MRPs) -
essentially proteins that help make other proteins. The genes for all of the MRPs are located in the nuclear DNA compartment, so MRPs must be imported into
mitochondria. A reduction in the level of MRPs at key points in development creates a normal cellular stress reaction known as the unfolded protein
response. Riekelt Houtkooper, Senior Scientist at the Academic Medical Center in Amsterdam, and Laurent Mouchiroud, an EPFL Post Doc in Biological Sciences
and Genetics, serve as the lead analysts of this study. They were able to follow and qualify the movements of many worms during their entire life span
after several different treatments that trigger the unfolded protein response. The surprising and consistent finding is that worms with slightly unbalanced
and stressed mitochondria had better endurance and their muscles were in better shape.

All indications are that the mechanisms in worms are shared with mice, but more work is needed to determine what level of mitochondrial imbalance works
best to extend life span and to make sure that we understand possible downsides before extrapolating to humans. Still, this research does give hope not
only for increasing longevity, but also for lengthening the period of adult vitality. This research is also a good example of the type of international
collaboration between teams of investigators with completely different areas of expertise.

“As science gets more sophisticated and complex, it becomes critical to team up across scientific and national borders to get to answers quickly,” Drs.
Auwerx and Williams stressed.

As Tennessee’s only public, statewide academic health system, the mission of the University of Tennessee Health Science Center (UTHSC) is to bring the
benefits of the health sciences to the achievement and maintenance of human health, with a focus on the citizens of Tennessee and the region, by pursuing
an integrated program of education, research, clinical care, and public service. Offering a broad range of postgraduate and selected baccalaureate training
opportunities, the main UTHSC campus is located in Memphis and includes six colleges: Allied Health Sciences, Dentistry, Graduate Health Sciences,
Medicine, Nursing and Pharmacy. UTHSC also educates and trains cohorts of medicine, pharmacy and/or allied health students — in addition to medical
residents and fellows — at its major sites in Knoxville, Chattanooga and Nashville. Founded in 1911, during its more than 100 years, UT Health Science
Center has educated and trained more than 56,000 health care professionals in academic settings and health care facilities across the state. For more
information, visit www.uthsc.edu.

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