Background
Many consumers are familiar with antioxidants, which are marketed by food companies and promoted by health gurus as elements of a wholesome diet. The origins of this approach can be found in laboratory research on radiation dating back to the 1950s. When mice are exposed to heavy doses of radiation, their health soon deteriorates. One of the reasons is the chemical reaction called oxidation, which creates free radicals – compounds that will react with almost anything they come into contact with and wreak havoc in the cell. The final result, i.e., the damage caused to cells by oxidation, is called oxidative stress.
Antioxidants, molecules capable of neutralizing free radicals, can alleviate that stress. Thus, if antioxidants are administered to a mouse before it is blasted with radiation, it fares better than before.[114] Therefore, some scientists have explored the hypothesis that oxidative stress might be a cause of normal aging as well. After all, we produce plenty of free radicals even if we are not subjected to radiation. Normal metabolic activity and even exercise will cause oxidative stress,[115] which tends to increase with age.[116]
However, this theory has since been disproven. Extensive studies to determine the effect of antioxidant supplements have found that they do not help, and some even seem to do damage.[117][118]; Therefore, some proponents of the theory adjusted it accordingly, still suspecting that free radicals had some kind of role in aging, and hypothesized that the damage might only matter if it occurred in certain fragile places.
For instance, the mitochondria, where much of the cell metabolism takes place, create large amounts of free radicals as a byproduct. According to that theory, free radical damage might cause aging by making the mitochondria dysfunctional over time. Antioxidant supplements might not work, then, because they did not reach the mitochondria. This idea, however, also appears to be wrong: Mice that have been manipulated to experience more oxidative stress in their mitochondria get cancer more often, but ultimately do not live shorter lives.[119][120] It seems that antioxidants are simply not as big of a problem in aging as had been believed.
However, the proponents of this theory are right about one thing: Our mitochondria are negatively affected by age. They become worse at their job of harvesting energy for the cell and generally more dysfunctional as the body grows older.[121] Scientists have created mice that have dysfunctional mitochondria, but do not produce more free radicals. And these mice do show accelerated aging. The mitochondria are involved in aging, just not through free radicals.[122][123]
Exactly how this occurs is currently being investigated. In general, it is not hard to imagine how the dysfunction of one of our most important organelles can cause general dysfunction of the cells. Besides being the hub of our energy metabolism, mitochondria also play a central role in many forms of cellular signaling. For instance, they host one of the triggers for what is called apoptosis or “cellular suicide”.[124] If the cell is sufficiently damaged or hijacked by pathogenic microbes, or if it senses it is in danger of becoming cancerous, it can kill itself to save the rest of the body. If this process becomes dysfunctional, too many healthy cells might off themselves or bad cells might not.
Challenges
We know that mitochondrial dysfunction is a hallmark of aging, but the importance of this factor is sometimes questioned. As explained above, the Mitochondrial Free Radical Theory is contradicted by experimental evidence on a number of levels. Furthermore, even though mitochondrial function declines with age, it might be restorable with exercise. For these reasons, some of the hype surrounding the mitochondria has died down. However, healthy mitochondria are undoubtedly important, and there are many exciting ideas in circulation for improving their function.
Road to Success
Two of the approaches previously described could strengthen our mitochondria. The first one is hormesis. Hormetic challenges can be life-extending, and many work through the mitochondria. Exercise is an example of mitohormesis as it increases the production of free radicals in the mitochondria. These work as a signal that turns on several protective measures and strengthens the cells.[125] The other one is autophagy. While mitohormesis can strengthen our defenses, autophagy (in this case, mitophagy) can remove damaged mitochondria. This process ensures that dysfunctional mitochondria are removed and only healthy ones are allowed to proliferate. However, with age, mitophagy declines, and cells are left with more dysfunctional mitochondria.[126]
Companies
Cohbar Inc[127]
Website http://www.cohbar.com
Industry Biotechnology
Company size 11-50 employees
Headquarters Menlo Park, California
Type Public Company
Founded 2007
CohBar was founded by a group of anti-aging scientists. The company focuses on research and development of mitochondria-based therapies. This focus stems from the discovery of new mitochondrial peptides originating from the mitochondrial DNA that regulate metabolism and cell death, both of which become dysregulated with age. Currently, the company’s lead compound CB4211 is in Phase 1 clinical trials for non-alcoholic steatohepatitis and obesity. Furthermore, the company has four preclinical programs aimed at cancer, type-2 diabetes, and other conditions.
Eprium Bio[128]
Website https://www.epirium.com
Industry Pharmaceuticals
Company size 2-10 employees
Headquarters San Diego, California
Type Privately Held
Founded 2008
Epirium Bio is a pharmaceutical company that develops therapies to promote mitochondrial biogenesis – the formation of new mitochondria. The research team behind the company has discovered a novel hormonal pathway that does just this. So far, the company has conducted proof-of-concept studies into diseases such as Duchenne’s muscular dystrophy. In 2019, Epirium Bio raised US$85 mn in Series A financing from investors, including The Longevity Fund.[129]
Continuum Biosciences[130]
Website https://continuumbio.com/
Industry Biotechnology
Company size 51-200 employees
Headquarters Boston, Massachusetts
Type Privately Held
Founded 2017
Continuum Biosciences is a Life Biosciences company. It was founded by Webster Santos and Kyle Hoehn and develops drugs to improve mitochondrial health. Scientists at the company have identified molecules that target the mitochondria to increase energy usage. They plan to test this therapy first in non-alcoholic steatohepatitis, but increasing energy usage in the mitochondria could also have an application in life extension in the future.
Mitotech Pharmaceuticals[237]
Website https://www.mitotechpharma.com
Industry Biotechnology
Company size 2-10 employees
Type Privately Held
Founded 2009
Mitotech is developing a compound called SkQ1 (based on a mitochondria-targeted antioxidant) for treatment of a variety of diseases. The most advanced of these SkQ1-based drugs is Visomitin™, which has advanced to Phase 3 testing for Dry Eye Disease in the US and has received marketing approval in Russia. SkQ1 is also being tested in connection with several other conditions including Uveitis, Dry Age-related Macular Degeneration, Multiple Sclerosis, Acute Kidney Injury, and Barth syndrome (a genetic disorder).
Retrotope[238]
Website https://www.retrotope.com
Industry Pharmaceuticals
Company size 11-50 employees
Headquarters Los Altos, California
Type Privately Held
Founded 2006
Retrotope has developed a drug platform to preserve and restore mitochondrial health in degenerative diseases that uses stabilized (deuterated) fatty acid drugs to prevent lipid peroxidation damage. Clinical trials of Retrotope’s RT001 product are underway with tests in two rare diseases, Friedreich’s ataxia and Infantile Neuroaxonal Dystrophy.[239] The company hopes to develop other stabilized lipid drugs for treatment of other mitochondrial myopathies and neurodegenerative conditions.
References
[114] Kennedy, A.R. et al. 2008. Effects of dietary antioxidant supplementation on the development of malignant lymphoma and other neoplastic lesions in mice exposed to proton or iron-ion radiation. Radiation Research 169(6): 615-25.
[115] Kawamura, T. and I. Muraoka 2018. Exercise-induced oxidative stress and the effects of antioxidant intake from a physiological viewpoint. Antioxidants 7(9):119.
[116] Stadtman, E.R. 1992. Protein oxidation and aging. Science 257(5074):1220-4.
[117] Bjelakovic, G. et al. 2007. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: Systematic review and meta-analysis. Journal of the American Medical Association 297(8):842-57.
[118] This does not mean that antioxidants as found in fruits and vegetables are not a good thing. Just that taking highly concentrated versions of them as a supplement does not offer any benefits.
[119] Van Remmen, H. et al. 2003. Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiological Genomics 16(1):29-37.
[120] Zhang, Y. et al. 2009. Mice deficient in both Mn superoxide dismutase and glutathione peroxidase-1 have increased oxidative damage and a greater incidence of pathology but no reduction in longevity. The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences 64(12):1212-20.
[121] Green, D.R. et al. 2011. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 333(6046):1109-12.
[122] Trifunovic, A. et al. 2004. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429(6990):417-23.
[123] Edgar, D. et al. 2009. Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice. Cell Metabolism 10(2):131-8.
[124] Wang, C. and R.J. Youle 2009. The role of mitochondria in apoptosis. Annual Review of Genetics 43:95-118.
[125] Bárcena, C. et al. 2018. Mitohormesis, an antiaging paradigm. International Review of Cell and Molecular Biology 340:35-77.
[126] Chen, G. et al. 2020. Mitophagy: An emerging role in aging and age-associated diseases. Frontiers in Cell and Developmental Biology 8:200.
[127] https://www.cohbar.com/
[128] https://epirium.com/
[129] BusinessWire, “Epirium Raises $85 Million in Series A Financing to Advance Unique Scientific Platform Focused on Restoration of Tissue Bioenergetics and Function”, 18 December 2019. https://www.businesswire.com/news/home/20191218005433/en/Epirium-Raises-85-Million-Series-Financing-Advance (last accessed 6 August 2020).
[130] https://continuumbio.com/team
[237] https://www.mitotechpharma.com
[238] https://www.retrotope.com
[239] https://www.retrotope.com/clinical-proof-of-concept