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Jerry Shay – The Telomere Theory of Ageing – Interview At Undoing Ageing, Berlin, 2019

“When telomeres get really short that could lead to a dna damage signal and cause cells to undergo a phenomenon called ‘replicative senescence’…where cells can secrete things that are not necessarily very good for you..”

Why is it that immune cells don’t work as well in older age?

Listen to the interview here

Jerry and his team compared a homogeneous group of centenarians in northern Italy to 80 year olds and 30 year olds – and tested their immune cells (T-Cells) for function (through RNA sequencing) – what was observed was all the young people clustered apart from most of the old people clustered.. but the centenarians didn’t cluster in any one spot.  It was found that the centenarians clustered along side the younger cohorts had better telomere length.

Out of 7 billion people on earth, there is only about ~ half a million centenarians – most of them are frail – though the ones with longer telomeres and more robust T-Cell physiology seem to be quite different to the frail centenarians.   What usually happens is when telomeres wear down the DNA in the cell gets damaged, triggering a DNA damage response. From this, Jerry and his team made a jump in logic – maybe there are genes (i.e. telomere [telomere expression genes?]) that when the telomeres are long these genes are repressed, and when the telomeres short the genes get activated – circumventing the need for a DNA damage response.  What is interesting is that they found genes that are really close to the telomere genes (cytokines – inflammatory gene responses – TNF Alpha, Ennalucan 1 etc) – are being activated in humans – a process called ‘Telomere Looping’. As we grow and develop our telomeres get longer, and at a certain length they start silencing certain inflammation genes, then as we age some of these genes get activated – this is sometimes referred to as the ‘Telomere Clock’.  Centenarians who are healthy maintain longer telomeres and don’t have these inflammation genes activated.

 

During early fetal development (12-18 weeks) telomerase gets silenced – it’s always been thought that this was to stop early onset of cancer – but Dr Shay asked, ‘why is it that all newborns have about the same length of telomeres?’ – and it’s not just in humans, it’s in other animals like whales, elephants, and many large long-lived mammal – this doesn’t occur in smaller mammals like mice, rats or rabbits.   The concept is that when the telomere is long enough, it loops over and silences its own gene, which stays silent until we are older (and in need of it again to help prevent cancer).

This Telomere Looping probably evolved as part of Antagonistic Pleiotropy – where things that may have a protection or advantage early in life may have unpredicted negative consequences later in life. This is what telomerase is for – we as humans need it in very early development, as do large long-lived mammals, and  a mechanism to shut it off – then at a later older age it can be activated again to fight against cancer.

 

There is a fair amount of evidence for accumulated damage as hallmarks for ageing – can we take a damage repair approach to rejuvenation medicine?

Telomere spectrum disorders or telomeropathies – human diseases of telomere disfunction – diseases like idiopathic pulmonary fibrosis in adults and dyskeratosis congenita in young children who are born with reduced amounts of telomeres and telomerase – they get age related diseases very early in life.  Can they be treated? Perhaps through gene therapy or by transiently elongating their telomeres. But can this be applied for the general population too?  People don’t lose their telomeres at the same rate – we know it’s possible for people to keep their telomeres long for 100 years or more – it’s just not yet known how.  It could be luck, likely it has a lot to do with genetics.

 

Ageing is complex – no one theory is going to explain everything about ageing – the telomere hypothesis of ageing perhaps makes up for about on average 5% or 10% of aging – though understanding it enough might give people an extra 10% of healthy life.   Eventually it will be all about personalised medicine – with genotyping we will be able to say you have about a 50% chance of bone marrow failure when you’re 80 years old – then if so you may be a candidate for bone marrow rejuvenation.

What is possible in the next 10 years?

 

Inflammation is highly central to causing age related disease.  Chronic inflammation can lead to a whole spectrum of diseases. The big difference between the subtle low grade inflammation that we have drugs for – like TNF blockers (like Humira and Enbrel) which subtly reduce inflammation – people can go into remission from many diseases after taking this.

There are about 40 million people on Metformin in the USA – which may help reduce the consequences of ageing – this and other drugs like it are safe drugs – if we can find further safe drugs to reduce inflammation etc this could go a long way – Aspirin perhaps (it’s complicated) – but it doesn’t take much to get a big bang out of a little intervention – the key to all this is safety – we don’t want to do any harm – so metformin and Asprin have been proven to be safe over time – now we need to learn how to repurpose those to specifically address the ageing problem.

 

Historically we have more or less ignored the fundamental problem of ageing and targeted specific diseases – but by the time you are diagnosed, it’s difficult to treat the disease – by the time you have been diagnosed with cancer, it’s likely so far advanced that it’s difficult to stop the eventual outcomes.   The concept of intervening in the ticking clock of ageing is becoming more popular now. If we can intervene early in the process we may be able to mitigate downstream diseases.

Jerry has been working on what they call a ‘Telomerase Mediated Inhibitor’ (see more about telomerase meditation here) – “it shows amazing efficacy in reducing tumor burden and improving immune cell function at the same time – it gets rid of the bad immune cells in the micro environment, and guess what?  the tumors disappear – so I think there’s ways to take advantage of the new knowledge of ageing research and apply it to diseases – but I think it’s going to be a while before we think about prevention.”

Unfortunately in the USA, and really globally “people want to have their problems their lifestyles the way they want them, and when something goes wrong, they want the doctor to come and and give them a pill to fix the problem instead of taking personal responsibility and saying that what we should be doing is preventing it in the first place.”  We all know that prevention is important, though most don’t want to practise prevention over the long haul.

 

The goal of all this not necessarily to live longer, but to live healthier – we now know that the costs associated with intervening with the pathologies associated with ageing is enormous.  Someone said that the 25% of medicare costs in the USA is in treating people that are on dialysis – that’s huge. If we could compress the number of years of end of life morbidities into a smaller window, it would pay for itself over and over again.   So the goal is to increase healthspan and reduce the long period of chronic diseases associated with ageing. We don’t want this to be a selected subgroup who have access to future regenerative medicine – there are many people in the world without resources or access at this time – we hope that will change.

Jerry’s goal is to take some of the discovered bio-markers of both healthy and less healthy older people – and test them out on larger population numbers – though it’s very difficult to get the funding one needs to conduct large population studies.