The creation of eukaryotes
Made by using following images
Creation of Adam by Michaelangelo | Public Domain
Macrophage by A. Rad, Mikael Häggström, Spacebirdy, RexxS, domdomegg| CC BY-SA 4.0
Mitochondria by openclipart-vectors | pixabay

About 2.7 billion years ago, the earth was flourishing with life. Some bacteria and archaea floating in the waters. Life have just discovered to use sunlight and carbondioxide in the air to make its own food. They were pumping oxygen into the atmosphere. But oxygen was toxic, very toxic. But, life doesn't give up so easily. It found a way to use this oxygen for its own benefit. We were not there to witness our creation but on one of those days another prokaryote or a cell that has already evolved nucleus met this bacteria. The one that could use food produced by others and oxygen from the atmosphere to make energy. This bacteria and the other cell made pact, to stay together for eternity. The eukaryotic cell will provide it food, protection and well also carry some of its genes. The bacteria in return will provide the energy in form of numerous ATP molecules. This will mark the history of all the eukaryotes, even multicellular eukaryotes like us. We all carry this bacteria in our cells, we now call it mitochondria. Passed on from mother to the child. It makes energy for all the cellular processes. But, it also does something else as a side effect. It contributes to ageing. And in this episode we will explore how.

Recap

In the previous episode, in our quest for elixir of life - we encountered the DNA damage, that accumulate through our life. We figured that caloric restriction reduced the damage. We saw that, it achieves this feat by activating DNA repair pathways, which seem to be downregulated with ageing otherwise. We also saw two drugs - rapamycin and resveratol (the compound found in red wine) reduces DNA damage, and increases lifespan. However, what we did not see is how if caloric restriction works upstream of DNA damage? Does it reduce the damage causing factors itself? What about other damage endured by the tissues?

In this episode, we will look at the cellular metabolism angle of caloric restriction. We will focus on this cell organelle called mitochondria and ask how it contributes to ageing and what is affect if caloric restriction on it.

How mitochondria contributes to ageing

The mitochondria, popularly known as power house of the cell is responsible for producing energy for cellular processes. When glucose enters the cell it is broken down to pyruvate by glycolysis , giving us only tiny portion of energy. But then this pyruvate is taken up by mitochondria and is passed through series of enzymes in citric acid cycle. This is where electrons from food is transferred to oxygen, yielding carbon dioxide and water as by product. The energy yielded by this reaction is eventually used by enzyme called ATP synthase, which makes most of ATP molecules for energy requirement of cells.

Oxidative stress and cellular damage

But, the system is not free of creating byproducts. The electrons tend to leak from electron transport chain in mitochondria and end up giving rise to superoxide and hydrogen peroxide - the reactive oxygen species (ROS). Though, ROS comes handy at times - it participates in many signalling pathways, it can protect against pathogens, and activate autophagy and apoptosis during cellular stress - it also damages many macromolecules. No macromolecule, be it DNA, protein or lipids is spared by damage caused by ROS.

Given the damaging effect of ROS one might expect that, many of the damages caused by ROS are repaired but some of it accumulate over time in mitochondrial DNA and in cells. This would put ROS upstream of the oxidative DNA damage that we saw in previous blog. And, add to that the age dependent decrease in DNA repair capacity. It has also been reported that mitochondrial function declines with age, leading to low efficiency of energy production and increased ROS production. For instance, kuka et al., 2013 showed mitochondria of heart cells of an old rat produces much more ROS than young heart cells. Moreover, macrophages responding to injury old animals produce much higher amount of ROS than younger animals (Zhang et al., 2016). At the end of the day the job of scavenging ROS comes to enzymes such as Superoxide dismutase and catalase. The expression and efficiency of these enzymes have also shown to affected by ageing.

Beyond oxidative stress

Now, ROS may not be the only way by which mitochondria may contributes to aging. The favorite hypothesis for ageing few years back was that mitochondria produces ROS, which causes mitochondrial DNA damage, which causes it to produce even more ROS in a vicious cycle. But with time we are learning that DNA mutations arise independent of ROS as well, moreover over expression of enzymes that protect against oxidative damage doesn't always extend life span (Gladyshev, 2014). It is possible that while ROS does cause damage to molecules, but cells evolved to also an important signaling molecules. Also, low level of ROS may act like a vaccine, which keeps the wheel of antioxidant enzymes and turing on autophagy to get rid of damaged mitochondria. But, high levels might escape those check point and induce damage. The turnover and morphology of mitochondria is equally important. There is also an age related accumulation of abnormally shaped and giant mitochondria. This is likely to be byproduct of reduced regulation of mitochondrial fission/fusion, degradation and biogenesis. Whether these abnormalities are linked with ROS and it's increased production with age remains to be tested. These abnormalities may however increase cell death by apiptosis and hinder stem cell homeostasis (Seo et al., 2010, Zhang et al., 2018).

Given the above information, it becomes interesting to question that how the well known elixir of life - caloric restriction affects mitochondria. And, can we develop drugs that could mimic those affects.

Caloric restriction and mitochondria

Lopez-Lluch et al., 2006 demonstrated that caloric restriction has multiple effects on mitochondria. It increases the efficiency of energy production by mitochondria, while at the same time reduces ROS production and increases mitochondrial biogenesis. If this is true we can start testing if any of these mechanisms induced artificially can also extend lifespan?

Exogenous anti-oxidants

Sources of vitamin C
Image from MaxPixel | CC0

The first thing comes to mind is to feed the animals or humans with antioxidants, such as vitamin C and E, and see if it extends lifespan, or at least reduce some age related maladies. Studies in model organisms have yielded mixed results. Some showed promising life span extension effect of vitamin C, E and melatonin, while others show no effect and even negative in some cases. From studies where it works it seems there are at least two important factors for it to work. The window of intervention being most important. Then the how was the supplement given also matters. For instance giving vitamin C via simple oral route did not work as well, but giving it after packing it in liposomes did the trick. Then most interesting part of mice studies where it worked is that, in many of these studies it increased the median or mean lifespan, but did not affect maximum lifespan. This hints that while scavenging ROS by antioxidants keeps some age related diseases away, it does not do much to push the bar. It does not slow down the basal level of decay, that causes ageing (see Bartosz and Bartosz, 2014 for more details on antioxidant studies). As far as humans are concerned synergy is the key. Vitamin E alone did not help much in one of the large follow up human study. Well, at least it did not help men who between 60-70 years of age. But those crossing this 70 years line it increased life span by 2 years and decreased mortality by 24%. But here is the catch, it was beneficial to only those who smoked less and had good dietary intake of vitamin C.

Throws pack of cigarettes out of the window, and goes shopping for citrus fruits, nuts and green leafy veggies

Mitochondrial biogenesis

Nevertheless, it has been demonstrated in vivo and in vitro, that caloric restriction preserves the mitochondrial biogenesis (see Picca et al., 2013). And it seems to be upstream of ROS production. Which means new mitochondria are less likely to cause oxidative damage to begin with (and also less likely to interfere with stem cell pool). In this regard, the mitochondrial biogenesis is under the control of protein called PGC1-alpha. This protein is downstream of sirtuins and AMPK. If you recall from previous episode then sirtuin activation protected against DNA damage. Looks like sirtuins are doing more than just helping with DNA damage. So what if we could activate srtuins and AMPK by other methods?

How about exercise and red wine?

**Does resveratol affect mitochondrial function and oxidative stress? **
Image by MaxPixel | CC0

Exercise is another method that is known to stimulate mitochondrial biogenesis via activation of sirtuins and AMPK. Exercise along with CR is known for its lifespan extension effects. But what about reseveratol (that thing in red wine)? Activation of Sirtuins by Reserveratol is disputed and seem to be an experimental artifact. But nevertheless it does seem that resveratol can activate AMPK and sirtuins by indirect route. Resveratol causes glucagon and catecholamine release in the body. These hormones causes elevated calcium levels in cells which leads to AMPK activation. Then in presence of high NAD+ in cells AMPK leads to activation of SIRT1. The pathway eventually leads to activation of mitochondrial biogenesis by PGC1-alpha. Moreover, resveratol is also acts as antioxidant (see Madreiter-Sokolowski, 2018).

Grabs red wine! But wait, alcohol is toxic having too much of it may be rather counter productive.

Another way to induce mitochondrial biogenesis is by omega-3 fatty acids. It does so by activating a protein called NRF2 and extends lifespan of worms (see Qi et al., 2017). NRF1 and 2 are downstream of PGC1a (see Austin and St-Pierre, 2012. This is inline with human study where omega 3 fatty acids reduced oxidative stress (Laila et al., 2017).

So, maybe some fish, wine, green leafy veggies and exercise then? Sounds like a plan, eh! Worth a shot, at least?

The wonder of metformin

Ok, I am not gonna bug you a lot. I have a lot to say, but maybe we can stop with discussion of effect of insulin pathway on mitochondria for today. Well one of the pathway involved in lifespan extension by caloric restriction is - insulin/insulin like growth factor pathway. In fact giving exogenous insulin during caloric restriction can reverse the good things that happen to mitochondria (Lambert et al., 2004). And then having diet rich in sugar, esp those super sugar syrups we have as sodas, decreases lifespan. We can actually have a separate episode on sugar, insulin and ageing some other time. However, what is interesting to be noted that the well known diabetic drug - metformin also acts an anti-ageing drug, in animal models and in humans (Valencia et al., 2017). It turns out that among other things metformin activates AMPK and also inhibit mTOR pathway (another pathway we discussed in lifespan extension that we discussed in previous episode).

Closing remarks

Well, I think this should be enough for today. I have not gotten into details of mitochondrial fission and fusion dynamics in ageing. In case you are interested, look that up. I know that this episode was supposed to be about immuno-metabolism. But, then I thought it would be unjust to jump to immune cells without talking a bit about metabolism. So in next chapter, we will talk about role of inflammation in ageing and we may revisit bit of metabolism, yet again. In the meantime we can discuss this topic further in comments.

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References

1. The quest for elixir of life - understanding caloric restriction (episode 1 - DNA damage and repair)

2. Kuka S, Tatarkova Z, Racay P, Lehotsky J, Dobrota D, Kaplan P. Effect of aging on formation of reactive oxygen species by mitochondria of rat heart. Gen Physiol Biophys. 2013 Sep;32(3):415-20. doi: 10.4149/gpb_2013049. Epub 2013 Jul 2. PubMed
   PMID: 23817642.

3. Zhang B, Bailey WM, McVicar AL, Gensel JC. Age increases reactive oxygen species production in macrophages and potentiates oxidative damage after spinal cord injury. Neurobiol Aging. 2016;47:157–167. doi:10.1016/j.neurobiolaging.2016.07.029

4. Gladyshev VN. The free radical theory of aging is dead. Long live the damage theory!. Antioxid Redox Signal. 2014;20(4):727–731. doi:10.1089/ars.2013.5228

5. Seo et al., 2010. New insights into the role of mitochondria in aging: mitochondrial dynamics and more

6. Zhang et al., 2018. The role of mitochondria in stem cell fate and aging

7. 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

8. Sadowska-Bartosz I, Bartosz G. Effect of antioxidants supplementation on aging and longevity. Biomed Res Int. 2014;2014:404680. doi:10.1155/2014/404680

9. Harri Hemilä, Jaakko Kaprio, Vitamin E may affect the life expectancy of men, depending on dietary vitamin C intake and smoking, Age and Ageing, Volume 40, Issue 2, March 2011, Pages 215–220

10. Picca A, Pesce V, Fracasso F, Joseph AM, Leeuwenburgh C, et al. (2013) Aging and Calorie Restriction Oppositely Affect Mitochondrial Biogenesis through TFAM Binding at Both Origins of Mitochondrial DNA Replication in Rat Liver. PLOS ONE

11. Madreiter-Sokolowski CT, Sokolowski AA, Waldeck-Weiermair M, Malli R, Graier WF. Targeting Mitochondria to Counteract Age-Related Cellular Dysfunction. Genes (Basel). 2018;9(3):165. Published 2018 Mar 16. doi:10.3390/genes9030165

12. Qi W, Gutierrez GE, Gao X, et al. The ω-3 fatty acid α-linolenic acid extends Caenorhabditis elegans lifespan via NHR-49/PPARα and oxidation to oxylipins. Aging Cell. 2017;16(5):1125–1135. doi:10.1111/acel.12651

13. Austin S, St-Pierre J. PGC1α and mitochondrial metabolism--emerging concepts and relevance in ageing and neurodegenerative disorders. J Cell Sci. 2012 Nov 1;125(Pt 21):4963-71. doi: 10.1242/jcs.113662. Review. PubMed PMID: 23277535.

14. Lalia AZ, Dasari S, Robinson MM, et al. Influence of omega-3 fatty acids on skeletal muscle protein metabolism and mitochondrial bioenergetics in older adults. Aging (Albany NY). 2017;9(4):1096–1129. doi:10.18632/aging.101210

15. Lambert et al., 2004. Exogenous insulin can reverse the effects of caloric restriction on mitochondria.

16. Valencia WM, Palacio A, Tamariz L, Florez H. Metformin and ageing: improving ageing outcomes beyond glycaemic control. Diabetologia. 2017 Sep;60(9):1630-1638. doi: 10.1007/s00125-017-4349-5. Epub 2017 Aug 2. Review. PubMed PMID: 28770328;
    PubMed Central PMCID: PMC5709209.

Signing off
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