On the Free Radical Theory of Frailty

And the Role of Antioxidants and a Box of Chocolates

Sep 21, 2024

tray of chocolates — Photo by Monique Carrati on Unsplash

The Free Radical Theory of Frailty.

The name of the theory alone gets my intellectual gears spinning.

During my readings of Brain-Derived Neurotrophic Factor (BDNF—two articles back from this one), I came across this theory, which was born out of the Free Radical Theory of Aging.

Let’s take this from the beginning.

Deep breath…

First, a free radical is an atom or molecule that has an unpaired electron, often in its outer shell. As I understand it, that atom’s unpaired electron can steal an electron from another atom or molecule. Like most of us who might have something stolen, we want to keep our stuff, and when a free radical pulls an electron off of another molecule, that molecule becomes unstable and can’t function or can’t function properly.

Also, as that new molecule has just lost an electron, it then becomes another free radical itself, and it can start a chain of free radical creation, which only stops when the molecule becomes so dysfunctional it can’t do anything or when an antioxidant comes along and neutralizes it and/or repairs some of the damage done.

A free radical results from oxidative stress and damage but is also a natural byproduct of aerobic metabolism, but we run into trouble when there are too many and/or when there aren’t enough antioxidants around. And while those suckers are around, they’re creating havoc, even corrupting a cell’s DNA, and if those cells can replicate, we’re getting more damaged cells.

So, what can cause free radicals and oxidative damage?

Free radicals are generated from both endogenous and exogenous sources. Immune cell activation, inflammation, ischemia [diminished blood supply], infection, cancer, excessive exercise, mental stress, and aging are all responsible for endogenous free radical production. Exogenous free radical production can occur as a result from exposure to environmental pollutants, heavy metals… certain drugs… chemical solvents, cooking (smoked meat, used oil, and fat), cigarette smoke, alcohol, and radiations. When these exogenous compounds penetrate the body, they are degraded or metabolized, and free radicals are generated as by-products.1

As oxidative damage can mutate DNA and shorten telomeres, the caps at the end of chromosomes, it stands to reason that oxidative damage certainly contributes to aging. The Free Radical Theory of Aging proposed that aging is a result of this kind of damage—oxidative damage—to DNA and mitochondrial DNA;2 this damage also results in age-related diseases, like neurodegenerative ones and cancer. It’s logical, even to science whippersnappers like me, but it’s been pretty well refuted.

There are animals that have long lives and endure what should be abundant oxidative stress and do so in short supply of antioxidants. One such animal is the pigeon, which, believe it or not, can live up to 35 years. (Of all the birds, right?) Another is a small salamander called an olm, which has been documented to live up to 70 years.3 Naked mole rats can apparently live up to 25 years, whereas common rats can live for just a couple.

I think the issue in this argument is that the theory wants to explain aging through the lens of damage from free radicals, but others argue that aging occurs irrespective of this damage. In fact, some points argue that free radicals can be beneficial in that they act as signals that are akin to hormetic stressors—those beneficial stressors that trigger and initiate positive adaptation responses. In this case, these responses are the endogenous production of antioxidants, like glutathione.

Another hit to the theory of aging is all the interventions and supplementation with antioxidants, which often prove to be unfruitful. Yes, these studies show that exogenous antioxidants do not reduce free radical damage or improve aging, which I’ll circle back to shortly.

Thus comes the Free Radical Theory of Frailty,4 which works in a similar way to the theory of aging but that free radicals and oxidative damage result in frailty and not aging, and frailty can occur at any age, and that aging itself is not a precursor to frailty, though that’s usually the trend. The work of this this theory is led by Jose Viña, a researcher at the University of Valencia. He and his lab offer an operational definition of frailty:

Frailty is a geriatric syndrome by which an older person displays increased vulnerability to minor stresses. A frail person feels a lack of well-being, unintentional weight loss, a relatively low grip strength, slow walking speed, and difficulties to stand. If left untreated, frailty progresses to disability.5

Viña contends that unsuccessful aging occurs with oxidative damage, shortening a person’s healthspan. Oxidative damage interferes, obviously, with healthy aging.

In order to combat oxidative damage, Viña’s lab carried out experiments with mice and made the following conclusions:

Exercise does not prolong lifespan, but prevents frailty in mice: lack of activity is a cause of oxidative stress and frailty.

Frailty can be reversed. Treatment of frailty [is] with physical exercise.

Aerobic exercise activity is defined as sustained and rhythmic activity, which uses oxygen as its primary fuel. It’s sustained with an elevated heart and respiratory rate—a key distinction with just being physically active. Aerobic exercise activity is something like cycling or running, compared to physical activity like yard work or housework.

Being active is important for its own reasons, but yard work is not going to trigger and initiate any cardiorespiratory adaptations and responses, just like resistance exercise is necessary to stimulate the muscle’s adaptive response—growth—and carrying some grocery bags from the car to the house will not.

Additionally, exercise activity, so long as it’s not done in excess—that is, to the extent that it causes severe muscle damage—results in antioxidant responses and adaptations.

As I wrote in the last article about exercising with chronic health conditions, as well as the earlier one on BDNF, which is a protein that repairs nerve and brain cells and is upregulated in response to exercise, exercise is a natural medicine.

If you’re a person that gets a little loosey goosey with your dietary allowance of free radicals—whether it’s lifestyle or environmental, and we’ve all been there, knowingly or not—you might have considered taking exogenous antioxidants, that is, supplements.

It’s well discussed in the fitness spheres that antioxidant supplementation can inhibit muscle and fitness adaptations to training.6

Okay. That’s training. What about taking antioxidant supplements in between training sessions and workouts? Maybe when you’re in that window where you’re not sore?

According to Viña et al.:

Systematic reviews and meta-analysis of the antioxidant supplements have shown that they do not promote longevity and do not prevent major cardiovascular events (2, 3). Therefore, in our view, the prevalent scientific evidence at this moment is that antioxidant supplementation is not a good practice, at least as advice to the general population.

They continue:

There are many cases (like for instance exercise training) in which antioxidant supplementation is bad for you. And in general terms, it is much better to increase endogenous defences by nutritional or physiological manipulation than administering antioxidant compounds, such as vitamin C or E.

There are studies that show that antioxidant supplementation is helpful with people with clinical conditions, but it all depends on the content of the situation because there are also studies that show there are adverse side effects to antioxidant supplementation, especially in healthy individuals.

Like Forrest Gump’s box of chocolates, with supplements, we never know what we’re gonna get, either in the actual substance or the physiological effects thereafter. We should err on the side of caution and minimize any intake of anything outside of a multi-vitamin, which contains mostly water-soluble nutrients, which, after the body absorbs what it wants and needs, will just be passed through the urine, as well as creatine, vitamin D, and B12 for vegetarians, and maybe an omega-3 (a topic for another day).

We should aim to get our nutrients through our good ol’ fashioned whole foods and strive for antioxidant upregulation through exercise. IF we take anything, it should be under the guidance and recommendations of a trained professional, like a physician, who bases those decisions on some quantitative metric, like a blood panel.

I like the way the authors of this paper put their recommendations on the subject:

…It is best to follow a balanced and varied diet, including in its composition many grains, legumes, fruits and vegetables of different colors. In addition, healthy lifestyle habits should be included, such as exercise training on a regular basis to avoid obesity, not smoking and reducing alcoholic beverages intake. The intake of antioxidant supplements would only make sense in a case of deficits, trying to normalize their levels, but not as a usual intake.7

Quick recap:

Move frequently.
Move such that it requires sustained effort, both aerobically and anaerobically.
Eat at or near energy balance and maintain a healthy bodyweight.
Include in your menu a variety of whole foods, getting a range of colors.
Refrain from the bad stuff or keep it infrequent.
Don’t rely on exogenous supplements for any meaningful benefits.

Got it.

Doing the basics here will probably take us 80% of the way to maximizing our health, at a minimum. We’ll stay strong, forsake frailty, promote healthy and successful aging while foregoing unhealthy and unsuccessful aging; we’ll keep oxidative-induced and age-associated diseases at bay. We’ll maintain cognitive health and likely our independence as we age.

And it’s hard to imagine being any degree of unhappy with any of these as outcomes at any point in our lives.

Then, we can flip the script and have our own theory on aging:

The Radical Theory of Aging Free

The Flexitorium by Joseph Anthony

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