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Mitochondria



Lisbon, Portugal
April 2019

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Back in the 1980s, while in Vancouver visiting my grandparents, I chanced upon an old paperback book gathering dust in the basement. I do not recall the name of the book; I only recall that it was about something called the mitochondria free radical theory of aging. I opened it, and was transfixed.

​The theory spoke of mitochondria, tiny powerhouses inside nearly all our cells that use the energy of glucose to transport electrons along the chain of complexes lining their inner membranes, generating energy for the cell along the way. The theory outlined how this vital process also produces unwanted toxic intermediates called reactive oxygen species, or free radicals, that indiscriminately react with and oxidatively damage other molecules inside the cell. According to the theory, the gradual accumulation of oxidative damage over time resulted in aging of the cell and organism.
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​Proposed in 1957, the mitochondria free radical theory of aging has held its ground, remaining the predominant theory of aging for decades. It is supported by two facts in particular (1,2) - first, mitochondria produce more free radicals with age, and second, there is a decline in the activity of antioxidant enzymes (which protect the cell by scavenging free radicals) with age. The theory assumes that since free radicals increase with age whereas antioxidant enzymes decrease, the free radicals themselves must be the driving force behind aging. As is often the way in science, this correlation is interpreted as causation; they’re not the same thing. Finally, after a decades-long long run, recent data has emerged that seriously challenges the veracity of the free radical theory of aging.
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Mitochondria produce energy by transporting electrons along a chain of complexes lining their inner membrane.

First, free radical production and cell oxidative damage do not clearly correlate with longevity (1,2). One important example is the naked mole rat which lives up to 30 years, as opposed to mice which live a maximum of 3-4 years, yet both species produce similar amounts of free radicals (3). Moreover, the naked mole rat displays much higher levels of oxidative damage than the mouse, yet still manages to live nearly ten times as long (1,2). Furthermore, genetic manipulations that elevate the levels of free radicals do not accelerate aging in mice (1,2). In fact, elevated levels of free radicals are associated with prolonged lifespan in a number of animals (4,5); some people have even proposed that the high levels of free radicals are actually responsible for the extended longevity in these animals.
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Second, antioxidant efficacy does not clearly correlate with longevity (1,2). Overexpressing antioxidant enzymes in mice and other animals (6) does not extend longevity, and may even shorten their lifespan in some cases (2). Large interventional studies in humans suggest that supplementation with antioxidants such as vitamin A, vitamin E, and beta carotene does not prevent age-related disease, and may even be associated with increased mortality (7,8).
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Antioxidants have not proven to be effective in humans.

Although we can’t nail a stake through the heart of the mitochondria free radical theory of aging just yet, the above facts would suggest that rather that free radicals have, at best, a minor role in aging.

Declining Mitochondria Bioenergetics In Aging

The primary function of mitochondria is to produce energy for the cell; unfortunately, this critical mitochondria function declines with age (9). Thus, rather than focusing on free radicals, let’s focus on the substantial decline in mitochondria bioenergetic capacity that occurs with age, which results from the cumulative effect of a number of processes:
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​(1) Mitochondria produce less energy with age - As electrons flow down the electron chain, they bounce along a series of protein complexes numbered I to V. The activity of complexes I and IV decrease with age (10), resulting in as much as a 40% decrease in electron chain bioenergetic capacity (9); the activity of complexes II, III, and V remain relatively unaltered (11).

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(2) Mitochondria fuel is less available with age - Glucose is the main fuel needed by mitochondria to create energy. Glucose cell entry is controlled by insulin signalling, which allows glucose entry into cells and becomes less efficient with aging (1). Chronic overstimulation of the insulin signalling pathway results in decreased cell insulin sensitivity with age (12), depriving mitochondria of fuel, followed by a decline in their bioenergetic capacity.
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​The electron transport chain. Complexes I and IV decline with age (complexes I and III produce most of the free radicals) (2).

(3) Mitochondria quantity declines with age - Mitochondria lessen in number with age due to a decline in mitochondria biogenesis (the formation of new mitochondria) (2). Fewer new mitochondria means less overall mitochondria bioenergetic capacity (2).
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(4) Mitochondria quality declines with age - Mitochondria quality declines with age due to defective mitophagy (the degradation and recycling of old, inefficient mitochondria) (1,13-15), translating to an excess of old mitochondria and a decline in mitochondria bioenergetic capacity (1).

Clearly, we do not need to fall back on the mitochondria free radical theory of aging to explain how mitochondria dysfunction might contribute to aging. Upon reflection that the primary function of mitochondria is to produce energy (not free radicals), declining mitochondria bioenergetic capacity likely plays a major role in aging.


Enhancing Mitochondria Bioenergetics To Slow Aging

Given that mitochondria dysfunction likely stems more from a reduction in mitochondria bioenergetic capacity than it does from an increase in free radical production, it logically follows that we ought to focus on enhancing mitochondria bioenergetic capacity.

Calorie restriction remains one of the oldest, most tried-and-true therapies for extending longevity in animals, including non-human primates and possibly even humans (there is only one randomized controlled study in humans, which suggested that 3 years of alternate-day calorie restriction may reduce disease and enhance longevity) (16,17). The life-extending effects of calorie restriction are at least partly mediated by enhanced mitochondria bioenergetics due to the stimulation of a class of signalling molecules called sirtuins, which activate another molecule called PGC-1α, a “master regulator” of mitochondria composition, function, and biogenesis (18).

Unfortunately, calorie restriction is difficult to sustain long-term, largely due to hunger. However, there are other ways to simulate the metabolic benefits of calorie restriction, namely intermittent fasting and ketogenic diets, that do not typically produce significant hunger. Intermittent fasting is an extreme version of calorie restriction, in which calorie intake is voluntarily severely restricted, or abolished completely, for a pre-defined period of time (usually, at least 16 hours). Ketogenic diets are high-fat, adequate-protein, low-carbohydrate diets, designed to mimic the metabolic profile of fasting (19). Depending on the degree to which they are implemented, calorie restriction, intermittent fasting, and ketogenic diets all have the capacity to produce ketones, organic molecules that may be used as an energy source by various body tissues (19).
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Calorie restriction (and by extension, intermittent fasting and ketogenic diets) offers an array of mechanisms that might counteract the decline in mitochondria bioenergetic capacity associated with aging:

​(1) Mitochondria produce less energy with age - In the presence of ketones, Krebs cycle turnover is increased, feeding more electrons into the electron transport chain, resulting in an indirect complex I “bypass” that may enhance mitochondria bioenergetic capacity (18-20). Moreover, calorie restriction activates PGC-1α, the presence of which increases mitochondria bioenergetic capacity (21), possibly by elevating certain subunits of the electron chain complexes (18), thus remodelling the composition of the mitochondria and improving electron transport.

​(2) Mitochondria fuel becomes less available with age - Insulin-resistant cells that have difficulty metabolizing glucose can still readily metabolize ketones, allowing them to circumvent the insulin resistance and maintain mitochondria bioenergetic capacity (22). Moreover, calorie restriction attenuates deregulated insulin signalling, improving insulin sensitivity (2,12,23). 
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Insulin-resistant cells that have difficulty metabolizing glucose can still metabolize ketones, allowing them to circumvent the insulin resistance and maintain mitochondria bioenergetic capacity.

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​(3) Mitochondria quantity declines with age - Calorie restriction stimulates mitochondria biogenesis (2,24), partly due to activation of the sirtuins and hence PGC-1α, a central inducer of mitochondria biogenesis (18), thus increasing mitochondria bioenergetic capacity (25,26). Ketogenic diets may also stimulate mitochondria biogenesis (27).
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(4) Mitochondria quality declines with age - Intermittent fasting has been shown to maintain mitochondria health (28), presumably through its strong stimulatory effect on mitophagy (1,14) which removes damaged, inefficient mitochondria, thus maintaining mitochondria bioenergetic capacity.


Despite the powerful ability of calorie restriction (and by extension, intermittent fasting and ketogenic diets) to extend longevity in animals, the evidence in humans is still a bit weak. We need more randomized controlled studies to determine whether enhancing mitochondria bioenergetics can truly slow aging or not.

Focus: Mitochondria Bioenergetics

Substantial evidence argues for mitochondria dysfunction as a major driving force in aging. The question we have been debating here is how this occurs - via the production of excess free radicals, or via defective bioenergetic capacity?

For over half a century, the mitochondria free radical theory of aging has been the single most widely cited theory of aging. However, the theory is based largely on correlations, and a number of recent facts do not add up, suggesting that free radicals have, at best, a minor role in aging. In contrast, the obvious function of mitochondria is to produce energy for the cell. If their ability to produce energy declines, the cell runs short on energy. It is difficult to see how some cells, particularly neurons, could survive - let alone function - under such a constraint to their energy supply.

Calorie restriction extends life in every organism that it has been tested on. Calorie restriction is metabolically simulated by intermittent fasting and ketogenic diets; all three of these comprehensive metabolic therapies theoretically alleviate mitochondria dysfunction through a number of mechanisms, including altering the electron transport chain, bypassing complex I defects, improving insulin sensitivity, circumventing insulin resistance, enhancing mitochondria biogenesis, and enhancing mitophagy. The overall result is an enhanced mitochondria bioenergetic capacity - and quite possibly, life extension.
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Rather than focus on antioxidant supplements, perhaps we ought to concentrate our resources more on therapies that enhance mitochondria bioenergetic capacity.
 
Solace.

References
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(22) Castellano et al. 2015. Lower brain 18F-fluorodeoxyglucose uptake but normal 11C-acetoacetate metabolism in mild Alzheimer’s disease dementia. J Alzheimers Dis 43, 1343-1353.
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