Molecules of Aging
A Molecular Perspective on Aging: The SIR Genes
by John Medina, Ph.D.| Geriatric Times |  |
July/August 2000 | |
Vol. I | |
Issue 2 |
The aging process, at first blush, seems simple to comprehend. An organism lives for a while, undergoes some important time-related biological changes and dies when one of those changes turns life-threatening. Wound to zero at birth, some internal clock ticks away in our bodies with such inerrancy that we actually have a fairly predictable life span. The notion of longevity, which comes from this seeming solidness, is an idea that seeks to answer the question, "Given the current environment and culture, how long can a given person expect to hang around?" Many researchers believe that for humans, the magic number is an astonishing 115 years.
The concept of aging becomes less straightforward when one begins to look under the hood of human cells, however. The why of aging in our cells is much less easy to understand than the intuitive fact of aging. It is the general purpose of this column to report on a large body of data that seeks to understand the aging process at a molecular (read: genetic) level. It is the specific purpose of this month's article to focus on a recent breakthrough underscoring how complex it all is.
To understand this breakthrough, we will have to review a few items about gene regulation and some molecular contributions to the aging process. Feel free to skip to the section marked The Data on Aging if concepts such as histones and repressor sequences are working parts of your vocabulary.
Genes and Aging
To understand the importance of the breakthrough described here, it is critical to realize just how many genes have become associated with the aging process over the years. To many a scientist's dismay, a bewildering number of gene sequences in an equally bewildering number of animals have been found to be responsible for aging. Fortunately, many of these genes perform similar functions throughout the animal kingdom (many "aging" genes in yeast look similar and supervise identical processes in fruit flies and humans, for example). Figuring out how they all work together to create phenomena like life spans and longevities is one of the greatest frontiers of modern biology.
A specific set of mechanisms involved in the aging process turns genes on chromosomes on and off. As you recall from high school, genes are generally composed of two parts: an on/off switch and a region that encodes the instructions to make a biochemical (such as a protein). The on/off switch is termed the promoter region, and the encoding instructions area is the structural region. To get a gene to make the instructions necessary to create a protein, you have to turn the promoter switch to on.
Most of the genes associated with the aging process make their contributions by becoming selectively active or inactive over a period of time. This regulation can be controlled in the laboratory. Mutating "aging" genes can confer some extraordinary capabilities in the organisms carrying the mutations-such as dramatically increasing or decreasing life spans. A number of these genes have been isolated, and they go by names as diverse as ced-9, bax and bcl.
Histones
Another piece of information required to understand the breakthrough mentioned above has to do with proteins called histones, specifically the effects of histones on the above gene regulation. To describe histone biochemistry and demonstrate its contribution to aging, I'd like to digress for a moment and tell you about my grandmother, a woman well-acquainted with the aging process (her death came at age 92).
Grandmother was a Ukrainian with a penchant for making Christmas decorations. One of her favorites involved placing pieces of popcorn onto a cut length of fishing line and then stringing the resulting garland around a Christmas tree. She would take an individual piece of popcorn, wind the fishing line exactly twice around it and then slide the popcorn down the line. To provide structural support, she took the fishing line and made a small indentation into the popcorn just prior to winding it. I never could get the hang of that-the creation of a stabilizing groove followed by two rapid circular motions. I would just sit in amazement as she very quickly slid hundreds of popcorn pieces (often colored) onto the growing chain.
I use this model of popcorn strung along a fishing line to continue our story of gene regulation. In many ways, histone proteins and DNA molecules look-and act-a lot like my grandmother's Christmas garlands. All human DNA molecules possess spherical clusters of histone proteins spaced at regular intervals along the chromosome, surprisingly like the popcorn pieces I just described. The DNA is also wound exactly twice around these histone proteins. From the flexibility conferred by this winding, these histone proteins can literally slide up and down the DNA strand. It is possible to observe regions that possess large groupings of histones and regions that don't possess any histones in a typical human chromosome. A single chromosome contains thousands and thousands of these histone complexes.
What are the functions of histone proteins, and why are they allowed to slide? The positioning of histone proteins along the DNA molecule predicts the activity or inactivity of the genes with which these proteins come into contact. For example, if a histone protein complex slides into a promoter region (that on/off switch of DNA we discussed above), the gene will become "choked off" and will be rendered silent. The same thing is sometimes true of the structural region; if the histone slides into the coding sequences, the gene can be turned off. Conversely, if the histone is removed, the repressive input is eliminated, and the gene now has a chance at becoming active.
As you might suspect, this convenient sliding is a critical point of regulation for a cell's ability to control the activities of its genes. It has also led to an important series of questions such as "What controls the sliding?" and "Do the histones ever fall off?" The answers to questions like these play an important role in our understanding of the aging process, and I would like to address them before we turn to the data.
Bulldozers, Time Bombs
Considering their importance, you might suspect that individual cells pay a great deal of attention to histone placement. And that is the case, indeed. There are tiny molecular bulldozers that literally move histone protein complexes up and down the strands of DNA. There are enzymes called acetylases in the cell's nucleus that have the ability to attach side groups called acetyl groups to a histone protein complex. These acetyl groups act like time bombs. Once attached, they destabilize the histone complex with such violence that the "tagged" individual complex falls off the DNA molecule. After the histone is removed, the DNA is unencumbered, and a given gene may become activated.
Most relevant to the data on aging I am about to describe, researchers have also discovered that cells possess enzymes called deacetylases. As their name implies, deacetylase enzymes have the ability to remove acetyl groups from histones. In effect, they get rid of the time bombs before they go off. As a result of deacetylases helping to stabilize the histones at a given chromosomal location, the genes in the same area remain repressed.
What an interesting world in the nucleus! You have sappers that place tiny explosive-like devices on histones and bomb-removal squads that try to dislodge them before they go off. The way in which the cell balances these two opposing forces is one focus of intense research.
With the idea of age-related genes and histone regulation in our grasp, we can now turn to the data at hand and take a glimpse into the complex world of growing old. This work was originally done in yeast, although, true to form, the same genes have been found in humans and appear to perform similar functions. The data can be divided into three parts:
- Creation of the SIR mutation. A mutation was discovered in yeast
that dramatically shortened its life span. The mutation was called SIR2.
- Isolation of the gene that mutated SIR2. The gene responsible for
this phenomenon (called the SIR2 gene) was isolated. It was, indeed, confirmed
to be the factor that controlled the life span of the creature. This aging
control appeared to be a two-way street. If a researcher doubled the number of
SIR2 genes in a normal yeast through genetic manipulation, the yeast's life
span was dramatically increased. If a researcher turned off the gene by
creating a crippling mutation, the life span of the yeast carrying the mutation
was dramatically shortened.
- Characterization of the gene. Here's where the results got
interesting. When the researchers asked, "What does the protein that the SIR2
gene encodes actually do?", the answer they received was astonishing. The SIR2
gene was discovered to be a deacetylase enzyme! This enzyme had the ability to
survey histones for the presence of the acetyl time bombs we previously
discussed and, once found, take them off. Thus, the normal function of the SIR2
protein was to make sure histones didn't "explode." With intact histones
present, normal repression mechanisms could remain in place. In other words,
certain genes could be continually kept in the off position. Keeping those
genes in the off position dramatically increased the life span of the organism.
Conclusion
This is an important breakthrough. Here we have an intact aging mechanism being described at the molecular level. And we have uncovered an extremely important question: What genes are so important to the aging process that keeping them off can actually increase life span? In other words, what are the targets of the SIR2 genes? As with so many results, there is a great deal of work to be done, though the answer to this specific question is beginning to be uncovered. There are a number of targets for SIR2, ranging from structures called telomeres to regions of DNA-encoding ribosomal structures (as you recall, ribosomes help cells make proteins in the first place).
The next set of questions will undoubtedly focus on how these targets work with the aging process. In future columns, we will consider structures like telomeres and the ribosomal DNAs mentioned above. In many ways, these structures hint at still other mechanisms that control aspects of the aging process. The greatest illustration of these data is to show just how complex, and how varied, the whole process of aging is. If I can get that across in the years I hope we will have together talking about this process, then writing these columns will have been very much worth the effort indeed.
Dr. Medina is affiliate professor and senior research scientist in the department of bioengineering at the University of Washington School of Medicine.
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