Why We Age
All organisms age. Some faster and some slower, but eventually all life withers away, with time being its main enemy, so it seems. Up until recently, ageing was believed to occur due to the accumulation of breaks in DNA and/or mutations and due to the shortening of telomeres after every cell division. While the shortening of telomeres may play some role in ageing, many studies have shown, that in some cases telomeres don’t dwindle away with age due to upregulation of telomerase (an enzyme which lengthens telomeres) or that even with increased expression of telomerase in cells and fairly constant telomere lengths, organisms still underwent the process of ageing. As for DNA damage and mutations, assuming these occur at fairly constant rates throughout an organism’s lifetime, one would expect young individuals to have similar health problems (usually associated with ageing) as old individuals, due to DNA damage and lack of its repair, by chance. With these theories showing significant flaws, researchers turned to search for a new way of explaining ageing. With massive recent developments in the field of epigenetics, this was the place to look to find answers. After examining expression of proteins and their activity, researchers came up with a new theory of ageing — one based on the loss of epigenetic, rather than genetic, information over time.
This theory states that multiple proteins, but mainly one group — sirtuins are usually required for the maintenance of chromatin and the epigenome, allowing cells to retain their identity and express correct proteins in the right proportions. Nevertheless, when a break or mutation in DNA happens, sirtuins move to the damage site, where they recruit various DNA-repair proteins and assist the process until the DNA is back to normal, after which they return to their previous positions. Meanwhile, however, with the sirtuins away, chromatin around the sirtuins’ usual location is neglected and begins to show signs of gene misregulation. With no sirtuins to keep the epigenome in check, genes which would normally be silenced begin to become expressed and genes which would normally be expressed begin to become silenced, which leads to a slow loss of the cell’s identity. Moreover, if that wasn’t bad enough, not all sirtuins make it back to their usual location from the site of DNA repair. This usually happens to only a few proteins at any given time, but over time, this starts to accumulate and causes further epigenetic chaos, causing the cell to lose its identity and pushing it towards senescence. Senescent cells are usually cells which have completely lost their identity, but have withdrawn from the cell cycle and hence can no longer divide, leaving them residing in tissues with no real purpose, a sort of ‘zombie cell’, if you will. These cells have no beneficial effect on the organism, but can be harmful as they keep draining the organism’s nutrient supply. Even worse, however, if something goes wrong and these cells keep dividing, it can lead to diseases such as cancer or cause other problems in the organism. This new theory of ageing states that ageing is the process in which cells lose their epigenetic identity through distraction of sirtuin proteins, leading to accumulation of senescent cells, which can cause various age-related disorders.
One may think that if sirtuins leaving their rightful place is the main cause of ageing, why do cells not just make more sirtuins? Well, when sirtuins leave to go to a site of damaged DNA, sirtuin genes are, in fact, suppressed. This may sound counterproductive, but it is thought to be part of an ancient mechanism which arose in primordial cells. This mechanism is thought to have ensured that cells stop dividing while DNA was being repaired. Many genes are thought to have been silenced as part of this mechanism, ensuring the halting of all major intra-cellular processes other than DNA repair, stopping cell division before the damage was repaired, and ensuring daughter cells would have integral genomes.
Delving deeper into the various proteins that play crucial roles in ageing, and may be the answer to stopping or even reversing this process, let’s take a look at sirtuins along with mTORC1 and AMPK.
Sirtuins are a class of protein. There are 7 sirtuin proteins in humans, going from SIRT1 to SIRT7. All sirtuins have been shown to be histone deacetylases (HDACs). Histone acetylation is generally perceived to be an epigenetic modification used to promote gene expression as the acetyl group neutralises the histones’ positive charge and weakens the attraction between histones and DNA, forming heterochromatin (loosely wound DNA, accessible for transcription). From this, one can deduce that sirtuins tend to have a suppressive effect on gene expression as they remove acetyl groups from histones. As I have mentioned previously, sirtuins also play an important role in DNA repair. This is most relevant for SIRT1 and SIRT6. Both proteins have been shown to move to DNA damage sites and recruit DNA repair proteins, with involvement in homologous recombination, with SIRT6 showing additional involvement in non-homologous end joining and base excision repair. Another crucial thing to note about sirtuin proteins is that they require NAD to function.
Looking now at AMPK (AMP-activated protein kinase), it is an important protein which enhances sirtuin activity (in particular SIRT1) by increasing cellular NAD levels. It does this by phosphorylating, and thereby activating, NAMPT (nicotinamide phosphoribosyltransferase) which synthesises NAD. Apart from naturally occurring activation, AMPK is acutely activated by ionising radiation. This allows for rapid NAD production and an increase in sirtuin activity, in the case of DNA damage by ionising radiation.
The remaining protein, mTOR, is a serine/threonine kinase and is usually expressed when excessive amino acids enter the body. mTORC1 (one of the 2 mTOR protein complexes) has been shown to generally promote gene expression. This may not sound like a bad thing, but excess mTOR can lead to over-expression of genes or incorrect transcription and translation of genes, which can lead to severe problems. Moreover, mTOR is known to inhibit autophagy (the pathway in which cells recycle misfolded or old proteins), promoting the expression of protein aggregates and degenerate mitochondria, both of which are signs of age-related disorders.
Bringing all of this together, let’s summarise what happens during a DNA break. When DNA is broken (for example) by ionising radiation, AMPK is activated, phosphorylating NAMPT and promoting NAD synthesis. While the synthesis of NAD occurs, sirtuins move away from their usual position and go to the site of the DNA break to assist with repair. When the sirtuins arrive, they recruit and work in conjunctions with other proteins such as PARP1 (a protein which detects DNA breaks and facilitates a repair pathway) to fix the DNA break, using large amounts of NAD. Meanwhile, at the sirtuins’ usual site of action, chromatin is not properly maintained and epigenetic noise increases, slowly leading the cell to loss of identity. After the DNA break is fixed, sirtuins move back to their original sites of action, but some never make it back, further enhancing the misregulation of genes. Furthermore, when the sirtuins do finally arrive at their original sites, NAD levels are at a low, because so much has been used up for DNA repair, hindering the sirtuins’ normal function and causing further epigenetic disorder. On top of which, other factors such as increased levels of mTOR can wreak additional havoc by preventing autophagy and promoting gene expression where it need not happen. This multitude of molecular problems comes together to steer cells away from their determined identity, towards a state of disorder and senescence, causing ageing on the molecular, and eventually phenotypic scale.
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