It’s been 13 years in the making, but Dr. David Sinclair and his colleagues have finally answered the question of what drives aging. In a study published Jan. 12 in Cell, Sinclair, a professor of genetics and co-director of the Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School, describes a groundbreaking aging clock that can speed up or reverse the aging of cells.
Scientists studying aging have debated what drives the process of senescence in cells—and primarily focused on mutations in DNA that can, over time, mess up a cell’s normal operations and trigger the process of cell death. But that theory wasn’t supported by the fact that older people’s cells often were not riddled with mutations, and that animals or people harboring a higher burden of mutated cells don’t seem to age prematurely.
Sinclair therefore focused on another part of the genome, called the epigenome. Since all cells have the same DNA blueprint, the epigenome is what makes skin cells turn into skin cells and brain cells into brain cells. It does this by providing different instructions to different cells for which genes to turn on, and which to keep silent. Epigenetics is similar to the instructions dressmakers rely on from patterns to create shirts, pants, or jackets. The starting fabric is the same, but the pattern determines what shape and function the final article of clothing takes. With cells, the epigenetic instructions lead to cells with different physical structures and functions in a process called differentiation.
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In the Cell paper, Sinclair and his team report that not only can they age mice on an accelerated timeline, but they can also reverse the effects of that aging and restore some of the biological signs of youthfulness to the animals. That reversibility makes a strong case for the fact that the main drivers of aging aren’t mutations to the DNA, but miscues in the epigenetic instructions that somehow go awry. Sinclair has long proposed that aging is the result of losing critical instructions that cells need to continue functioning, in what he calls the Information Theory of Aging. “Underlying aging is information that is lost in cells, not just the accumulation of damage,” he says. “That’s a paradigm shift in how to think about aging. “
His latest results seem to support that theory. It’s similar to the way software programs operate off hardware, but sometimes become corrupt and need a reboot, says Sinclair. “If the cause of aging was because a cell became full of mutations, then age reversal would not be possible,” he says. “But by showing that we can reverse the aging process, that shows that the system is intact, that there is a backup copy and the software needs to be rebooted.”
In the mice, he and his team developed a way to reboot cells to restart the backup copy of epigenetic instructions, essentially erasing the corrupted signals that put the cells on the path toward aging. They mimicked the effects of aging on the epigenome by introducing breaks in the DNA of young mice. (Outside of the lab, epigenetic changes can be driven by a number of things, including smoking, exposure to pollution and chemicals.) Once “aged” in this way, within a matter of weeks Sinclair saw that the mice began to show signs of older age—including grey fur, lower body weight despite unaltered diet, reduced activity, and increased frailty.
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The rebooting came in the form of a gene therapy involving three genes that instruct cells to reprogram themselves—in the case of the mice, the instructions guided the cells to restart the epigenetic changes that defined their identity as, for example, kidney and skin cells, two cell types that are prone to the effects of aging. These genes came from the suite of so-called Yamanaka stem cells factors—a set of four genes that Nobel scientist Shinya Yamanaka in 2006 discovered can turn back the clock on adult cells to their embryonic, stem cell state so they can start their development, or differentiation process, all over again. Sinclair didn’t want to completely erase the cells’ epigenetic history, just reboot it enough to reset the epigenetic instructions. Using three of the four factors turned back the clock about 57%, enough to make the mice youthful again.
“We’re not making stem cells, but turning back the clock so they can regain their identity,” says Sinclair. “I’ve been really surprised by how universally it works. We haven’t found a cell type yet that we can’t age forward and backward.”
Rejuvenating cells in mice is one thing, but will the process work in humans? That’s Sinclair’s next step, and his team is already testing the system in non-human primates. The researchers are attaching a biological switch that would allow them to turn the clock on and off by tying the activation of the reprogramming genes to an antibiotic, doxycycline. Giving the animals doxycycline would start reversing the clock, and stopping the drug would halt the process. Sinclair is currently lab-testing the system with human neurons, skin, and fibroblast cells, which contribute to connective tissue.
In 2020, Sinclair reported that in mice, the process restored vision in older animals; the current results show that the system can apply to not just one tissue or organ, but the entire animal. He anticipates eye diseases will be the first condition used to test this aging reversal in people, since the gene therapy can be injected directly into the eye area.
“We think of the processes behind aging, and diseases related to aging, as irreversible,” says Sinclair. “In the case of the eye, there is the misconception that you need to regrow new nerves. But in some cases the existing cells are just not functioning, so if you reboot them, they are fine. It’s a new way to think about medicine.”
That could mean that a host of diseases—including chronic conditions such as heart disease and even neurodegenerative disorders like Alzheimer’s—could be treated in large part by reversing the aging process that leads to them. Even before that happens, the process could be an important new tool for researchers studying these diseases. In most cases, scientists rely on young animals or tissues to model diseases of aging, which doesn’t always faithfully reproduce the condition of aging. The new system “makes the mice very old rapidly, so we can, for example, make human brain tissue the equivalent of what you would find in a 70 year old and use those in the mouse model to study Alzheimer’s disease that way,” Sinclair says.
Beyond that, the implications of being able to age and rejuvenate tissues, organs, or even entire animals or people are mind-bending. Sinclair has rejuvenated the eye nerves multiple times, which raises the more existential question for bioethicists and society of considering what it would mean to continually rewind the clock on aging.
This study is just the first step in redefining what it means to age, and Sinclair is the first to acknowledge that it raises more questions than answers. “We don’t understand how rejuvenation really works, but we know it works,” he says. “We can use it to rejuvenate parts of the body and hopefully make medicines that will be revolutionary. Now, when I see an older person, I don’t look at them as old, I just look at them as someone whose system needs to be rebooted. It’s no longer a question of if rejuvenation is possible, but a question of when.”
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