Brainstorming session
Can hormesis slow down senescence by altering DNA methylation fingerprint?
By Aohona Datta on Aug 20, 2020
[1] Pan, Yong et al. “Regulation of yeast chronological life span by TORC1 via adaptive mitochondrial ROS signaling.” Cell metabolism vol. 13, 2011, p. 668-78
[2] Calabrese, Edward J, and Mark P. Mattson. “How Does Hormesis Impact Biology, Toxicology, and Medicine?” Npj Aging and Mechanisms of Disease 3, 2017, p. 13.
[3] Levine, Morgan E., et al. “A DNA Methylation Fingerprint of Cellular Senescence.” BioRxiv, Jan. 2019, p. 674580.
Creative contributions
Anti-aging effects of hormesis-induced epigenetic alterations
Epigenetic changes (not just methylation) alter gene expression to buffer the organism against environmental changes and support adaptability to the life-course conditions. A whole-organism epigenetic transcriptional reorganization appears to underlie different hormetic effects. Caloric restriction increases life span, partly via hormetic mechanisms that increase cellular stress resistance by up-regulation of vitagenes. [1,2] Exposure of human skin fibroblasts to a single dose of radiation changed the expression of more than 100 genes within 2 h. These included stress response genes that were different from those expressed in cultures exposed to a higher dose. Genome- wide changes in expression were observed in low-dose irradiated Drosophila with enhanced longevity. Approximately 13% of the genes exhibited changes in expression, along with a number of ageing-related genes. [3] Mild stresses at a young age can protect from severe stresses at old age as well as delay ageing and increase longevity. Single or multiple exposures to low doses of otherwise harmful agents can cause a variety of anti-ageing and longevity-extending hormetic effects. [4–6] In honey bees, the queen and worker female castes, although share the same genome, show different DNA methylation patterns as a result of differential intake of the royal jelly (environmental factor). [7–9] The queens live up to 500 times longer than males and 10 times longer than workers. [10] References: 1. Calabrese V, Cornelius C, Trovato-Salinaro A, Cambria M, Locascio M, Rienzo L, et al. The Hormetic Role of Dietary Antioxidants in Free Radical-Related Diseases. Curr Pharm Des [Internet]. 2010 Mar 1;16(7):877–83. Available from: http://www.eurekaselect.com/openurl/content.php?genre=article&issn=1381-6128&volume=16&issue=7&spage=877 2. Calabrese V, Cornelius C, Dinkova-Kostova AT, Calabrese EJ, Mattson MP. Cellular Stress Responses, The Hormesis Paradigm, and Vitagenes: Novel Targets for Therapeutic Intervention in Neurodegenerative Disorders. Antioxid Redox Signal [Internet]. 2010 Dec;13(11):1763–811. Available from: http://www.liebertpub.com/doi/10.1089/ars.2009.3074 3. Seong KM, Kim CS, Seo S-W, Jeon HY, Lee B-S, Nam SY, et al. Genome-wide analysis of low-dose irradiated male Drosophila melanogaster with extended longevity. Biogerontology [Internet]. 2011 Apr 9;12(2):93–107. Available from: http://link.springer.com/10.1007/s10522-010-9295-2 4. Neafsey PJ. Longevity Hormesis. A review. Mech Ageing Dev [Internet]. 1990 Jan;51(1):1–31. Available from: https://linkinghub.elsevier.com/retrieve/pii/004763749090158C 5. Le Bourg É, Rattan SIS. “Is Hormesis Applicable as a Pro-Healthy Aging Intervention in Mammals and Human Beings, and How?” Dose-Response [Internet]. 2010 Jan 11;8(1):dose-response.0. Available from: http://journals.sagepub.com/doi/10.2203/dose-response.09-052.LeBourg 6. Rattan SIS. Hormesis in aging. Ageing Res Rev [Internet]. 2008 Jan;7(1):63–78. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1568163707000360 7. Foret S, Kucharski R, Pittelkow Y, Lockett GA, Maleszka R. Epigenetic regulation of the honey bee transcriptome: unravelling the nature of methylated genes. BMC Genomics [Internet]. 2009;10(1):472. Available from: http://bmcgenomics.biomedcentral.com/articles/10.1186/1471-2164-10-472 8. Corona M, Hughes KA, Weaver DB, Robinson GE. Gene expression patterns associated with queen honey bee longevity. Mech Ageing Dev [Internet]. 2005 Nov;126(11):1230–8. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0047637405001740 9. Lyko F, Foret S, Kucharski R, Wolf S, Falckenhayn C, Maleszka R. The Honey Bee Epigenomes: Differential Methylation of Brain DNA in Queens and Workers. Keller L, editor. PLoS Biol [Internet]. 2010 Nov 2;8(11):e1000506. Available from: https://dx.plos.org/10.1371/journal.pbio.1000506 10. Keller L, Jemielity S. Social insects as a model to study the molecular basis of ageing. Exp Gerontol [Internet]. 2006 Jun;41(6):553–6. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0531556506001057
by Shubhankar Kulkarni on Aug 21, 2020
Hormesis vs. Time
I have never done deep research on hormesis, but I realized I might have had some close encounters lately. By repetitive treatment of human ovarian cancer cells with rising concentrations of chemotherapeutic drugs, we developed a model with each cell line being more resistant than the previous. As it contains a series of morphologically and molecularly different cells with a significant increase in drug resistance, the model allowed us to observe and report on changes in transcriptome and proteome. Could it be hormesis, at least in the case of cancer stem cells that survived and continued proliferation after every treatment? Probably not, because the experiment was designed to collect information after a longer period (weeks). Nevertheless, translated to your brainstorming idea, it would be very interesting to develop and analyze DNAmSen profiles of tissues subjected to hormetic doses of stressors to evaluate the aging-retardation process. If you design it wisely, it could allow you to follow the underlying mechanisms of hormesis from the early beginning. I suppose that the effect of hormesis would then be defined as an epigenetic change observed shortly after the stressor application. But not every change in gene or regulator is equal. Sometimes, changes in upstream regulators can drive a bigger change, resulting in bigger and more permanent changes. At the moment, I can't tell if hormetic mechanisms are responsible for the observed resistance/aging retardation, or are these subsequential and more permanent changes induced by hormesis. Is the hormesis a driver of the change or just a switch? Also, what happened in our ongoing study is that we started to rely more on signaling pathways than on specific genes. Shutting down the gene with the highest expression change (FC=120), resulted in non-significant differences in survival of cells after drug treatment. Conversely, inhibition of the most enriched pathways was much more fruitful. Therefore, I would suggest designing a series of experiments with DNAmSen where you would overlap the results of all the epigenomic changes (above-defined threshold) reported in all the above-mentioned anti-aging methods used. I would expect that intersect to result in a small list of candidates or enriched pathways leading to new biomarker candidates involved in the aging process.
by Juran K. on Sep 01, 2020