“Old” Food Reduces Lifespan
Photograph by Justin Ide/Harvard Public Affairs & Communications
Photograph by Justin Ide/Harvard Public Affairs & Communications
What causes aging? “Scientists have been thinking about this question for centuries,” says Harvard professor of medicine Vadim Gladyshev. It sounds almost simple, but in fact it’s thorny and complicated, and although several theories have emerged—that organisms are “programmed” by nature to die, or that aging is the result of “hyperfunction” of biological activities, or that it’s controlled by genetics—there are as yet no settled answers. But a study published today in Science Advances, coauthored by Gladyshev, offers evidence bolstering one long-held theory: that aging is caused, at least in part, by molecular damage accumulating in the cells. “This damage is generated by nearly every cellular process,” he says—by the work of enzymes and proteins and the life-sustaining metabolic processes that occur at every level of complexity, from simple molecules and cell components to whole cells and entire organs. “So over time we have many, many ‘damage forms,’ millions or billions”—unavoidable byproducts of enzyme function, for example, or of protein-to-protein interactions, errors in DNA transcription or translation. “And as a function of age, they accumulate.” Eventually, it’s more than the body can cope with.
In a series of experiments, Gladyshev and his collaborators found that feeding a diet of “old” organisms to yeast, fruit flies, and mice shortened their lifespans by roughly 10 percent. Here’s how it worked: for yeast, the researchers formulated one cell-culture medium composed of extracts from young yeast cells and another of extracts from old ones. They then grew new yeast cells on each medium and watched to see which set would live longer. As Gladyshev explained: “Our hypothesis was that as yeast ages, it accumulates certain damage forms, and we wanted to test that specific damage and find out if it is deleterious for yeast.”
The team replicated the same basic procedure in fruit flies and mice: they collected 5,000 freshly dead flies that had lived an average of 45 days, and sacrificed 5,000 others that were three to five days old. Then they prepared two homogenized diets, one composed of young flies and the other using the old ones. They fed these diets to young female fruit flies (not males, though: the experiment was limited by the number of old flies the researchers were able to collect; to do the experiment, they had to vastly expand their colony and then wait for thousands of flies to die—“It is easy to get flies,” Gladyshev quips, “but not easy to get a lot of freshly dead flies”). The mice were fed diets of skeletal muscle—“meat, basically,” Gladyshev says—from young and old farmed red deer (three years old versus 25) that replaced the animal-product components (insects, carrion, worms, etc.) of a normal mouse diet. Using mouse tissue was not feasible, he explains, because of the large quantities needed for the experiment; deer meat was a suitably close match.
The experiments raise new questions—in a field that’s full of them—and some of the results were a little unexpected. In the mouse study, the old diet shortened the animals’ lifespans, but only in females. In male mice, the shortening of lifespan was not statistically significant. Gladyshev attributes that to the limitations of the experiment itself. Because they had limited deer meat, the researchers tested only 60 mice, rather than two or three times that many. “Also,” he says, “we began feeding the mice not from when they were first weaned but when they were 12 months old. So for the first year, they lived on a regular diet. It’s possible there wasn’t enough time for the diet to have a full effect.”
Mostly, though, Gladyshev had expected to see larger differences in the test organisms’ relative lifespans. The effect of consuming an old versus a young diet, he says, was “statistically significant, but it wasn’t huge. Honestly, I thought it would have a much larger effect on lifespan, but it was on the order of about 10 percent.” The effect was consistent, however, across all three species. “That shows us that these age-related changes that accumulate are truly deleterious,” he argues. “And that provides a fundamental insight into the aging process.” In the study, the authors interpret the minor-but-consistent effect to mean that damage accumulation may be only one contributing factor in aging, and also that damage caused by internal molecular changes may have a stronger effect than damage introduced through the diet.
It’s also likely that the damage arises from many processes. “And they all work together in a deleterious way,” Gladyshev says. “So the question is, how do we slow down this process? How do we restructure cellular metabolism so that this damage accumulates at a slower rate?” He doesn’t yet have an answer, although he believes the approach will have to be holistic—cells accumulate so much damage, from so many metabolic processes, that intervening in one or another type of damage would have little effect on the whole. “Even if we remove some damaged forms, others will still be generated…But if we alter the state of the cell itself”—genetically, perhaps, or with diet—“so that many cellular systems are affected, then they would generate somewhat different damage forms and generate them at a different rate.”
These questions lead into wooly thickets that confound biology’s usual, reductionist methods for teasing out and analyzing components one by one. In research on aging, Gladyshev explains, it is difficult even to design experiments that test causal relationships. But finding a way through the forest is essential. He directs redox medicine at Brigham and Women’s Hospital—an experimental therapy that aims to treat disease by varying pro-oxidant and antioxidant factors in cells—and says that, from his perspective, “Aging is the most important biological question.” It is at the root of so many diseases. “Even if we eliminate cancer, for example, the effect would be minor, because of all the other diseases of aging: diabetes, Alzheimer’s, sarcopenia, cardiovascular disease, and so on and so on.” All of those maladies will still add up. “But if we can learn how to slow down the aging process, we can deal with all of those diseases at once. We delay their appearance. That’s why it’s important to study these fundamental questions, to ask: what is aging?”