Antioxidants- relevant for life extension?

Harman published his free radical theory of aging in 1956 and in the following decades it slowly became probably the most popular explanation of the mechanism of aging (Ashok & Ali, 1999). Because the theory claims that reactive oxygen species damage macromolecules (more details in my previous article “Aging theories: Is there a unifying factor in aging?”), the effects of substances known as nutritional antioxidants have received a lot of attention. The underlying theory that has been long accepted says that antioxidants may  improve health (and eventually prolong lifespan) by lowering the level of oxidative stress present in the organism because they eliminate free radicals, usually by 'donating' a free electron.   
However, there is a controversy about validity of this theory because some researchers reached the opposite conclusion. They view reactive oxygen species as signal molecules important for mitochondrial processes and cellular communication (Hamanaka & Chandel, 2010; Ristow & Schmeisser, 2011). It becomes clear that reactive oxygen species are not necessarily always harmful  (Brigelius-Flohé, 2009). A research of EGCG from green tea suggested antioxidants may be potent agents causing reductive damage (Lu, Ou, & Lu, 2013). It was observed that antioxidant consumption may neutralize any positive outcomes of exercising (Ristow et al., 2009). According to the meta-analysis of available clinical data about vitamin supplementation, the consumption of beta-carotene, vitamin A, or vitamin E has been associated with higher all-cause mortality (Bjelakovic, Nikolova, Gluud, Simonetti, & Gluud, 2012). One Danish research group found association between supplemented folic acid and increased all-cause mortality (Roswall et al., 2012). On the other hand, other researchers did not identify any effects on mortality (Henríquez-Sánchez et al., 2015) or even found the inverse association (Zhao et al., 2016; Bastide et al., 2017). It is possible that some unknown factors are in play which lead to controversy and confusion caused by so many different results.

The most well-known antioxidant is probably L-ascorbic acid, so-called vitamin C. Human body is unable to synthesize it and its absence or deficiency in diet causes fatal disease known as scurvy. However, the level of vitamin C in blood plasma is strictly regulated by organism, therefore high oral doses of L-ascorbic acid in any form do not elevate its plasma levels accordingly (Padayatty et al., 2004). There has been a lot of research done about potential effects on aging-related diseases, but the currently available evidence does not support any benefits (“Vitamin C Fact Sheet for Health Professionals,” 2016). Although, according to some researchers, there is a potential to use L-ascorbic acid intravenously in cancer treatment (Padayatty, Riordan, Hewitt, Katz, Hoffer, & Levine, 2006).

Another antioxidant which received a lot of attention is alpha-tocopherol, the only form of vitamin E with high enough biological activity to meet human requirements. Recommended daily intake is less precisely determined, compared to vitamin C. No beneficial effects were confirmed in studies with high number of participants (“Vitamin E Fact Sheet for Health Professionals,” 2016), some researchers even proposed possible harmful effects, such as increased general mortality in supplemented groups (Bjelakovic, Nikolova, Gluud, Simonetti, & Gluud, 2007).

Carotenoids also display antioxidant properties, the most popular of them is beta-carotene, sometimes called provitamin A (“Vitamin A Fact Sheet for Health Professionals,” 2016). Unfortunately, no benefits have received sufficient support by multiple studies. And it has been suggested that beta-carotene was found to increase the risk of lung cancer and cardiovascular diseases (The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group, 1994; Goodman et al., 2004). Another molecule from this group is lycopene, results of studies are mixed but the data from The Health Professionals Follow-up Study indicate a reduced risk of prostate cancer (Giovannucci, Liu, Platz, Stampfer, & Willett, 2007). Lutein seems to decline age-related macular degeneration (Richer et al., 2004). Astaxanthin is the strongest carotenoid antioxidant (Ursoniu, Sahebkar, Serban, & Banach, 2015) and researchers claim it has beneficial effects on humans (Cohaire, Garem, Mahmoud, Eertmans, & Schoonjans, 2005) but no large study was yet concluded.

Plant polyphenols (and their most numerous subgroup flavonoids) are abundant in nature as well as in our diet, and are generally nontoxic (Yao et al., 2004; Manach, Scalbert, Morand, Remesy, & Jimenez, 2004). In spite of these facts, they received scientific attention only for a short period of time, compared to aforementioned antioxidants. It is worth to note that recent research shows their potential benefits go often well beyond antioxidant mechanism (Scalbert, Johnson, & Saltmarsh, 2005; Kim, Quon, & Kim, 2014; Srivastava & Mishra, 2015).

The grape derived flavonoid polyphenolic substance resveratrol became widely known in anti-aging circles but shows very little bioavailability in vivo (Goldberg, Yan, & Soleas, 2003) and no lifespan extension in mammals has been conclusively shown.

Good, popular and easy-to-access source of catechins and other flavonoids is tea. According to many studies, its chemical composition provides antioxidant, anticancer, neuroprotective, cardioprotective and other beneficial health effects (Fujiki et al., 1999; Rietveld & Wiseman, 2003; Caruana & Vassallo, 2015). EGCG, or epigallocatechin-3-gallate, is a major tea polyphenol (Nagle, Ferreira, & Zhou, 2006; Singh, Shankar, & Srivastava, 2011). Interestingly, bioavailability of tea polyphenols does not change with the addition of milk (Kyle, Morrice, McNeill, & Duthie, 2007).

Curcumin, the main physiologically active polyphenol of turmeric, shows antioxidant and anti-inflammatory properties in humans (Ursoniu, Sahebkar, Serban, & Banach, 2015) and exhibits high level of safety and tolerability (Gupta, Patchva, & Aggarwal, 2013). Although, its bioavailability is very poor if taken alone, but drastically increases by about 2000% if consumed with an addition of piperine (Shoba et al., 1998). Other promising techniques of enhanced drug delivery are also being investigated (Prasad, Tyagi, & Aggarwal, 2014).

The most important antioxidant for humans is probably endogenous glutathione which is abundantly present in our cells. It scavenges free radicals very efficiently, directly regulates immune functions and levels of oxidative stress (Wu, Fang, Yang, Lupton, & Turner, 2004; Pizzorno, 2014). Furthermore, recent research conducted on humans showed that daily glutathione consumption can significantly increase its body stores (Richie et al., 2014). N-acetylcysteine supplementation boosts glutathione biosynthesis (Pendyala & Creaven, 1995).

Alpha lipoic acid (and its reduced form, dihydrolipoic acid), another interesting endogenous antioxidant, is crucial for mitochondrial functions (Palaniappan & Dai, 2007). It is also a chelator substance as it has the ability to eliminate metal ions but do not cause metal depletion in organism. Alpha lipoic acid is able to reduce the oxidized forms of vitamin C and E (Gomes & Negrato, 2014). Orally supplemented lipoic acid accumulates in tissues and evidence suggests its antioxidant properties are indirect but still beneficial (Shat, Moreau, Smith, Smith, & Hagen, 2009).

Coenzyme Q10 plays a key role in mitochondrial and other metabolic processes. It displays antioxidant properties and can be supplemented orally (Littarru & Tiano, 2007). Aging related Q10 deficiency has been linked to cardiovascular diseases (Singh, Devaraj, & Jialal, 2007). Research showed that sufficient intake can prevent or treat these issues (Kumar, Kaur, Devi, & Mohan, 2009; Mortensen et al., 2014) but another review study calls for trials with better design (Flowers, Hartley, Todkill, Stranges, & Rees, 2013).

Melatonin also participates in the protection from oxidative damage by stimulation of glutathione production (Fusco, Colloca, Lo Monaco, & Cesari, 2007). Particularly high concentrations were found in cell nucleus and mitochondria (Aydogan, Yerer, & Goktas, 2006). Melatonin is well-known as a sleep hormone and in darkness is naturally produced by brain (Peuhkuri, Sihvola, & Korpela, 2012).

Typical age-related diseases are cardiovascular, cancer, type 2 diabetes, Alzheimer’s disease (Everitt et al., 2006). Interestingly, they cause about 90 percent of deaths annually in industrialized countries (de Grey, 2007). Therefore, if antioxidants were effective in reducing these health problems, we could claim they are relevant for life extension, even if they are not relevant for the extension of maximal lifespan. However, whether or not this is the case remains controversial, especially in the case of certain vitamins (as described above). One speculation would be that the contradicting results might be explained by the non-homogeneous of vitamins among the population (Semba, 2012). Antioxidants in the diet seem to be a necessity but the benefits of dietary supplement consumption remain questionable. Some supplements contain unnecessarily high doses which do not offer any benefits but may even lead to adverse effects. On the other hand, the health impact of some polyphenolic antioxidants seems to go well beyond their basic antioxidant mechanism (Scalbert, Johnson, & Saltmarsh, 2005). 


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---- LongeCity comment ---
This article serves as a brief introduction into a complex and controversial topic in life extension science. For decades, anti-oxidants were almost synonymous with anti-aging. Current evidence suggests that the picture is more complex. Yet despite the potential for inefficiency and harm that antioxidants may pose, their role in modulating aging-related health cannot be ignored.
Continue the discussion of individual antioxidants in our supplements forum.