A recently recognized biological mechanism that switches genes on and off may play a larger role in aging than previously thought.
That mechanism involves short stands of RNA, about 1/100th the length of a typical gene, called microRNAs, which are only 22 nucleotides in length (nucleotides comprise the rungs on the DNA ladder), which may interfere with normal messenger RNA in the production of protein.
As a briefing to readers, when genes are activated, a process called gene expression, they produce protein. When genes are switched off, called gene silencing, no protein is made. MicroRNAs interfere with this protein-making process and thus switch genes off.
Normally a strand of RNA is copied from DNA and exits the cell nucleus (center of a living cell) into the watery compartment called cytoplasm. It is here that messenger RNA, which contains codes to assemble protein, puts gene-control into action. (See graphic above.)
However, not all RNA copies made in the cell nucleus contain code to make protein. Some are short-strands of non-coding RNA and if these so-called microRNAs mesh with normal messenger RNA, they can interfere with protein making and silence a gene, or maybe we should say the entire genome. After all, biologists now realize microRNAs have a more pervasive effect over the entire library of 25,000 human genes (genome) than first imagined.
But before this report proceeds further with an explanation of how microRNAs switch genes, readers will need a short explanation of the conventional understanding of how genes are switched on and off.
Only in recent years has the public learned that the 25,000 human genes housed in each cell of the body are not fixed, they do not predetermine biological destiny and they can be switched on or off by a process called epigenetics.
The two prominent mechanisms of switching genes are (a) the donation of methyl groups, for example vitamin B12 and vitamin B9 (folic acid), and the (b) coiling or uncoiling of a strand of histone around a bundle of DNA called chromatin. Resveratrol (rez-vair-ah-trawl), a red wine molecule, is an example of an agent that switches genes by this latter method. (See diagram below)
The high interest in resveratrol in recent years is that it is known to target the Sirtuin1 gene (also called SIRT1), known as a survival and longevity gene. Resveratrol inhibits an enzyme called histone deacetylase, which then influences the coiling of histone around chromatin bundles of DNA.
The discovery in 1993 of a novel class of RNAs in roundworms, which control various genes and biological processes, changed the understanding of how genes are switched on and off. At first, the broad impact of microRNAs on gene expression went unrecognized. But a decade later, an article in Nature Magazine referred to small microRNAs “the genome’s guiding hand.”
Even as recently as 2004 it was believed that microRNAs represented just 1% of the human genome and influenced only 10% of genes. By 2008 it was estimated microRNAs influenced a third of the human genome.
It is now predicted that microRNAs regulate up to 90% of the genes in the human body. MicroRNAs may control every cellular process in all cells and tissues of the human body! Normal microRNA function is required for maintenance of health and prevention of disease.
Today geneticists know that the role of microRNAs in gene expression could be as important as that of methylation or histone modification.
Biologists now recognize there are approximately 1000 molecules of microRNA per cell, with some cells exceeding 50,000 molecules.
Even as early as 2002 one forward-thinking biologist said:
“It is rapidly becoming apparent that another whole level of (gene) regulation lurks, unsuspected, in living cells, hidden from our notice in part by the conventional approaches that we usually use to study gene regulation, and in part because these regulators are very small targets and are not easily found from gene sequences alone. These stealth regulators, operating below our radar, if not that of the cell, are small regulatory RNAs, adding to control the genome.”
MicroRNAs are now being referred to as “a fundamental regulator of gene expression.”
It is stunning to realize that out of 25,000 human genes or so, only about 6% are functionally classified as transcription factors that is, genes which facilitate protein making. However, since some 93% of our genome is transcribed from DNA into a copy called RNA, by far the greatest part of the expressed genome is non-protein-coding RNAs!
Tantalizing correlations between microRNA and human diseases have recently been demonstrated. Since microRNAs exceed the action of most drugs, which are largely targeted at single genes, while microRNAs regulate complex networks of genes, there is feverish work being done to create drugs that influence microRNA.
For example, it is known that microRNA-21 is only weakly up-regulated in normal healthy hearts, but is markedly up-regulated in most models of heart failure and enlargement, which suggests microRNA-21 plays a key role in this condition. Inhibition of microRNA-21 reduces fibrosis (scarring), heart enlargement and improves cardiac function.
But readers at ResveratrolNews.com are likely more interested in the influence microRNAs may have over aging rather than disease.
Some 800 longevity-associated genes have been identified thus far. This is why biologists are so excited by microRNAs and their broad effects over networks of genes.
In 2005 it was reported that microRNA determined the lifespan of a roundworm.
At least one longevity pathway known as IGF-1 (insulin growth factor-1) is controlled by microRNAs. In particular microRNA lin-4 expression is linked with longevity. Animals which cannot produce lin-4 have shortened lifespans. IGF-1 is linked to the SIRTUIN1 gene pathway, a gene that is widely known as a mimic of calorie restricted diets. microRNA miR-217 increases Sirtuin1 gene activity and therefore might act in a similar manner to resveratrol.
In the Ames dwarf mouse, known for its remarkable propensity to delay the onset of aging, it was found that microRNA-27a influences the metabolic pathways involved in its longevity.
Of interest to the field of aging, microRNA expression is more often up-regulated than down-regulated with advancing age. For example, in laboratory mice microRNAs 93 and 214 exhibit significant up-regulation beginning at 33 months of age, which is close to the end of this animal’s normal lifespan (~36 months). Very few microRNAs are down-regulated with age.
MicroRNA-34a has been shown to regulate the SIRTUIN1 gene, known as a survival gene that is activated during calorie restriction — a known longevity pathway.