On Saturday I ran 12 miles. “Well, at least I have staved off apoptosis in my peripheral blood mononuclear cells” I thought as I hobbled down the stairs on Sunday morning. Normally I don’t think about mononuclear cells on Sunday mornings, only of coffee. However, a paper published last week in BMC Physiology changed that for me, at least temporarily.
The paper, by Marfe et al, investigated whether the physiological stress associated with strenuous exercise may cause apoptosis and contribute to loss of lymphocytes. This paper investigated whether apoptosis is increased in cells of the immune system after running a marathon. The authors studied the expression of various stress-related proteins in peripheral blood lymphocytes in 10 male amateur runners, examining the expression of various antioxidants, stress proteins and apoptotic markers before and after (2-hours post-race) running a marathon. They found that expression of the apoptotic marker bax was decreased significantly after the marathon, while levels of antiapoptotic bcl-2 RNA increased. The amount of propcaspase 9 did not change pre and post race, indicating that there was no change in levels of apoptosis before and after the race.
Expression of the stress-associated proteins HSP70, and HSP32 increased substantially after the marathon, as did levels of the antioxidants Cu-Zn-SOD and Mn-SOD. Transcription of the sirtuin family protein SIRT1 was also increased after the marathon, but levels of SIRT3 and SIRT4 decreased.
So, this paper showed that apoptosis did not occur after the stress of running a marathon and, for the first time, showed that exercise modulates expression of sirtuin family proteins in people.
What does this mean?
Sirtuins are known to be part of a signaling system that enhances survival during times of stress. They are thought to be involved in the observed increases in lifespan associated with calorie restriction in yeast, drosophila and nematodes (1). SIRT1 is a key regulator of cellular metabolism, being involved in insulin signaling, glucose metabolism, and response to reactive oxygen species, to name but a few. SIRT1 activators include calorie restriction (2), which is known to be associated with increased lifespan in certain species, and controversially, resveratrol (3), the proposed anti-aging ingredient in red wine.
Consequently, there has been a lot of interest in the potential of sirtuin activators as anti-aging (or healthy aging) drugs. The search is on for SIRT activators that may have benefit in treatment of diseases associated with aging such as type 2 diabetes (4) and certain cancers (5). This recent study in mice showed that:
..old Sirt1-transgenic mice are partially protected from the development of pathologies typically associated with ageing, such as glucose intolerance, osteoporosis and poor wound healing (5).
Given their role as part of the response to stress, and their implied benefits in healthy aging, it is perhaps not surprising that the oxidative stress arising as a result of marathon running results in sirtuin activation. The paper by Marfe et al adds an interesting facet to the sirtuin story. SIRT1 is activated by the stress associated with strenuous exercise and responds by inducing protective mechanisms to enhance cell survival. So now, in addition to calorie restriction and red wine (resveratrol), we can add marathon running to the list of SIRT1 activators.
The role of sirtuins in cellular metabolism is undoubtedly complex and still to be fully understood. They may have huge potential for understanding and treating diseases associated with aging. As far as a miracle anti-aging pill or fountain of youth? That is up for debate. One message of the sirtuin story so far may simply be this: No pain, no gain. There are no easy answers. And that is the message that resonates with the runner.
References
Marfe, G., Tafani, M., Pucci, B., Di Stefano, C., Indelicato, M., Andreoli, A., Russo, M., Manzi, V., & Sinibaldi-Salimei, P. (2010). The effect of marathon on mRNA expression of anti-apoptotic and pro-apoptotic proteins and sirtuins family in male recreational long-distance runners BMC Physiology, 10 (1) DOI: 10.1186/1472-6793-10-7
- Wood, J.G., et al. (2004) Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430, 686-9.
- Crujeiras, A.B., et al. (2008) Sirtuin gene expression in human mononuclear cells is modulated by caloric restriction. Eur. J. Clin. Invest. 38, 672-78.
- Dimond, P.F. (2010) Sirtuins. Antiaging medicines or marketing? GEN Feb 16 2010.
- Milne, J.C., et al. (2007) Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450, 712-16.
- Herranz,D. et al. (2010) Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nature Communications 1, 3.
Read more news about thie Marfe et al paper here:
Running a marathon halts cellular suicide
ScienceDaily (2010-05-11) — Apoptosis, the natural ‘programmed’ death of cells, is arrested in the aftermath of strenuous exercise. Researchers studied peripheral blood mononuclear cells (PBMCs), isolated from whole blood samples taken from people after finishing a marathon, finding that the balance between expression of pro- and anti-apoptotic genes is shifted after the race. … > read full article
Isobel Maciver
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Interestingly, whilst it might not affect the WBC – running at marathon length levels can affect erythrocyte / Red Blood Cells – all that trampling – aka foot strike hemolysis.
http://runningtimes.com/Article.aspx?ArticleID=4009
Wonder what level this hemolysis is at, and what effects it has.
Hello Tom,
I had not heard of footstrike hemolysis before, thanks for the article! Doing a quick search I found the following paper from 2003 that you might be interested in.
http://jap.physiology.org/cgi/content/full/94/1/38
Wonder what level this hemolysis is at, and what effects it has.
+1
Because at least three of the SIRT genes show a response in terms of gene expression after the marathon, it indicates that genetic differences in these genes may be found and that those differences may lead to allele-specific responses to long-distance running. There are many papers in the body of scientific literature that show gene-by-physical activity interactions. One example shows that higher levels of physical activity may be protective for HDL-cholesterol (“good” cholesterol) concentrations while low activity puts an individual at risk, according the alleles of a specific variant of gene LIPG (endothelial lipase). See http://www.ncbi.nlm.nih.gov/pubmed/19380136. Thus, one can imagine SIRT gene polymorphisms where one allele confers the benefits observed and other alleles do not.