Break the Vicious Circles of Aging

he ancient Greek philosopher Heraclitus, who saw the world in terms of change, would have agreed with Socrates, Plato, and Aristotle that all men are mortal. And so, once upon a time, it may have been true. But that was the past, and we are in the present on our way to the future. While man's search for the cup of immortality is not new, it now appears for the first time that the attainability of extremely long lifespan may be a reality.

Once the providence of gods and goddesses, significantly increased lifespan - perhaps even immortality - could belong to those who are willing to spend the time and effort to understand the advances in nutrition, genetics and other developing technologies, such as robotics and nanotechnology, through which infinitesimal biocomputers might be built in every one of our cells. Don't laugh! It's theoretically feasible, and a company called Molecular Electronics is working on producing a storage device for this purpose. Prolonged lifespan could also belong to those brave enough to apply these ideas as they cross over from one discipline to another and as they are rendered safely and intelligently into the practicality of life-extending gene-support dietary supplements.

In Greek mythology, the mighty Hercules, who was born of a mortal mother by the god Zeus (making him 50% mortal by birth), was eventually fully immortalized for his heroics. Likewise, the heroine Ino (25% mortal) was elevated from a mortal to an immortal because of her filial connection to the principal occupant of Mount Olympus, her grandfather Zeus.

On the other hand, despite his two-thirds divinity (33% mortal), the hero Gilgamesh of the Sumerian epic tales (circa 2000 B.C., Babylon) fails to cross over into infinity; immortality slips from his reach. The curse of Gilgamesh is that he wants his friend to live forever too, but his friend is a mere mortal (100%).

FINDING THE GENES OF LONGEVITY
Prometheus decided to make men stand upright, as the gods did, and he gave them fire, which he stole from Mount Olympus. He also taught mankind many arts and sciences. Unlike the heroes and heroines of yesteryear, who achieved immortality through their descent from the gods, today's aspirants rise up from the fire of the ideas whose time has come. "For the past ten years, we've sought genes that confer longevity," says Leonard Guarente, a professor of biology at Massachusetts Institute of Technology in Cambridge.¹ And not for naught, as Professor Guarente and his associate fire-bearers strongly believe: they have found the genes of longevity. So much for the deities.

Ironically, Prometheus - whose name stands for "forethought" - was himself a Titan (and thus a god), but the penalty Zeus imposed on him for his treacherous heroics was to have his flesh torn open and his liver devoured by an eagle every day (the liver kept growing back) for eternity. At the modern end of punishment for heroics, Professor Guarente appears to be suffering nothing worse than the scorn of evolutionary biologists, who say his theories can't be correct. But he gives them little thought - he is too occupied - saying, "Genetics is a thrill a minute . . . you never know what to expect next."² Although these expectations certainly do not carry the odds a gambler might prefer, the probability of success is rapidly improving, and the new percentages favor not the deities but the "dietaries" - that is, those who practice enlightened dietary supplementation.

BREAKING THE VICIOUS CIRCLES OF AGING
How the work of researchers whose forte has been the metabolism of yeast can rise to the heights of significantly extended human lifespan is one of the thrills (and wonders) of genetics. The thought processes that led to the discovery of the Sir2 (silent information regulator) gene of longevity regulation (see "New Gene Supplements May Extend Your Life," Life Enhancement, April 2000) seem oddly circular, in that the seminal idea moved downward, so to speak, from humans to yeast and then back up again. It was also circular in another sense. The researchers Sinclair, Mills, and Guarente set out to see whether the yeast's counterpart to the human mutant gene that causes radically accelerated aging in a condition called Werner syndrome had the same effect on the yeast cells.³

While quickly determining that the yeast gene did also cause accelerated aging, the scientists found something peculiar. As the mutant-gene-infected cells spiraled toward senescence, they were found to contain coiled arrays of repeated rDNA (ribosomal DNA) units called extrachromosomal rDNA circles, or ERCs.⁴ The older the cell, the more ERCs were found. Could these ERC(ircles) be byproducts of aging, or could they be an actual cause of aging?

The life-extending role of the proteins produced by the Sir2 gene could be explained by ERCs, for several reasons. For starters, it was known that these proteins suppressed gene mutation. Could they also reduce ERC formation, and if so, how? Perhaps by preventing DNA breaks, the scientists speculated, and also by altering the balance of repair mechanisms that result in ERCs. Wasn't this process similar to some aspects of caloric restriction in that it somehow slowed metabolism?⁵ Could there be something more significant? Many separate studies have shown that the restriction of caloric intake to 30% less than normal levels significantly extends the lifespans of yeast, earthworms, mice, and possibly primates.⁵ Could there be something more significant to the similarity, such as a relationship between the silencing aspect of the genes and slower metabolism?

STOPPING THE MESSAGES OF AGING
After studying the Sir2 gene for more than a decade, Guarente and his colleagues found that the presence of an extra copy of this gene in organisms such as yeast resulted in longer lifespans. When yeast is deprived of the gene, the lifespan of its cells decreases.

As we humans age, certain "keyboards" of the genome get turned on and played, to the detriment of normal cellular function and housekeeping. The chief finding of Guarente et al. is that Sir2 can help create an off-limits or "silent" zone, helping to prevent the messages that cause aging from getting out and shutting down the cell - an action that leads to cell paralysis, cell death, and finally the death of the organism.

The mode of action of the Sir2 gene is to produce a silencing protein that turns off sections of the genome that control ERC generation. But the gene, the protein it produces (called Sir2p), and that protein's enzymatic activity are less effective by themselves. Here lies the genius of Guarente and his colleagues as scientists: They have discovered that the process of lifespan extension as demonstrated in caloric deprivation studies can be produced more reliably without deprivation. This requires the activity of a cofactor molecule, in abundance, in concert with Sir2p. This molecule is nicotinamide adenine dinucleotide (NAD), which they conjecture is more abundant when caloric deprivation and the resulting lower metabolic rate leave a relatively large amount of it unused.
 

GENE LINK IS METABOLIC
NAD is a coenzyme, made in every cell of our bodies, that plays an important role in intracellular energy production.⁶ Without adequate levels of NAD, the genetic silencing mechanism that inhibits cellular aging does not operate, and accelerated aging results. According to Professor Guarente, NAD could well be a metabolic signal that increases the silencing activity of Sir2, shielding the cell from shutdown messages that decrease lifespan - thereby increasing lifespan. When NAD levels are high, silencing takes place.

In a component of the cell known as the nucleolus, changes are synonymous with aging. Such changes might entail the pinching off of a portion of the cell's genetic material.⁷ Circular in shape, this piece of rDNA is broken off from the chromosome, and when enough of these fragments accumulate in the cell, death follows - but not if the Sir2 gene is activated to direct the production of Sir2p and there is an abundance of NAD. Through the evolution of many organisms, from yeast, bacteria, and flatworms to rodents, primates,⁸ and humans - various versions of Sir2 exist, enough so to make the mechanism of the evolutionary link, the role that NAD plays in metabolism, viable.

ALL ROADS LEAD BACK TO SILENCING GENE
Because all avenues of investigation led back to the Sir2 gene, the thrust of the decade-long inquiry has been to understand what it does and how it works. And now, at last, Guarente thinks that they understand enough to be able to say, "If we can keep Sir2 active for longer, we may slow down aging."

To which we add: There is no evidence that the Sir2 gene is any more or less active in producing its progeny, the Sir2 protein, during caloric deprivation experiments. Therefore, if we can make the most of these proteins - if we can keep Sir2 active longer - we should be able to unlock the mechanism of lifespan extension that caloric deprivation studies have shown to be real in laboratory rodents and primates.

Ultimately, we are the stewards of our own health, so the knowledge we acquire is crucial. It gives meaning to the widening choices that confront us in the core issues. Do we settle for health maintenance, ultimately an illusory benefit because the "time bandits" are ever at work, or do we move forward to enhancement and enablement? The choice is ours, to be decided as each of us sees fit.

References

1. Norton A. Cell protein may explain diet link to longevity. ReutersHealth Feb 18, 2000; http://www.reutershealth.com/
2. Guarente L. Leonard Guarente's 703's course notes. http://web.mit.edu/biology/www/7.03index.html
3. Sinclair DA, Mills K, Guarente L. Accelerated aging and nucleolar fragmentation in yeast sgs1 mutants. Science 1997 Aug 29;277(5330):1313-6.
4. Defossez PA, Park PU, Guarente L. Vicious circles: a mechanism for yeast aging. Curr Opin Microbiol 1998 Dec;1(6):707-11.
5. Imai S-I, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 2000;403:795-800.
6. Micheli V, Simmonds HA, Sestini S, Ricci C. Importance of nicotinamide as an NAD precursor in the human erythrocyte. Arch Biochem Biophys 1990 Nov 15;283(1):40-5.
7. Sinclair DA, Guarente L. Extrachromosomal rDNA circles - a cause of aging in yeast. Cell 1997 Dec 26;91(7):1033-42.
8. Roth GS, Ingram DK, Lane MA. Calorie restriction in primates: will it work and how will we know? J Am Geriatr Soc 1999 Jul;47(7):896-903.

The Benefits of Caloric Deprivation Without Going Hungry