The quest for elixir of life - understanding caloric restriction (episode 1 - DNA damage and repair)
The alchemists thought that consuming some special potion will make us live forever. They called it elixir of life. However, knowledge what can increase our lifespan, and slow down the process of ageing is rather surprising. The real deal was to consume less of potions in life, overall. Or less calories to be precise. But, something must happen in our body when we eat less. Some molecules and cell may hop here and there. So, say if we do understand how caloric restriction works, can we make the dream of eternal youth come true?
What is recipe for elixir of life?
Illustrated using following images:
DNA circle by GDJ
Science lab equipment by Clker-Free-Vector-Images
Sacred geometry by TheDigitalArtist
Pixabay license
Background
Lifespan increase in mice by caloric restriction
Graph showing effect of caloric restriction in mice, when given diet with different percentage of caloric restriction 25% - 65%. With X axis showing age of mice in months and Y axis showing percent of mice surviving.
Image by Kuebi (Armin Kübelbeck), based on data from Weindruch et al., 1986.
CC BY-SA 3.0
The anti-ageing and lifespan extension effects of caloric restriction approach has been shown over and over again. It has been shown in multiple species, ranging from yeast to primates (Heilbronn and Ravussin, 2003). Be careful that when I say caloric restriction, I don't really mean starving yourself like crazy. It simply means cutting down your daily caloric intake by some ammount, than what you have been eating, or what is recommended for your body parameters. The idea is not to become malnutritioned, but just to trim those calories a bit. Remember that there is a fine line between caloric restriction and starvation (Szafranski and Mekhail, 2014).
Most et al., 2016 summarises effects of caloric restriction in humans. From, whatever data we have it is clear that caloric restriction, with adequate nutrition improves age related biomarkers in humans, and seem to improve metabolic health status. And, as Heilbronn and Ravussin point it out, this knowledge is nothing new to us. The 1st evidence for this was in fact presented in 1930s. But from scientific point of view the most intriguing question is how? How does trimming those calories, slow down ageing? The answer to this question is interesting not just because of scientific curiosity, but due to possible implications that it has. If we know how, we can just make a drug (I am going to mention a couple in the article), that mimics caloric restriction, without really cutting off calories. We can give life to the dream of ancient alchemists - the dream of a potion they called elixir of life.
How on freaking earth?
There is a constant fight in our body between processes that cause deterioration of tissues, and organs and processes that work hard to keep them intact. But in the long run and especially after reproductive age the deterioration wins. Hence, if caloric restriction works it has to work by either slowing down the deterioration, or by promoting mechanism that keeps us fresh and young.
The curse of DNA damage
DNA damage - source and repair pathways. Infographic showing how different insults to DNA can cause lesions in the genes and mechanisms by which those lesions are repaired
Image by Bernstein0275 | CC BY-SA 3.0
One of the reason why deterioration eventually takes over is because the DNA damage and mutation accumulate in our cells. In fact it is well known that any perturbation of pathways that maintain genome integrity - the DNA repair pathways - lead to premature ageing (Gonzalo et al., 2015). The accelerated ageing phenotype caused by genomic instability is also marked by all the age related diseases - cataract, type 2 diabetes, auto immune diseases, hypertension and cancer (Domínguez-Gerpe et al, 2008).
In this regard it has also been observed that as we age, mutations accumulate in our genes (Lodato et al.,2017, Marticorena et al., 2018). In both genomic DNA and in mitochondrial DNA. Moreover, the chromosomal ends known as telomeres shortens as cell divide. In embryonic stage these DNA ends are efficiently elongated by an enzyme called telomerase. But as we age the activity of this enzyme decreases. Increasing genomic instability further and also hampering ability of our cells to replenish our tissue (Choudhary et al., 2012).
Can caloric restriction slow down mutation accumulation?
Which gets us to our first question does caloric restriction somehow retard the process of DNA damage and mutation accumulation?
In fact caloric restriction was shown to reduce the DNA damage and mutation accumulation in 1990s at least in lab rats (Haley-Zitlin and Richardson, 1993, Raffoul et al., 1999). However, what was not clear how? Why would eating slightly less than normal decrease DNA damage? Is it because it hyper-activates some DNA repair pathways? Or, it retards what causes the damage in first place? Or, both?
Since, DNA damage has been threat to living organisms since dawn of life. They have also evolved ways to deal with it. But ability to repair DNA also decrease with agening. For instance, expression of DNA pol beta, an enzyme involved in base excision repair is reduced with age. If caloric restriction improves performance of DNA repair pathways, then one thing we may expect to see is upregulation of DNA pol beta, downstream of caloric restriction. This is in fact what Cabelof et al., observed in 2003. Then it was shown by Guo et al., 1998, that ability to repair DNA damage caused by UV was lower in old rats. However, it was improved in diet restricted rats. Giving a hint that caloric restriction also enhanced Nucleotide excesion repair pathway. Then, decline of proteins associated with double started break repair, such as Ku70/80, was also shown to be prevented by caloric restriction, at least in some tissues (Um et al., 2003).
So we know that caloric restriction is preventing the age associated decline of DNA repair efficiency. However, that makes one wonder that, how does eating less cause upregulation of DNA repair pathways?
The nutrient sensing systems
mTOR pathway
The mTOR complex is active, when there is signal for enough energy in the environment. However, in lack of energy Rheb-GTP is not activated and neither is mTOR.
Image by Fred the Oyster | CC BY-SA 4.0.
The sensing of low calories and nutrient deficiency happens at two levels. The cell senses amount of nutrients in its environment by insulin/insulin like growth factor pathway and via mTOR pathway. TORC1 has been shown to interact with DNA repair proteins. The fate of another key player in ageing - mitochondria with damaged DNA which we will see later also depend on state of mTOR pathway (Ma et al., 2018). So it may appear that lack of nutrients inhibits mTOR pathway, which then leads to upregulation of DNA repair in our genome and mitochondria.
But, is it just a mere correlation with this pathway or is it essential in regulating ageing? If, our hypothesis is true then the drug rapamycin which inhibits TORC1 should mimic the affects of caloric restriction and also protect against DNA damage. The effect of rapamycin in extending life span has been documented in many species (Vaquero and Rainberg, 2009). Rapamycin, has also been show to reduce the DNA damage accumulation during accelerated ageing (Saha et al., 2014). Well, looks like the pathway is indeed involved in DNA repair and ageing.
The sirtuins
GIF showing sirtuins interacting with histones to regulate gene expression
Image by Gavin Schlissel | CC0 1.0
On the other hand the reduction of nutrients inside the cells causes change in NAD+/NADH and ATP/ADP ratio. This is sensed by NAD+ dependent enzymes. One such class of enzymes are sirtuins - the NAD+ dependent histone deacetylases (Vaquero and Rainberg, 2009). The sirtuins, can interact directly with chromatin. They can deacetylate histones and interact with transcription factors. As a result they tune gene expression levels. SIRT1, SIRT6 and SIRT7 plays an important role in DNA repair. The mice lacking either of these protein making genes shows signs of premature ageing. SIRT6 is involved in base excision repair (Mostolavasky et al., 2006), and in double stranded break repair by activating PRAP1; and act upstream of DNA pol beta (Chalkiadaki and Leonard Guarente, 2015). They also interact with Ku protein to improve double stranded break repair. Sirt1 on the other hand interacts with WRN and NBS1 to promote homology directed repair. Similarly SIRT7 also enhances double stranded break repair.
In this regard resveratol, the famous compound found in red wine, can directly activate sirtuins (Gertz et al., 2012). It has been shown that this drug can mimic affects of caloric restriction, at least partially (Chung et al., 2012). The partial effect is perhaps because it doesn't activate SIRT6. Nevertheless, it does establish a good case for role of Sirtuins in regulating speed of ageing.
Summary
Now, there are other pathways of interest for sure - p38, AMPK etc. But going into detail of each will be too much info for now. Anyhow, what we did see till this point is that caloric restriction slows down ageing by enhancing DNA repair pathways. But if that is the case then why do we still have no potion for eternal youth? Why not pop rapamycin and reseveratol or other sirtuin activators to stay young forever? Perhaps because that's not the only mechanism causing ageing.
For instance, we have not yet talked about affect of caloric restriction on factors that causes DNA damage in first place? What about tissue level damage? That is also a part of ageing. Right?
We will look into that in next episode. We will try to focus on immunometabolism. That is role of metabolism and immune cells in causing cellular and tissue damage and how caloric restriction plays a role in slowing that down. Maybe we need a few more drugs for our potion. Let's see if we can be any better than those alchemists.
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References
Vaquero and Reinberg, 2009. Calorie restriction and the exercise of chromatin
Angeliki Chalkiadaki & Leonard Guarente, 2015. The multifaceted functions of sirtuins in cancer
Signing off
