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.