The Good, Bad and the Ugly of Reactive Oxygen Species

Like Clint Eastwood, I have always enjoyed the liberation of doing things a bit different from the standard way, but when it comes to the Free Radicals (peroxides, superoxide, hydroxyl radical, singlet oxygen and alpha-oxygen), one needs to question the intent and effect.

Intriguingly, a little bit of free radical action can extend lifespan (Wang and Hekimi 2015), as demonstrated from C. elegans work where, at under 0.1 mM paraquat, the low levels of superoxide anion lead to longer lifespan (Yang and Hekimi 2010; Yee, Yang, and Hekimi 2014). In fact, these longevity finding led this group to speculate:

“Superoxide generation acts as a signal in young mutant animals to trigger changes of gene expression that prevent or attenuate the effects of subsequent aging.”

Yet it is clear that in C. elegans, when the dose reaches 0.4 mM for paraquat, the animals can no longer reach adulthood (Senchuk, Dues, and Van Raamsdonk 2017). And above this concentration, (at either 2-4 mM chronic exposure for days, or > 20mM acute exposure for a few hours), the effects are lethal to life. So, perhaps a bit like getting exercise, a little bit can do some good, but way too much and it will bring you down. So there appears to be an optimal level of ROS in the cell (“the Good”), where the levels of ROS signalling are good for growth, survival and apoptosis, and yet when ROS is pushed above this low level toxicity to the animal starts to prevail. This helps explain the strange is the “inverted U effect” seen in C. elegans, where antioxidants at low doses may DECREASE lifespan while oxidants at low doses can INCREASE lifespan. Yet at higher doses the effect becomes switched and oxidants compromise lifespan while antioxidant tend to extend it (Desjardins et al. 2017).

In a recent comprehensive review (Shields, Traa, and Van Raamsdonk 2021), this paradox is acknowledged but the general trend is:

“Interventions that increase ROS tend to decrease lifespan, while interventions that decrease ROS tend to increase lifespan.”

Further, this trend provides support for:

“The free radical theory of aging (FRTA), proposes that oxidative damage caused by reactive oxygen species (ROS) is the primary cause of aging.”

Gene Disruption can Manifest as Shorter Lifespan

Progeria (Hutchinson-Gilford Syndrome) is an extremely rare, progressive genetic disorder that causes children to age rapidly, starting in their first two years of life. The LMNA gene is the sole cause of this syndrome, although there are at least a dozen other gene dysfunctions that lead to progeroid syndromes of shortened life (POLR3A, BANF1, WRN, PYCR1, PDGFRB, RECQL2, B4GALT7, SLC25A24, BSCL2, GORAB, ERCC8, ERCC4) or a prematurely-age appearance (LTBP4, FBLN5, ATP6V0A2, ATP6V1A, EFEMP2, ALDH18A1, ELN). Many of these genes are lethal when made as a homozygous KO disruption, but some genes are not essential and can lead to premature aging when removed from the genome in certain organisms. One such gene is DYRK1A. Although the homozygous knockout in mice is lethal (Fotaki et al. 2002), the removal of this gene in C. elegans renders an animal that can survive but have a shortened lifespan.

Specifically, in the loss-of-function KO of the DYRK1A ortholog (mbk-1), the lifespan was found to be about 30% shorter than wild type. When a human coding sequence for DYRK1A was inserted as gene replacement of mbk-1 (hDYRK1A), an intermediate level was achieved for rescue of function. When a clinical variant was installed into the humanized locus (R467Q), a partial loss-of-function defect was observed and one of our clinical partners at the Mayo Clinic, Dr Tom Caulfield, was able to use the assessment to indicate the clinical variant has abnormal DYRK1A function.

Does exposure to antioxidant conditions lead to longer lifespan?

In laboratory studies on genetically-modified model organisms, two generalities prevail. The overexpression of antioxidant enzymes has a tendency to extend lifespan (yeast, flies and worm), while their elimination has a tendency to shorten lifespan (yeast, worms, flies and mice) (Shields, Traa, and Van Raamsdonk 2021). For “chemically-modified” model organisms, these same authors note that a variety of antioxidants (N-Acetyl Cysteine, Vitamin C, and Vitamin E) are known to extend lifespan in some organism (worms, flies and mice), but it remains controversial if there is benefit in humans (Bjelakovic et al. 2012; Bjelakovic, Nikolova, and Gluud 2013).  Even more contradictory, exposure to low levels of ROS generating chemicals (2-deoxy-d-glucose, juglone, paraquat, plumbagin, menadione, rotenone, arsenite, metformin and d-glucosamine) all lead to increased lifespan (yeast, worms, and mice) (Shields, Traa, and Van Raamsdonk 2021).  So in the “chemically-modified” animals due to chemical supplementation, both oxidants and antioxidants can help increase lifespan.  As a result, to get answers for any given compound, a bit of trial and error testing is what is needed (and perhaps a “fist full of dollars”)

Bjelakovic, Goran, Dimitrinka Nikolova, and Christian Gluud. 2013. “Antioxidant Supplements to Prevent Mortality.” JAMA: The Journal of the American Medical Association.

Bjelakovic, Goran, Dimitrinka Nikolova, Lise Lotte Gluud, Rosa G. Simonetti, and Christian Gluud. 2012. “Antioxidant Supplements for Prevention of Mortality in Healthy Participants and Patients with Various Diseases.” Cochrane Database of Systematic Reviews , no. 3 (March): CD007176.

Desjardins, David, Briseida Cacho-Valadez, Ju-Ling Liu, Ying Wang, Callista Yee, Kristine Bernard, Arman Khaki, Lionel Breton, and Siegfried Hekimi. 2017. “Antioxidants Reveal an Inverted U-Shaped Dose-Response Relationship between Reactive Oxygen Species Levels and the Rate of Aging in Caenorhabditis Elegans.” Aging Cell 16 (1): 104–12.

Fotaki, Vassiliki, Mara Dierssen, Soledad Alcántara, Salvador Martínez, Eulàlia Martí, Caty Casas, Joana Visa, Eduardo Soriano, Xavier Estivill, and Maria L. Arbonés. 2002. “Dyrk1A Haploinsufficiency Affects Viability and Causes Developmental Delay and Abnormal Brain Morphology in Mice.” Molecular and Cellular Biology 22 (18): 6636–47.

Senchuk, Megan M., Dylan J. Dues, and Jeremy M. Van Raamsdonk. 2017. “Measuring Oxidative Stress in : Paraquat and Juglone Sensitivity Assays.” Bio-Protocol 7 (1).

Shields, Hazel J., Annika Traa, and Jeremy M. Van Raamsdonk. 2021. “Beneficial and Detrimental Effects of Reactive Oxygen Species on Lifespan: A Comprehensive Review of Comparative and Experimental Studies.” Frontiers in Cell and Developmental Biology 9 (February): 628157.

Wang, Ying, and Siegfried Hekimi. 2015. “Mitochondrial Dysfunction and Longevity in Animals: Untangling the Knot.” Science 350 (6265): 1204–7.

Yang, Wen, and Siegfried Hekimi. 2010. “A Mitochondrial Superoxide Signal Triggers Increased Longevity in Caenorhabditis Elegans.” PLoS Biology 8 (12): e1000556.Yee, Callista, Wen Yang, and Siegfried Hekimi. 2014. “The Intrinsic Apoptosis Pathway Mediates the pro-Longevity Response to Mitochondrial ROS in C. Elegans.” Cell 157 (4): 897–909.

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