Smokers are two to four times more likely to have a heart attack than nonsmokers (Elkhader 2016; PubMed Health 2014). In contrast, an 84-year-old man’s risk of having a heart attack is 25 times greater than that of a 45-year old (Gillinov M 2012)!
Clearly, just getting old is an enormous risk factor for heart disease. Not surprisingly, most of the other chronic killer diseases of our modern world – e.g., cancer, type 2 diabetes, and Alzheimer’s disease – increase with age as well (Payne 2015).
While researchers continue to seek better treatments for each of these age-related conditions, other scientists are turning their attention to the aging process itself. By identifying strategies to slow aging and extend “health span,” the diseases of aging may be delayed.
Mitochondria – the energy-generating batteries in our cells – has been the focus an explosive growth of research in the last two decades. As we age, these critically important rod-shaped compartments within our cells become impaired and dysfunctional. Mitochondrial dysfunction, in turn, is a major contributor to aging and the development of age-related disorders (Madreiter-Sokolowski 2018; Cedikova 2016; Payne 2015).
Dysfunctional mitochondria have the potential to act as targets for a variety of therapeutic interventions aimed at counteracting aging. The good news, as you will discover in this article, is that many of today’s popular anti-aging modalities – including exercise, metformin, and polyphenols – have already been shown through scientific studies to successfully rejuvenate dysfunctional mitochondria (Madreiter-Sokolowski 2018).
How Does Aging Affect Mitochondria?
During aging, mitochondria undergo some significant changes that make them dysfunctional. These include alterations to their structure, damage to their own DNA, and changes in their capacity to generate energy and free radicals, as well as regulate calcium levels inside cells (Madreiter-Sokolowski 2018).
Energy Production and Free Radicals
Animal studies and laboratory experiments suggest that changes in mitochondrial energy production during aging occur in two phases. In middle age, energy production is increased to compensate for (age-related) mitochondrial inefficiency (Madreiter-Sokolowski 2018).
However, energy production comes at a price – free radical formation. In the mitochondria, cell-damaging free radicals are created as a by-product whenever food energy is converted to ATP – the energy currency of the cell. These free radicals may then cause long-term injury to the cell, leading to constant decline in ATP production in old age (Madreiter-Sokolowski 2018).
Mitochondrial DNA Mutations
While the vast majority of our genetic material – DNA – is stored in the nucleus of the cell, mitochondria have their own DNA. The rate of mutation formation is 10 to 17 times higher in mitochondrial DNA (mtDNA) than in the DNA of the cell’s nucleus. The mitochondria’s own production of free radicals is the primary culprit behind the DNA damage (Tuppen 2010).
Mitochondrial DNA is vital for the harnessing of energy through a series of chemical reactions occurring in the inner-membrane of mitochondria. The mtDNA code for pivotal proteins that are essential components of this energy creating process. Consequently, a high rate of mutations in mtDNA can cause dysfunction in the energy producing system along with increased free radical generation. Ultimately, a decline in overall cell function can lead to degenerative diseases (Lin 2016; Otten 2015).
Mitochondrial DNA mutations increase with age. In a cell culture study using aged human muscle fibers, mtDNA mutations were shown to accumulate to levels greater than 90% of the total mtDNA (Bua 2006)!
Mass and Structure
The size and shape of mitochondria are continually changing. Mitochondria that become damaged and defective are degraded and disposed of through a housekeeping mechanism called mitophagy. New mitochondria are then created (“mitochondrial biogenesis”) to maintain a balance in the cell. This turnover of mitochondria requires fission, or splitting in two ‘daughter’ mitochondria (Palikaras 2015; Youle 2012).
The process of mitophagy declines with age. As a result, the removal of damaged mitochondria and the creation of new mitochondria are impaired. Dysfunctional mitochondria progressively accumulate and cause deterioration of cell function. This buildup of defective mitochondria during aging is reflected in a larger mitochondrial mass (Palikaras 2015; Madreiter-Sokolowski 2018).
Restoring Mitochondrial Function to Slow Aging and Combat Age-Related Disease
A review of studies offers evidence that various interventions widely used to extend health span and resist the diseases of aging are associated with enhanced mitochondrial function (Madreiter-Sokolowski 2018).
Calorie restriction (30-60% reduction in calorie intake below normal) in the absence of malnutrition extends average and maximal life span in a range of animal species. In humans, calorie restriction promotes longevity and helps prevent age-related diseases such as diabetes, cancer, and cardiovascular disease (Al-Regaiey 2016).
In an animal study, calorie restriction was shown to shift metabolism in the mitochondria from burning glucose to burning fat as the major fuel. Since fat is a “cleaner” burning fuel compared to glucose, fewer mitochondrial free radicals are generated (Bruss 2010).
Even short-term calorie restriction has been reported to improve mitochondrial function. In a study in healthy adults, a 25% calorie deficit for six months increased the number of mitochondria in muscle tissue. In addition, the overall calories burned for body functions decreased over 24 hours. This finding, along with reduced oxidative stress (free radical damage) in muscle, indicates that the newly created mitochondria were more efficient at creating energy (Civitarese 2007)!
Severely rationing calories, however, is very challenging and often not practical. Fortunately, studies suggest that intermittent fasting (or time restricted eating) provides many of the same anti-aging benefits as calorie restriction. Thus, intermittent fasting may be a more viable alternative (Moro 2016; Lee 2016).
Both animal and human studies have provided indisputable evidence that endurance exercise extends life expectancy and lowers the risk of chronic diseases (Safdar 2016). Exercise is the only known intervention that can slow down sarcopenia – the loss of muscle mass and strength with age. Defective turnover of mitochondria is a major factor contributing to sarcopenia and muscle atrophy during aging. Exercise restores balance to the mitochondrial pool. Specifically, exercise (particularly intense exercise) drives mitochondrial biogenesis while also activating mitophagy, whereby damaged mitochondria are targeted for destruction and elimination (Joseph 2016; Calvani 2013).
Drugs and Nutraceuticals
Metformin – the medication of choice for type 2 diabetes – may be the first FDA approved anti-aging drug! It is undergoing a large-scale clinical trial to evaluate its ability to slow aging. Metformin mimics some of the anti-aging effects of calorie restriction. Like calorie restriction, metformin is a potent activator of AMPK – a “master regulating switch” that acts as a sensor of cellular energy levels. Accordingly, one mechanism by which metformin activates AMPK (adenosine monophosphate-activated protein kinase) is by inhibiting mitochondrial energy production. The resulting low levels of ATP trigger activation of AMPK (Hur 2015). By switching on AMPK, metformin boosts mitochondrial biogenesis (Marin 2017; Alcocer-Gomez 2015).
Quercetin and resveratrol, two powerful disease-fighting polyphenols with anti-aging potential, enhance mitochondrial function and trigger mitochondrial biogenesis (Madreiter-Sokolowski 2018; Abharzanjani 2017). Quercetin may also act as a senolytic agent by destroying senescent cells that build up as the body ages. These senescent cells no longer divide and function normally but secrete inflammatory factors that damage nearby cells and tissues (Malavolta 2016).
By scavenging mitochondrial free radicals, a mitochondria-targeted-antioxidant (SkQ1) was shown to extend health span and lifespan in a mouse model of premature aging (Shabalina 2017). Omega-3 fatty acids, aspirin, and other senolytic drugs have also been reported to combat age-related disease by improving mitochondrial health (Madreiter-Sokolowski 2018).
Mitochondria provides the vast majority of our cellular energy. The flip side is that mitochondria are both the primary source of free radicals and targets of destructive free radical reactions (Cedikova 2016). With advancing age, free radical damage to mitochondrial DNA accumulates in cells, leading to mitochondrial dysfunction and the development of age-related diseases. Organs with high-energy demands (e.g., brain, heart and muscle) are mostly affected, thus increasing risk for Alzheimer’s disease, heart attack, and sarcopenia (Madreiter-Sokolowski 2018).
Lifestyle interventions such as calorie restriction and exercise, as well as various drugs (e.g., metformin) and nutraceuticals (e.g., polyphenols) can effectively re-energize mitochondria and delay aging and age-related diseases. However, since the degree of mitochondrial activity significantly varies throughout life, the timing of these interventions should be a major consideration (Madreiter-Sokolowski 2018).
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