The reactive oxygen species (ROS) are a diverse group made up of free radicals, ions or small molecules – their common feature is that they need another electron to form more stable configurations. They grab this electron indiscriminately from any weak point on another molecule (fatty acid, protein, DNA etc, usually at a double-bond). There are also reactive nitrogen species (RNS) and other reactive species, however ROS command the most attention.
At low levels, they are a normal part of our biology. We need ROS because they are a crucial component of our immune defence, and because they can be involved in certain cellular signals, hormone synthesis (thyroid) and some cellular reactions (redox). Under usual conditions, ROS production is kept to a necessary minimum, however toxins, environmental factors, ultraviolet radiation or disease can increase their production and disrupt their regulation. This is oxidative stress.
The everyday cellular process of burning fuel (with oxygen) for energy unavoidably produces ROS. Another significant source of ROS is our innate immune system – it produces them in specialised cells (macrophages, dendritic cells) to use as weapons in the fight against invading pathogens (e.g. a virus) or infected/damaged cells in our bodies. Exercise temporarily increases ROS, however over the longer term it increases antioxidant production. Finally, cells in adipose tissue manufacture and release ROS – hence obesity increases oxidative stress (it’s been suggested that adipose tissue was a primal immune system).
The free radicals are the most reactive of the ROS group – they stabilise themselves by damaging other molecules and convert the bit they damage into another radical which propagates the process. When molecules are lined up, as in a cell wall, this produces a domino effect in which each damaged molecule damages the one next to it, ultimately compromising the cell. Most vulnerable is the membrane housing the cell’s powerhouses (the mitochondria) because this is where the cell burns fuel for energy and it is a source of ROS.
Oxidative stress and ROS are associated with many serious diseases such as cardiovascular disease, diabetes, neurodegenerative diseases (e.g. Alzheimer’s disease, Parkinson’s disease) and epilepsy. The ROS are particularly relevant to cancer, because cancer cells have a strongly-increased glucose metabolism that produces excess ROS that can damage the cell’s DNA or other cells in their vicinity (there’s a post here). Finally, an influential theory of ageing is that it results from a life-long accumulation of free radical cellular damage (particularly in the mitochondria).
The ROS are ultimately neutralised by meeting another ROS and cancelling each other, or by specialised enzymes that are maintained in the cell (such as the enzyme abbreviated SOD) and that dismantle the ROS, or by anti-oxidants (uric acid, vitamin E, C) that can donate an electron without themselves becoming a radical.
While it may seem sensible to treat oxidative stress with dietary antioxidants (supplements or dietary sources) this mostly misses the point. Oxidative stress is usually a symptom of some other problem, and the first step is to treat the problem.
But what if it is the diet itself that is the problem?
Finally, with that background, I get to the point of this post. There is reason to think that a ketonic-diet (KD) might reduce oxidative stress:
- Burning ketones for fuel produces fewer ROS than burning glucose (and generates more unit-energy).
- Ketones release a ‘brake’ (a molecule called HDAC) normally applied to a cell’s DNA that limits its ability to produce antioxidants. Release of this break means the DNA will make more antioxidants for the cell.
- Ketones are themselves antioxidants, and can neutralise certain ROS directly.
This is a powerful trio of complementary mechanisms – less ROS (for more energy) combined with more antioxidants (from DNA and the ketones themselves). Because this goes on relentlessly in every metabolically-active cell of the body day and night, it could be a powerful strategy against systemic oxidative stress.
I say ‘could be’, because while these mechanisms have been identified in animal and laboratory models, less is known of their efficacy in the human. This seems to be due, in part, to a shortage of reliable human blood biomarkers for oxidative stress. The ROS, by virtue of their reactivity, are short-lived and therefore not easily detected (except in laboratory studies). Further, their actions are diverse, so that identifying them by their effects on other molecules is also problematic. Using markers of inflammation is a second-best.
However, there are some teasers. While we do not fully understand the mechanisms of epilepsy, or why a KD can be an effective therapy, one idea is that oxidative stress increases neuronal membrane excitability in epilepsy, and that a KD treats the oxidative stress. Caloric restriction, which induces ketosis, has long been known to increase lifespan in mammals across species. If the free radical theory of ageing is correct, then the increase in lifespan could be because ketones reduced oxidative stress.
The relevance of a KD in the human should become more apparent with time, however we have plausible mechanisms from experimental studies. These mechanisms are coordinated and multifaceted. They suggest that ketosis may well be our natural state for managing systemic oxidative stress. It adds weight to the concept that a ketogenic diet is not a diet at all, but rather that ketosis could be our default metabolic state. Everything else is a diet.
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PS: A post on ROS and oxidative stress is incomplete without a discussion of inflammation and the immune response, especially as ROS are produced by the immune system. But this is too much for the present post – it will be discussed separately.
For more on the ketogenic diet, visit my keto-page.