Research into longevity, that most fundamental and intractable of all human health challenges, is slow moving. It deserves to be described in terms of years, not individual studies. But once in a rare while, a finding has the potential to be a landmark.
Such is the case with a new experiment that flushed old, broken-down cells from the bodies of mice, slowing their descent into the infirmities of age.
The usual caveats that inevitably apply to mouse studies still apply here. But even with those, the findings mark the first time that cellular senescence — its importance debated by biologists for decades — has been experimentally manipulated in an animal, demonstrating a fantastic new tool for studying its role in human aging.
And even if the results are applicable only to one strain of genetically modified mice, it’s hard to not at least notice what happened to them. Already programmed to die from heart disease, they didn’t live longer than usual, but they were far healthier.
“Their healthspan was extended,” said gerontologist Darren Baker of the Mayo Clinic. “They were healthier until the time they died.”
Baker and colleagues’ experiment, described Nov. 2 in Nature, killed mouse cells producing a protein called p16Ink4a.
On its own, p16Ink4a — p16 for short — is just one part of the story. It’s a tumor inhibitor, but more importantly it’s what researchers call a biomarker, a sign that something else is going on. When p16 is found in a cell, that cell is probably reaching its replication limit and grinding to a senescent halt.
This slowdown, first identified in 1961 by biologists Leonard Hayflick and Paul Moorhead, is a normal part of cellular life cycles. The name for cells that divide without stopping is cancer. But research in subsequent decades, and in particular since the late 1990s, suggested that cellular senescence came with a price.
'Now we've got a technique to do this, and it sets the stage for really big stuff in the future.'Slowed-down cells didn’t simply die. If they did, tissues would flush them out. Instead they linger, oozing inflammatory proteins and other cellular pollutants. Many researchers think senescence-related tissue dysfunction contributes to heart disease and cancer and other conditions that become more likely with age.
But however plausible it may look in cell cultures and cadaver tissue samples, this hypothesis hasn’t been tested in living, aging animals.
“The bottom-line question is, what happens when you increase or decrease cellular senescence in an animal? That’s where this comes in, and that’s why it’s so important,” said Felipe Sierra, director of the National Institute on Aging’s Division of Aging Biology, which helped fund the research.
Baker’s team, led by himself and Mayo Clinic gerontologist Jan van Deursen, started by engineering a mouse strain that aged unnaturally fast. When they inactivated p16 and other senescence-linked genes in embryonic mice, aging proceeded normally.
It hinted at the importance of cellular senescence, but wasn’t so convincing as if the mice had senesced over the course of their lives, then been treated. To accomplish this, Baker and van Deursen designed a fast-aging mouse strain that would, upon receiving a drug trigger, expel p16-producing cells from fatty tissues, muscles and eyes.
When the mice were given the drug, muscle wasting stopped. Cataracts didn’t grow. Health was maintained until their hearts, which were unaffected by the senescence-clearing hack, gave out.
Senescence “appears to be relevant,” said Sierra. “It plays a role in age-related diseases.”
However, both Sierra and Baker advised caution: Intervening in a mouse model of disease, maintained in pathogen-free settings, is far easier than treating healthy mice. Other, as-yet-unanticipated effects could still emerge. Baker called it a “proof of principle,” and Sierra described the findings as “low-hanging fruit.”
Their cautions were seconded by gerontologist Steven Austad of the University of Texas, who was not involved in the study. He noted that many mouse-level successes prove far more complicated than they initially seem. Most recently, a much-hyped longevity drug target fell into disrepute after new studies failed to support its early promise.
“The most interesting thing is not the effect that knocking out senescent cells had on this animal, but the demonstration that there’s a technology we could use to knock out senescent cells in specific tissues,” said Austad. “Now we’ve got a technique to do this, and it sets the stage for really big stuff in the future. This has the potential to answer a really big question that has bedeviled the field for a long time: How important is cellular senescence for whole-animal senescence?”
High-hanging fruit, said Sierra, would be senescence in other types of tissues, especially brain cells, and in multiple strains of healthy, genetically normal mice. Baker said those tests are already underway.
“This area has been developing for the last 50 years,” said Sierra. “It’s getting extremely exciting.”
Image: At left, two mice, one (top) treated to rid it of senescent cells, and the other untreated; at right, untreated bone marrow cells (top) and treated cells. (Baker et al./Nature)
Citation: “Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders.” By Darren J. Baker, Tobias Wijshake, Tamar Tchkonia, Nathan K. LeBrasseur, Bennett G. Childs, Bart van de Sluis, James L. Kirkland & Jan M. van Deursen. Nature, Vol. 478 No. 7370, Nov. 3, 2011.