Dr. Clarfield is the Chief of Geriatrics, Soroka Hospital Centre, Professor, Faculty of Medicine, Ben Gurion University of the Negev, Beersheva, Israel. Professor (Adjunct), Division of Geriatric Medicine, McGill University and Jewish General Hospital, Montreal, QC, Canada.

Have you ever heard of the wonderful one-hoss shay.
That was built in such a logical way.
It ran a hundred years to a day.
And then, of a sudden, it-ah, but stay.
I'll tell you what happened without delay.
Scaring the parson into fits.
Frightening people out of their wits,
Have you ever heard of that, I say?
Oliver Wendell Holmes

My own grandfather died when he was over 100 years old. Why? We don't know because, for religious reasons, no autopsy was performed. Even if it had been, what might it have shown? Possibly a Whitmore stage A or B carcinoma of the prostate, maybe a tumour in the cecum, perhaps the scars of previous myocardial infarcts, but very likely nothing that a pathologist could confidently have labeled as the cause of death.

So why do old people die? Is aging a disease or is it simply a normal life stage? Or, as Crapo and Fries have so elegantly described in their book "Vitality and Aging" (from which the above quote was lifted), is it simply the final disintegration of the old buggy?

In order to come to some understanding as to what aging actually comprises, it might be helpful to examine what pertains in other mammalian species.

Anna Liachenko, BSc, MSc,
Managing Editor,
Geriatrics & Aging

We take for granted that aging is a natural process. We accept this belief, even as we witness the disease-driven ravages of old age. We separate the diseases of old age from the process itself, as if the diseases of old age take place against a backdrop of biological changes that are somehow removed and independent of the diseases themselves. This separation of the two--aging and the classic diseases of the elderly--may be false and may undermine our ability to understand the real nature of aging.

A number of extraordinary new studies may forever jettison this dichotomy between the diseases that seem to characterize old age and the so-called natural process of aging. Some of the diseases that are characteristic of old age are senile dementia, cataracts, arteriosclerosis, cancer, diabetes, hypertension, osteoporosis, etc. We need to ask whether these diseases are a normal part of the aging process. Alternatively , we could pose the more counter-intuitive and, perhaps, more difficult question, "Is aging a Disease"?

Two recent studies offer unprecedented insight into the genetics of aging, along with evidence for a "general and global explanation of the process itself". If correct, these studies are suggesting that a small set of genes involved in cell division might have broad effects throughout the body and cause the wide spectrum of phenotypic, metabolic, physiological and cellular changes that we associate with aging.

These aging studies are based upon a revolutionary new technology, known as microarrays or, as they are called in the popular press, "gene chips". The reference to chips and microchips is not a misnomer. Gene chips are actually based upon the same technological principles and same technologies that are used in making silicon-based chips. Silicon fabrication technology and various photolithographically-layered masks are used to lay down thousands, or even hundreds of thousands of oligonucleotides of DNA on a postage-stamp-size piece of glass; amplified genetic samples can then be hybridized with these pieces of DNA. Using lasers to scan the chips, an enormous amount of genetic information can be ascertained. This technology promises for biology some of the extraordinary economies and efficiencies that have transformed all of electronics. The implications for aging research could be enormous.

The study supports a possible global explanation of aging as "an impairment of the machinery needed for the normal separation of the chromosomes during cell division."

In the March 31, 2000 edition of Science (page 2486), Richard Lerner and Peter Schultz report the use of microarrays to take a snapshot of aging-related changes in fibroblasts. The study supports a possible global explanation of aging as "an impairment of the machinery needed for the normal separation of the chromosomes during cell division." The study makes note of an "up-regulation of genes involved with inflammation, which has been linked with a variety of ills of old age, including heart disease and Alzheimer's" (in this regard, it may be supporting the recently-confirmed efficacy of NSAIDs and COX-2 inhibitors). Perhaps even more interesting is the "down-regulation of 15 genes that help control mitosis". These genes are "known to cause genetic instability, a known contributor to cancer." The author of the study, Richard Lerner is quoted as saying that "aging is predominantly a disease of mismanagement of cell division checkpoints". The gene chip study also seems to confirm increasing evidence that a very small percentage of our total genetic endowment plays a role in aging. The researchers found that of the 6,300 genes checked, only 63 genes changed with age. This small ratio of age-related gene expression coincides with an important study by Richard Weindruch and Tomas Prolla of the University of Wisconsin, who used microarrays to probe aging in the skeletal muscle of mice (Science 27, August 1999, p. 1390). In this study, it was found that less than 1% of those genes assayed increased or decreased activity.

Perhaps of even deeper interest to the whole question of whether aging is a disease, is the work performed by the Scripps team, comparing aging fibroblasts with fibroblasts from children suffering from Hutchinson-Gilford's progeria. A rare condition, that is caused by a single gene defect, Hutchinson-Gilford children experience what, phenotypically, seems to be an accelerated form of aging. That a single genetic defect could cause such a wide spectrum of aging-related alterations, has long been a source of curiosity and interest. These children appear old at ten years of age and rarely live past their eighteenth birthday.

The Scripps study seems to confirm that Hutchinson-Gilford patients do not just mimic aging phenotypically, but that they are indeed experiencing accelerated aging. This extraordinary result lays out part of what might emerge as a genetic program that dictates the aging process. Apart from outward manifestations of aging, Hutchinson-Gilford victims experience rapid onset of old skin, hair loss, arteriosclerosis, cancer, osteoporosis and hypertension. These results force us to ask whether these diseases, the diseases that take the largest toll on humanity, are, perhaps, part of the pathophysiology of aging.

These results are fascinating and as genetic chip technologies advance and as more information emerges from the human genome project, deeper insights will become possible into the genetics of aging. Aging, cancer, and many of the most common diseases of old age may indeed be part of a similar genetic complex, that is regulated by a surprisingly small gene set. Molecular medicine in the very near future may begin to address these diseases at the genetic level. With cellular markers for aging we may begin to develop means to modify genes in order to optimize our maximum life span and to lessen the burden of the most common diseases of old age.

Geriatrics & Aging will be at the forefront in reporting these exciting developments. I would be very interested in hearing your thoughts on whether "Aging is a Disease", please e-mail me at: geriatrics@ribosome.com.