New study on slowing aging
Looking at fish oil, vitamin D, and exercise to slow down aging...
There's a new study in the journal Nature Aging that looks at how three common interventions - fish oil, vitamin D, and exercise - affect biological aging according to different epigenetic age clocks.
Epigenetic age clocks are one way researchers try to quantify the effects of different interventions on lifespan. There are now several "biological age clock" algorithms that have been refined and updated in recent years. This study used four different biological age algorithms (PhenoAge, GrimAge, GrimAge2, and DunedinPACE) to test the effect of the interventions.
This was a fairly large study that looked at data from 777 participants who were followed for three years. It was a post hoc analysis using data from an even larger study done in older adults from Switzerland (average age 75).
The participants were divided into groups with some taking vitamin D (2,000 IU per day), some taking an omega-3 supplement (1g/day), some doing a home exercise program, and some doing all three together.
The researchers found that the omega-3 supplement alone slowed biological aging based on three of the epigenetic age tests. The addition of vitamin D and exercise along with the omega-3 supplement showed additional benefits on one of the four epigenetic age tests (PhenoAge).
Without getting into the weeds on the test details, I wanted to dive into a few things that struck me:
First, there seems to be a clear benefit for higher omega-3 fatty acid intake in slowing the rate of biological age.
Second, neither vitamin D nor exercise by themselves moved the needle there. Both have a role in health, but perhaps not in the epigenetic age. Or, it could be that the dose of vitamin D (2,000 IU/day) wasn’t enough since 30% of the participants were deficient at baseline. For exercise, it could be that adding more exercise wasn’t beneficial since 88% of the participants were already physically active.
So why fish oil (or omega-3 oil)?
The researchers in the epigenetic aging study mention a couple of things that fish oil affects, like plasminogen activation inhibitor 1, for which higher levels increase the risk of cardiovascular disease.
To me, the big picture on fish oil is more fundamental, affecting all biological systems — and somehow missed by so many people (and researchers).
Simply put, DHA and EPA are essential for the synthesis of pro-resolving mediators.
DHA, EPA, and specialized pro-resolving mediators:
The resolution of inflammation is an active process. Inflammation doesn’t just fade away completely when it isn’t needed. Instead, there are active processes for the resolution of inflammation that go on concomitantly with the onset of inflammation.
Without the resolution of inflammation, low levels of inflammatory cytokines linger. Chronic inflammation. Which is at the root of almost all chronic diseases.
DHA and EPA are the building blocks for specialized pro-resolving mediators (SPMs). When inflammation occurs, such as due to a wound or pathogen, pro-resolving mediators are produced at the site. These SPMs kick off a cascade of events, modulating the immune response, promoting healing, and bringing stem cells to the tissue for regeneration.
SPM levels decline in aging, as inflammation increases.[ref][ref]
Read the details on SPMs and the resolution of inflammation here.
Here’s a sample of chronic diseases for which research shows low SPM levels play an integral role:
Heart failure[ref]
Alzheimer’s and Parkinson’s diseases[ref]
Chronic lower back pain due to neuroinflammation[ref]
Arthritis (rheumatoid, osteoarthritis, and gouty arthritis[ref]
Sources of DHA and EPA:
DHA and EPA levels are often the limiting factor for producing SPMs when needed in a tissue.
Fish oil, assuming that it is high quality, not rancid, and not laced with heavy metals, is one way to increase DHA and EPA levels. Krill oil and algae oil are also solid sources of supplemental DHA and EPA. Here’s what I’m currently using. Costco has it on sale right now. I do switch it up and change brands periodically, and I don’t take it every day if I’m getting a lot of DHA/EPA from other sources.
There are also SPM supplements, but they can get expensive when taking the higher doses needed to increase your levels. I’ve tried several brands and am not sure that I saw a benefit over what I notice from fish oil.
Eating fish and seafood is, of course, a great way to get dietary DHA and EPA. The key is to find fish that isn’t high in mercury (or microplastics).
Other than fish, foods high in DHA and EPA include
Eggs from omega-3 supplemented-feed[ref]
Grass-fed beef has a higher EPA/DHA ratio and lower levels of omega-6s.[ref]
Increasing the effect of “fish oil”
DHA and EPA are converted to the specific SPMs when needed. The conversion process involves special enzymes that facilitate the synthesis reactions.
There are several ways that you can increase the conversion of DHA and EPA into SPMs.
Aspirin increases the conversion of a specific SPM called resolvins. Aspirin is unique among NSAIDs in that it acetylates COX2, which then triggers the formation of ‘aspirin-triggered specialized pro-resolving mediators‘ or AT-SPMs. [ref][ref] Aspirin-triggered SPMs have a prolonged half-life, acting to resolve inflammation for longer.[ref]
Aspirin is not for everyone. For some, the risk of bleeding outweighs the benefits. (Talk to your doctor if you need help figuring it out for your situation.)
Blueberries have recently been shown to also increase the conversion of the precursor fatty acids to SPMs. A recent study showed that 1 cup/day of blueberries for 18 days significantly increased SPMs in ‘weekend warriors’. The researchers looked at the effects of freeze-dried blueberries, equivalent to 1c per day, compared to a placebo powder in adults who worked out hard for 90 minutes once a week. The results showed increases in SPMs and metabolites only in the group consuming the antioxidant-rich blueberries.[ref]
The study used freeze-dried blueberry powder, such as this one, to keep it consistent. Other options would include a cup of fresh or frozen blueberries. Costco has organic frozen blueberries at a reasonable price. They also carry dried blueberries, which are a tasty treat.
The omega-6 to omega-3 ratio plays a role in converting EPA and DHA to pro-resolving mediators. The same ALOX enzymes that convert omega-6 fatty acids into pro-inflammatory lipids are also used in the conversion of some of the pro-resolving mediators.[ref] With a large imbalanced ratio of omega-6 to omega-3, which is common in our modern diet, it can affect the ability to convert DHA and EPA when needed for SPMs.
Vitamin D: A study in patients with diabetes found that increasing vitamin D also increased the enzyme that converts DHA/EPA to SPMs.[ref]
Will taking fish oil cause atrial fibrillation?
A 2022 study using information on almost 500,000 people in the UK found that people who took fish oil were ~1% more likely to have atrial fibrillation. This association was seen only in people who were not diagnosed with cardiovascular disease. There are questions on whether it is the consumption of cheap, oxidized fish oil supplements or if there is a true risk from high DHA and EPA. The same study showed that eating oily fish did not increase a-fib.[ref] Additionally, a clinical trial using 4g/day esterified EPA/DHA was halted early when it didn’t show benefits for heart attacks and strokes. Noted in the paper is that a tertiary endpoint did show an increased rate of new-onset a-fib (0.9% more in the EPA/DHA group than in placebo).[ref] If you are prone to Afib, talk with your doctor about whether fish is oil a good idea for you.
Conclusion:
While I'm not overly focused on epigenetic age clocks, it's interesting to see what interventions might move the needle on slowing aging a bit. In an already active group of older people, adding more exercise didn't show any effect. Similarly, a low dose of vitamin D didn't move the needle. However, omega-3 supplements at 1 g/day had a positive effect.
While the positive effect of omega-3s could be due to changes in plasminogen activation inhibitor-1, as the researchers mentioned in the paper, I suspect that reducing inflammation by increasing specialized pro-resolving mediators also plays a big role.
There are several ways to increase SPMs - increase fish, reduce omega-6 seed oils, eat pasture-raised eggs, or take a DHA/EPA supplement. Personally, I'm doing a mish-mash of all of these. The only new addition for me is that I'm increasing my consumption of blueberries, based on the study of "weekend warriors" showing an increase in SPMs with one cup of blueberries per day.
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