A new antidote to aging
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In a sense, your body is a junkyard, slowly filling up with defective cells that clutter your vital organs. The accumulation of these cells—known as senescent cells—has long been thought to be an important reason why people deteriorate physically as they age. Now new research proposes an antidote: remove senescent cells from the body and you can slow the hands of time.
The study, published in Nature in early February, was conducted on mice. Researchers used a chemotherapy-style approach to target and kill senescent cells. They found that compared to controls, mice who underwent this treatment lived about 25 percent longer.
"The removal of cells had the same effect as not accumulating senescent cells to begin with," says Jan van Deursen, a researcher at the Mayo Clinic and coauthor of the paper. "It had profound beneficial effects."
Cellular senescence was discovered in the 1960s and has come to be understood as a defense mechanism against cancer. Under normal conditions, cells reproduce by making exact copies of themselves. Yet sometimes the genetic code in a cell gets damaged, at which point further reproduction becomes dangerous, because it could introduce a mutation that spawns cancer. So, when cells become irretrievably damaged, they undergo the process of senescence, after which they remain alive in the body, but cease to further divide.
"The evidence is strong that senescence is a tumor suppressor mechanism. Cells are damaged, they know they're damaged, they know continued proliferation could be bad and [the body] averts malignancy by having those cells go to this sort of molecular jail," says Norman Sharpless, professor at the University of North Carolina School of Medicine and an expert on cellular senescence.
Senescence may thwart cancer, but it also carries costs. For reasons biologists don't completely understand, senescent cells secrete proteins that cause chronic inflammation, a problem for many elderly people. They also build up exponentially over time—very slowly at first, then more rapidly as people get older, so that by advanced age, about 1 out of every 100 cells in some tissue of the body is thought to be senescent.
"There's only so much space in body, so if your spots for good cells are filled up by senescent cells, that can be a bad thing," says Sharpless.
Jan van Deursen and his colleagues understood this, and wanted to see what would happen if they removed senescent cells from mice. They knew they couldn't just short-circuit the process of senescence, because previous research had shown that when that happens, mice quickly develop tumors and die young anyway.
Instead, van Deursen and his coauthors went looking for a genetic signature unique to senescent cells—a feature that would allow a drug to specifically target those cells while leaving normal cells alone. They found it in the form of the p16 gene, which is always "on" in senescent cells. Then they injected mice with a drug that sought out p16 positive cells and tricked them into undergoing "apoptosis," the technical term for cellular suicide.
The researchers began administering the drug when mice were one year old. They found that mice who received it lived longer, had greater peak cardiac capacity, healthier kidneys and eyes, and even started to behave like they had when they were young.
"Young mice are exploratory and active and as mice age, they like to sit in a corner of a box and not move around a lot," says van Deursen. He adds that mice who received the drug maintained this frisky, curious behavior, even as they aged.
The researchers have started a company, Unity Biotechnology, which is beginning to develop similar drugs for use in human beings. If successful, the effort would reflect a shift in the medical approach to aging and age-related diseases. Most current ideas focus on preventing aging from ever happening, through lifelong consumption of products like green tea or resveratrol. These approaches are hard to test scientifically, because that would require running decades-long clinical trials. By killing senescent cells, however, scientists would be aiming to treat aging rather than prevent it, and the effectiveness of a treatment is easier to establish.
"Moving [aging] into human therapeutics is pretty difficult if you rely on prevention. If it were that easy, people would have done it already," says Sharpless. "This paper provides the means not to slow aging, but to treat it as a therapeutic paradigm."