The Pursuit of Rejuvenation: Unraveling the Secrets of Aging
Written on
The Science of Rejuvenation
In a dimly lit lab, a frail black mouse lies motionless, suffering from progeria—a condition characterized by rapid aging due to a genetic flaw. At just three months old, it is on the brink of death. However, the scene shifts dramatically when Juan Carlos Izpisúa Belmonte, a researcher at the Salk Institute, reveals a transformed version of the same mouse, now vibrant and energetic after receiving a revolutionary age-reversal treatment. "It completely rejuvenates," Izpisúa Belmonte exclaims with a twinkle in his eye. "Inside, all the organs and cells are rejuvenated."
Izpisúa Belmonte, a thoughtful and measured scientist, wields an astonishing capability: he can reverse the aging process in dying animals. Yet, alongside this excitement lies a stark caution; the rejuvenation treatment is so potent that it often leads to fatal cell malfunctions or tumor development shortly after administration—a perilous dose of youth.
Epigenetic Reprogramming Explained
The method behind this remarkable transformation is known as "reprogramming," a technique that resets the epigenetic marks within cells—chemical indicators that regulate gene expression. By erasing these marks, cells can revert to an earlier, more primitive state, akin to embryonic cells. While often utilized in stem cell research, Izpisúa Belmonte is at the forefront of applying this technique to whole organisms, with aspirations to extend its benefits to humans.
He posits that epigenetic reprogramming could serve as a potential "elixir of life," significantly prolonging human lifespan. Life expectancy in developed nations has more than doubled over the last two centuries, thanks to advancements like vaccines and safety measures. However, there remains a natural limit to human longevity, attributed to the inevitable degradation of our bodies. "Aging," he asserts, "is simply molecular breakdown at the cellular level." He believes that the child destined to live to 130 years is already among us.
The Promise of Epigenetic Resetting
The epigenome undergoes a reset during reproduction, akin to a fresh start for the organism. Cloning exploits this reprogramming, as seen in calves that share DNA with their adult progenitors, yet lack accumulated age-related markers. Izpisúa Belmonte aims to achieve a similar reset without creating a new individual. This involves reversing age-related changes in epigenetic marks—specifically histones and methylation groups, which wrap around DNA and control gene activation. The accumulation of these changes may underlie the aging process, and if reversed, could potentially halt aging itself.
While Izpisúa Belmonte acknowledges that these epigenetic modifications won't grant eternal life, he is optimistic about extending human lifespan by 30 to 50 years. He firmly believes that the next generation is already here.
The Yamanaka Factors: A Breakthrough
The rejuvenation treatment utilized by Izpisúa Belmonte is based on a groundbreaking discovery by Shinya Yamanaka, who, starting in 2006, demonstrated that introducing just four proteins to adult cells could reprogram them to resemble embryonic cells. These proteins, known as the Yamanaka factors, effectively erase epigenetic marks, allowing cells to start anew.
"He went backwards in time," Izpisúa Belmonte explains. "All the methylation marks are cleared away, and you're beginning life again." Remarkably, even skin cells from centenarians can be reverted to a youthful state, termed induced pluripotent stem cells (IPSCs), capable of developing into any cell type given appropriate signals.
Yamanaka's discovery initially sparked interest for its potential in generating replacement tissues for transplants. In Japan, researchers successfully reprogrammed cells from an elderly woman suffering from macular degeneration, leading to the first transplant of lab-grown tissue in 2014. Though her vision did not improve significantly, she noted that it appeared "brighter," and the deterioration ceased.
The Dangers of Cellular Reprogramming
However, researchers at the Spanish National Cancer Research Centre explored the implications of the Yamanaka factors further, demonstrating that activating these factors in adult mice resulted in successful cell reprogramming within their bodies. This revelation suggested a new paradigm in medicine—potentially rejuvenating entire organisms—but it also highlighted inherent risks. Excessive removal of epigenetic markers could lead cells to lose their identity, risking their ability to perform designated functions and potentially resulting in cancer.
This risk was evident in the mice observed in Izpisúa Belmonte's lab, which often developed tumors, underscoring the lethal consequences of unchecked cellular reprogramming.
Finding a Balanced Approach
Motivated by the regenerative abilities of salamanders, which can regrow limbs, Izpisúa Belmonte sought to administer a more controlled dose of reprogramming. In 2016, his team devised a strategy to partially rewind cells in progeria-affected mice by genetically modifying them to produce Yamanaka factors only when exposed to the antibiotic doxycycline.
By allowing some mice to consume doxycycline continuously, while others received it intermittently, the team could effectively control gene expression. The mice that received limited doses showed improved health without developing tumors and lived 30% longer than their untreated counterparts.
The Future of Rejuvenation Research
When Izpisúa Belmonte published his findings in the journal Cell, the implications resonated throughout the scientific community, likening his work to Ponce de Leon's search for the fabled fountain of youth. "His paper awakened many," says Michael West, CEO of AgeX, a company pursuing similar technologies. "Suddenly, leaders in aging research were excited about the potential for human applications."
However, skepticism remains. Experts like Jan Vijg caution that aging is a multifaceted process, making simple solutions improbable. While Izpisúa Belmonte's work offers exciting possibilities, some question whether the epigenetic changes he targets are truly the root cause of aging or merely symptoms—akin to wrinkles on skin.
A pressing question remains: while rejuvenation has been demonstrated in progeria mice, can it be replicated in naturally aged animals? Vittorio Sebastiano of Stanford emphasizes that natural aging involves complex mechanisms. Izpisúa Belmonte's team is currently testing rejuvenation techniques in standard mice, though the longer lifespan of these animals means results will take time to gather.
Towards Targeted Treatments
Wholesale rejuvenation may still be a distant goal, but targeted therapies addressing specific age-related diseases could emerge within a few years. Rather than a broad approach, researchers are developing refined techniques that allow for precise control over gene expression.
At Salk, scientists adapted CRISPR-Cas9 technology to serve as a volume control for gene activity rather than a blunt editing tool. In experiments on mice with muscular dystrophy, researchers enhanced the expression of a compensatory gene, resulting in improved muscle mass and grip strength.
Additionally, researchers at the University of California, Irvine, have shown that activating a single gene can restore memory in aging mice, while Duke University teams are exploring gene regulation to manage conditions like Parkinson's disease and cholesterol levels.
The first human trials of these innovative techniques are anticipated in the near future, with companies like AgeX and Turn Biotechnologies leading the charge. AgeX aims to regenerate heart tissues, while Turn seeks regulatory approval for treatments targeting aging-related muscle loss and osteoarthritis.
In parallel, GenuCure, a biotech firm founded by former Salk researcher Ilir Dubova, is exploring rejuvenation techniques for cartilage. Dubova envisions a treatment that would activate silenced genes in osteoarthritis patients, potentially reducing the need for costly surgical interventions.
"After injection, these genes that were silenced due to aging would be turned on, thanks to our witchcraft, and initiate the rejuvenation process," Dubova asserts. "I think turning back the clock is an appropriate way to describe it."
Erika Hayasaki is an Alicia Patterson Fellow specializing in science and environmental reporting.