Dihomo-γ-linoleic Acid as a Basis for Senolytic Therapy
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
Borage and Evening Primrose have DGLA. There will be unknown consequences of altering your fatty acid profile.
There are easily available tests to measure your blood DGLA content. Genova has a dried blood spot test available for about $250 retail.
"Treatment with super evening primrose oil increased red-cell membrane concentrations of dihomogamma-linolenic acid (DGLA) by 40% at 6 months (P < 0.05"
A randomized controlled study of evening primrose oil and fish oil in ulcerative colitis
https://pubmed.ncbi.nlm.nih.gov/8485269/
The claim that as a senolytic, DGLA "works at a dose that is over 1,000 times lower than fisetin" is interesting, although perhaps that's because fisetin powder, like most flavenoids, has very low bioavilability because of its low solubility in water. A quick web search finds no explicit DGLA supplements, although Lee (see above) claims that evening primrose oil (which is available as a supplement) increases DGLA concentration by 40%. Evening primrose oil contains GLA, but the body must convert that to DGLA, and that conversion efficiency probably varies with the individual. In any case, Life Extension sells Mega GLA (30 x 400 mg) for $9.90, and we are already taking one of these each evening.
I stand corrected on the content of DGLA in borage and Evening Primrose. Not sure how I missed that it wasn't "dihomo" gamma linoleic, just gamma linoleic.
With that said, consuming the fairly rare GLA probably makes production of DGLA easier for your body by cutting out one enzymatic step from having to start with linoleic acid.
Linoleic --> delta 6 desaturase --> GLA --> elongase 5 --> DGLA
Interesting that as we age we produce less gla. gla is essential for skin health and to slow wrinkling and prevent dry skin. I take it every day. First I've heard that it can have senolytic properties. Better than fisetin? I take 8 of the more bio available tablets a week, along with let's sa. How many things do we need and how often to kill off these things? Seems like we can overdo it, even without resorting to using chemo drugs?
As for the indirect senolytic effects of GLA, my family has been taking 400 mg GLA caps every night, and the report suggests that one needs only a few mg of DGLA to have the same effect as a few grams of Fisetin. With Fisetin, one is supposed to do the senolytics in "burst" doses for 2-3 days, spaced a few months apart. So maybe it isn't a good idea to take GLA daily, at least for senolytics. Perhaps one should take 2 g (5 caps) every two months ...
I concur with John G about a 'burst' dosing of GLA likely being more effective as a senolytic.
My blood results show I have 47 μmol/L of DGLA (lab reference range 27-140) without consuming any GLA or DGLA.
I don't understand how taking some small amount of DGLA will eliminate senescent cells. If it really worked, do the people that have any circulating DGLA not have any senescent cells? Not likely.
Should I worry about excess DGLA spilling over into arachidonic acid through the action of the Delta 5 desaturase enzyme? If so, will the excess or arachidonic acid subsequently spill over into excess inflammatory leukotrienes and other inflammatory series 2 prostaglandins?
Is there a balance point with GLH supplementation where in one can get the benefit without creating the harmful inflammatory metabolites? Would taking a large periodic dose actually be worse in these regards then taking a consistent daily dose of GLA?
@Lee it's been found to eliminate senescent cells in mice, so what that suggests in that it might turn out that it eliminates a type of senescent cell that exists in mice but not humans, as humans already have the ability to eliminate that type.
https://www.cell.com/cell-metabolism/pdf/S1550-4131(21)00115-7.pdf
Aspirin inhibits the synthesis of Oxylipins via COX enzymes. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996307/
The compound Wiley is referring to may be Compound 326 a Delta 5 Desaturase inhibitor. It decreases AA and increases DGLA.
https://jpet.aspetjournals.org/content/371/2/290.abstract