This is pretty important, even though it’s only a proof of concept – not even a first step to developing a useful therapy for age-related health afflictions. What’s been done is to show that a state (senescence), which old cells reach when they near the limit of their useful lives, is not just a somewhat benign way of stopping the cell from becoming cancerous. Instead, senescent cells that aren’t eliminated naturally (by the immune system or by apoptosis) and remain in the body can degrade the health of the organism. Further, causing such cells to be eliminated is not only possible, but improves the organism’s overall health even though it does not lengthen lifespan. (And even this much has only been demonstrated in genetically altered mice, not humans.)
Research into longevity, that most fundamental and intractable of all human health challenges, moves slowly. 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 large caveats that inevitably apply to mouse studies still apply here, in spades. 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.
The research involved a series of experiments, and if you’re up on your molecular biology, the details are interesting.
The first issue concerns the nature of senescent cells. Because of their age, they may have telomeres that are too short or DNA damage that can lead to cancer. Consequently, nature has evolved mechanisms to detect such conditions that can’t be repaired and to take action to prevent completion of the normal cell division cycle, so that such cells do not proliferate cancerously.
Unfortunately, senescence is just a stopgap measure, and senescent cells do not simply remain harmlessly in place. They also increase production of signaling proteins (cytokines), which normally would produce inflammation and attract the immune system to dispose of the cell. But in older organisms, the immune system itself is weakened and does not properly do its job, leaving just the inflammation, which is harmful in itself.
This process is mediated, once a cell has become senescent, by increased expression of a particular gene, p16. Although this gene can be expressed into several slightly different proteins (by alternative splicing), one of its protein products (p16Ink4a) inhibits cyclin-dependent kinase 4 (CDK4), which is necessary for the normal progression of the cell cycle.
It’s not a good thing to try to prevent senescence by inhibiting p16, because of the vital purpose it serves. However, senescent cells need to be efficiently cleared away, and p16Ink4a can be used as a biomarker to identify a cell that’s become senescent. Using a trick that had been used in other studies to induce apoptosis, the researchers created a mouse strain with a new gene (that they called INK-ATTAC, standing for INK apoptosis through targeted activation of caspase). In mice with this gene, a specific drug (AP20187), in the presence of p16Ink4a, activates a caspase, which promotes apoptosis.
Voilà. Senescent cells eliminated.
Mice given the drug cleared their body tissues of senescent cells and had less age-related muscle loss, less thinning of skin and a lower rate of cataracts than mice that did not receive the drug. The results of the experiment suggested to Kirkland that “senescent cells can cause dysfunction in tissue and removing them can restore function.”