Epigenetic Clock Data from a Larger Study Population

There are presently a few different biomarkers of aging under development based on changes in patterns of DNA methylation, an epigenetic decoration to DNA that determines the rate at which specific proteins are manufactured. The molecular damage that causes aging is the same in all of us, and thus some portion of the cellular reaction to environment and circumstances will also be the same in all of us: as damage accumulates, cells change their behavior in response. A good biomarker that accurately reflects biological age can, once validated, be used to greatly speed up development of therapies that slow or repair the causes of aging. At present the only reliable way to assess outcomes is to run life span studies, something that is for many organizations prohibitively expensive when carried out in mice, and out of the question when it comes to gathering human data. If lengthy life span studies can be replaced with a biomarker measurement before and after a short period of treatment, then the cost and time taken to evaluate potential rejuvenation therapies will be greatly reduced, and many more research groups will participate in the research and development process.

A team of 65 scientists in seven countries recorded age-related changes to human DNA, calculated the biological age of blood and estimated a person's lifespan. A higher biological age - regardless of chronological age - consistently predicted an earlier death. Drawing on 13 sets of data, including the landmark Framingham Heart Study and Women's Health Initiative, a consortium of 25 institutions analyzed the DNA in blood samples collected from more than 13,000 people in the United States and Europe. Applying a variety of molecular methods, including an epigenetic clock developed in 2013, the scientists measured the aging rates of each individual. The clock calculates the aging of blood and other tissues by tracking methylation, a natural process that chemically alters DNA over time. By comparing chronological age to the blood's biological age, the scientists used the clock to predict each person's life expectancy.

"Our findings show that the epigenetic clock was able to predict the lifespans of Caucasians, Hispanics and African-Americans in these cohorts, even after adjusting for traditional risk factors like age, gender, smoking, body-mass index and disease history. We discovered that 5 percent of the population ages at a faster biological rate, resulting in a shorter life expectancy. Accelerated aging increases these adults' risk of death by 50 percent at any age." For example, two 60-year-old men both smoke to deal with high stress. The first man's epigenetic aging rate ranks in the top 5 percent, while the second's aging rate is average. The likelihood of the first man dying within the next 10 years is 75 percent compared to 60 percent for the second. The preliminary finding may explain why some individuals die young - even when they follow a nutritious diet, exercise regularly, drink in moderation and don't smoke. "While a healthful lifestyle may help extend life expectancy, our innate aging process prevents us from cheating death forever. Yet risk factors like smoking, diabetes and high blood pressure still predict mortality more strongly than one's epigenetic aging rate."

The precise role of epigenetic changes in aging and death, however, remains unknown. "Do the epigenetic changes associated with chronological aging directly cause death in older people? Perhaps they merely enhance the development of certain diseases - or cripple one's ability to resist the progression of disease after it has taken root. Future research is needed to address these questions." Larger studies focused only on cases with well-documented causes of death will help scientists tease out the relationship between epigenetic age and specific diseases. "We must find interventions that prolong healthy living by five to 20 years. We don't have time, however, to follow a person for decades to test whether a new drug works. The epigenetic clock would allow scientists to quickly evaluate the effect of anti-aging therapies in only three years."

Link: http://newsroom.ucla.edu/releases/epigenetic-clock-predicts-life-expectancy-ucla-led-study-shows


Epigenetic marks such as DNA methylation change substantially when animals age. However, overexpression of a small number of factors can push the cell to transition to a new stable state that is associated with changes in the activity of thousands of genes. It became possible to obtain iPSC from adult and even elderly patients. The reprogramming leads to the restoration of embryonic telomere length and mitochondria recovery and so illustrate the reversibility potential of aging. Unfortunately, the reprogramming into iPSC in vivo leads to the formation of tumors. So, why not to try to reprogram in vivo cells of elderly patients only to the safe junior stage instead of the embryonic stage (with oncological danger). Even a non-specific action on DNA methylation (experiments with 5-azacytidine - inhibitor of DNA methyltransferase enzyme, Dnmt1, allows to reprogram the cells in vitro into safe tissue-regenerative multipotent stem cells (doi: 10.1073/pnas.1518244113). The DNA methyltransferase inhibitor, RG108 treatment of human bone marrow mesenchymal stromal cells resulted in increased activity of the anti-senescence genes TERT, bFGF, VEGF, and ANG while activity of the senescence-related genes ATM, p21, and p53 were decreased. The number of β-galactosidase-positive cells was significantly decreased (DOI: 10.1002/bab.1393)
Now we can selectively enforce silence or action to the elected genes by using reprogrammable CRISPR/dCas9-based systems armed with activators and repressors of transcription, and also with epigenetic modulators such as DNA methylation (Dnmt3) and demethylation (TET1) enzymes. It's time to use these tools, which do not introduce mutations in genomic DNA for search and for development of the methods of radical rejuvenation.

Posted by: Dmitry Dzhagarov at September 30th, 2016 2:30 PM

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