As we age our hair turns gray, our skin wrinkles and our muscles lose their tone. Some turn to surgical remedies to combat these less-than-glamorous side effects of aging. Beyond surgical reversal, scientists have worked diligently to understand the fundamental mechanisms of aging, knowing that a clearer understanding may reveal ways to slow the aging process.
Genetically speaking, a person remains virtually unchanged through the course of his or her life. In contrast, a person's physical appearance changes dramatically throughout the years. If a person's genes are largely unchanged, what accounts for these striking physical differences?
This month's Genome Advance of the Month compares newborns and centenarians to see if epigenetic changes, or alterations in the signals on the genes rather than the genes themselves, could be associated with aging.
There are thousands of genes in the human genome, but by turning on and off a specific combination of genes, a cell can develop into a heart, skin, or the other diverse tissues of the human body. To allow the right combination of genes to be expressed for a particular cell, proteins mark genes with flags, or epigenetic changes, that tell the cell to turn the gene on or off. One type of flag, methylation, occurs in large repetitive "CG" sequences called CpG islands.
Methylation can happen anywhere in the DNA, but a concentrated area of methylation in CpG islands can turn off the nearby gene. In contrast, reduced methylation can turn on the nearby genes. Thus, genes can be turned on and off simply by changing their methylation patterns.Changes in methylation could cause abnormal gene expression, which may help explain some of the physical changes associated with aging.
To test this hypothesis, a group of international scientists led by Jun Wang, Ph.D., from the University of Copenhagen, Denmark, and Manel Esteller, M.D., Ph.D., from the University of Barcelona, Spain, used state-of-the-art technology to examine the methylation status of nearly every "C" (cytosine) in the human genome. They compared the genome-wide methylation patterns of a newborn and a centenarian, hoping to uncover distinct methylation patterns and to reveal a clear correlation between altered methylation and aging.
The researchers used a comprehensive sequencing technique to identify methylated Cs in the genome of donor blood cells. This technique allowed researchers to determine the methylation status of over 90 percent of the genome's CpGs and what fraction of the cell population was methylated at each site. In general, the researchers determined that the centenarian had fewer total methylated CpGs (nearly 500,000 fewer) and a lower average methylation level of CpGs at 73 percent, compared to the newborn at 80.5 percent. Importantly, they discovered that tissue-specific genes had fewer methyl flags in the centenarian sample.
Since decreased methylation can activate genes, this finding suggests that some genes may be inappropriately expressed as a person ages. The consequence of aberrantly expressing, say, a single heart gene in the skin is not clear, but erroneous expression of multiple genes will use valuable cellular resources and may hamper cellular function and survival.
Intrigued by these clear differences in newborns and centenarians, the researchers examined a sample from a 26-year-old. This sample revealed intermediate levels of both total methylation and average methylation status. This result suggests that the methylation changes may occur gradually, but progressively, as a person ages.
These studies are an important first step in confirming what has been previously suggested — that epigenetic changes occur as we age. Building on these studies, future work will need to explore the altered expression of the differentially methylated genes and determine if these findings extend to other tissues since aging is clearly a whole-body phenomenon.
Now that it is clear that these epigenetic changes occur throughout the life cycle, we can more readily probe the mechanisms behind these changes. Scientists have wondered whether epigenetic changes occur due to random methylation changes or due to an organized aging program, similar to the tissue development program,that coordinates the age-associated methylation changes. Interestingly, previous studies have shown that at least some epigenetic changes are conserved in multiple tissues, suggesting that an organism-wide, epigenetic plan may be in place.
If an epigenetic blueprint of aging exists, scientists now have the background and tools to examine it, and the potential to reveal a genetic Fountain of Youth.
Heyn H, Li N, Ferreira HJ, Moran S, Pisano DG, Gomez A, Diez J, Sanchez-Mut JV, Setien F, Carmona FJ, Puca AA, Sayols S, Pujana MA, Serra-Musach J, Iglesias-Platas I, Formiga F, Fernandez AF, Fraga MF, Heath SC, Valencia A, Gut IG, Wang J, Esteller M. Distinct DNA methylomes of newborns and centenarians. Proc Natl Acad Sci U S A, 109(26):10522-7. 2012. [PubMed]
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Last Updated, September 4, 2012