Google co-founders Sergey Brin and Larry Page founded the biotech corporations Calico in 2013. The goal is to uncover the secrets of aging and dramatically extend human life. Not by 10 or 20 years, but to 500 years or more.
The animal Calico chose as a model for life extension is the naked mole-rat (scientific name Heterocephalus glaber). This animal, which lives in East Africa, has a body length of 8–10 cm and weighs 30–35 g, and as its name suggests, it has almost no hair. It may look unimpressive, but its lifespan is a surprising 32 years—more than 10 times that of other mice of the same size. In human terms, that would be equivalent to living past 800.
Naked mole-rats do not get cancer and do not feel pain. They can even endure 18 minutes without oxygen. Chinese scientists have newly identified the secret to their cancer resistance and longevity. It is a protein that repairs damage to DNA, which carries genetic information, as soon as it occurs. In humans, this protein promotes cancer, but in the mole-rat, a mutation makes it do the opposite. It is as if a troublemaker has turned into a dutiful child.
◇From troublemaker to dutiful child, a difference of four amino acids
Professor Mao Zhiyong's team at Tongji University in China said in a paper published in Science on the 10th that "we discovered that the naked mole-rat's secret to longevity is thanks to mutations in cGAS (cyclic GMP-AMP synthase), an enzyme that detects external invaders and triggers an immune response."
cGAS emits a specific signal when it detects DNA outside the cell nucleus. DNA from the outside can be a sign of cancer or a viral attack. But inside the nucleus, cGAS behaves in the opposite way. In humans and mice, it has been found to suppress DNA repair, increasing the risk of genetic mutations and cancer. The exact reason remains unclear.
Professor Mao's team proved that the naked mole-rat's cGAC protein promotes DNA repair in the nucleus. Although it is the same enzyme, the reason it performs the opposite function in humans and mole-rats lies in just four changes among the amino acids that make up the protein.
When the researchers changed these four amino acids in naked mole-rat cells to the human versions, cGAS no longer promoted DNA repair. Conversely, when they changed four amino acids in human cGAS to the naked mole-rat versions, it no longer suppressed DNA repair as before.
In actual experiments, the life-extending effect of the mutant enzyme was confirmed. The team experimented with fruit flies that carry the human-like cGAS gene. They altered the gene so that it produced the naked mole-rat form of cGAS. The typical lifespan of a fruit fly is about 60 days, but the genetically altered flies lived for 70 days, an increase of about 16%. Given that the life expectancy of Koreans is 85.3 years, that would be like extending it by 12 years to 97.4 years.
◇Result confirms a 12-year extension of human lifespan
The researchers said human lifespan could be extended if human cells are made to produce the naked mole-rat version of cGAS. That is because we now have tools to freely edit genes. Enzyme complexes such as CRISPR gene scissors can cut and edit genes at will. And messenger RNA (mRNA) technology, proven in COVID-19 vaccines, can deliver genetic information to the body to produce needed proteins.
One could also consider a method that does not alter genes. Mao also suggested another approach: finding a small-molecule drug that binds to human cGAS protein and switches its function to the naked mole-rat version.
Vera Gorbunova, a professor at the University of Rochester in New York, wrote in an accompanying commentary in Science that "this study suggests that cGAS affects lifespan," and assessed that "modulating cGAS activity with drugs or genetic methods could have beneficial effects on health and lifespan."
Scientists have been steadily uncovering the secrets behind the naked mole-rat's longevity. In 2018, Calico researchers reported in the international journal eLife that naked mole-rats do not age until they die. Rochelle Buffenstein's team at Calico examined husbandry records for about 3,000 naked mole-rats raised at the Buck Institute for Research on Aging in the United States over the past 30 years. They confirmed that from 6 months of age through life, the daily mortality risk remained almost unchanged at about 1 in 10,000.
Caleb Finch, a professor at the University of Southern California, wrote in an eLife commentary that "this is the first confirmation of a mammal whose mortality risk does not increase with age." According to an 1825 study by British mathematician Benjamin Gompertz, after age 30, a person's risk of death from disease doubles every eight years.
◇The first animal to defy the "Gompertz law of aging"
The naked mole-rat is the first case to deviate from the Gompertz law. Calico researchers said, "Even after a time span 25 times as long as the period it takes for a naked mole-rat to mature to reproductive age, its mortality risk does not increase." If humans become physically mature at 12, that would mean not aging even at 300.
Naked mole-rats have another longevity trick honed under extreme conditions. A joint team from Germany, the United States, and South Africa reported in Science in 2017 that "naked mole-rats can survive in an environment where oxygen is completely absent by producing ATP (adenosine triphosphate), the body's energy currency, from fructose instead of glucose."
Humans cannot live without oxygen because oxygen is essential for our bodies to break down glucose to obtain ATP. Fructose can be broken down without oxygen to produce ATP. Thanks to this, naked mole-rats can endure for five hours even when the oxygen concentration drops to 5%, one-fourth of normal (21%). When oxygen disappears completely, they lose consciousness and almost all bodily activity stops, but they can survive for 18 minutes. When oxygen is supplied again, they return to normal without any problems.
Before this, in 2023, Professor Vera Gorbunova of the University of Rochester found that a molecule called hyaluronic acid contributes to the naked mole-rat's longevity. Hyaluronic acid draws in moisture, keeping the skin hydrated and elastic.
Steven N. Austad, a distinguished professor at the University of Alabama and a leading scholar in aging research, said in an interview with this newspaper in 2022 that "the naked mole-rat's hyaluronic acid has a very large molecular size, unlike in humans," and "when the naked mole-rat gene that produces high–molecular weight hyaluronic acid is transferred to mouse cells, they exhibit the same contact inhibition."
Contact inhibition is the ability of a cell to stop replicating when it merely brushes against another cell. It prevents excessive cell proliferation and thus stops cancer from occurring. In naked mole-rats, this contact inhibition appears to an extreme degree. The day is approaching when a small animal from underground may usher in an era of human longevity.
References
Science (2025), DOI: https://doi.org/10.1126/science.adp5056
bioRxiv (2023), DOI: https://doi.org/10.1101/2023.05.04.539405
eLife (2018), DOI: https://doi.org/10.7554/eLife.31157
Science (2017), DOI: https://doi.org/10.1126/science.aan1505