Oxidative Stress and Cognitive Decline: A Practical Guide to Reducing Oxidative Stress and Damage

As we grow older, our organs become less efficient at performing their functions – in other words they decline, and the brain is no exception. Although scientists don’t yet understand exactly what drives the aging process, we are investigating this question carefully, due to the implications that it has for the future of brain health. What we do know so far is that a process called ‘oxidative stress’ plays an important role in aging and we call this the ‘free radical’ theory of aging – a theory which we will explore in more detail below.

What is Oxidative Stress – Free Radicals

What exactly are free radicals? These are molecules in the body that are produced through chemical reactions(1). These chemical reactions are called oxidation - this is where the ‘oxiditave’ comes from in oxidative stress/damage. Free radicals are potentially harmful because of their chemical reactivity: they damage parts of our cells and other important substances that allow us to function normally, including DNA, proteins, carbohydrates, and lipids(2). For this reason, they are thought to contribute to the aging process. However, when free radicals come into contact with antioxidants – a range of substances including certain foods and vitamins – the damaging quality of free radicals can be neutralized.

Interestingly, studies have shown a link between aging and molecules that produce free radicals known as ‘reactive oxidative species’(3). As with free radicals, these molecules contribute to the process of oxidative stress. Where do these damaging reactive oxidative species come from? They are produced in the mitochondria: a part of the cell that functions as the power generator for the cell. It makes sense, then, that the mitochondria play an important role in aging; and we can see this, interestingly, in birds!

Birds have a higher overall metabolic rate than mammals – so we would expect them to age faster. However, birds have a much greater life expectancy than mammals, as anyone who has had a parrot as a pet would know. One study showed bird mitochondria produce up to ten times less reactive oxidative species(4), which has led scientists to believe that the mitochondria are closely linked to the aging process.

Oxidative Stress and Aging

So, now that we have covered some background on reactive oxidative species and the role of the mitochondria in aging, let’s return to the free radical theory of aging. Dr. Denham Harman was the first to propose this idea in the mid-1950s. Harman’s ideas gained leverage once an enzyme called ‘superoxide dismutase’ was discovered. This enzyme was designed specifically to neutralize the harmful free radicals(6). 

Later, Harman expanded his theory further, by mentioning the central role that mitochondria play in the aging process. In his view, mitochondria determine how long a person or animal will live for, since most oxidative species are generated through them. This is because mitochondria play an important role in cellular metabolism, whereby cells consume oxygen to break down nutrients in exchange for energy(7). Subsequent research that started in the 1970s has supported the idea that mitochondria play an important role in the free radical aging process – more specifically, that mitochondria serve as both the primary generators and receivers of oxidative damage(3). 

We could say then that aging, as well as certain neurodegenerative diseases associated with aging, is linked to the inability of antioxidant enzymes to stop free radicals and reactive oxidative species from causing oxidative injury(8).

One study compared six different species of mammals, all of them having different life span potentials. It was shown that damage to the mitochondria (specifically, to the DNA that is contained in mitochondria) was correlated with maximum life span, meaning that mitochondria damage is linked to how long a person or animal lives(11).  

Mitochondria and Oxidative Damage

Why are mitochondrial so vulnerable to oxidative injury? First, there is an absence of any repair machinery for the mitochondrial DNA. Second, there is a lack of histone proteins that regulate and shield DNA from environmental insults. Third, mitochondrial DNA are close to the inner mitochondrial membrane that generates reactive oxidative species during cellular respiration. For these reasons, we suspect that mitochondrial DNA changes at a much higher rate than nuclear DNA(3). It’s not surprising then, that neurodegenerative diseases associated with aging – including Alzheimer’s, Huntington’s and Parkinson’s diseases – are associated with higher levels of mitochondrial deletion, where a part of the DNA is lost(12, 13, 14).

Fats as Sources of Oxidative Damage

Lipids (i.e. fats) and proteins are also sources of reactive oxidative species and free radicals. We know that the breakdown of certain fats is harmful because when certain fats (such as arachidonic and linoleic acid, both polyunsaturated fats) undergo this process, reactive oxidative species associated with aging, cognitive decline, and neurodegenerative diseases (such as Parkinson’s and Alzheimer’s) are produced.

So, while some fats are linked to oxidative damage, other fats ( monosaturated and saturated fats) are more resistant to this form of damage than others (like polyunsaturated fats). We know this because of studies that look at the cell membrane fatty acid make-up of different birds and mammals, comparing this to their maximum lifespan. The animals with exceptionally long lifespans have cell membrane compositions that are better at shielding against destructive free radicals. Furthermore, birds and mammals (including humans) that have these shielded cell membranes tend to live longer. Interestingly, studies showed that rats and mice which consumed fewer calories were more likely to produce cell membranes that were resistant to peroxidation(15), but we discuss this in a bit more detail further down.

Inflammation and Oxidative Damage

Many researchers now believe that inflammation is a primary driver in the aging process and chronic diseases of old age. This is linked to resident immune cells of the central nervous system called ‘reactive microglia’, which play a key role in the inflammation that underlies the brain’s decline. When microglia cells are activated over a long period of time, this leads to the release of potentially harmful neurotoxins and proinflammatory cytokines, including what are known as interleukins 1 and 6 and tumor necrosis factor, amongst others.3 Elderly animals have been shown to have higher levels of proinflammatory cytokines in several studies(17, 18).

Activated microglia are generators of reactive oxidative species in the brain, releasing a host of harmful free radicals. All of these are potentially damaging to cells, causing oxidative injury and neuronal cell death in the case of certain diseases of the central nervous system(3, 19)

How to Fight Oxidative Damage?

How can you combat oxidative stress in order to reduce cognitive decline? One simple strategy is to go on a diet! Evidence suggests that when you limit the number of calories that you consume, your mitochondria produce fewer free radicals and are better shielded from oxidative damage(20). In a study of rats, for example, both young and old rats were put on a low calorie diet to see how this affected their spatial memory(21). Although the older rats had poorer memory than the younger ones, both young and old animals improved when they were on the calorie restricted diet.

Vitamin E also has the capacity to protect against oxidative stress and aging. For example, in another study on rats, this vitamin reversed age-related memory problems. This study examined a process between nerve cells (called long-term potentiation or LTP) that takes place in the hippocampus, the memory center of the brain, and is associated with learning(22).

Finally, some other antioxidant-enhancing strategies that may help reduce cognitive decline (particularly when they are combined) include taking micronutrients, such as zinc, selenium, and glutathione peroxidase; and eating diets that are rich in polyphenol (i.e. grapes, apples, pears, cherries, various berries, tea, coffee, red wine, legumes, and nuts) or long chain omega 3 fatty acids (DHA and EPA). Finally, ketogenic diets, Mediterranean diets, and regular exercise are all helpful in fighting oxidative damage and cognitive decline(23).




1)      Harman, Denham. "Aging: a theory based on free radical and radiation chemistry." Science's SAGE KE 2002.37 (2002): 14.

2)      Lobo, Vijaya, et al. "Free radicals, antioxidants and functional foods: Impact on human health." Pharmacognosy reviews 4.8 (2010): 118.

3)      Gemma, Carmelina, et al. "Oxidative stress and the aging brain: from theory to prevention." (2007).

4)      Barja, Gustavo. "Mitochondrial free radical production and aging in mammals and birdsa." Annals of the New York Academy of Sciences854.1 (1998): 224-238.

5)      McCord, Joe M., and Irwin Fridovich. "Superoxide dismutase an enzymic function for erythrocuprein (hemocuprein)." Journal of Biological chemistry244.22 (1969): 6049-6055.

6)      Harman, Denham. "The biologic clock: the mitochondria?." Journal of the American Geriatrics Society 20.4 (1972): 145-147.

7)      Finkel, Toren, and Nikki J. Holbrook. "Oxidants, oxidative stress and the biology of ageing." Nature408.6809 (2000): 239.

8)      Pappolla, M. A., et al. "Immunohistochemical evidence of oxidative [corrected] stress in Alzheimer's disease." The American journal of pathology 140.3 (1992): 621.

9)      Mecocci, Patrizia, et al. "Oxidative damage to mitochondrial DNA shows marked age‐dependent increases in human brain." Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society 34.4 (1993): 609-616.

10)   Barja, Gustavo, and AsunciÓn Herrero. "Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals." The FASEB Journal 14.2 (2000): 312-318.

11)   Corral-Debrinski, Marisol, et al. "Marked changes in mitochondrial DNA deletion levels in Alzheimer brains." Genomics 23.2 (1994): 471-476.

12)   Horton, T. M., et al. "Marked increase in mitochondrial DNA deletion levels in the cerebral cortex of Huntington's disease patients." Neurology45.10 (1995): 1879-1883.

13)   Ikebe, Shin-ichiro, et al. "Increase of deleted mitochondrial DNA in the striatum in Parkinson's disease and senescence." Biochemical and biophysical research communications 170.3 (1990): 1044-1048.

14)   Hulbert, Anthony J. "Explaining longevity of different animals: is membrane fatty acid composition the missing link?." Age 30.2-3 (2008): 89-97.

15)   Smith, C. D., et al. "Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease." Proceedings of the National Academy of Sciences 88.23 (1991): 10540-10543.

16)   Gemma, Carmelina, et al. "Diets enriched in foods with high antioxidant activity reverse age-induced decreases in cerebellar β-adrenergic function and increases in proinflammatory cytokines." Journal of Neuroscience 22.14 (2002): 6114-6120.

17)   Terao, Akira, et al. "Immune response gene expression increases in the aging murine hippocampus." Journal of neuroimmunology 132.1-2 (2002): 99-112.

18)   Dringen, Ralf. "Oxidative and antioxidative potential of brain microglial cells." Antioxidants & redox signaling 7.9-10 (2005): 1223-1233.

19)   Gredilla, Ricardo, et al. "Caloric restriction decreases mitochondrial free radical generation at complex I and lowers oxidative damage to mitochondrial DNA in the rat heart." The FASEB Journal 15.9 (2001): 1589-1591.

20)   Stewart, Jane, John Mitchell, and Norman Kalant. "The effects of life-long food restriction on spatial memory in young and aged Fischer 344 rats measured in the eight-arm radial and the Morris water mazes." Neurobiology of aging 10.6 (1989): 669-675.

21)   Murray, Ciara A., and Marina A. Lynch. "Dietary supplementation with vitamin E reverses the age-related deficit in long term potentiation in dentate gyrus." Journal of Biological Chemistry 273.20 (1998): 12161-12168.

22)   Vauzour, David, et al. "Nutrition for the ageing brain: towards evidence for an optimal diet." Ageing research reviews 35 (2017): 222-240.


Dr. Ari Magill is a former staff neurohospitalist at Northwest Medical Center in Tuscon, AZ. Dr. Magill has a special interest in cognitive, behavioral, and memory disorders and is passionate about advancing dementia treatment through clinical research. He enjoys medical writing and  currently performs independent VA disability exams on veterans who sustained traumatic brain injury.  Dr. Magill completed neurology residency at the University of Arizona in Tucson, AZ and completed a movement disorders neurology fellowship at the University of Colorado Anschutz Medical Center in Aurora, CO. He received a B.S. in Zoology from University of Texas in Austin and his M.D. from UT Southwestern Medical School in Dallas.