If you think of your inherited genetics, your DNA, as a piano keyboard, then epigenetics determines how the keys play music. The primary players in this concert are molecular substances that affix to our genome and leave markers. These markers, in turn, give cells specialized functions and regulate how they function. If too many markers accumulate—if there is too much “epigenetic noise”--the directions become muddled, and the cells become dysfunctional.
Over the past decade, researchers have learned that these markers can offer a remarkably accurate measurement of biological age, to within a few years. That insight has been quickly followed by growing evidence for a more startling idea: That the epigenetic markers don’t just measure aging but help to cause it.
When researchers at the Harvard Medical School’s Sinclair Lab (run by one of this article’s co-authors, Dr. Sinclair) added epigenetic accretions to the genomes of young mice in 2015, the mice experienced an accelerated loss of muscle and bone mass, turned gray, lost sight and became more easily confused. The mice’s birthdays didn’t change compared with their siblings, only their epigenomes did.
“ We suffer from aging, in short, as a side effect of a primeval program that helps to regulate and repair our cells. ”
The results of that experiment and others like it are helping solidify an “information theory” of aging, which says that an accumulation of epigenetic noise interferes with genetic data. The chaos eventually causes cells to become senescent and stop reproducing and influences adjacent cells to do the same. That is the experience we have come to know as aging.
The origins of this process can be found in the earliest era of microscopic life on earth. Simple organisms evolved signals to reproduce cells when conditions were favorable and to shut down and attend to any damage when conditions were poor.
We suffer from aging, in short, as a side effect of a primeval program that helps to regulate and repair our cells. In this way, aging is not unlike cancer, which some scientists believe also initially evolved as a survival mechanism, allowing cells to abandon higher functionality in order to proliferate unchecked.
Before we knew why cancer happens, we considered it just a part of life. Now, we correctly call cancer a disease—a bug, not a feature—and fight against it with all our might. We don’t generally regard aging in the same way, but we should. After all, what is a disease but a condition that prevents the body or mind from working normally? That’s exactly what aging does.
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Indeed, aging might rightfully be called “the mother of all diseases.” Consider: While smoking increases the risk of getting cancer several-fold, simply being 50 years old increases cancer risk more than 100 times over people who are a few decades younger. By the age of 70, it is more than 500 times. Aging is also a major factor in heart disease, dementia, stroke and Type 2 diabetes.
If we were to cure any one of these diseases, we might increase the average human lifespan by only a few years. Why? Because the risk of all of those other diseases would continue to increase, thanks to the driving force of aging. But reduce them all, by addressing conditions at the cellular level, and the potential for extending productive, healthy human lives is much more significant.
The notion of a world in which we could slow, stop or reverse aging is very foreign to us, so a high degree of skepticism is warranted. But there is no law of biology that says we must age at the rate at which we do now. Some other forms of life don’t. The bristlecone pine can survive for 5,000 years and does not appear to experience aging. The jellyfish known as Turritopsis dohrnii is made up of cells that can reverse course to become juvenile cells, and seems to be functionally immortal. Humans don’t have much in common with either of those species, of course. But closer to us on the tree of life is the Greenland shark, which can live to 500 years. Closer still is the bowhead whale, a fellow mammal that outlives us by a century.
“ If something as complex as a retina can be rebooted to a youthful state, what else can? ”
We now know that epigenetic markers of deterioration and aging can accumulate from unhealthy inputs: for instance, if our DNA is damaged by overexposure to sun or if we eat poorly or smoke. End those behaviors and cell deterioration slows. Better yet: If we can reboot the cell, we would have the potential to stem or even reverse cellular aging. It would allow an older body to heal and to fight against age-related diseases more like young people do.
At the Salk Institute in San Diego, researchers in the lab of Juan Carlos Belmonte showed in a 2016 study published in the journal Cell that the lifespan of mice suffering from premature aging could be extended by 30% by transiently turning on four genes that are known to wipe away accumulated epigenetic markers and induce “pluripotency,” the ability of a cell to develop into any other form of cell in an adult body. By partially resetting the program, the mice seem to have experienced a taste of what life is like as an immortal jellyfish.
In the Sinclair lab at Harvard, researchers administered a combination of three genes to blind old mice and turned the genes on for three weeks. The treatment rejuvenated their optic nerve cells and restored their vision. If something as complex as a retina can be rebooted to a youthful state, potentially multiple times, what else can?
Dr. Sinclair, Dr. Belmonte and Steven Horvath at UCLA have started a company to develop medicines for eye diseases based on this science, and Dr. Sinclair has been involved in other such commercial ventures. But to be clear, there is a great distance between what can be done with mice in a lab and what can be done to help humans fight diseases and extend their healthy years. And the “healthy” part is vitally important: You would be hard-pressed to find anyone who thinks it would be a good idea to lengthen human lives if we cannot substantially improve the part of life that is lived free of debilitating diseases.
Dr. Horvath and his colleagues at UCLA recently published a small study of human subjects in the journal Aging Cell. They reported that nine patients treated with a cocktail of three molecules—growth hormone, DHEA, and metformin—experienced an epigenetic age reversal, shedding two years off their biological ages.
There was no control group, and the results must be considered preliminary unless larger, more rigorous studies replicate the results. But it is no longer completely crazy to talk about having birthdays in reverse.
—Dr. Sinclair is a professor of genetics and co-director of the Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School. Mr. LaPlante is an associate professor of journalism and communication at Utah State University. This essay is adapted from their book, “Lifespan: Why We Age—and Why We Don’t Have To,” published by Atria Books.