In what scientists believe is a first, they have successfully rewound the age clock in a living organism. While the only beneficiaries thus far have been mice, and more studies will be needed before we’re all doing our best Benjamin Button impression, this is a significant step toward what has long been a medical and societal holy grail — age reversal.
David Sinclair, co-director of a Harvard Medical School research center focused on aging, has been fascinated by the process of growing old since he was a kid. “We just regard it as natural,” he says, pointing out that people in the past thought of cancer as natural and unavoidable too. If we could figure out why we age, he reasoned, we might be able to prevent many of the diseases that eventually kill us. “If we can extend the time our organs stay young, we will push diseases out into the future,” he says.
Like many researchers who focus on aging, Sinclair has spent a considerable amount of time studying telomeres. If our chromosomes are akin to shoelaces, telomeres are the caps on the end of those chromosomes that keep them from fraying. Scientists have known that older people have shorter telomeres than young people, and speculated that finding a way to preserve telomere length might help stave off the effects of aging.
Sinclair has a new theory about that. Since the 1990s, he has been studying a group of proteins known as sirtuins that exist in everything from yeast to humans. They’re protective proteins, activated by all the things that are supposed to be good for you: exercise, dieting, fasting. But over time, these proteins lose their activity. As that happens, cells begin to go haywire. Genes turn on and off at the wrong times. Telomeres shrink. And the epigenome — a layer of information that sits on top of our DNA and governs which genes are active — loses its effectiveness.
What Sinclair has found, he argues, is a unified theory. Telomeres aren’t the cause of aging, he believes, but one of its earliest victims. It’s the activity of these sirtuin proteins, the ones responsible for protecting our epigenomes and our telomeres, that governs the cascade of youth or aging. About “these health-promoting enzymes,” Sinclair says “their main job is making sure our cells stay young.”
But these proteins need a molecule known as NAD (which stands for nicotinamide adenine dinucleotide, if you must know), which becomes less abundant in our bodies as we age. When these molecules are boosted in old mice, Sinclair says, “they run much further, they have more energy, they generally appear more youthful.”
So why aren’t we all freebasing NAD supplements? As it turns out, swallowing pills is not the best way to get these important molecules delivered to every cell in the body. Sinclair’s team is working on a more effective gene therapy approach that resets the cells to their younger state. And it appears to have worked.
First, the scientists had to prove that their theory about what causes aging was correct. They accomplished that in mice through a lab technique designed to prematurely trigger the aging process. At a recent scientific conference, Sinclair showed photos of two mice from this experiment, that were the exact same age. One was a normal, healthy mouse. The other was prematurely aged. It looked wizened and gray. Deeper inspection showed that the “old” mouse had a fragmented epigenome, matching the damage seen in truly old cells.
But understanding the process of aging is not nearly as exciting as gaining mastery over it, and that’s what Sinclair and his team tackled next. They focused on the mouse eye, which is often a starting point for gene therapy because it’s a closed system; the molecules used for gene editing in an eye can’t leak out to the rest of the body.
According to Sinclair’s data, the experimental procedure done in his lab was a triumph. The weathered eye tissue transformed into healthy young tissue, restoring youthful vision and repairing damage from injury. “We found that we could reset the system [and] reboot the software of the cell,” Sinclair says.
This work appears so promising that Sinclair has already spun out a company called Iduna that is planning to start clinical trials for human glaucoma patients in the next two years. He’s also looking at other possibilities, such as using the approach to reverse hearing loss or to increase memory retention by resetting the age of the brain. (Sinclair also co-founded a related company in 2017 called Life Biosciences. Mehmood Khan, the CEO of that company, spoke about it at the Techonomy NYC conference in 2019 in a session entitled “The Science and Economics of Aging.”)
The ultimate goal, though, of course, is whole-body rejuvenation. Sinclair has already tried this in mice and found it appeared to be safe for them, though his team has not yet performed the studies needed to understand efficacy at the whole-body level. Delivering gene therapy throughout any mammal’s entire body will be a serious technical challenge.
Still, Sinclair’s work means that we could be closer to the grand prize: being able to reverse aging. “You could imagine a future where, if we could deliver this therapy evenly across the body, we could reset our bodies” to a younger state, he says.