For years, antioxidants were hailed as miracle compounds that could slow aging, improve heart health, and enhance physical performance. Then, almost as quickly as they rose to fame, they fell out of favor. But now, new evidence is challenging everything we thought we knew.
In this article, we’ll explore the rollercoaster history of antioxidant science, what recent studies reveal, and whether you should reconsider taking antioxidant supplements—especially as you age.
Table of Contents
Antioxidant Excitement & Disappointment
Ever wondered why, 10 or 20 years ago, antioxidants were all the rage? They were supposed to extend lifespan, reduce heart disease, and improve muscle performance. Then all that excitement quietly died.
Now though, after a new study, the excitement is about to come roaring back.
Researchers initially thought they had discovered a magic antioxidant lever to counter the effects of aging. Every time your body turns food into fuel, it creates a byproduct: free radicals. These unstable molecules are missing an electron and can damage surrounding cells and tissues—a process called oxidative stress.
While your body has natural defenses against oxidative stress, the theory was that increasing our intake of antioxidant-rich foods like fruits and vegetables—or antioxidant supplements—could minimize this damage and potentially slow the aging process.
Initial studies of this incomplete and flawed hypothesis appeared to point in a positive direction.
A 1993 study published in the New England Journal of Medicine examined data from the massive Nurses’ Health Study, focusing on 87,245 female nurses aged 34 to 59 who were free of diagnosed cardiovascular disease and cancer. They were followed for up to eight years [1].
Researchers zeroed in on vitamin E, a lipid-soluble antioxidant carried in LDL cholesterol. Since oxidative stress was thought to be a key contributor to plaque buildup in arteries, they theorized that higher vitamin E intake could reduce the risk of heart disease.
Compared to women in the lowest fifth of vitamin E intake, those in the highest fifth had a 34% lower risk of major coronary disease. Specifically, the relative risk was 0.66 (95% confidence interval, 0.50 to 0.87) [1].
Most of the variability in intake and reduction in risk came from vitamin E supplements. Women who had taken them for more than two years had a 41% reduced risk, with a relative risk of 0.59 (95% CI, 0.38 to 0.91) [1].
This was promising—but it was an observational study. It couldn’t prove causality. Randomized controlled trials were needed.
In 1996, the Cambridge Heart Antioxidant Study (CHAOS) put that theory to the test. It included 2,002 patients with confirmed plaque in their arteries. Participants were given either 800 IU or 400 IU of vitamin E daily, or a placebo, and followed for a median of 510 days [2].
The results appeared to support earlier findings. The group receiving vitamin E had a 47% lower risk of cardiovascular death and non-fatal heart attacks. Specifically, the relative risk was 0.53 (95% CI, 0.34–0.83; p=0.005). This was driven largely by a sharp drop in non-fatal MIs: 14 events in the vitamin E group versus 41 in the placebo group [2].
But there was a catch. Cardiovascular deaths actually went up slightly in the vitamin E group—27 deaths compared to 23 in the placebo group. It wasn’t statistically significant (RR 1.18; 95% CI, 0.62–2.27), but it was unexpected. All-cause mortality was also higher in the vitamin E group: 36 deaths versus 27 [2].
This was the first warning sign that the antioxidant theory might be flawed. More research was needed.
But despite these red flags, antioxidant supplement sales exploded. This mirrors what we see today with NMN supplements—despite limited evidence of human benefit so far.
By the late 1990s, vitamin E had become one of the most widely consumed supplements, primarily due to its presumed effects on coronary heart disease and other conditions [3].
But by 2008, the optimism had largely faded. A Cochrane meta-analysis reviewed 67 randomized trials involving 232,550 participants, covering various antioxidant supplements including vitamins A, C, E, beta-carotene, and selenium [4].
The findings were damning. Antioxidant supplements didn’t improve lifespan. In fact, when the analysis focused on the highest-quality trials (low risk of bias), it found that antioxidant supplements increased overall mortality by 5% (RR 1.05, 95% CI 1.02 to 1.08) [4].
Worse still, some individual antioxidants were even more harmful. Vitamin A was found to increase mortality by 16% (RR 1.16, 95% CI 1.10 to 1.24) [4].
The antioxidant theory that once seemed so promising had now taken a surprising and concerning turn. Antioxidant supplements weren’t extending life—they might have been shortening it.
To make matters worse, a 2014 study on exercise found that taking vitamin C and E supplements could actually interfere with the beneficial adaptations that come from endurance training [5].
When you exercise, your body produces free radicals, which act as a signal to cells, triggering them to become stronger and more efficient. But antioxidant supplements can blunt that signaling response [6].
This suggested that taking antioxidant supplements might block the very benefits you’re hoping to get from physical activity.
And so, enthusiasm cooled. But questions lingered. Was oxidative stress really a central driver of aging—or had we misunderstood its role?
Interestingly, antioxidant benefits didn’t vanish entirely. For example, some studies found improved cognitive performance in older adults using vitamin C and E supplements, especially in combination with NSAIDs [7].
The theory that oxidative stress drives aging still made sense. But perhaps we were looking at it the wrong way.
As more data emerged—including a new human study just published—we’ve begun to develop a much clearer understanding of how oxidative stress works, and how to use antioxidants correctly.
One crucial insight: free radical production increases with age, and this might actually be an adaptive signal—much like the oxidative stress from exercise. But as we continue to age, that signal can reach a tipping point, where the level of free radicals overwhelms the body and starts causing damage [8].
So we don’t want to eliminate free radicals entirely. Instead, we want to balance them [9].
The Plot Thickens
Let’s return to that 2014 study on antioxidants and exercise. There’s an important detail that’s easy to miss—but incredibly important: the participants were all young, in their 20s [5].
As we age, free radical production increases. In early stages, this may help the body cope with aging. But eventually, the rising levels become harmful. Young people don’t face this problem yet, which is why taking antioxidant supplements may blunt the helpful oxidative signals produced by exercise.
But in older adults, who are overwhelmed by free radicals, it’s a different story.
A 2022 study explored this idea further. Researchers looked at the effects of Glycine and N-Acetylcysteine (GlyNAC) in young and older adults. GlyNAC isn’t an antioxidant itself, but a precursor to glutathione—your body’s master antioxidant [10].
Their earlier research in animals had shown promising results, and this study aimed to test whether GlyNAC could improve glutathione levels and reduce markers of oxidative stress, mitochondrial dysfunction, inflammation, and more.
The results were striking.
Compared to young adults, the older participants had deficiencies in glutathione, oxidative stress markers, mitochondrial function, physical performance, and multiple hallmarks of aging. After GlyNAC supplementation (but not placebo), these markers improved significantly—but only in the older group [10].
The younger group experienced no benefit.
This suggests the effects of antioxidants (or their precursors) vary depending on age. It’s one reason I’ve said for the last four years that I plan to start taking GlyNAC at age 45.
That study, however, was small—just 36 participants (24 older adults and 12 younger adults) [10].
New Study
That’s what makes a brand-new meta-analysis so significant. It compiled 39 randomized controlled trials involving 1,714 participants over age 55 to evaluate the effects of antioxidants on muscle condition in older adults [11].
Unlike earlier studies that found antioxidants blunted physical adaptations, this one found that in older adults, antioxidants alone improved leg muscle strength (1-rep max) and physical function [11].
Exercise alone also helped, especially in improving walking distance over 6 minutes [11].
But the most important question was this: What happens when antioxidants are combined with exercise?
The answer: even better results.
In older adults, combining antioxidants with exercise led to greater improvements in leg strength, walking speed, walking distance, and handgrip strength than either intervention alone [11].
In young people, oxidative stress is like a controlled burn—it strengthens the forest. If we suppress it, we miss the benefit. But in older adults, oxidative stress becomes a wildfire. In this case, antioxidants help restore balance.
The researchers wrote: “We didn’t find that antioxidants had negative effects on the muscle condition of the elderly… perhaps this is because, as age progresses, ROS are continuously produced in large amounts, and simultaneously, the endogenous antioxidant system becomes increasingly inefficient” [11].
But the study authors offered several caveats:
- The effect sizes, while statistically significant, were often small. For example, walking speed increased by just 0.13 m/s, which may not be clinically meaningful [11].
- Most studies didn’t assess biomarkers of oxidative stress, inflammation, or molecular signaling pathways (e.g., glutathione peroxidase, IL-6, mTOR), so the underlying mechanisms remain unclear [11].
- Some trials had small sample sizes, limiting the strength of the conclusions. Larger studies are needed to confirm the results [11].
So at this point, there’s still a lot we don’t know—like which specific antioxidants work best, what the optimal dosage is, and who should be taking them.
That’s why I still wouldn’t supplement with Vitamin A or E, and don’t plan to include them in MicroVitamin. Instead, I’ll stick with the plan I made four years ago: I’ll start taking GlyNAC at age 45.
Why GlyNAC? Because it’s a precursor to glutathione. It enables your body to regulate its antioxidant levels, rather than flooding the system with external antioxidants. This makes it less likely to upset the delicate oxidant–antioxidant balance [10].
And why age 45?
A study from 2002 found that while oxidative stress increases throughout adulthood, the body’s ability to maintain glutathione levels remains stable until about age 45—and then begins to decline sharply [12].
Key Takeaways
- Oxidative stress isn’t always harmful. In controlled amounts, it’s an important signal that helps our cells adapt.
- That’s why I don’t include Vitamin A or E in MicroVitamin.
- In young people, the oxidant–antioxidant balance is usually intact. Supplementing can disrupt beneficial processes like exercise adaptation.
- But in adults over 45, oxidative stress can overwhelm the body’s defenses.
- That’s when supplementing with precursors—like GlyNAC—may help restore balance.
References
1. https://www.nejm.org/doi/full/10.1056/NEJM199305203282003
2. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(96)90866-1/fulltext
3. https://www.mayoclinicproceedings.org/article/S0025-6196%2811%2962503-2/fulltext
4. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD007176/full
5. https://pmc.ncbi.nlm.nih.gov/articles/PMC4001759/
6. https://www.sciencedirect.com/science/article/pii/S2095254624000620
7. https://pmc.ncbi.nlm.nih.gov/articles/PMC2684982/
8. https://pmc.ncbi.nlm.nih.gov/articles/PMC3836174/
9. https://www.nature.com/articles/s41420-024-02278-8
10. https://pmc.ncbi.nlm.nih.gov/articles/PMC9879756/
11. https://pmc.ncbi.nlm.nih.gov/articles/PMC12491480/
12. https://pubmed.ncbi.nlm.nih.gov/12398937/
