By Dr. Neil Goodman, MD

As a result of prolonged exposure to oxidative stress our mitochondria become less efficient at producing energy and also tend to generate even more free radicals, which further impacts the cell’s ability to function optimally and carry out its duties.

What is the Mitochondrial Theory of Aging? 

The lives we live, the food we eat, and the daily exposure to the multitude of environmental assaults of our world, mean our 37 Trillion cells are exposed to the cumulative incremental effects of free radicals and other oxidative stressors. This oxidative stress affects all of our cellular material including the nucleus, where our genetic blueprint is housed, the cytoplasm,  and especially the mitochondria – the energy producing factories in our cells.

As a result of prolonged exposure to oxidative stress our mitochondria become less efficient at producing energy and also tend to generate even more free radicals, which further impacts the cell’s ability to function optimally and carry out its duties. Free radical formation is a natural consequence of the metabolic expenditure of the cell, but the mitochondria being the primary source of ATP (Adenosine TriphosPhate) formation, are also the primary producer of free radicals that produce the effects of oxidative stress. This natural decline in mitochondrial function and other cellular processes is at the core of the “Mitochondrial Theory of Aging”. 

The Mighty Mitochondria 

The mitochondria are part of a class of small subcellular compartments called organelles. All organelles have a specific function within the cell. So why are mitochondria so important? They make energy. They are essential to proper cellular function. Without functioning mitochondria, the cell has a significantly diminished capacity to generate or utilize energy for all its important metabolic processes. When they stop working, the cell stops working, and we stop working. 

Approximately 95% of the energy we need to function at any given moment in time, is produced by the ever present and powerful mitochondria. The resultant energy molecule that the mitochondria produces for the cell is called ATP. Without ATP or the mitochondria that produce it, we cease to exist. 

One of the things that many people don’t realize, is that in the process of breaking down food and converting it to energy, high energy electrons are generated. These electrons are usually captured by the mitochondria where they harness their stored, potential energy in a series of steps, and then ultimately bound to oxygen to form water and are rendered harmless. However, in the process of making ATP, some of these electrons are shed, and often escape being detoxified to oxygen and go on to create free radicals and other oxidants. As mitochondrial function declines over time the conversion process becomes less efficient. Unfortunately, these metabolic by-products of energy formation (free radicals) contribute to mitochondrial decline. 

What is Oxidative Stress? 

The opposing and neutralizing enemy of the free radicals and other oxidants are antioxidants. Oxidative stress is the term used to describe the naturally occurring imbalance between free radicals and antioxidants in your body. Oxidative stress occurs when the number of free radicals produced is no longer held in check by adequate numbers of available antioxidant molecules. This leads to a progressive and cumulative impact on the cell, referred to as “oxidation,” which essentially causes the cell to oxidize or “rust,” and contributes to the normal aging process. 

It is the cell’s normal production of ATP, the foods we eat, exercise, the air we breathe, and environmental assaults, as well as our continual need for cellular energy that produces free radicals. More energy expenditure and usage yields even more free radicals. Remember the saying, “Burning the candle at both ends”? This is an analogy for the normal aging process. In fact, so important is the recognition of cellular “rusting” or oxidative stress, that it has become one of the hottest topics in medicine and the focus of much investigation. 

Mitochondria are continually being replaced as part of normal cell function and this natural mitochondrial turnover is necessary for cells to survive. When mitochondria are removed from service as part of the natural cellular clean-up, the term mitophagy becomes important. 

Mitophagy is a natural process of cell maintenance, and also requires energy to perform. Additionally, the production of new mitochondria to keep the cell alive is termed mitochondrial biogenesis, meaning new mitochondrial formation. This too, requires energy. 

How can someone reduce their free radical levels? 

Free radical production happens normally upon exposure to radiation, pollution, UV light, and introduction of toxic substances and harmful food. It is also a by-product of cellular metabolism, in particular mitochondrial function. As previously mentioned, the opposing and neutralizing enemy of the free radical and other oxidants are antioxidants. Antioxidants are found in nature, in the food we eat and, in the vitamins, and minerals that we ingest. These antioxidants that come from the diet are termed dietary antioxidants. There are a number of antioxidants and nutrients that have been shown to support mitochondrial health. They include alpha-lipoic acid (ALA), acetyl-L-carnitine, and coenzyme Q10. 

ALA is both water and fat soluble. It has 400 times the antioxidant power of vitamin E and C combined and has been shown to neutralize oxidants that damage mitochondria. ALA can help to recycle other antioxidants, and even regenerate glutathione. Acetyl-L-carnitine is an amino acid that is naturally produced in the body and helps to generate energy. It is responsible for transporting fatty acids into the mitochondria where they can be used to generate energy. Coenzyme Q10 is a fat-soluble antioxidant that is concentrated in the mitochondria. It is essential to move electrons through ATP-generating steps called the electron transport chain. 

Other dietary antioxidants, while beneficial, cannot be ingested in quantities that are enough to neutralize the many millions of free radicals that the body makes and is subjected to. However, we are also equipped with endogenous antioxidants (antioxidants made by the cell) such as superoxide dismutase (SOD), catalase and glutathione peroxidase. These endogenous antioxidants are produced naturally in high enough quantities early in human life to deal with the constant onslaught of free radical and oxidant exposure, but over-time and as we age, the body becomes less and less efficient and production of our primary antioxidants begins to fall in our twenties. This is a sign that cellular “rusting” is occurring and that the natural aging process is taking place. The good news is that our cells contain signaling pathways that can be stimulated to increase production of these endogenous antioxidants to help us maintain good health as we age. 

Three signaling pathways include the Nrf2 pathway, which is a master regulator of cell protection, the NAD (Nicotinamide Adenine Dinucleotide) biosynthetic pathway which is involved in NAD, sirtuin protein synthesis activation, and energy production and also the NRF1 pathway which is a major signaling pathway involved in mitochondrial health. 

The NRF1 Signaling Pathway 

As mentioned above, the NRF1 (nuclear factor erythroid 2-related factor 1) pathway is involved in keeping mitochondria healthy. Two main functions of NRF1 are to increase the biogenesis of mitochondria and to enhance mitophagy to ensure healthy mitochondrial turnover. The NRF1 pathway stimulates an Nrf1 protein (Nuclear respiratory factor-1) which in turn activates key genes involved in metabolism, cellular growth, energy production, and mitochondrial DNA transcription and replication. When combined with the actions of the Nrf2 pathway, Nrf1 also coordinates the essential function of gene expression between nuclear and mitochondrial genetic code. 

Another protein that is stimulated by the NRF1 pathway is that of PGC1-alpha. PGC1-alpha (peroxisome proliferator-activated receptor gamma coactivator-1-alpha) is a transcriptional coactivator that regulates genes involved in energy metabolism and is the master regulator of mitochondrial biogenesis and turnover. It also supports healthy blood pressure and cholesterol levels already within a normal range. 

Clearly, since biogenesis is enhanced by NRF1 pathway signaling, the cells are able to produce new mitochondria. When this happens, the increase in new mitochondria helps to increase energy formation and utilization within the cell and hence improve the cell’s survivability, functioning, and continued performance with better efficiency. 

NRF1 is further enhanced by the presence of Nrf2 signaling which works in a cooperative and supportive fashion for mitochondrial function. More recently, further research supports the evidence that concomitant activation of NAD gene signaling and sirtuin protein synthesis may further amplify the already acknowledged benefits of mitochondrial biogenesis and recycling. 

Why does NRF1 Matter? 

NRF1 is necessary to keep the cells functioning at full capacity. It supports the vital processes of energy formation by the mitochondria. It is needed to ensure that enough mitochondria are produced, replicated, rejuvenated, repaired, and that bad mitochondria are removed to allow the cell to continue performing its vital functions. Mitochondrial energy formation is required for the cells internal clean-up processes, mitophagy, and mitochondrial biogenesis and to enhance Nrf2-driven antioxidant and detoxification mechanisms of the cell as well. The NRF1 signaling pathway has been determined to be yet another master regulator of cell survival, protection, and to support the healthy aging process. 

Conclusion: 

Mitochondria are organelles that function as energy factories and are essential for cellular function. While they produce energy using electrons that are captured during the breakdown of food, they are also subject to the effects of free radicals and oxidative stress. This stress gradually makes the mitochondria less efficient and less capable of capturing electrons which consequently allow them to produce even more free radicals, which cumulatively results in slower cellular metabolism. This results in less energy to support normal cellular and mitochondrial repair and rejuvenation functions. Moreover, reduced mitophagy and mitochondrial biogenesis results in less energy to support cellular function as a whole. 

The NRF1 signalling pathway provides a mechanism for overall cellular health and to increase mitochondrial biogenesis, mitophagy and turnover. The benefits are further amplified when combined with the benefits of dietary antioxidants, Nrf2 pathway and NAD activation. Dietary antioxidants, as well as Nrf2-stimulated primary antioxidants further enhance mitochondrial health, and also support detoxification pathways used by the cell and the organism. In this way, the consequences of the “Mitochondrial Theory of Aging” can be mitigated by supporting the primary functions that the mitochondria need to survive.