Fight Aging!

This interview with a researcher working on the biochemistry of senescent cells notes the exploration of dihomo-γ-linoleic acid and derived compounds as potential senotherapeutics, capable of reducing the burden of senescent cells in old animals. At the end of the day there will be a very large number of such approaches, as the animal data for rejuvenation resulting from the clearance of senescent cells is impressive enough to drive a considerable growth in funding and interest. A sizable number of biotech companies are working on drugs to selectively destroy senescent cells, and many more programs are in earlier stages in academic labs.

There is a specific fatty acid made in small amounts in the body called dihomo-gamma-linoleic acid or DGLA. It's also present in tiny amounts in the diet. When I gave aged mice larger amounts of DGLA, they went from having quite a few senescent cells to having significantly fewer. This presents a new therapeutic target. I identified a candidate compound using the DGLA metabolic pathway that works at a dose that is over 1,000 times lower than fisetin, so you can imagine we're quite excited by these results.

Like many biomedical discoveries, it was accidental. DGLA makes anti-inflammatory lipids, which help alleviate conditions such as rheumatoid arthritis. I was studying this aspect of DGLA when I was surprised to discover that it killed senescent cells. My work is in its very early stages, and we've only studied a small number of mice, so it's too early for even tentative conclusions, although I'm obviously pleased that we've seen the elimination of a meaningful number of senescent cells in old mice. We'll be closely monitoring DGLA's positive effects as well as any negative effects on the mice.

First, we have to figure out how DGLA is killing senescent cells in mice. Again, not all studies with mice yield similar results in humans, so we are very careful about how we convey our findings and possible future actions. But I have met USDA researchers and nutrition scientists, and discovered that some of those folks were developing DGLA-enriched soybeans. In one scenario, you might go out for sushi and get a little bowl of DGLA-enriched edamame as a side. By the time you're done eating, you've helped reduce the odds of getting some age-related pathology. I don't know if it will play out that way, but it's an idea we're working toward. I also am working on therapies that elevate the amount of naturally occurring DGLA in senescent cells that I am very excited about, so this would be an alternative approach.

I am developing a quick and easy test to tell if senolytic therapy is working. Testing for senolytic effectiveness is not really being done now - you just look for improvement in symptoms or functioning and essentially conclude that it's due to the therapy. One way to solve this dilemma is to identify a biomarker, a measurable compound that consistently and reliably can confirm an intervention's effectiveness. For example, we know that a certain lipid, dihomo-15d-PGJ2, accumulates in large amounts inside of senescent cells. When we give a senolytic therapy that kills these cells in mice or human cells, this lipid is liberated. Detecting it in blood and urine is far less invasive, so that's what I'm working on now. Our aim is to be able to test people receiving senolytic therapy for the presence of dihomo-15d-PGJ2 in their blood and urine by the end of the summer.

Link: https://now.tufts.edu/articles/taking-harmful-cells-contribute-disease