Nav: Home

Putting the brakes on aging

February 19, 2019

LA JOLLA--(February 18, 2019) Aging is a leading risk factor for a number of debilitating conditions, including heart disease, cancer and Alzheimer's disease, to name a few. This makes the need for anti-aging therapies all the more urgent. Now, Salk Institute researchers have developed a new gene therapy to help decelerate the aging process.

The findings, published on February 18, 2019 in the journal Nature Medicine, highlight a novel CRISPR/Cas9 genome-editing therapy that can suppress the accelerated aging observed in mice with Hutchinson-Gilford progeria syndrome, a rare genetic disorder that also afflicts humans. This treatment provides important insight into the molecular pathways involved in accelerated aging, as well as how to reduce toxic proteins via gene therapy.

"Aging is a complex process in which cells start to lose their functionality, so it is critical for us to find effective ways to study the molecular drivers of aging," says Juan Carlos Izpisua Belmonte, a professor in Salk's Gene Expression Laboratory and senior author of the paper. "Progeria is an ideal aging model because it allows us to devise an intervention, refine it and test it again quickly."

With an early onset and fast progression, progeria is one of the most severe forms of a group of degenerative disorders caused by a mutation in the LMNA gene. Both mice and humans with progeria show many signs of aging, including DNA damage, cardiac dysfunction and dramatically shortened life span. The LMNA gene normally produces two similar proteins inside a cell: lamin A and lamin C. Progeria shifts the production of lamin A to progerin. Progerin is a shortened, toxic form of lamin A that accumulates with age and is exacerbated in those with progeria.

"Our goal was to diminish the toxicity from the mutation of the LMNA gene that leads to accumulation of progerin inside the cell," says co-first author Hsin-Kai Liao, a staff researcher in the Izpisua Belmonte lab. "We reasoned that progeria could be treated by CRISPR/Cas9-targeted disruption of both lamin A and progerin."

The researchers utilized the CRISPR/Cas9 system to deliver the gene therapy into the cells of the progeria mouse model expressing Cas9. An adeno-associated virus (AAV) was injected containing two synthetic guide RNAs and a reporter gene. The guide RNA ushers the Cas9 protein to a specific location on the DNA where it can make a cut to render lamin A and progerin nonfunctional, without disrupting lamin C. The reporter helps researchers track the tissues that were infected with the AAV.

Two months after the delivery of the therapy, the mice were stronger and more active, with improved cardiovascular health. They showed decreased degeneration of a major arterial blood vessel and delayed onset of bradycardia (an abnormally slow heart rate)--two issues commonly observed in progeria and old age. Overall, the treated progeria mice had activity levels similar to normal mice, and their life span increased by roughly 25 percent.

"Once we improve the efficiency of our viruses to infect a wide range of tissues, we are confident that we will be able to increase life span further," says Pradeep Reddy, a postdoctoral fellow in the Izpisua Belmonte lab and an author of the paper.

Taken together, the results suggest that targeting lamin A and progerin using a CRISPR/Cas9 system can dramatically improve the physiological health and life span of progeria mice. These results provide a significant new understanding of how scientists may eventually be able to target molecular drivers of aging in humans.

Future efforts will focus on making the therapy more effective and will refine it for human use. Currently, there is no cure for progeria, so the symptoms are managed and complications are treated as they arise.

"This is the first time a gene editing therapy has been applied to treat progeria syndrome," says Izpisua Belmonte, holder of the Roger Guillemin Chair. "It will need some refinements, but it has far fewer negative effects compared to other options available. This is an exciting advancement for the treatment of progeria."
-end-
Other authors included Ergin Beyret, Mako Yamamoto, Reyna Hernandez-Benitez, Yunpeng Fu and Galina Erikson of the Salk Institute for Biological Studies.

The work was funded by the Catharina Foundation, the Muscular Dystrophy Association, NIH-NCI CCSG: P30 014195, the Helmsley Trust, The Progeria Research Foundation, Universidad Catolica San Antonio de Murcia (UCAM), Fundacion Dr. Pedro Guillen, the G. Harold and Leila Y. Mathers Charitable Foundation, The Glenn Foundation and The Moxie Foundation.

About the Salk Institute for Biological Studies:

Every cure has a starting point. The Salk Institute embodies Jonas Salk's mission to dare to make dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new understandings in neuroscience, genetics, immunology, plant biology and more. The Institute is an independent nonprofit organization and architectural landmark: small by choice, intimate by nature and fearless in the face of any challenge. Be it cancer or Alzheimer's, aging or diabetes, Salk is where cures begin. Learn more at: salk.edu.

Salk Institute

Related Aging Articles:

Researchers discover new cause of cell aging
New research from the USC Viterbi School of Engineering could be key to our understanding of how the aging process works.
Deep Aging Clocks: The emergence of AI-based biomarkers of aging and longevity
The advent of deep biomarkers of aging, longevity and mortality presents a range of non-obvious applications.
Intelligence can link to health and aging
For over 100 years, scientists have sought to understand what links a person's general intelligence, health and aging.
Putting the brakes on aging
Salk Institute researchers have developed a new gene therapy to help decelerate the aging process.
New insights into the aging brain
A group of scientists at the Gladstone Institutes investigated why the choroid plexus contains so much more klotho than other brain regions.
We all want 'healthy aging,' but what is it, really? New report looks for answers
Led by Paul Mulhausen, MD, MHS, FACP, AGSF, colleagues from the American Geriatrics Society (AGS) set looking critically at what 'healthy aging' really means.
New insight into aging
Researchers at the Montreal Neurological Institute and Hospital (The Neuro) of McGill University examined the effects of aging on neuroplasticity in the primary auditory cortex, the part of the brain that processes auditory information.
Aging may be as old as life itself
Aging has had a bad rap since it has long been considered a consequence of biology's concentrated effort on enhancing survival through reproductivity.
A new link between cancer and aging
Human lung cancer cells resist dying by controlling parts of the aging process, according to findings published online May 10th in the Journal of Biological Chemistry.
American Federation for Aging Research experts featured in PBS special: Incredible Aging
Fourteen AFAR experts are among those featured in
More Aging News and Aging Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

Accessing Better Health
Essential health care is a right, not a privilege ... or is it? This hour, TED speakers explore how we can give everyone access to a healthier way of life, despite who you are or where you live. Guests include physician Raj Panjabi, former NYC health commissioner Mary Bassett, researcher Michael Hendryx, and neuroscientist Rachel Wurzman.
Now Playing: Science for the People

#543 Give a Nerd a Gift
Yup, you guessed it... it's Science for the People's annual holiday episode that helps you figure out what sciency books and gifts to get that special nerd on your list. Or maybe you're looking to build up your reading list for the holiday break and a geeky Christmas sweater to wear to an upcoming party. Returning are pop-science power-readers John Dupuis and Joanne Manaster to dish on the best science books they read this past year. And Rachelle Saunders and Bethany Brookshire squee in delight over some truly delightful science-themed non-book objects for those whose bookshelves are already full. Since...
Now Playing: Radiolab

An Announcement from Radiolab