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You are here: Biology of Aging >

Mechanisms of Aging: Gene Deregulation

Everybody knows that the Great Recession (a.k.a. the financial crisis of the late 2000s) was at least partly caused by deregulation of banks and investment firms. The primary economic tenet of laissez-faire capitalism ("There is no such thing as too much deregulation") had to be revised. It became obvious that in a complex system too much deregulation may not only be counterproductive but potentially catastrophic.

Ironically, the timing of the financial crisis roughly coincided with the discovery that excessive deregulation may be detrimental not only to the economy but to all living systems. In fact, deregulation appears to be one of the fundamental mechanisms of aging and age-related degradation for most (if not all) species, from yeast to mice to humans. To be specific, I am talking about deregulation of the activity of genes. Genes are the fundamental blocks of genetic information containing the blueprint of an organism. However, a blueprint does not perform any useful function by itself. To yield the intended structure, the blueprint needs to be put to use by engineers and builders. Similarly, to create a trait in an organism (e.g. the eye color pigment), a particular gene(s) needs to be put to use, i.e. it needs to be read, copied and translated into some useful structure, most commonly a protein.

Under normal circumstances, the activity of genes (a.k.a. gene expression) is tightly regulated. In particular, in each cell of the body, most genes are not expressed (i.e. they are switched off or silenced). This makes good sense. Every cell in the body contains the full complement of genes yet it only needs relatively few to perform the specific functions required of the tissue it belongs to. Therefore, in each cell, the genes required for the cell's tissue-specific duties are expressed whereas all the genes specific to other tissues are not. For example, a skin cell expresses the genes responsible for the synthesis and recycling of the dermal matrix whereas its genes for blood filtering or nerve impulse conduction are switched off - otherwise chaos and malfunctions would ensue.

As we age the genes in our cells tend to become deregulated. Most importantly, many genes that are supposed to stay switched off become active (expressed) in the "wrong cells and at the wrong times". This appears to contribute to many detrimental characteristics seen in aged cells, such as abnormal size and shape, accumulation of molecular junk (e.g. pigments) and vesicles (e.g. lysosomes), overproduction of unnecessary and tissue-inappropriate proteins, and so forth.

Cells have two primary mechanisms for switching off genes (a.k.a. gene silencing). One such mechanisms is called histone deacetylation, a process where DNA packaging proteins (histones) are chemically modified to adhere to the DNA more tightly, which makes it harder for genes to be active. (Notably, a reverse process, histone-acetylation, helps activate silenced genes.) The other mechanism of gene silencing is called DNA methylation and involves direct chemical modification of DNA. If a gene's DNA is methylated (i.e. molecular tags called methyl groups are attached to it), the gene becomes inactive. Conversely, the removal of methyl groups (demethylation) increases activity of genes.

Generally, histone deacetylation/acetylation is a more dynamic and more easily disrupted mechanism of gene regulation (as compared to methylation/demethylation). This may be one reason why it appears to play an particularly important role in the aging process.

The enzymes responsible for histone deacetylation and thus for gene silencing have been known for some time. Arguably the most important such enzymes are a group of proteins called sirtuins. Not coincidentally, sirtuins are known to play a role in the aging process and life extension. In fact, the most effective known method of life extension in animals, caloric restriction (reduction of food intake), works in part by increasing the activity of sirtuins.

Dr. Phillip Oberdoerffer, from Harvard Medical School, and other researchers found that in mammals (most of the studies were in mice) the primary function of sirtuins is to regulate gene expression -- most importantly to switch off the genes that should be inactive. Dr. Oberdoerffer's research indicates that the sirtuin called SIRT1 is especially important as a gene expression regulator. The problem is that SIRT1 (and possibly other sirtuins) has another key function: aiding the process of DNA repair. If DNA is damaged by free radicals, mutagenic chemicals or UV light, sirtuins stop doing their "day-job" of gene silencing and rush to help perform emergency DNA repairs. As a result, the genes that are supposed to stay silent become unnecessarily and disruptively active. Such deregulation contributes to cell damage and thus accelerates the other mechanisms of aging. Conversely, the other mechanisms of aging contribute to gene deregulation, creating a vicious cycle. In particular, such mechanisms as free radicals, mitochondrial burnout, glycation, and inflammation can all lead to DNA damage and thus draw sirtuins away from their primary job of gene silencing. As the rate of DNA damage increases with age, the ability of sirtuins to effectively enforce gene silencing correspondingly decreases.

It appears that DNA methylation, another gene regulation mechanism mentioned above, also contributes to the aging process via gene deregulation. However, the connection between DNA methylation and aging is less well understood and requires further research.

How to prevent or reverse gene deregulation?

Whether you found the above discussion refreshingly interesting or excruciatingly boring, you would probably want to ask: What can we do in practice to avoid the damaging deregulation of our genes?

First, keep in mind that gene deregulation appears to be intertwined with other mechanisms of aging. The majority of anti-aging measures discussed throughout this site will reduce the progression of gene deregulation. Such measures include achieving ideal body weight; optimizing carbohydrate metabolism (via diet, exercise and, possibly, supplements); reducing the level of inflammation in the body (e.g. by increasing intake of omega-3 fatty acids); minimizing exposure to UV light; reducing stress; and so forth.

The approaches specifically targeting gene regulation are also possible. It is likely that drugs helping to restore normal gene regulation in aging cells will eventually be developed. Unfortunately, at present there is only one widely available agent with proven potential to inhibit or even reverse age-related gene deregulation - resveratol. Resveratol is a natural substance found in grapes and certain other plants. It mimics some of the life-extending effects of caloric restriction by increasing the production and activity of sirtuins, including SIRT1. As a result, sufficient sirtuins are made available for both proper gene silencing and DNA repair, thus preventing or reducing gene deregulation. Notably, resveratol has been shown to increase longevity and reduce the rate of age-related diseases in mice. It is likely to produce at least somewhat similar benefits in humans. Unfortunately, human clinical studies of resveratol have not yet been conducted. Even though resveratol is widely available as a food supplement, it remains unclear how to use it in humans safely and effectively. For more details, please see our article about sirtuins and resveratol


Related Links

Sirtuins, longevity and skin rejuvenation
Mechanisms of aging
SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging



     


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