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Dean Pomerleau

ALS, Exercise and Genetics

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ALS (otherwise known as motor neuron disease or Lou Gehrig's disease) is a very scary condition of some nagging concern for CR folks, since CR pioneer Roy Walford died of complications of ALS at age 79.

So this new study [1] (popular press article) linking intense exercise to increased risk of ALS  caught my eye. First they looked at 125K people in the UK with ALS and 250K people without.

They found that 'frequently' engaging in 'strenuous sports' (more than twice per week for 15-30min or more) was associated with an increased risk of ALS. From the full text:

Movement alone [e.g. walking or other low-intensity physical activity - DP] was not significantly associated with ALS, which is consistent with our hypothesis that ALS is linked to strenuous exercise... Overall, our data are consistent with the hypothesis that risk of ALS is linked to frequent and intense leisure-time physical activity.

Interestingly, being sedentary was not protective against ALS:

We argued that if strenuous exercise is a risk factor for ALS, then sedentary behaviour may be protective. However, our MR study does not support this conclusion. Sedentary behaviour is not significantly related to ALS.

They then looked at the exercise history of a few dozen people with ALS and found that among people with a particular genetic mutation (in gene C9ORF72) that predisposes someone to ALS, increased physical activity was associated with an earlier onset of ALS. Here is graph of ALS age of onset vs. history of high, medium or low amounts of physical activity (PA) in people with the genetic mutation:

Screenshot_20210612-133044_Chrome.jpg

 

In other words, more physical activity correlated with earlier ALS onset in people with the mutation.

From the discussion section:

Exercise is not one homogeneous exposure; in reality different types of exercise can impact different biological pathways and even different subtypes of motor neurons. Early in the disease process ALS is known to selectively affect motor neurons supplying type IIb fast twitch muscle fibres important for high intensity anaerobic exercise [16,17]. Consistent with this, our MR study does not support a causal role for low-intensity, infrequent exercise, but does support toxicity resulting from high-intensity, frequent, leisure-time exercise. 

From the conclusion:

The key objective for future research is to understand which individuals are at risk of developing ALS if they exercise excessively and provide appropriate lifestyle counselling. Our work goes some way towards developing this aim and in particular, we propose that C9ORF72 penetrance may be influenced by high levels of physical activity.

Translating that last highlighted sentence, they are suggesting that people who have the C90RF72 mutation that predisposes them to ALS may go on to develop ALS and/or develop it earlier if they frequently engage in strenuous exercise. 

Since I exercise alot (albeit not very strenuously, mostly walking), I was quite interested to learn my C90RF72 status. Fortunately 23andMe has two SNPs for it - rs3849942 and rs2814707. For 23andMe customers, you can check your status for these two SNPs here and here.

I was relieved to learn I'm CC for both SNPs (equivalent to GG in the SNP database), which means I have the 'normal' non-risky variant of the C90RF72 gene.

--Dean

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[1] EBioMedicine, Volume 68, 2021, 103397, ISSN 2352-3964,
https://doi.org/10.1016/j.ebiom.2021.103397.
Free full text: https://www.sciencedirect.com/science/article/pii/S2352396421001900

Physical exercise is a risk factor for amyotrophic lateral sclerosis: Convergent evidence from Mendelian randomisation, transcriptomics and risk genotypes,

Thomas H Julian, Nicholas Glascow, A Dylan Fisher Barry, Tobias Moll, Calum Harvey, Yann C Klimentidis, Michelle Newell, Sai Zhang, Michael P Snyder, Johnathan Cooper-Knock, Pamela J Shaw,

Abstract: Background
Amyotrophic lateral sclerosis (ALS) is a universally fatal neurodegenerative disease. ALS is determined by gene-environment interactions and improved understanding of these interactions may lead to effective personalised medicine. The role of physical exercise in the development of ALS is currently controversial.
Methods
First, we dissected the exercise-ALS relationship in a series of two-sample Mendelian randomisation (MR) experiments. Next we tested for enrichment of ALS genetic risk within exercise-associated transcriptome changes. Finally, we applied a validated physical activity questionnaire in a small cohort of genetically selected ALS patients.
Findings
We present MR evidence supporting a causal relationship between genetic liability to frequent and strenuous leisure-time exercise and ALS using a liberal instrument (multiplicative random effects IVW, p=0.01). Transcriptomic analysis revealed that genes with altered expression in response to acute exercise are enriched with known ALS risk genes (permutation test, p=0.013) including C9ORF72, and with ALS-associated rare variants of uncertain significance. Questionnaire evidence revealed that age of onset is inversely proportional to historical physical activity for C9ORF72-ALS (Cox proportional hazards model, Wald test p=0.007, likelihood ratio test p=0.01, concordance=74%) but not for non-C9ORF72-ALS. Variability in average physical activity was lower in C9ORF72-ALS compared to both non-C9ORF72-ALS (F-test, p=0.002) and neurologically normal controls (F-test, p=0.049) which is consistent with a homogeneous effect of physical activity in all C9ORF72-ALS patients.
Interpretation
Our MR approach suggests a positive causal relationship between ALS and physical exercise. Exercise is likely to cause motor neuron injury only in patients with a risk-genotype. Consistent with this we have shown that ALS risk genes are activated in response to exercise. In particular, we propose that G4C2-repeat expansion of C9ORF72 predisposes to exercise-induced ALS.
Funding
We acknowledge support from the Wellcome Trust (JCK, 216596/Z/19/Z), NIHR (PJS, NF-SI-0617-10077; IS-BRC-1215-20017) and NIH (MPS, CEGS 5P50HG00773504, 1P50HL083800, 1R01HL101388, 1R01-HL122939, S10OD025212, P30DK116074, and UM1HG009442).
Keywords: Amyotrophic lateral sclerosis; Mendelian randomisation; Physical exercise; C9ORF72

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Interesting. But even for the carriers, the chances are rather remote, exercise or not.

I've had myself sequenced almost 15 years ago (Nebula Genomics' complete 30x was my third time) and if I trust every study, I would live longer than 100, but should be obese, with high blood pressure, and suffer from a host of other diseases, including lactose intolerance and Cron's.

I've learned to pay attention only to stuff that really pops out in terms of significance and has plenty of support. Most of it is noise, but I am glad that so many are working hard to advance the science.

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