ageing

What has my age got to do with having MS?

Barts-MS rose-tinted-odometer: ★★★ (some readers have asked for this feature to stay)

How old are you? It depends. You may be aware that there can be a disconnect between your chronological or actual age and your biological age. As ageing or senescence is a biological process driven by metabolic, genomic and environmental factors you can see how there can be a disconnect between the two. As a result, many of us in medicine are beginning to think about unhealthy or accelerated ageing as a disease process. Making ageing a disease will create incentives for pharmaceutical and nutraceutical companies to invest in ageing R&D with the hope of producing medications or dietary supplements to slow-down or reverse the effects of ageing.

Ageing is important in MS as there is emerging evidence that MS causes premature ageing of the CNS (central nervous system), which means that pwMS are more likely to experience age-related neurodegeneration sooner than they have to and this almost certainly contributes to delayed disability worsening in pwMS.

It is clear that ageing impacts one’s ability to recover from CNS damage. It has been known for some time from clinical and animal studies that remyelination and neuronal plasticity are less efficient as you get older, which is why older pwMS recover from relapses less well than younger people. The animal studies below show that there is real biology behind these observations. Oligodendrocyte (myelin-producing) progenitor cells (OPCs) isolated from the brains of neonate, young and aged female rats show an approximately 50% difference in the levels of proteins they make. Differences were noted in both myelin-associated proteins and proteins that control several metabolic pathways. This study has clinical implications and can act as a read-out for finding drugs that could be used as anti-ageing agents.

There are several interesting biological targets and drugs that already exist for targeting ageing. Metformin, a drug for treating diabetes, is one of the lead compounds going in an MS clinical trial at the moment. It is believed that its antiageing effects of performing are mediated via the so-called NRF2 or programmed cell survival pathway. Interestingly, fumarates (e.g. dimethyl fumarate) and ketogenesis also activate this pathway. Could DMF, and the other fumarates, be the panacea antiageing drug we need for tackling progressive or more advanced MS? Yes, I think so but to convince Biogen to follow the money is proving more difficult than we anticipated. We approached them recently to do a combination DMF-plus trial with another class of drug to augment DMF’s response and they said no. Pity because I think they are missing a trick and an opportunity to create new intellectual property.

Physiological ketosis from caloric restriction, intermittent fasting or low-carbohydrate diets is another way of activating the NRF2 pathway. The biology behind this is probably via β-hydroxybutyrate, a ketone body, which works via the hydroxycarboxylic acid receptor 2 (HCA2). Interestingly, this is the same receptor DMF activates.

Other anti-ageing treatments and strategies include exercise and avoiding getting comorbidities, which accelerate ageing, in particular, the metabolic syndrome (obesity, hypertension, glucose intolerance or diabetes) and smoking. The driver of the metabolic syndrome seems to be hyperinsulinaemia and the diets referred to above are all very effective in suppressing or reducing circulating insulin levels.

So in 2021 if you have MS you need to think seriously about what you can do to tackle early and accelerated ageing. Most of the things you can do now involve lifestyle changes, which are often hard to implement. My advice would be to implement the changes slowly and you may find over time that the behavioural changes you make will stick. There is a lot of evidence for this from the field of behavioural psychology.

The above advice is part of the holistic approach to the management of MS I have been pushing for several years and my adoption of the ‘marginal gains philosophy’ for managing MS.

“If we break down everything we can think of that goes into improving MS outcomes, and then improving each by 1%, we will get a large improvement in MS outcome when we put them all together.”

“Ask not what your neurologist and HCP can do for you, but what you can do yourself to optimise your own MS management and long-term MS outcome.”

de la Fuente et al. Changes in the Oligodendrocyte Progenitor Cell Proteome with Ageing. Mol Cell Proteomics. 2020 Aug;19(8):1281-1302.

Following central nervous system (CNS) demyelination, adult oligodendrocyte progenitor cells (OPCs) can differentiate into new myelin-forming oligodendrocytes in a regenerative process called remyelination. Although remyelination is very efficient in young adults, its efficiency declines progressively with ageing. Here we performed proteomic analysis of OPCs freshly isolated from the brains of neonate, young and aged female rats. Approximately 50% of the proteins are expressed at different levels in OPCs from neonates compared with their adult counterparts. The amount of myelin-associated proteins, and proteins associated with oxidative phosphorylation, inflammatory responses and actin cytoskeletal organization increased with age, whereas cholesterol-biosynthesis, transcription factors and cell cycle proteins decreased. Our experiments provide the first ageing OPC proteome, revealing the distinct features of OPCs at different ages. These studies provide new insights into why remyelination efficiency declines with ageing and potential roles for aged OPCs in other neurodegenerative diseases.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

Barts-MS rose-tinted-odometer ★★★

I belong to an international group that addresses important issues in multiple sclerosis that arise between HCPs and pwMS. For 2020 I have suggested we tackle the issue of ageing in MS. I have been asked why I think ageing an important topic in MS. I have put forward the following list of issues that have come to mind. Can you help me with suggestions or specific age-related issues I may have left off the list? Thanks.

As the MS population gets larger we are seeing more people with MS becoming old. This raises several important issues around their management.

Most clinical trials exclude older people with MS. Can we be sure that DMTs have the same risk-benefit ratio in the older MS population as the younger population?
Comorbidities are commoner in the older population. How do these affect the safety profile of DMTs? For example, the recent vascular complications seen with alemtuzumab were much commoner in patients with vascular comorbidity, who tended to older. Another example is PML; there is little doubt that age is a risk factor for developing PML.
Non-specific white matter lesions or vascular lesions are common as you get older. How are we the MS community going to deal with these when we are so dependent on MRI as a monitoring tool for the effectiveness of DMTs. How do we differentiate between new MS lesions and new vascular lesions? Will the central vein sign be sufficient for this?
Brain volume loss (BVL) accelerates with ageing. Does this also happen in MS? As we start to use annual brain volume loss as a treatment target in MS should we not be age-adjusting for what is considered normal BVL?
Neurological function and cognition fall off with age. How do we know that it is ageing or MS that is causing the loss of neurological function?
Because MS reduces brain and cognitive reserve are pwMS more likely to get other neurodegenerative diseases and at an early age?
As you get older your immune systems don’t function well. This is called immunosenescence. How does this impact on the safety of immunosuppressive DMTs?
Ageism is a problem in medicine; how do we prevent it from affecting how we manage older people with MS?
DMTs become less effective as you get older. How can we be sure they are working in the older MS population?
How do you stop DMTs in the older MS patient who is stable?
Are their DMTs that are safer in the older population? Are their DMTs with greater risk in the older population? For example, I am sure anti-CD20 therapies and other continuous immunosuppressive therapies will have a worse risk profile in the older MS population, compared to, for example, cladribine that only causes short-term immunosuppression.
Does MS cause premature ageing, i.e. premature biological ageing?
Lifestyle and wellness programmes for helping to manage MS tend to be for younger people. How can we adapt these for the older MS population?
We are seeing an increasing number of people presenting with syndrome compatible with demyelination in their fifties and sixties. How do the McDonald diagnostic criteria perform in this age-group? Do we need to modify our diagnostic criteria for the older population?
Most of the information resources for pwMS is designed for younger people. Are the information resources appropriate for the older MS population? Do we need age-adjusted information resources? Do you think the current educational resources for the ageing MS population are adequate?
How does ageing affect MS? Is premature ageing a driver of delayed worsening in MS?
What can I do to prevent age-related neurodegeneration making MS worse?
Do the anti-ageing interventions that work in the general population work in pwMS?
What about advanced directives or living wills? Are these more important for the older MS population?
Social isolation becomes more pronounced with ageing and increasing disability. Should there be age-specific social prescribing programmes?
Sexual function is a problem in MS but is often ignored in the elderly. Should sexual function and other symptomatic problems be looked at in the older MS population to define the problem in this population group?

CoI: multiple

Premature Ageing

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

What has getting old got to do with MS?

The brain and spinal cord were not necessarily designed by evolution to last longer than approximately 35 years. It is only relatively recently that as a species we have extended our lifespans. Once you go beyond approximately 35 years of age there is a gradual loss of nerve cells, axons and synapses. This explains why as we get older we notice the effects of ageing; reduced vision, loss of hearing, poor balance and, sadly, age-related cognitive impairment. In short, life after 20 or 30 years is an age-dependent neurodegenerative disease, which is sexually transmitted.

If we live long enough we will all develop cognitive impairment. What protects us from age-related changes is so-called brain reserve, i.e. the size of the brain and spinal cord, and cognitive reserve, which relates to education level and environmental enrichment. We know that MS reduces both brain and cognitive reserve and as a result MSers have reduced reserve and hence the buffer that protects them from the impact of ageing. In other words MSers age earlier.

Another downside of ageing is that repair mechanisms also start to fail. In the paper below neural progenitor cells (NPCs) from MSers with progressive MS have been found to express cellular ageing markers when compared with age-matched controls, implying that cellular ageing or senescence is an active process in progressive MS and contributes to limited remyelination and recovery.

I suspect one of the reasons why the effectiveness of DMTs fall-off with age is that some of the treatment effects are due to the recovery of function when you switch off inflammation. The less recovery of function the less the will be the relative effectiveness of the particular DMT being studied.

Can you do anything about premature or early ageing? Yes, you can. We know from studies in the general population there are many things that MSers can do to maximise brain and cognitive reserve. This is called Brain Health and involves lifestyle factors such as exercise, diet, sleep and avoiding smoking and excessive alcohol consumption. It is also important to screen pwMS for comorbidities or other diseases and have them treated; these include smoking, hypertension, diabetes, obesity and abnormal lipids. As for diet, there have not been any that have been studied extensively enough in MS. However, data from animal models and other fields indicate that calorie restricted, intermittent fasting and ketogenic diets have the most promise with regard to brain health. However, I need more evidence of their beneficial effects before promoting these diets as an adjunctive treatment for MS.

For those of you are interested dimethyl fumarate (DMF) triggers some of the anti-ageing pathways linked to these diets. Therefore, DMF may be working in MS as an anti-ageing drug already. The question I have is does enough DMF get into the CNS to have an effect on the end organ or is its potential anti-ageing mechanisms limited to the systemic compartment?

Please note that ageing is a biological process and as we decode the molecular programmes that cause ageing we may be able to develop treatments that reverse or slow down ageing. An example of this is metformin, a drug for treating diabetes that has recently been shown by Robin Franklin in Cambridge to reprogramme oligodendrocyte precursors in older animals to behave as if they were young cells and become more efficient at remyelinating axons. I, therefore, envisage a future in which we use anti-ageing drugs as add-on therapy to treat MS.

Nicaise et al. Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis. Proc Natl Acad Sci U S A. 2019 Apr 30;116(18):9030-9039.

Cellular senescence is a form of adaptive cellular physiology associated with aging. Cellular senescence causes a proinflammatory cellular phenotype that impairs tissue regeneration, has been linked to stress, and is implicated in several human neurodegenerative diseases. We had previously determined that neural progenitor cells (NPCs) derived from induced pluripotent stem cell (iPSC) lines from patients with primary progressive multiple sclerosis (PPMS) failed to promote oligodendrocyte progenitor cell (OPC) maturation, whereas NPCs from age-matched control cell lines did so efficiently. Herein, we report that expression of hallmarks of cellular senescence were identified in SOX2+ progenitor cells within white matter lesions of human progressive MS (PMS) autopsy brain tissues and iPS-derived NPCs from patients with PPMS. Expression of cellular senescence genes in PPMS NPCs was found to be reversible by treatment with rapamycin, which then enhanced PPMS NPC support for oligodendrocyte (OL) differentiation. A proteomic analysis of the PPMS NPC secretome identified high-mobility group box-1 (HMGB1), which was found to be a senescence-associated inhibitor of OL differentiation. Transcriptome analysis of OPCs revealed that senescent NPCs induced expression of epigenetic regulators mediated by extracellular HMGB1. Lastly, we determined that progenitor cells are a source of elevated HMGB1 in human white matter lesions. Based on these data, we conclude that cellular senescence contributes to altered progenitor cell functions in demyelinated lesions in MS. Moreover, these data implicate cellular aging and senescence as a process that contributes to remyelination failure in PMS, which may impact how this disease is modeled and inform development of future myelin regeneration strategies.

The new black death is ageing

I say to many of patients one of the most powerful predictors of progressive, or more correctly worsening, MS is ageing. Age also predicts recovery of function; the younger you are the better you do. This study shows that ageing restricts the ability of stem cells to make oligodendrocytes to promote remyelination.

As you are aware age also predicts response, or lack or response, to DMTs. The older you are the less effective DMTs are. The list linked to ageing and poor prognosis goes on ….

I have always said ‘life is a sexually transmitted neurodegenerative disease with a 100% mortality’. This usually gets a mutated laugh until people start pondering the joke and its implications and then gradually realise that I am being serious.

Evolution never designed, and selected, the human brain and nervous system to function much past the age of 35. It is only relatively recently that life expectancy has increased dramatically with the requirement of our brains to function into ‘old age’. It is clear that when we measure cognitive function, and brain volume, it is all downhill from about 35 years of age.

Those of us who are older than 35 notice the subtle cognitive impairments that increase with age and the gradual malfunction and deterioration in our nervous systems. When last have you tried tight-rope walking? Your failing balance system is simply a reflection of the global rot that is also shredding your cognition. Fortunately, we have enough reserve to adapt and cope with the slow decline in our mental faculties. However, if we live long enough we are all likely to become demented. Dementia in this setting is simply the reduction of cognition to a point when you can’t manage socially and occupationally. To prevent the inevitable consequence of ageing is there anything we can do to optimise our brain health so our ‘brains outlive’ our ‘bodies’?

There is a lot we can do to improve brain health. However, some of the interventions may require the administration of medications in the future. For the anti-ageing revolution to happen, and be adopted by society, we need to make ageing a disease.

By defining ageing as a disease it changes everything. Firstly, it creates incentives for the pharmaceutical industry to invest in the necessary R&D to get drugs to market. If ageing is a disease healthcare providers will pay for interventions. The corollary is that if ageing is not defined as a disease, any interventions to delay or modify ageing, will be limited to lifestyle interventions. By defining ageing as a disease it will allow us to develop tools for population screening to identify people who are either healthy or in the presymptomatic phase of known neurodegenerative disease. This will then allow us to test preventive strategies to delay the onset of symptomatic disease.

If on the other hand, you have MS we already know you have a neurodegenerative disease that shreds reserve capacity and brings forward ageing mechanisms, which is why we need to manage MS as early and as effectively as possible and holistically. This is why the new treatment target is ‘to maximise brain health for the lifetime of the person with MS’.

Please be aware that ageing is a biological process and hence we can target the biology with both lifestyle interventions and drugs. For example, recent evidence suggests metformin, a diabetes drug, may reverse some of the ageing programmes. Dimethyl fumarate (DMF), a licensed MS DMT, seems to activate antiageing pathways that overlap with pathways linked to specific dietary interventions, i.e. calorie-restricted, intermittent fasting and ketogenic diets. Should all MSers be on metformin and/or DMF and/or one of these diets? We need trials to test these hypotheses. But at least there are investigators exploring the questions.

Please let me know if you find the anti-ageing hypothesis of MS compelling; it overlaps with diet, sleep, exercise and many other things that I can discuss in future blog posts.

Rivera et al. Aging restricts the ability of mesenchymal stem cells to promote the generation of oligodendrocytes during remyelination. Glia. 2019 Apr 30. doi: 10.1002/glia.23624.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that leads to severe neurological deficits. Due to their immunomodulatory and neuroprotective activities and their ability to promote the generation of oligodendrocytes, mesenchymal stem cells (MSCs) are currently being developed for autologous cell therapy in MS. As aging reduces the regenerative capacity of all tissues, it is of relevance to investigate whether MSCs retain their pro-oligodendrogenic activity with increasing age. We demonstrate that MSCs derived from aged rats have a reduced capacity to induce oligodendrocyte differentiation of adult CNS stem/progenitor cells. Aging also abolished the ability of MSCs to enhance the generation of myelin-like sheaths in demyelinated cerebellar slice cultures. Finally, in a rat model for CNS demyelination, aging suppressed the capability of systemically transplanted MSCs to boost oligodendrocyte progenitor cell (OPC) differentiation during remyelination. Thus, aging restricts the ability of MSCs to support the generation of oligodendrocytes and consequently inhibits their capacity to enhance the generation of myelin-like sheaths. These findings may impact on the design of therapies using autologous MSCs in older MS patients.

CoI: multiple

Old age; how is it going to affect me?

Is ageing a disease? It is if you have MS.

We have been making the argument for moving our treatment target in MS to focus on old age; i.e. how do we your HCPs get you to old age with enough brain to deal with the ravages of age-related cognitive impairment?

It is clear that your brain and cognitive reserves are what protects you from the ‘normal age-related neuronal drop-out’, which occurs as part of normal life. We know that MS shreds both brain (size) and cognitive (synapses) reserve and hence it should bring forward age-related cognitive impairment in MSers. The latter was a hypothesis, but the study below shows it is not necessarily a hypothesis anymore. In summary, older MSers are more likely to be cognitively impaired (77%) compared to younger MSers (43%). The challenge is to prevent this. How? Early effective treatment to stop the shredder and to make sure we tackle smouldering MS.

Do you need any more evidence? Please ask your neurologist if you have NEDA is there any evidence of smouldering MS? He/She may want to know what smouldering MS is. You can then tell them it is what is happening at the bottom of the treatment pyramid that is out of sight of our routine monitoring. This is the reason why you need to self-monitor and if you are getting worse you need to ask what can be done about it.

Branco et al. Aging with multiple sclerosis: prevalence and profile of cognitive impairment. Neurol Sci. 2019 Apr 23. doi: 10.1007/s10072-019-03875-7.

BACKGROUND: The increase in life expectancy of patients with multiple sclerosis (MS) requires a better knowledge of disease features in the older patients group.

OBJECTIVE: To describe the prevalence and profile of cognitive impairment (CI) in older patients with MS and perform a comparison with younger patients.

METHODS: Patients were consecutively recruited for 6 months. Cognitive performance was assessed through the Brief Repeatable Battery and the Stroop Test. CI was defined as impairment in ≥ 2 cognitive domains.

RESULTS: We identified 111 patients older than 55 years (mean age 59.7 years). The prevalence of CI was 77.4%, which was significantly higher than in younger patients (42.8%; p < 0.01). Information processing speed was the most impaired domain (68.8%), followed by verbal learning (49.5%), executive function (47.7%), and visuospatial learning (26.6%). We found no significant differences in the prevalence of impairment in the distinct cognitive domains between older and younger patients with CI. Depression and fatigue were not associated with increased CI among patients in the older age group (p > 0.70).

CONCLUSION: There is a remarkably high frequency of CI in older patients with MS. The similar profile of CI between older and younger patients suggests that CI is mostly directly related to MS itself and not to comorbid age-related disorders.

CoI: multiple