'Premature telomere attrition' and chronic fatigue syndrome

I'm always a little cautious these days when I hear any disease/condition/label linked to telomeres. These biological aglets (the plastic tips at the end of shoelaces) are quite wonderful bits of genetic engineering found at the ends of chromosomes, and serve an important protective biological function. The trouble is that, as with various other areas of science, a whole slew of articles has linked [prematurely] shorted telomeres to this, that and t'other and it has subsequently become a bit confusing as to what effects are 'real' and which ones might be more coincidental or spurious...

I cautiously then approach the findings reported by Mangalathu Rajeevan and colleagues [1] and their observations of a "significant association of ME/CFS [myalgic encephalomyelitis/chronic fatigue syndrome] with premature telomere attrition that is largely moderated by female subjects < 45 years old." Given that ME/CFS has already been subject to spurious preliminary findings not-so-long-ago (see here), such associations need to be treated cautiously.

Rajeevan et al started with the hypothesis that "ME/CFS is associated with accelerated aging and that shorter telomeres will serve as a marker of this association." While it is certainly true that ME/CFS produces some debilitating symptoms that are not a million miles away from something like extreme ageing, I've not yet heard too many people talk about the condition(s) in the context of such ageing. That's not to say it might not be a good comparator; just that it's not commonly referenced in this context. The addition of the word 'immunosenescence' by the authors, describing how the immune system gradually wanes with advancing age, is also perhaps pertinent to ME/CFS, bearing in mind what science is starting to discover about immune function in the context of ME/CFS (see here for example) and also what something like physical activity *might* do for immunosenescence (see here). I also cautiously use the word 'burnout' when it comes to the immunological picture emerging for at least some ME/CFS but it could be relevant...

With a total participant group numbering 639 participants (adults, mostly female) including "64 CFS, 77 CFS-X [CFS but with exclusionary conditions], 302 ISF [unexplained chronic illness with insufficient symptoms/fatigue to meet all of the criteria for CFS] (with and without exclusionary conditions), and 196 NF [non-fatigued] without exclusionary conditions", the authors describe relative telomere length (T/S ratio) and other physiological data parameters. Some of the other parameters reported on were "HDL cholesterol (mg/dL), triglycerides (mg/dL), fasting glucose (mg/dL), insulin (µIU/mL), C-reactive protein (CRP, mg/dL), and albumin (g/dL)."

Results: "This study demonstrates a significant association of ME/CFS with premature telomere attrition." I've already mentioned how this finding was "largely moderated by female subjects < 45 years old"; taking into account other data that has observed that in a general population sense, females tend to have longer telomeres when compared with age-matched males. This sex-related general trend was not however observed among the fatigue group participants. The telomere attrition differences reported also survived when other potential confounders were included in the statistical mix. This included: "age, sex, body mass index, waist–hip ratio, post-exertional malaise and education attainment." Ergo, telomere length and attrition probably needs further study with CFS/ME in mind. That might also include some focus on telomerase activity too.

Another result reported on by Rajeevan and colleagues also caught my eye: "mean CRP level in CFS-X and CFS groups being 93% greater than in NF group." CRP denoting levels of C-reactive protein, is a pentraxin that is elevated in response to inflammation. I note that inflammation as characterised by various inflammatory markers has been described in some cases of ME/CFS [2] but surprisingly little seems to have been done with CRP specifically in mind [3]. Maybe the Rajeevan results will also spur on a little more investigation to rectify this issues too.

The authors conclude that their telomere results combined with evidence of inflammation (low-grade inflammation) and "metabolic decline/mitochondrial dysfunction" (see here) "provide multiple levels of support to include ME/CFS to the list of conditions associated with accelerated aging that could be triggered by genetic, epigenetic, infection, stress or other environmental factors." At the current time, and subject to further studies being undertaken, I would struggle to disagree with such a conclusion. The next important question: what can be done about reversing this accelerated/premature ageing?

And while on the topic of biological research starting to take its [rightful] place in the context of ME/CFS, I'll direct you to some observations from someone diagnosed with the condition...

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[1] Rajeevan M. et al. Association of chronic fatigue syndrome with premature telomere attrition. Journal of Translational Medicine. 2018; 16: 44.

[2] Maes M. et al. Evidence for inflammation and activation of cell-mediated immunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): increased interleukin-1, tumor necrosis factor-α, PMN-elastase, lysozyme and neopterin. J Affect Disord. 2012 Feb;136(3):933-9.

[3] Spence VA. et al. Low-grade inflammation and arterial wave reflection in patients with chronic fatigue syndrome. Clin Sci (Lond). 2008 Apr;114(8):561-6.

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High risk for autism = shortened telomeres?

I don't want to spend too long discussing the paper by Charles Nelson and colleagues [1] suggesting that: "Families of children with ASD [autism spectrum disorder] who have an infant show shortened telomeres relative to families with no history of ASD" but it is worth blogging about.

As per a previous entry on telomeres and autism (see here), telomeres - the biological equivalent of plastic aglets on shoelace tips to prevent fraying - are starting to enter the autism [peer-reviewed] research psyche on top of their more traditional role suggested in ageing and cancer for example (see here). Indeed, telomeres and cellular ageing are getting quite a bit of press these days with psychiatry in mind [2] as per the goings-on with schizophrenia in mind [3] and psychotic symptoms [4].

The Nelson study started from the angle that: "Exposure to psychological stress is associated with accelerated telomere shortening, and a well-established body of evidence indicates that families with a child with autism spectrum disorder (ASD) experience heightened levels of psychological stress." They also make mention of the words 'oxidative stress' and 'DNA methylation' as also potentially impacting on telomere length and at the same time having some research 'form' when it comes to autism (see here and see here respectively).

With that all in mind, saliva samples were analysed for family members designated as 'high risk for ASD (HRA)' or 'low risk for ASD (LRA)' as a function of "older siblings' diagnostic status." Relative average telomere length was the chosen variable analysed by a "real-time polymerase chain reaction (PCR) telomere assay."

Results: "HRA families demonstrated significantly shorter telomere length relative to LRA families." This was noted across the board when it came to family members analysed (infants, older siblings parents) although the group data comparing fathers between the groups were not significantly different. The authors conclude that: "such "high-risk" families should be monitored for the physical and mental health consequences that are often associated with accelerated telomere shortening."

This is interesting work (isn't is always?) but I'm going to advise a little caution before anyone goes assuming that telomere length is the be-all-and-end-all of autism research. The inevitable hype that has followed telomere research down the years has done some real damage to the credibility of some of the findings on telomeres in other areas so one treads a little carefully. That telomere length seems also to correlate with quite a few other interesting concepts such as inflammation for example [5] is also of potential interest, particularly when inflammation seems to crop up time and time again with [some] autism in mind (see here). I dare say that future studies of telomere length and autism might want to take quite a wide view of any association including the analysis of telomerase too.

Music: The Charlatans - The Only One I Know.

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[1] Nelson CA. et al. Shortened Telomeres in Families With a Propensity to Autism. J Am Acad Child Adolesc Psychiatry. 2015 Jul;54(7):588-94.

[2] Lindqvist D. et al. Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging. Neurosci Biobehav Rev. 2015 May 18;55:333-364.

[3] Polho GB. et al. Leukocyte telomere length in patients with schizophrenia: A meta-analysis. Schizophr Res. 2015 Jul;165(2-3):195-200.

[4] Pawelczyk T. et al. Telomere length in blood cells is related to the chronicity, severity, and recurrence rate of schizophrenia. Neuropsychiatr Dis Treat. 2015 Jun 22;11:1493-503.

[5] Jurk D. et al. Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nat Commun. 2014 Jun 24;2:4172.

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Nelson CA, Varcin KJ, Coman NK, DeVivo I, & Tager-Flusberg H (2015). Shortened Telomeres in Families With a Propensity to Autism. Journal of the American Academy of Child and Adolescent Psychiatry, 54 (7), 588-94 PMID: 26088664

Significantly shorter leukocyte telomere length in childhood autism

"These results provided the first evidence that shorter leukocytes telomere length is significantly associated with childhood autism." So said the results reported by Zongchang Li and colleagues [1] (open-access) based on quite a well-powered study (for an initial research foray anyway) looking at "110 autism patients (male 98 and female 12) and 129 healthy controls (male 98 and female 31)".

On the behalf of scientists everywhere,
I am ashamed to count you amongst us.

Quite a good introduction to telomeres can be found here and how: "Telomeres have been compared with the plastic tips on shoelaces, because they keep chromosome ends from fraying and sticking to each other, which would destroy or scramble an organism's genetic information." Because I couldn't have said it better myself, I won't try, other than to direct you to some of the other collected research on telomere length being related to all-manner of things including ageing [2], schizophrenia [3] and possibly even social environment [4].

The Li paper is open-access but here are a few pointers:

• Based on the fact that: "increasing evidence has demonstrated that leukocytes telomere length is also associated with increased risk of some psychiatric diseases including schizophrenia, mood disorders and anxiety disorders" authors set about looking at leukocytes telomere length (LTL) in cases of paediatric autism compared with aged-matched asymptomatic controls. Clinical assessment of autism by the way, was based on DSM-IV criteria as well as assessment "using the childhood autism rating scale (CARS) and autism behavior checklist (ABC)."
• Real-time PCR was the analytical weapon of choice for looking at relative telomere length (RTL) - "a modified version of the quantitative real-time PCR method originally described by Cawthon" [5] apparently - though I hasten to add, that I'm no expert on the ins-and-outs of this technique.
• Results: "there was a significantly shorter leukocyte telomere length in patients with childhood autism" compared with controls. Taking it another way: "When participants were divided into long and short groups according to the median RTL value of healthy controls, we observed a significantly increased presence of autism for individuals with shorter RTL... compared with those with longer RTL." The age side of things also seemed to hold true for the Li results as per their results revealing: "a significant inverse correlation between RTL and age in controls". You will however note the 'in controls' part of that last sentence which did not hold [significantly] true for autism cases.
• Interestingly, authors also reported that: "among the subjects with childhood autism those who received family training interventions have significantly longer RTL than those without family training interventions." They did find that clinical symptoms were decreased in those taking part in such intervention but drew back from suggesting a link given that lower clinical symptoms scores were also noted in those with "medication exposure" without any corresponding effect on RTL.
• The conclusion: a bit of a first attempt looking at telomere length in relation to autism finding something potentially important but with the need for further, independent replication. Also, a little more investigation on the hows, whys and implications of such results are required.

The first thing that crossed my mind having read the Li paper was the the idea that shorter telomere length is related to DNA damage and "genomic instability" and how that might play out with regards to autism. Not so long ago on this blog, I discussed the recent paper by Penelope Main and colleagues [6] (see here) who, from a slightly different analytical perspective, concluded: "it appears unlikely that genomic instability is a feature of the aetiology of autism". Quite the contrast by all accounts.

That being said, Li et al do discuss the possibility that: "telomeric DNA was highly sensitive to be damaged by the oxidative stress" which does bring their results and other findings from Main and colleagues [7] potentially back into some sort of stellar alignment as linking back into quite a body of research talking about oxidative stress and autism in mind [8]. I say that acknowledging that there is much more research to do in this area but templates for such an association might already exist [9] in the peer-reviewed arena.

Again, perhaps showing my lack of insight into this area, a quick read around this topic also pointed to another possible area of interest when it comes to telomeres and autism: telomerase. This enzyme which apparently might serve as a bit of a double-edged sword when it comes to reversing ageing (see here) but also being a key expression ingredient in tumor cells (see here), has something of an important effect on telomeres with regards to prevent shortening. As far as I can ascertain, the sum total of current research on telomerase and autism is zero aside from peripheral discussion of issues with genes such as PINX1 noted in some cases of autism and it's described inhibition of telomerase activity [10]. I'd be minded to suggest that looking at the activity of telomerase as well as telomere length might be an important part of any future scientific inquiry with autism in mind.

I might also suggest that further research inquiry be focused on the possible ways and means that telomere length might be affected by intervention as per the possible effects from family intervention detailed in the Li data. I'm not specifically talking about the psychological aspects, which I'll leave others to decide whether they're important or not, but rather other data on for example, how exercise might show a beneficial effect on telomere length [11] and whether this might be pertinent to at least some cases of autism (see here). Dare I also even mention the possible relation between vitamin D and telomeres [12] again in light of some recent findings with autism in mind, bearing in mind correlation is not the same as causation?

Finally: a paradox... The 'Leukocyte Telomere Length and the Father’s Age Enigma' [13]? Older fathers apparently pass on longer telomeres to their offspring, but older paternal age is also apparently a risk factor for autism. OK, the Li paper looked at telomere data in children with an average age of about 4 years so there may be some scope for factors to affect telomere length in the time from entry into the world. They also did report on father and mother age for autism participants (see here) but not for controls so unfortunately we can't say too much more on that topic. Again, perhaps something to be looked at in subsequent studies?

Music to close: Street Fighting Man by the Stones (with hat-tip to Fantastic Mr Fox).

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[1] Li Z. et al. Shorter telomere length in peripheral blood leukocytes is associated with childhood autism. Sci Rep. 2014 Nov 17;4:7073.

[2] Müezzinler A. et al. A systematic review of leukocyte telomere length and age in adults. Ageing Research Reviews. 2013; 12: 509–519.

[3] Kota LN. et al. Shortened telomere in unremitted schizophrenia. Psychiatry Clin Neurosci. 2014 Nov 27. doi: 10.1111/pcn.12260.

[4] Mitchell C. et al. Social disadvantage, genetic sensitivity, and children’s telomere length. PNAS. 2014; 111: 5944–5949.

[5] Cawthon RM. Telomere measurement by quantitative PCR. Nucleic Acids Res. 2002 May 15;30(10):e47.

[6] Main PA. et al. Lack of Evidence for Genomic Instability in Autistic Children as Measured by the Cytokinesis-Block Micronucleus Cytome Assay. Autism Res. 2014 Nov 4. doi: 10.1002/aur.1428.

[7] Main PA. et al. Necrosis is increased in lymphoblastoid cell lines from children with autism compared with their non-autistic siblings under conditions of oxidative and nitrosative stress. Mutagenesis. 2013 Jul;28(4):475-84.

[8] Rossignol DA. & Frye RE. Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism. Front Physiol. 2014 Apr 22;5:150.

[9] Yu WY. et al. Short telomeres in patients with chronic schizophrenia who show a poor response to treatment. J Psychiatry Neurosci. 2008 May;33(3):244-7.

[10] Zhou XZ. et al. The telomerase inhibitor PinX1 is a major haploinsufficient tumor suppressor essential for chromosome stability in mice. J Clin Invest. 2011 Apr;121(4):1266-82.

[11] Ludlow AT. et al. Do telomeres adapt to physiological stress? Exploring the effect of exercise on telomere length and telomere-related proteins. Biomed Res Int. 2013;2013:601368.

[12] Richards JB. et al. Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women. Am J Clin Nutr. 2007 Nov;86(5):1420-5.

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Li Z, Tang J, Li H, Chen S, He Y, Liao Y, Wei Z, Wan G, Xiang X, Xia K, & Chen X (2014). Shorter telomere length in peripheral blood leukocytes is associated with childhood autism. Scientific reports, 4 PMID: 25399515