In the laboratory of molecular biologist David Sinclair at Harvard Medical School, older mice are getting young again.
Using proteins that can turn an adult cell into a stem cell, Sinclair and his team reset aged cells in mice to earlier versions of themselves. In his team’s first breakthrough, published in late 2020, old mice with poor eyesight and damaged retinas could suddenly see again, with vision that sometimes rivaled that of their descendants.
“It’s a permanent reset, as far as we know, and we think it could be a universal process that can be applied throughout the body to reset our age,” said Sinclair, who has spent the past 20 years studying ways to reverse the ravages of time.
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“If we reverse aging, these diseases shouldn’t happen. We have the technology today to be able to make it to the centenary without worrying about having cancer at 70, heart disease at 80 and Alzheimer’s at 90,” Sinclair told an audience at Life Itself, a health and wellness event.
“This is the world that is coming. It’s literally a matter of time, and for most of us, it’s going to happen in our lifetimes,” Sinclair told the audience.
“His research shows that you can change aging to make life younger for longer. Now he wants to change the world and make aging a disease,” said Whitney Casey, an investor who is partnering with Sinclair to create a do-it-yourself biological age.
While modern medicine addresses disease, it doesn’t address the underlying cause, “which for most diseases is aging itself,” Sinclair said. “We know that when we reverse the age of an organ like a mouse brain, the diseases of aging disappear. The memory comes back, there is no more dementia.
“I believe that in the future, slowing and reversing aging will be the best way to treat the diseases that afflict most of us.”
A reset button
In Sinclair’s lab, two mice sit side by side. One is the image of youth, the other gray and weak. However, they are brother and sister, born from the same litter – only one has been genetically altered to age faster.
If this could be done, Sinclair asked his team, could the reverse also be done? Japanese biomedical researcher Dr. Shinya Yamanaka had already reprogrammed adult human skin cells to behave like embryonic or pluripotent stem cells, capable of developing into any cell in the body. The 2007 discovery won the scientist a Nobel Prize, and his “induced pluripotent stem cells” soon became known as “Yamanaka factors”.
However, the adult cells fully reverted to the stem cells through Yamanaka factors, losing their identity. They forget that they are blood, heart and skin cells, making them perfect for rebirth as “day cells” but terrible for rejuvenation. You don’t want Brad Pitt in “The Curious Case of Benjamin Button” to become a baby all at once; you want him to age backwards while still remembering who he is.
Laboratories around the world have looked into the problem. A study published in 2016 by researchers at the Salk Institute for Biological Studies in La Jolla, California, showed that signs of aging can be eliminated in genetically aged mice, exposed for a short time to four main Yamanaka factors, without erasing identity. of the cells.
But there was a downside to all this research: in certain situations, the altered mice developed cancerous tumors.
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Looking for a safer alternative, Sinclair lab geneticist Yuancheng Lu chose three of the four factors and genetically added them to a harmless virus. The virus was designed to deliver Yamanaka’s rejuvenating factors to damaged retinal ganglion cells in the back of an aged mouse’s eye. After injecting the virus into the eye, the pluripotent genes were activated by feeding the mouse an antibiotic.
“The antibiotic is just a tool. It could be any chemical, just a way to make sure the three genes are turned on,” Sinclair said. “Typically, they are only turned on in very young developing embryos and then turn off as we age.”
Surprisingly, damaged neurons in the eyes of mice injected with the three cells rejuvenated, even growing new axons, or projections from the eye to the brain. Since that original study, Sinclair said his lab has reversed aging in the muscles and brains of mice and is now working on rejuvenating a mouse’s entire body.
“Somehow, cells know that the body can reset itself, and they still know which genes they should have turned on when they were young,” Sinclair said. “We think we’re tapping into an ancient regeneration system that some animals use – when you cut off a salamander’s limb, it grows back. A fish’s tail grows back, a mouse’s finger grows back. ”
This finding indicates that there is a “backup copy” of youth information stored in the body, he added.
“I call it the information theory of aging,” he said. “It’s a loss of information that makes aging cells forget how they work, forget what kind of cell they are. And now we can tap a reset button that restores the cell’s ability to read the genome correctly again, as if it were young.”
While the changes lasted for months in mice, the renewed cells don’t freeze in time and never age (like, say, vampires or superheroes), Sinclair said. “It is as permanent as aging. It’s a reboot, and then we see the mice age again, so we repeat the process.
“We believe we have found the master control switch, a way to turn the clock back,” he added. “The body will then wake up, remember how to behave, remember how to regenerate and be young again, even if you are already old and have a disease.”
Studies of whether the genetic intervention that revitalized mice will do the same for people are in the early stages, Sinclair said. It will be years before human trials are completed, analyzed and, if safe and successful, scaled to the mass needed for a federal seal of approval.
While we wait for science to determine whether we can reset our genes, too, there are many other ways to slow down the aging process and reset our biological clocks, Sinclair said.
“The main tips are simple: focus on plants for food, eat less often, get enough sleep, get out of breath for 10 minutes three times a week doing exercises to maintain your muscle mass, don’t worry about small things and have a good social group,” Sinclair said.
All of these behaviors affect our epigenome, proteins, and chemicals that sit like freckles on each gene, waiting to tell the gene “what to do, where to do, and when to do it,” according to the National Human Genome Research Institute. The epigenome literally turns genes on and off.
What controls the epigenome? Human behavior and a person’s environment play a key role. Let’s say you were born with a genetic predisposition to heart disease and diabetes. But because you exercised, ate a plant-based diet, slept well, and managed your stress for most of your life, it’s possible these genes never turn on. This, experts say, is how we can take part of our genetic destiny into our own hands.
The positive impact on our health of eating a plant-based diet, having close and loving relationships, and getting adequate exercise and sleep are well documented. Calorie restriction, however, is a more controversial way to add years to life, experts say.
Cutting back on food – without inducing malnutrition – has been a scientifically known way to prolong life for nearly a century. Studies of worms, crabs, snails, fruit flies and rodents have found that restricting calories “delays the onset of age-related disorders” such as cancer, heart disease and diabetes, according to the National Institute on Aging. Some studies have also found extensions in life expectancy: in a 1986 study, mice fed only a third of the calories of a typical day lived up to 53 months – a mouse kept as a pet can live for about 24 months.
Studies in people, however, have been less enlightening, in part because many have focused on weight loss rather than longevity. For Sinclair, however, cutting back on meals was a significant factor in resetting his personal clock: Recent tests show he has a biological age of 42 in a body born 53 years ago.
“I’ve been doing biological testing for 10 years and I’ve been getting younger and younger over the last decade,” Sinclair said. “The biggest change in my biological clock occurred when I ate less often – I only have one meal a day now. It made the biggest difference in my biochemistry.”
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