Engineering the End of Aging

Seung Lee

A new drug that promises to stop muscles and brains from getting old.

Image: Beatrice/Flickr

From the basement of a University of California-Berkeley building, Irina Conboy has been fighting back Father Time.

For over a decade, Conboy and her colleagues at UC Berkeley have been searching for ways to slow down or even reverse aging. Their latest discovery—a small-molecule drug that restored brain and muscle tissues to youthful levels in old mice through stem cells—signalled that the prospect of anti-aging therapy for humans may be on the horizon.

Published in the latest issue of the scientific journal Oncotarget this May, the discovery has been called "fountain of youth" or the "secret to eternal youth" by the media.

Comfortably clad in an oversized hoodie, Conboy burst the bubble in her high-pitch, Eastern European accent: Sorry, the drug won't keep us young forever, and we will all eventually die.

But what her research hopes to accomplish, Conboy said, is a painless, cost-effective way to live when we are old.

The image of the brain's hippocampus show that the TGF-beta1 (stained in red in the old) disappeared in the young tissue after Alk5 kinase inhibitor was applied to the mouse. Image: University of California-Berkeley

Aging-related diseases like adult-onset diabetes, cancer, Alzheimer's, and Parkinson's disease kill millions every year while draining the economy of billions of dollars on health care costs, and a treatment that keeps people healthier in old age would cut the costs significantly down. A drug that tackles these diseases at its root would also give people more agency how they choose to live late in their lives.

"Aging is a synonym with diseases," Conboy said. "When we are young, we don't have these diseases. But when we are old, it doesn't matter what background or gender or culture, we all have them. If we can better understand the aging process, then we don't need to have different hospitals, departments, and institutes that deal with each disease."

The drug, known as Alk5 kinase inhibitor, target a growth factor called TGF-beta1 pathway which, at old age, overproduce itself and inhibits other pathways to stimulate stem cells. As our body breaks down over time, stem cells—which are responsible for repairing the body and live huddled together in pockets called niches—are prevented by TGF-beta1 from doing its job.

But the TGF-beta1 pathway is no villain. The protein promotes division of embryonic stem cells and then promotes differentiation into functional tissues and organs—a critical component in organizing our body cells. Without it, the body's organs will begin to fail.

As the body ages, however, the TGF-beta1 begins to overexpress itself and become a deterrent for yet unknown reasons. What the Alk5 kinase inhibitor sought to do was not rid the body of the pathway but rather regulate it by attaching itself to the pathway and dulling its signal asking for more expression.

Now with the TGF-beta1 down to youthful levels, stem cells are able to freely repair the body.

"If you have a very bright light but you have sunglasses on, you can look at the light even though the light didn't diminish," Conboy said. "The inhibitor works like the sunglasses and prevents damage even though the light hasn't diminished. When there is too much TGF-Beta, it's blinding organs and tissues and impairs its function."

Due to its crucial role during early development, the TGF-beta1 is found all across the body, from brain to bones. The inhibitor, which was injected into the bloodstreams of mice during its experiments, is able to rejuvenate tissues regardless of its components or purpose. It is already being trialled as an anticancer agent.

Microglia, a type of glial cells found in the brain and the spine as the first defensive line in the immune system, shows little TGF-beta 1 (stained in green) in the young brain (top). In the old brain (bottom), TGF-beta 1 is seemingly everywhere. Image: University of California-Berkeley

In the hippocampus part of the brain, where increased levels of TGF-beta1 was discovered to impair memory and cognition by fellow UC Berkeley researcher David Schaffer, the drug began to generate new neural stem cells which creates neurons responsible for memory formation.

As for using the inhibitor for cosmetic rejuvenation, to not only feel but also look younger, Conboy said the application is theoretically possible, considering stem cells exist in skin cells and hair follicles.

"We haven't really focused on that because our focus has been on diseases," Conboy said.

This one-size-fits-all drug may approach medical use for humans sooner than later. Like mice, the treatment can happen with an injection to our bloodstreams much like a flu shot.

Conboy and the researchers are currently in the fundraising phase to start conducting clinical trials on human beings. But due to limited federal funding on research and development, progress has been slow.

According to a 2014 interview from National Institutes of Health director Francis Collins to USA Today, the NIH rejects half of worthwhile biomedical proposals due to budget constraints.

Death would no longer come with pain or suffering at some hospital with wires and machines keeping the body alive

"Research for biomedicine right now is very scarce," Conboy said. "If you want to have clinical trials or develop new medicine, there are very limited resources for that."

Private funds has been on the rise for anti-aging research, especially among Silicon Valley venture capitalists and tech giants looking for the next frontier to conquer. One of the most active donors has been PayPal co-founder Peter Thiel, who donated $35 million to an anti-aging researcher in Cambridge Universtiy in 2006 and $500,000 to a biotech start-up in 2010.

Google has joined the fray last year with the foundation of Calico. Described as mysterious and Google's mad science project, Calico revealed plans to build an anti-aging research facility in the San Francisco Bay Area with a cost of up to $1.5 billion.

So far, the Alk5 kinase inhibitor has yet to draw any funds from firms and investors some forty-odd miles away, even though Conboy considered these discoveries "low-hanging fruit."

The researchers remain hopeful that the drug will continue to move forward in pace with the explosive growth of the larger anti-aging research community.

"I look at it as more promising than anything," said Hanadie Yousef, the lead author of the Oncotarget study and currently a postdoctoral scholar at Stanford University. "When I was starting graduate school five years ago, there was absolutely nothing known about how aging actually happened. The field is growing so rapidly that I would bet within the next decade we'll see effective anti-aging therapeutic methods."

With the probability of anti-aging therapy on the horizon, death may take a different shape in the future. Death, as Conboy's team hoped to accomplish, would no longer come with pain or suffering at some hospital with wires and machines keeping the body alive.

Instead, death will come by more natural causes such as cardiac arrest or a stroke—a relatively quick way to die than fighting years against cancer or similar diseases.

"I hope we'll just die in our sleep with no cancer or disease eating up our organs," Yousef said. "The goals of my colleagues and I are not to live forever. Instead of becoming old and becoming a burden on society, we can age ourselves more with integrity."