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Diet and lifestyle

Antioxidants can become too much of a good thing

In recent decades, many people have been taking dietary supplements to get enough antioxidants to reduce the harmful effects of free radicals and thereby stay healthy. A few years ago, researchers warned that people with cancer should not take antioxidants, and new research now questions whether these supplements benefit healthy people at all. Paradoxically, excessive intake of antioxidants may instead increase harmful free radicals in the body.

Pairs of electrons are essential for molecules to be stable. By contrast, when free electrons are created, molecules can react – by transferring an electron from or to another molecule. This creates free radicals in the body and thereby chain reactions that can potentially damage our genes or proteins. For years, the theory has been that antioxidants in our diet could stop these chain reactions. The hype has been so great that antioxidants have been available as dietary supplements, but several years of research has led to advising caution.

“If you take antioxidants briefly and in moderate doses, they probably do what they should, but taking a higher dose or for a longer period can induce reductive stress that, paradoxically, increases the production of free radicals. So whether antioxidants are beneficial or harmful really depends on the situation, but if I were to recommend anything, it would be to avoid overloading the body with this type of dietary supplement unless there is a clear indication,” explains Ingrid Wernstedt Asterholm, Senior Lecturer, Department of Physiology, Institute of Neuroscience and Physiology, University of Gothenburg, Sweden.

Surprising oxidants

The results emerged from a somewhat unexpected quarter because the Swedish researchers were actually investigating something completely different: how to preserve or improve the functionality of white adipose tissue. Functional white adipose tissue can effectively store excess energy in the form of fat (triglycerides) and thereby prevent the harmful effects of excessive lipids and/or glucose in the bloodstream. White adipose tissue can be transformed into beige adipose tissue through a process called browning that involves increasing mitochondrial biogenesis and activation. This increase in mitochondrial activity implies that the adipose tissue, besides storing fat, also can metabolize nutrients and thus become an even better sink for excess energy. Adipose tissue is normally browned when we are exposed to cold temperatures, but pharmaceutical treatment can also trigger browning. Researchers are therefore currently very interested in this browning process and whether it is a possible therapeutic target for obesity and its associated diseases.

“There are many theories about this browning process. We know that adipose tissue browning involves increased release of fatty acids from the fat cells. High levels of fatty acids can be toxic, whereas browning increases the fat cells’ capacity to metabolize fatty acids. We therefore theorized that browning should be seen as an physiological adaptation to metabolic stress.”

Based on previous results, the researchers thought that the molecular mechanism of this browning process involves an increase in the quantity of reactive oxygen species (free radicals). So a shifted balance towards a more oxidative state in the fat cells would activate signalling pathways that are essential for browning. This is where the antioxidants come in, because the researchers then assumed that using them as supplements would inhibit the browning process in adipose tissue, and it worked.

“We were pleased that we were right. But then the problems arose.”

Contradicting existing theories

The researchers tried to determine exactly which mechanisms stopped the browning process and were very surprised. Pathways that antioxidant treatment was supposed to have downregulated were, if anything, upregulated, and the antioxidant supplements (N-acetylcysteine, vitamin E or glutathione ethyl ester) led to producing more and not fewer free radicals. This result contradicted existing theories that antioxidants should reduce free radicals.

“We found the opposite, and we think the slowed-down browning process we observed results from cells or mitochondria defending themselves from excessive levels of free radicals, since increased mitochondrial metabolism will generate additional free radicals on top of those caused by the antioxidant supplements. In these experiments, we also found that the fat cells’ own mitochondrial antioxidant enzymes were upregulated, and there is probably also a mechanism we have not yet identified that brakes the mitochondrial metabolism when the oxidative stress is too high.”

Thus, it is still too early to speculate about the exact mechanisms behind the surprising and contradictory effect of the antioxidants. For now, the researchers hypothesize – based on preliminary results – that the cells can adapt to any antioxidants used for a long time, so that the increased presence of free radicals eventually leads to upregulation of the cells’ own antioxidant-based defence and upregulation of the proteins involved in mitochondrial function.

“So maybe the body supercompensates over time, which makes the cells stronger and able to withstand these types of challenges. We recently tried different doses of the antioxidants and different periods of time, and we found a dose at which the mitochondrial function in fat cells worsens initially but improves after prolonged treatment.”

Providing actual dietary or treatment recommendations based on these experiments is premature before researchers understand the actual mechanisms and whether antioxidants have physiological significance in the quantities we ingest through our diet and supplements. This apparently depends on the dose and duration.

“If you use them briefly and in moderate doses, they probably do what they should, eliminating free radicals. If you take a higher dose and over longer time, you risk harmful effects. So, for example, if you give antioxidants to sick people, whose cells are often already under oxidative stress, predicting the outcome is difficult. As a healthy person, I would personally be a little cautious about disturbing this balance too much.”

Recovering flexibility in the system

The researchers are continuing to investigate the mechanisms for adipose tissue functionality that began their study. The metabolic function of adipose tissue critically relies on optimal interaction with the immune system. The researchers have found that a potent proinflammatory response is a key factor involved in both browning and healthy adipose tissue expansion.

“Blocking inflammation locally in adipose tissue in mice inhibits healthy adipose tissue expansion during weight gain associated with harmful lipid deposition in the liver. The subcutaneous adipose tissue becomes fibrotic – a bit like a wound that heals with scar tissue – so this demonstrates that an optimal immune response is necessary to sustain adipose tissue functionality. But this is very complex, because many overweight people have a continuous overactive immune response – chronic inflammation – that also leads to fibrosis and keeps the tissue from expanding in a healthy way.”

Although the fat surrounding the organs – the visceral adipose tissue –is typically associated with increased disease risk, the researchers are especially focusing on the fat just below the skin – the subcutaneous adipose tissue. Their theory is that things first start to go wrong there.

“We hypothesize that this adipose tissue does not expand in a healthy way at some point, and then the fat begins to surround the organs. So if we can determine what goes wrong, maybe we can find a way to stimulate healthy expansion so we can recover flexibility in the system.”

Antioxidant treatment induces reductive stress associated with mitochondrial dysfunction in adipocytes” has been published in the Journal of Biological Chemistry. The Novo Nordisk Foundation awarded a grant in 2012 to Ingrid Wernstedt Asterholm for the project Key Components of the Dynamic Reshaping of Adipose Tissue and a grant in 2019 for the project New Mechanisms Underlying Whole-body Metabolic Regulation.

Ingrid Wernstedt Asterholm
Senior lecturer
We are interested in the role of adipose tissue for whole-body metabolic regulation as well as the connection between obesity and increased cancer risk. In particular, we focus on the role of local phenomena within adipose tissue for local and systemic metabolic health as well as tumor progression. Healthy adipose tissue stores and releases just the right amount of energy to meet the body’s metabolic demand. This function requires metabolically healthy adipocytes, which are characterized by e.g. a high sensitivity to insulin and adrenergic agonist and many and functional mitochondria. Furthermore, proper interplay between adipocytes and other adipose tissue-resident cells (such as various leukocytes) is also essential for adipose tissue functionality. Just consider the dramatic tissue remodeling necessary for accommodating growing or shrinking adipocytes as we gain or lose weight! Unhealthy adipose tissue fails at all levels. The adipocytes are insensitive to metabolic cues and the interactions with the immune system leads to chronic inflammatory processes rather than proper remodeling. Furthermore, the production adiponectin, an adipocyte-derived hormone with many positive effects on metabolic health, decreases. Such dysfunctional adipose tissue cannot effectively store excess energy and put thereby body at risk for toxic side effects from too high levels of circulating nutrients.