Mitochondrial function decline - one of the aging reasons 

What are mitochondria? 
A mitochondrion, plural - mitochondria, is an organelle within our cells (the exception is mature red blood cells that have no mitochondria).
​Mitochondria play multiple roles, the most well known of which is to absorb nutrients from a cell, break them down, and convert them into energy (called ATP, adenosine triphosphate) that the cell can use.

​As an interesting side note, mitochondria have their own DNA (MtDNA), and it is only passed to a child from Mother, never from Father. Thus, if you do your genetic testing, just like X chromosome can be used to discover a strictly paternal lineage, MtDNA shows a strictly maternal lineage.
What are mitochondrial functions?
​The role of mitochondria in aging
​Reversing the mitochondrial clock - lifestyle changes and supplements
References and Literature

What are mitochondrial functions?

Mitochondria hold one of the central positions in a human cell, and with that they also play one of the key roles in the aging process. How mitochondria affect our aging rises from the functions it performs. Mitochondria perform a number of interrelated roles that extend beyond the energy production. 
Energy Production or cellular respiration
Mitochondria convert biochemical energy from the nutrients we consume into ATP that powers cells and, thus, the body. ATP production happens during three phases of cellular respiration: Glycolysis, the Kreb's cycle, and the Electron Transport Chain. These processes are so complex and also extensively covered in many sources, so we will not go into details here. What's important to know is that mitochondria produce cellular energy. These processes are supported by vitamins, minerals, and co-enzymes. ​​
Regulation of innate immunity
Mitochondria create a protein that regulates innate immunity. Innate immunity is the part of the immune system we are born with, not immunity we acquire in response to a disease or a vaccine. Innate immunity recognizes pathogens and provides non-specific, immediate response. The protein is called MAVS - mitochondrial antiviral signaling protein; it helps activating antiviral and anti-inflammatory pathways. If MAVS production is compromised, the immune protection goes down. 
Activation of programmed cell death
Mitochondria control intrinsic pathways that activate apoptosis or programmed cell death. We want to have sufficient and properly controlled levels of apoptosis to dismantle and eliminate damaged and old cells. To control the apoptosis, mitochondria create and release specific proteins such as cytochrome c, which is also crucial for ATP production. A disruption of this process is associated with the development of cancer and with one of the main aging reasons, senescent cells accumulation. 
Calcium levels regulation 
Mitochondria absorb and store calcium ions and release them when they are needed; this process is called mitochondrial calcium exchange. This calcium exchange is important in metabolic regulation of a cell, release of neurotransmitters from nerve cells, release of hormones from endocrine cells, in muscle function, fertilization, blood clotting etc.
​A recent paper (Luongo, 2017) also identified that the mitochondrial calcium exchange plays a vital role in heart function. 
pluripotent stem cell regulation 
Pluripotent stem cells are naturally only present in developing babies (in utero). In adults, some stem cell/regenerative therapies create "induced pluripotent" or "reprogrammed pluripotent" stem cells. Mitochondria participates in the regulation of those pluripotent stem cells. This mitochondrial function does not relate to the aging topic, but is still worth mentioning.​
NON-shivering thermogenesis
Thermogenesis means heat production. Mitochondria fascilitate production of heat off the brown fat tissue when we are cold. 
REgulation of adult neurogenesis
Recent finding suggest that mitochondria play a critical role in the neurogenesis in adults, and hence the cognitive function and decline of thereof through regulating the fate of neural stem cells (Khacho, 2018). 

The role of mitochondria in aging 

​Mitochondrial function has long been recognized to decline during aging (Shigenaga, 1994).
By now we know that mitochondrial impairment is not only associated with aging, but a direct cause-and-effect relationship has been demonstrated by numerous studies. The underlying molecular mechanisms and aging phenotypes are very complex and as of today, science does not offer a full and definitive explanation of the mitochondrial role in aging. Nonetheless, we know the following - 
Mitochondrial decline means an impairment of all mitochondrial functions
We can reasonably conclude, that with the aging, all of the mitochondrial areas of responsibility are affected: energy production, apoptosis regulation, calcium levels regulation, innate immunity, neural stem cells regulation.
That on its own is enough to see the importance of mitochondria and its role in our aging. However, there is more - 
Mitochondrial free radical theory of aging has been primarily refuted 
Once popular and widely accepted Mitochondrial Free Radical Theory of Aging (MFRTA) has been primarily refuted, because mitochondria can cope with the physiological levels of oxidative damage. At any rate, even if ROS in the context of mitochondrial aging contribute to the aging, they no longer appear to be the initial cause or the main reason (Bratic, 2013)
Mitochondrial aging triggers inflammation in reposne to leaking MtDNA and proteins
One of the recently discovered and currently studied roles that mitochondria play in our aging and age-rated disease is inflammation. This inflammation is the immune system's response to the leaking of MtDNA and mitochondrial proteins into intracellular and extracellular environment.
Science cannot yet fully explain how exactly this leakage occurs. However, it has been established that the circulating levels of MtDNA go up as we age, especially after 50, and the circulating MtDNA levels are used as a reliable biomarker of aging.
​Presumable because originally mitochondria were a foreign organism (mitochondria seem to have originated as a foreign bacteria engulfed by cells), our immune system is reacting to the circulating MtDNA and mitochondrial proteins as it would react to pathogens - by creating inflammation. Unlike a temporary inflammation in response to true pathogens, this inflammation becomes chronic (Boyapati, 2017; Nakayama, 2018)
Mitochondrial decline affects nutrient-sensing life-span regulating pathways (IIS and TOR)
Some studies show that mitochondrial metabolism affects longevity through nutrient-sensing pathways and dietary restriction (Bratic, 2013). The two main nutrient-sensing pathways that have been linked to the regulation of longevity are Insulin/IGF-1 signaling (IIS) and target of rapamycin (TOR) signaling pathways. The decline of or a dysfunction in the mitochondrial metabolism may negatively affect those two life-span regulating pathways
Mitochondrial dysfunction is implicated in the neurodegenerative disease 
Recent evidence suggests that mitochondrial aging and dysfunction play a role not only in the brain aging as such, but also in the development of the neurodegenerative diseases (Johri, 2012)
Age reated decline in the mitochondrial energy production may by partly caused by other age-related changes
  • Mitochondrial biogenesis is controlled simultaneously by different mechanisms. For example, thyroid hormones, estrogens, and glucocorticoids, besides their other roles, are also important regulators of the mitochondrial biogenesis (Chen, 2009; Scheller, 2003; Weitzel, 2003) . This brings us to two points 1) age related decline in Respiratory Chain (energy production) function may at least partly be caused by other age-related changes, e.g., decline in hormonal levels or peripheral insulin resistance, 2) an effective anti-aging approach should combine different measures to take into account that processes in our bodies are interrelated and interlinked.​

Reverse the Mitochondrial Clock

1. Lifestyle changes and bio hacks 
Consider all the usual anti-aging recommendations:
2. Supplements
I will be gradually covering supplements in detail in the subsequent posts on the web-site. For now, here is a list of the supplements that may help with the mitochondrial function or compensate for its decline: 

  • Ubiquinol - the reduced [bio-active] form of CoQ10, preferably combined with vitamins K2 and D3;
  • Acetyl L-Carnitine, which shuttles fatty acids to the mitochondria;
  • R Alpha-Lipoic acid (ALA). There is some limited evidence that CoQ10, Acetyl L Carnitine, and R Alpha Lipoic Acid exert combined/synergetic effect in reviving mitochondrial function;
  • Possibly, indirectly - L-Carnosine;
  • Resveratrol, acting possibly as a mimetic of a dietary restriction;
  • D-ribose, which is raw material for ATP molecule;
  • Magnesium;
  • Omega-3 fatty acids;
  • All B vitamins, particularly riboflavin, thiamine, and B6;
  • Curcumin.

References and Literature

Baker DJ, Betik AC, Krause DJ, Hepple RT. No decline in skeletal muscle oxidative capacity with aging in long-term calorically restricted rats: effects are independent of mitochondrial DNA integrity. J Gerontol A Biol Sci Med Sci. 2006;61(7):675–684. doi: 10.1093/gerona/61.7.675.
https://www.ncbi.nlm.nih.gov/pubmed/16870628
​
Boyapati RK, Tamborska A, Dorward DA, Ho GT. Advances in the understanding of mitochondrial DNA as a pathogenic factor in inflammatory diseases. F1000Research. (2017) 6:169. 10.12688/f1000research.10397.1 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321122/​  

Bratic A, Larsson NG. The role of mitochondria in aging. J Clin Invest. 2013;123(3):951-7.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3582127/

Chen J-Q, Cammarata PR, Baines CP, Yager JD. Regulation of mitochondrial respiratory chain biogenesis by estrogens/estrogen receptors and physiological, pathological and pharmacological implications. Biochim Biophys Acta. 2009;1793(10):1540–1570. doi: 10.1016/j.bbamcr.2009.06.001. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2744640/​
​
Colman RJ, Anderson RM, Johnson SC, et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science. 2009;325(5937):201–204. doi:10.1126/science.1173635
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812811/​ 

Hasan-Olive M.M., Lauritzen K.H., Ali M., Rasmussen L.J., Storm-Mathisen J., Bergersen L.H. A ketogenic diet improves mitochondrial biogenesis and bioenergetics via the PGC1alpha–SIRT3–UCP2 axis. Neurochem. Res. 2019;44:22–37. doi: 10.1007/s11064-018-2588-6. 
https://www.ncbi.nlm.nih.gov/pubmed/30027365

Jang J. Y., Blum A., Liu J., Finkel T. (2018). The role of mitochondria in aging. J. Clin. Invest. 1283662–3670. 10.1172/JCI120842 
https://www.ncbi.nlm.nih.gov/pubmed/30059016

Johri A, Beal MF. Mitochondrial dysfunction in neurodegenerative diseases. J Pharmacol Exp Ther. 2012;342(3):619–630. doi:10.1124/jpet.112.192138
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422529/
​
Kephart WC, Mumford PW, Mao X, et al. The 1-Week and 8-Month Effects of a Ketogenic Diet or Ketone Salt Supplementation on Multi-Organ Markers of Oxidative Stress and Mitochondrial Function in Rats. Nutrients. 2017;9(9):1019. Published 2017 Sep 15. doi:10.3390/nu9091019
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622779/
​
Khacho M, Harris R, S. Slack, R. Mitochondria as central regulators of neural stem cell fate and cognitive function. Nature Reviews Neuroscience. 2018/11/2110.1038/s41583-018-0091-3
https://www.ncbi.nlm.nih.gov/pubmed/30464208​ 

López-Lluch G, Hunt N, Jones B, et al. Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc Natl Acad Sci U S A. 2006;103(6):1768–1773. doi:10.1073/pnas.0510452103
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1413655/​ 

Luongo TS, Lambert JP, Gross P, et al. The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability. Nature. 2017;545(7652):93–97. doi:10.1038/nature22082
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731245/

Miller VJ, Villamena FA, Volek JS. Nutritional Ketosis and Mitohormesis: Potential Implications for Mitochondrial Function and Human Health. J Nutr Metab. 2018;2018:5157645. Published 2018 Feb 11. doi:10.1155/2018/5157645
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828461/
​
Nakayama H, Otsu K. Mitochondrial DNA as an inflammatory mediator in cardiovascular diseases. Biochem J. 2018;475(5):839–852. Published 2018 Mar 6. doi:10.1042/BCJ20170714
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840331/​ 

Nisoli E. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science. 2005;310(5746):314–317. doi: 10.1126/science.1117728.
https://science.sciencemag.org/content/310/5746/314.long​ 

Radak Z, Zhao Z, Koltai E, Ohno H, Atalay M. Oxygen consumption and usage during physical exercise: the balance between oxidative stress and ROS-dependent adaptive signaling. Antioxid Redox Signal. 2013;18(10):1208–1246. doi:10.1089/ars.2011.4498
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3579386/​ 

Scheller K, Sekeris CE. The effects of steroid hormones on the transcription of genes encoding enzymes of oxidative phosphorylation. Exp Physiol. 2003;88(1):129–140. doi: 10.1113/eph8802507. 
https://www.ncbi.nlm.nih.gov/pubmed/12525861

Shigenaga MK, Hagen TM, Ames BN. Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci U S A. 1994;91(23):10771–10778. doi: 10.1073/pnas.91.23.10771.
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC45108/

Sun N, Youle RJ, Finkel T. The Mitochondrial Basis of Aging. Mol Cell. 2016;61(5):654–666. doi:10.1016/j.molcel.2016.01.028
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779179/​ 

Theurey P, Pizzo P. The Aging Mitochondria. Genes (Basel). 2018;9(1):22. Published 2018 Jan 9. doi:10.3390/genes9010022 
​https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793175/ 

Weitzel J, Iwen K, Seitz H. Regulation of mitochondrial biogenesis by thyroid hormone. Exp Physiol. 2003;88(1):121–128. doi: 10.1113/eph8802506. https://www.ncbi.nlm.nih.gov/pubmed/12552316