For thousands of years, our thirst for the legendary Fountain of Youth has been nearly as strong as our propensity for perpetuating the myth.
However, over the last 20 years, the fertile headwaters of molecular biology have been pumping out anything but folklore. Not only have these waters yielded a precipitous stretch in understanding the aging process, they're potentially guiding us closer to the source of everlasting youth.
From this flow now comes word that biologists from the University of California, Berkeley have tapped an influential longevity gene that can reverse cell degeneration associated with aging. That's right, they're not just offering a sip from the fountain, they're turning back the clock at the molecular level.
The new study, published in Cell Reports, represents a major discovery and offers new hope for development of targeted treatments for a long list of age-related degenerative diseases, such as heart disease, Alzheimer's and arthritis, just to name a few.
The biologists, lead by UC Berkeley assistant professor of nutritional science and toxicology Danica Chen, focused their attention on one protein in particular: SIRT3. It's one in a class of proteins called surtuins, long known to regulate aging.
Biologists found that SIRT3 plays a significant role in helping aged blood stem cells cope with the oxidative stress of the aging process. When the blood stem cells of aged mice were infused with SIRT3, it regenerated new blood cells, providing evidence of a reversal in the age-related degeneration of the cells' function.
"This is really the first demonstration that sirtuins may be able to actually reverse aging-associated degeneration," Chen told Discovery News.
"We known aging can be regulated so we may be able to manipulate the molecular pathways and slow down the process," she added. "But there's never been a demonstration where we could reverse age. It's really the next big step."
Chen cited molecular biologist Cynthia Kenyon's pioneering work in the early 1990s as perhaps the biggest breakthrough in understanding that aging is not a random, uncontrolled process, but rather a highly regulated development. In 1993, Kenyon published a study in Nature that showed a single gene mutation in a tiny worm (C. elegans) could double its lifespan, opening up the floodgates of intensive studies on age manipulation.
"We know there are a lot of techniques out there," said Chen. "For example, you can use transgenic mouse models to upregulate sirtuins" to increase the quality of a cell "but those only address the question of whether you can slow aging. But you can't really address the question of whether you could reverse aging."
Unless, of course, you find the right key, which Chen and colleagues may have found in SIRT3.
"We're particularly interested in SIRT3," Chen said, "because we found that it's highly enriched in hematopoietic stem cells." These are blood stem cells, highly regarded for their ability to completely reconstitute the blood system, the underlying capability of a successful bone marrow transplant.
Also of interest is the location of where SIRT3 is found – in the mitochondria, the cell compartment that helps control growth and death.
"What I liked so much about our study is that SIRT3 is mitochondrial," said study co-author Dr. Katharine Brown. "It's certainly not acting as a transcription factor, it's effecting metabolism and other aspects of cell signaling, which is clearly very important in aging." Brown conducted the research as a Ph.D. student in Chen's lab.
To gauge the effects of aging, researchers observed the blood system of young mice that had the SIRT3 gene disabled. At first, the absence of SIRT3 made no difference on the young mice.
"This study definitely took a few years," said Brown. "It was kind of frustrating at the beginning because we weren't seeing any differences between the wild mice and the SIRT3 knockout mice."
But why no difference in the knockout mice, if SIRT3 is such a key component? In a typical display of youthful exuberance, the blood stem cells of the young mice were able function well enough to stave off oxidative stress, which many believe causes aging when our bodies metabolize oxygen.
"A young person is able to handle the oxygen – making sure that the oxygen is going to the right place," Brown said. "As we age, our ability to appropriately handle the oxygen and its chemical process is not as good, and because of that, it starts wreaking havoc."
Sure enough, as the mice aged, the SIRT3-deficient mice started slowing down, showing significantly fewer blood stem cells and a decreased ability to regenerate new blood cells.
As we age, our normal antioxidative system struggles to take care of our cells. That's when SIRT3 can provide a well-needed boost to our antioxidant system. Unfortunately, SIRT3 levels diminish with age, so eventually our system is engulfed in degeneration.
So researchers decided to see what happened when they boosted the SIRT3 levels in the blood stem cells of the aged mice.
"Our first inclination was that the reason the SIRT3 knockout mice's blood cells were not doing so well was due to a build up of oxidative damage," said Brown. "But the surprise was when I reintroduced a mutated form of SIRT3 to the aged knockout cells. It improved their function as well."
In other words, their experiment rejuvenating the aged stem cells' regenerative potential.
"Aging is just an accumulation of damage," said Chen. "If you think that way, then it's probably not reversible, because cells are already damaged and no longer functional. But what we show here is that oxidative stress-induced damage, in fact, is reversible."
While further studies will be needed to see if this SIRT3 boost can actually make people live longer, Chen asserts that there's more to this field of study than just the thirst for everlasting youth.
"It's not so much about expanding lifespan. More so, I think the most important goal is to prevent and ultimately treat age-related diseases," she said. "The idea is that if we can prevent aging, we can prevent all the diseases that are associated with aging. That's really the major goal."
When it comes to age-related diseases, Brown says there's one aspect about SIRT3 she particularly likes.
"While it seems to be helping function, other researchers have found that it can also act as a tumor suppressor," she said. "One of the problems that you have when you have a ‘molecular fountain of youth' is you might be making a cell more useful, but then elsewhere you may be increasing the risk of cancer."
Asked if this study takes us another step closer to this "molecular fountain of youth," Brown hesitated with a pregnant pause before ultimately saying, "Yes." Duly noted, however, was her reluctance about throwing around the phrase "molecular fountain of youth."
"A lot of times people use phrases and a lot of times I feel like that's an oversimplification because biology is incredibly complicated," she said. "But I think that it is interesting because SIRT3 is a single molecule that can have a pretty dramatic effect. It is working at the molecular level."