Why telomeres shorten and restoration strategies in aging

this video is sponsored by longevity technology so hello and welcome to the cheeky science show where in this video we're going to talk all about telomeres and the role that telomeres play in the aging process so we'll begin by looking at what telomeres are so that will be in terms of the molecular underpinnings of telomeres and then we'll look at the implications of telomere shortening at the cellular level and what happens to cells when they have short telomers and then we'll extend this further by looking at the organismal level and some of the mouse models that have been used to investigate this and then we'll look at the current evidence that shows links between telomere shortening and the aging process and then lastly we'll address the question of whether increasing telomere length could be beneficial and look at some of the strategies in which this could be achieved so let's begin with the fundamentals what actually are telomeres well the name derives from greek with telos meaning enz and meros meaning part talking about the end part the end part of what well telomeres refer to the end parts of dna and so dna contains all the genetic information that makes us us and that genetic information is stored within the nucleus of a cell and so dna contains the four different nucleotides adenine guanine thymine and cytosine and our dna contains more than three billion base pairs and the way that this is organized within a cell is in separate linear chromosomes so the important word to take from that for this video is the word linear the dna has a linear structure which means it has ends and so you might think well big deal who cares well there are actually several reasons firstly due to the way in which dna is replicated every time a cell divides it has a so-called end replication problem and this is due to the nature of the polymerases and rna templates that are used to synthesize dna and basically what happens is that one of the strands of dna isn't fully replicated and so it's an end replication problem because each time the dna is replicated a fragment of it gets lost and so this results in progressive chromosomal shortening and so this would be particularly bad if these ends of chromosomes contain genes that are important for the cell to survive but instead what's at the end of dna are these tandem repeats of six nucleotide sequences in humans the sequence is tta ggg and so telomeres just refer to these repetitive sequences found at the end of dna and these sequences are actually wrapped up in a protein complex called sheltering and this sheltering complex is actually really important because it hides the ends of dna out of sight from the dna damage response machinery within a cell that would otherwise recognize the ends of the dna as a double stranded break and try and fuse two ends back together which could end up in some interesting fragments of chromosomes which isn't good and so for these reasons telomeres are often described as being like the shoe caps at the end of your shoelaces like how she caps protects the the laces from unthreading the telomeres help to maintain chromosomal stability so each time i cell divides these telomeres are going to get shorter because of the end replication problem interestingly though work conducted by elizabeth blackburn carol greider and jack shostak discovered the enzyme telomerase that can actually extend telomeres and prevent them from shortening over time and this work led to them being awarded the nobel prize in physiology or medicine in 2009 and so the interesting thing about telomerase is that it's a ribonucleoprotein complex and what that means is that there's a protein component of telomerase and there's also a rna component which explains the ribone nuclei parts and so the protein component that has the enzymatic activity to synthesize these telomeric repeats is known as telomerase refers transcriptase or tarts and then the other important aspect is this rna component which is what mediates the recognition of the complex to the telomeres and that's the rna component known as telomerase rna component tuc so we have tarte and tarc and this makes up telomerase now the reason i went into so much detail was because we'll come back to this later on when we look at strategies of extending telomeres and that's because a majority of cells telomerase isn't expressed and so actually the telomeres shorten over time so this brings us on to looking at the cellular level implications of telomere shortening and how it relates to the aging process the best way to explain this is with the graph i am drawing out now the x-axis represents the number of divisions a cell has undergone whilst the y-axis shows the length of the telomeres as we've discussed the length of telomeres in the absence or minimal telomerase activity will decrease over time since telomeres are important for maintaining chromosome stability and cell function when their length reaches a telomere length limit the cell stops dividing and enters so-called replicative senescence this is a cell state whereby the cell is still active but it's just not dividing and this limits you may have already heard of before is called the hayflick limit after leonard hayflick who noticed that normal human cells stopped dividing after replicating around 50 times cells that break through this limit and keep dividing reach the next stage referred to as crisis by this stage the telomeres have become so short the sheltering complexes collapse dna ends get exposed and get fused together aberrantly and chromosome mayhem and shoes basically now there are two outcomes from this one the cell will die or two the cell can reactivate telomerase and restore telomere lamps or achieve this by alternative mechanisms and continue dividing but now the cell has got mixed up dna and accumulated different mutations so when these cells divide results in uncontrolled growth which can result in tumor genesis so what's this got to do of aging well the accumulation of senescent cells and the risk of developing cancer increase with age moreover the reduced ability of cells to replicate from telomere shortening can reduce regenerative potential and repair of different tissues and so this is where we now come to the organismal level and some mouse studies that support the link between telomere shortening and aging so to study this link mouse models have been made whereby mice lack telomerase activity so either the mice lack the gene encoding tart or tug the protein or rna components of telomerase that i mentioned earlier and in both cases loss of telomerase which causes telomere dysfunction resulted in a shortened life expectancy aged appearance decline in tissue stem cell reserves and reduced capacity to cope with injury and to further prove causality between telomere length from aging the opposite experiments have been done whereby mice lacking telomerase activity have had the activity restored which then was seen to restore telomere length and reversed tissue degeneration including the testes spleen and intestines and so the way that they do this in these mouse models is they have genetically modified mice that have tart expression that can be controlled by the presence of a drug and we also have evidence from human studies as well in particular from patients who have telomere pathies whereby they have mutations in the genes encoding tart and tuck but also other proteins that are involved in regulating the maintenance of telomeres and patients with these conditions are shown to have many different aging phenotypes such as depletion of hematopoietic stem cells which can lead to bone marrow failure immunosenescence of lymphocytes so white blood cells and increased incidence of idiopathic pulmonary fibrosis liver cirrhosis and kidney diseases and so that 2011 nature paper that i recently showed you whereby they restore telomerase activity and hmis that had short telomeres suggest that reactivating telomerase is potentially a promising anti-aging strategy but would increasing telomere length actually be beneficial and how would it potentially be achieved so unsurprisingly given the link between telomere dysfunction and hallmarks of aging there has been much interest in telomerase restoration therapies as potential anti-aging strategies and for treatment of patients with telomeres the obvious approach is to activate tart or turk activity either at the gene expression level or by enhancing the activity of the protein itself for example small molecules have been identified to activate heart including ta-65 also known as cyclostragonal and histone diocese laser inhibitors however the mechanism of action of these compounds seems quite unclear at the moment plus there's quite limited clinical trial data moreover there seems to be interest in hormonal agents such as danazole and 5-alpha dihydrotestosterone but again only very early work has been conducted and so it all seems quite inconclusive at the moment alternative approaches would be to have transient ectopic expression of tart either by using viral factors or modified rna but one of the issues with these approaches is getting widespread tissue exposure and to get them to target stem cells which are the regenerative cells of the body another approach that i think is quite cool is to stabilize tuck so remember that this is the rna component of telomerase and so tuck gets tagged for degradation by protein pap d5 and a study that came out last year identified a small molecule inhibitor of this protein which they showed in a study to extend telomeres of cells and culture as well as showing it to be well tolerated in mice for several months so what are the potential concerns of these strategies well ultimately one concern is that it could potentially drive a cell that has entered crisis and allow it to escape by reactivating telomerase activity and this could therefore increase the cancer risk and this is supported by the fact that telomerase inhibitors are being investigated as anti-cancer strategies so what would an optimal strategy be well given the potential hazard of increasing the telomeres of cancerous cells or cells that are in crisis or making tumor growth more aggressive it would seem that a good strategy would have transient telomerase induction which hopefully would be less likely to fuel cancer grave that could result from having constitutive telomerase expression but in reality our understanding of how telomerase activity is controlled and regulated in a cell and how that balance of over and under activity is controlled is still incomplete and many knowledge gaps still remain for example further understanding the non-canonical functions of the telomerase complex and the interplay between telomere dysfunction and pathological processes such as inflammation fibrotic and degenerative diseases is needed so i think this quote from elizabeth blackburn nicely summarizes the complexity of the fields that aging is so many different things and cells being able to sell from you is part of the picture but not all of it and so there is still ongoing interest in these telomerase reactivation strategies but it's also evident that much more workers needed to further investigate this and to really evaluate the potential risks so hopefully this video has given you some insight into how telomeres fit into the aging process and why understanding their regulation by telomerase may aid potential interventions for aging so with that i'd like to thank the sponsor for this week's video longevity technology longevity technology delivers high quality daily news and insights on research investments and technologies that extend health span and lifespan find the link to their website in the description so i hope you've learned something in this video thank you to my patreon supporters and thank you for listening