Taming the "Mortal Coil" of Aging

For in that sleep of death, what dreams may come when we have shuffled off this mortal coil . . . .
 - Shakespeare, Hamlet

ging is a process in which an individual's health and vitality decline to the point where the organism shuts down and life ends. Ironically, Hamlet's phrase denoting mortality - the "mortal coil" - portrays a stage of fatal activity within the cell - the formation of supercoiled DNA - from which arises a new vision. While Shakespeare may never have dreamed the dream of immortality, countless others over the course of history have sought to retard the aging process. However, few advances of any consequence occurred until the twentieth century (remember that one?).

After much wrestling with competing theories about the causes of aging, scientists seem at last to be making substantial headway. Not only has theoretical understanding increased, but so have the studies that test the theories. Just as important, the technology to exploit the results of the studies has developed rapidly. For example, if a nutrient is tested that produces promising results, but it's only available at an astronomical cost, research is unlikely to continue. So, technology that can rapidly and economically meet demand while maintaining quality is crucial.

Now, for the first time, it is conceivable that we may be able not only to extend our mean lifespan, so that we all tend to live longer, but also to extend our maximum lifespan - i.e. to live beyond the known limits of lifespan for the species.

DISCOVERING THE AGING CLOCK IN ERCs
Among the more significant recent developments in aging research are the discoveries concerning:

  1. The role of extrachromosomal rDNA circles (ERCs), leading to what could be called "the ERC theory of aging."
  2. The function of the metabolism molecule, NAD.
  3. The facilitation of the silencing gene Sir2 and its protein.

ERCs belong to a class of supercoiled maverick DNA molecules that can jam normal cellular operation if allowed to proliferate. Leonard Guarente and David Sinclair have speculated that this mechanism is the long-sought "aging clock." They have observed that once an ERC is formed or inherited, the period of time until a lethal number of them has accumulated appears to be fixed for each mother cell. Thus, the replication of ERCs may be the "clock" that determines the lifespan of the cell.

SILENCING STOPS DEATH
The phenomenon of runaway replication of ERCs occurs when a genetic process known as transcriptional silencing breaks down. When silencing is working, the intracellular messages that generate deadly maverick ERCs are inhibited. Silencing stops the exponential accumulation of ERCs that ultimately result in cell death.

As we age, however, the silencing of the messages facilitated by the Sir2 gene becomes more problematic. An enzymatic protein produced by Sir2 becomes dysfunctional without an adequate supply of NAD, a coenzyme cellular energy-metabolism molecule that partners with the Sir2 protein to squelch the deadly messages. Together, NAD and the Sir2 protein accomplish their task of roping and tying down a substance know as chromatin that loosely wraps the individual genes, but normally allows transcription to operate. As a direct consequence of roping down the gene's chromatin "garment" through the removal of acetyl groups, the fatal messages are stopped cold. The lifespan of the cell and the organism are thus extended.

Reference

  1. Sinclair DA, Guarente L. Extrachromosomal rDNA circles - a cause of aging in yeast. Cell 1997 Dec 26;91(7):1033-42.

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