Premature Ageing

P

One of my colleagues, with whom I was co-authoring an editorial on smouldering MS, demanded I delete the section on premature ageing being a factor driving delayed worsening of disability in people with MS (pwMS). I refused so we had to pull the editorial. The fact that he is quite old and doesn’t like the hypothesis of brain & cognitive reserve being neuroprotective explains his position. He criticised my theory for being ageist.

I am more convinced than ever that premature ageing is a big driver of delayed worsening in MS. 

A few years ago I was asked to see a patient from the North of England who has presented in her early 60’s with SPMS. She had had three spinal cord attacks in her late teens and had been in remission until her late 50’s when she noticed increasing weakness in her weaker leg with foot drop. In the intervening 40 years since her last attack, she had been relapse-free and fully functional apart from mild persistent weakness in her one leg that prevented her from running. 

As part of her work-up, I repeated her MRI of the brain and spinal cord and we performed a lumbar puncture. Her CSF showed local synthesis of oligoclonal IgG bands consistent with her diagnosis of MS and her neurofilament levels were low. Her MRI showed no active or new lesions and apart from some brain and spinal cord atrophy, there was nothing extraordinary about her imaging. When I saw her in outpatients I explained to her that she did not have active MS and that her diagnosis was now non-relapsing or inactive secondary progressive MS; I now refer to this as smouldering MS.

She then volunteered that she didn’t think her worsening was due to MS, but rather ageing. I couldn’t disagree with her and explained that her previous MS attacks had probably reduced the number of axons or nerve fibres in the motor pathway to her leg, which was now ageing as the surviving nerve fibres were gradually dying off she was seeing increasing weakness in the leg. This is called the premature ageing theory of progressive MS. Is there any proof for it? 

We know from other neurological diseases that ageing can cause delayed worsening. The most well know one is post-polio syndrome. This is when people who have had polio notice increasing weakness in previously affected muscles decades later as they start to age. In HIV we see age-related neurodegenerative diseases present decades earlier than one would expect. The theory being that HIV infection of the brain reduces reserve and triggers premature ageing mechanisms. Even with Alzheimer’s disease factors that are associated with reduced brain reserve result in an earlier age of onset of dementia. 

I suspect MS is not and exception and that ageing, or premature ageing, is part of the disease. The problem we have is that disease duration and disability are strongly correlated with ageing. This makes it difficult to unentangle ageing from disease duration. One way to look at this is to use biomarkers of ageing. As you get older the ends of your chromosomes or telomeres get shorter. Telomere length is used as a biomarker of physiological and not chronological ageing. By using telomere length instead of your age we may be able to unpick the impact of ageing on disease worsening. 

In this study below there was a clear gradient in terms of disability and telomere length. Shorter telomere length was associated with disability independent of chronological age, suggesting that biological ageing is contributing to neurological injury in MS. 

The implications of this are enormous and imply that we should be targeting age-related mechanisms as a therapeutic strategy in MS. This is why I also include ageing in my holistic management of MS talks and why focusing on all of those lifestyle issues and comorbidities is so important in MS. Interestingly, I made this a major theme in my talk at ACTRIMS last year when I had to predict what was going to happen in MS in 5 years time (slides below). 

So the time for biohacking (diet) and aggressive lifestyle interventions have arrived in the MS space. The million-dollar question is how to we get the MS community to buy into this as a therapeutic strategy. 

Krysko et al. Telomere Length Is Associated With Disability Progression in Multiple Sclerosis. Ann Neurol, 86 (5), 671-682 Nov 2019. 

Objective: To assess whether biological aging as measured by leukocyte telomere length (LTL) is associated with clinical disability and brain volume loss in multiple sclerosis (MS).

Methods: Adults with MS/clinically isolated syndrome in the University of California, San Francisco EPIC cohort study were included. LTL was measured on DNA samples by quantitative polymerase chain reaction and expressed as telomere to somatic DNA (T/S) ratio. Expanded Disability Status Scale (EDSS) and 3-dimensional T1-weighted brain magnetic resonance imaging were performed at baseline and follow-up. Associations of baseline LTL with cross-sectional and longitudinal outcomes were assessed using simple and mixed effects linear regression models. A subset (n = 46) had LTL measured over time, and we assessed the association of LTL change with EDSS change with mixed effects models.

Results: Included were 356 women and 160 men (mean age = 43 years, median disease duration = 6 years, median EDSS = 1.5 [range = 0-7], mean T/S ratio = 0.97 [standard deviation = 0.18]). In baseline analyses adjusted for age, disease duration, and sex, for every 0.2 lower LTL, EDSS was 0.27 higher (95% confidence interval [CI] = 0.13-0.42, p < 0.001) and brain volume was 7.4mm3 lower (95% CI = 0.10-14.7, p = 0.047). In longitudinal adjusted analyses, those with lower baseline LTL had higher EDSS and lower brain volumes over time. In adjusted analysis of the subset, LTL change was associated with EDSS change over 10 years; for every 0.2 LTL decrease, EDSS was 0.34 higher (95% CI = 0.08-0.61, p = 0.012).

Interpretation: Shorter telomere length was associated with disability independent of chronological age, suggesting that biological aging may contribute to neurological injury in MS. Targeting aging-related mechanisms is a potential therapeutic strategy against MS progression. ANN NEUROL 2019;86:671-682.

CoI: multiple

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

28 comments

  • It was so lovely to meet you yesterday Prof G and your team thank you so much. I feel like I have someone who cares about me and my M//S now. I am so looking forward to the future of my test results and answers to whether there is a medication out there for me. I will also educate myself on here too. I wonder if I have smouldering M/S ? xx

  • Prof G,

    Thanks for your post.

    ‘The implications of this are enormous and imply that we should be targeting age-related mechanisms as a therapeutic strategy in MS”.

    I’m a 55 year old male who was diagnosed with RRMS at 40. Lemtrada in my early 40s shut the active disease down. Like the woman you mention, lesions on the spinal cord affected my right leg. I am on no other MS treatment.

    In terms of my approach to keeping as healthy as possible, I take VIt D supplementation (10000 a day), normal blood pressure, getting near to ideal weight, one comorbidity which is under control, walk dog twice a day, and cycle 2-3 times a week. Is there anything else I can do to reduce the impact of premature ageing? Are there any trials that I should be looking at? At my recent neuro appointment, my neuro, in passing, mentioned a possible metformin trial. Does this look a promising agent for helping reduce the impact of premature ageing (I thought metformin was a possible therapy for remyelination)?

    Regards

  • Aren’t signs of Premature aging a Symptom of Multiple Sclerosis? Is that what you’re saying? Is this a chicken or egg argument? Maybe Aging is the term that also stumped your “old” (tsk, tsk) colleague. As a nurse I worked with people in their 80’s, 90’s, or 100. Some Seemed as old as I expected. Stooped over, creaky, deteriorated, sick, weak. Some were spry and lively, moving without pain, active, memory sharp. Either category, dying or spry, might have completely lost their memory. I keep comparing myself to other 60 somethings. I can’t work anymore, can barely get around a store. Fatigue, weakness. MRI unchanged in 10 +years. Now B/p up, type 2 diabetes, more pain of arthritis. Always obesity which I know Doctors want me to change. Years of smoking. New insomnia. Pain that wears me out. So bad I get nauseated. My theory about the repeated gadolinium injections you might not believe. My Dad lived into his 90’s. He was pretty functional but mentally miserable with his body that wouldn’t die. He didn’t like the confinement of Being in an assisted living facility. Especially after Mom died. He always told Mom, Walk more, you’ll get better. Then he would tell me the same thing. Like my Mom, I couldn’t, I cannot walk more. I do the best I can. As a nurse I walked a lot. Weekends we cut and loaded our firewood, did chores. I was active and still obese. Flat feet so restrictive. Painful arthritis. Fatigue. My friends in their 80’s work their farm, travel, run, Very Active. We are all so unique. Lifestyle changes are so difficult to accomplish. This disease so painful. I will follow your thoughts and consider your advice. I have lost a few pounds, working with my PCP and getting B/P, glucose under control. I walk when I can, Reduced carb intake, especially empty processed sugars. At 61 I feel Old. Am I smoldering? When I have all these spots in my brain and cord, is it any wonder I can think at all? When a fire smolders, sometimes a part starts burning again. It looked almost dead. When you look at our MRI’s are they Really the Same Lesions? Or are they dying embers, sometimes burning under the ashes. You certainly are making me think. I hope your elder colleague doesn’t stay stuck. We should be open to all ideas about MS and comorbitities. Feeling my age this morning.

  • As an 80 year old female with ppms dxd in 2016 I have to agree. At times in my 50s, I felt my legs were not mine, they worked independently of my brain – as it happened and disappeared quickly, I didn’t attach any significance to the events. I am now unable to walk and so use a wheelchair but whereas I used to be able to sit I’m almost as unbalanced sitting as I am standing on a standaid. I used to walk 3 miles a day from my 50s until balance issues precluded it in my 70s. To sum up I feel I have prematurely aged compared to contemporaries

  • I don’t get what the fuss is about. Of course ageing causes deterioration in this, that, the other, and eventually, everything. At some point, something fails catastrophically. That’s life. If a person has had elements of their system damaged by disease, of course these bits will not fare so well with time.

    I don’t think telomeres can be lengthened or stretched as such. So all that remains is just to look after the body as best you can and hope for the best. Pointless navel gazing just wastes precious life energy and time.

  • So would this lady,who had nothing new really from late teens to fifties, been have classed as a sucessful patient if she’d been on a DMT/MS treatment?

    So would the DMT/MS treatment have got the credit and been classed as sucessful, or would she have been “ok” for those 30 years anyway?

    • Yes and no. We know that DMTs have an average effect that is superior to placebo or no treatment. However, there will always be a small number of pwMS who do well without treatment. So if this woman had been on a DMT we would have said it was the DMT that had kept the shredder at bay, when in fact it could have simply been her MS in remission.

      • Apologies for the length …. To return to the main thread.

        There is now a wealth of evidence on how to ward off the worst effects of ageing – including physical morbidity and dementia – by adapting ‘healthy’ lifestyles, particularly those that look to preserving brain health. Studies within populations have shown the likely benefits to be 5 years or more of healthy and independent old age. (The benefit is more years of good health than extra years. As you get older you realise this is what is important.) There is not one ‘magic lifestyle bullet’ that produces a cure, just lots of sensible and simple things that tip the odds in your favour. Does this work for smouldering MS? From my experience as a ppmser it has done and the good news is that at any age you can improve how you function – well parts of you anyway!

        However, one of the main challenges of poverty is that it can be very hard to follow such a lifestyle or get access to professional support to achieve it. Is this also the case with those with MS and similar conditions? I think so. If you already have already physical disability, comorbidities, fatigue, stress etc it is not easy to eat and sleep well let alone change to a more active lifestyle.

        For example, at the moment you only get access to rehab once you are disabled. Just as with DMTs that is too late. So I think Prof G is right, but here is my challenge to you. We also have to tip the pyramid with healthy living support and ensure that on diagnosis of MS a coordinated programme of neuro- rehabilitation kicks in from day one with advice and support where needed such as access to physiotherapists. Its a lot cheaper than DMTs and for the majority of us progressives its the only option we have.

  • “One of my colleagues, with whom I was co-authoring an editorial on smouldering MS, demanded I delete the section on premature ageing being a factor driving delayed worsening of disability in people with MS (pwMS). I refused so we had to pull the editorial. The fact that he is quite old and doesn’t like the hypothesis of brain & cognitive reserve being neuroprotective explains his position. He criticised my theory for being ageist.”

    With all do fairness we are only hearing your side of the story

    It would been nice to see the arguments of your colleague

    Assuming that he read the blog i thing he has the right to is opinion

    (in a sea of opinion)

    😉

    Obrigado

    • Re: “With all do (sic) fairness we are only hearing your side of the story”

      Because this is a Barts-MS blog, this person doesn’t work here and he doesn’t do social media. This person thinks our blog is a waste of time and that better use of my time would be writing grants, articles and doing research. Very few neurologists run blogs; in fact, very few neurologists do social media. Maybe he is right? I definitely shouldn’t be wasting time responding to trolls.

      I am not sure if you realise that blogging is our side hustle; we have daytime jobs to do!

      I am beginning to wonder if it is time for us to stop blogging; obviously some people don’t appreciate our efforts.

  • I have RRMS since 1999 and am in Tecfidera. Occasional relapses every couple of years, I try to eat well and exercise by swimming & doing weights, Was feeling optimistic today because I got a reading of my Base Metabolic age as being 30., For a nearby 45 yr old that is not bad.. I hope it helps my prematurely aging brain !

    • We do post your comments, but we are about to stop posting your comments on the grounds that you promote/advertise HSCT and that you are a troll.

      • Appreciate you taking the time to respond

        I think this post was not about hsct (then again i might be wrong)

        What is evident is that you dont like criticism even from your colleagues

        Diferents opinions (in a sea of opinions) makes you uncomfortable so you have the need fight back

        That attitude its dangerous for science evolution and you know it

        If you treat one of your colleague that way right there you are not caring about his or her arguments

        As far as being a troll hsct zealot

        I might have a bias towards one of the most efective treatments out there

        Why ?

        I had hsct and i like the true about the treatment to be told

        Ps: You or any of your staff can block me any time i wont be anonymous

        Coi : I have Ms

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