Why is it bad manners to look a gift horse in the mouth?Because _ as horse dealers know _ inspecting theequine oral cavity reveals the state of the animal's teeth,and thereby its age. That's why "long in the tooth" meansold or advanced in years.
Counting tree rings is more precise. Dendrochrono-logistsbore a core from a tree's outer bark to its center, and sodetermine its age, as well as the annual climaticconditions through which it grew. That's why bristleconepines, at 8,200 years the oldest known tree on earth, wereused for the initial calibration of carbon dating.
Neither tooth gazing nor core sampling can tell the age ofa human being, but chromosomes can reveal the age of acell. The cytogenetic equivalent of a tree ring is thelayered stack of DNA sequences, called telomeres, thatcap the tip ends of every chromosome. (See BioWorldToday, Oct. 4, 1995, p. 2 and April 12, 1994, p. 1.)
Every time a cell divides and replicates, the silence of anenzyme called telomerase causes it to lose some of itstelomeric length. When the last stretch is gone, the cellhas used up its life-span, the so-called Hayflick number,and starts over the hill of senescence.
Once this aging process overtakes the endothelial cellsthat pave an artery's inner wall _ namely, its tunicaintima _ that blood vessel falls prey to atherosclerosis.So a handy method of counting the endothelium'sremaining telomeric length in a patient's coronary arterywould give cardiovascular surgeons a tool to gauge thatintimal cell's life expectancy.
Such a technology peers over the horizon in the currentProceedings of the National Academy of Sciences(PNAS), dated Nov. 21, 1995. The paper presaging thisclinical capability bears the title, "Telomere length andreplicative aging in human vascular tissues." Its seniorauthor is cell biologist Calvin Harley, vice-president ofresearch at the Geron Corp., in Menlo Park, Calif.
Like other cells in the body, arterial intimal endotheliadivide in order to cope with injury to their tissue. Thisinner arterial lining consists of a smooth, seamless low-friction surface which spreads out into the interior of theheart.
White-Water Rivers; Red-Blood Arterial Turbulence
As Harley told BioWorld Today, a common cause ofinjury to the body's zigging, zagging and bifurcatingarterial network is hemodynamic stress. This is the samefluid turbulence that thrills and spills white-water rafters,and gouges out river banks. In the wild water andonrushing blood flow alike, the dynamic shear forceexerted by the fast-moving liquid molecules denudes thesurface they repeatedly buffet.
When that surface is the pristinely smooth intima,Harley's paper suggests, such injury may be "theinitiating event to vascular dysfunction." The damagedcells initiate wound healing by replicating, thendispatching platelets and macrophages to the scene of theinsult. There they form plaques, which in the case ofcoronary arteries, pile up to pinch and eventually dam theflow of blood to the heart.
"High blood pressure is a contributing cause ofatherosclerosis," Harley pointed out, "because it builds uphemodynamic stress, which brings on plaques."
To estimate the telomeric aging effect on beleaguered,plaque-forming endothelial cells, Harley and his cellbiologist associate at Geron, Edwin Chang, dissectedhuman iliac arteries. These vessels, Harley said, "are amajor area of atherotic plaque formation. The descendingaorta," he explained, "branches at two large iliac arteriesthat go down into the legs. At that bifurcation, there is amajor turbulence."
They obtained this arterial and venous material from 13autopsy cadavers, ranging in age from 3.5 years old to102. In the endothelial cells of these blood vessels theydetected an inverse relationship between donor age andtelomere length.
In each subject, they compared the telomeric length of thehemodynamically stressed iliac arteries with the calmerinternal thoracic artery, which courses down the trunkfrom below the shoulder blades. "That artery is long andstraight," Harley observed, "there's not as much dynamicblood flow in it and very little atherosclerosis."
Clinical Tool Seeks Handle
In clinical practice, Geron's PNAS paper noted, "currentmarkers for atherosclerosis include bioassays of the[blood's] plasma, the [endothelial] cytoplasm and the cellsurface . . . None of the above directly monitors the cellturnover of cardiovascular tissue.
"If the response-to-injury hypothesis for the pathogenesisof atherosclerotic plaques is correct," the articlecontinued, "then a convenient clinical assay requires amarker of cell turnover for endothelial cells . . ."
But as Harley pointed out, a biopsy of the arterial intimato sample telomeric DNA might itself induce plaqueformation.
He added that "analysis of telomere lengths may give anindication of the cells'capacity to divide, whether you'regoing to get repair of the intima, or end up with plaques."
Geron, Harley said, "sees future opportunities intelomerase modulation, primarily for therapeutics and,probably, diagnostics. We are pursuing very early stagediscussions in these areas with possible corporatepartners, probably separate ones for diagnostic andtherapeutic applications.
"Our strategy," he explained, "is to modulate either thecells' life spans or the aberrant pattern of gene expressionin these senescent cells."
Oncologist and immunologist Richard Hodes is directorof the National Institute on Aging, (NIA), in Bethesda,Md.
Commenting on Harley's PNAS paper, Hodes toldBioWorld Today in an interview, "His findings are ofgreat interest as they relate to the amount of cellreplication that may be a part of the pathologic process.But the results, as I interpret them, have their principaland immediate use in stimulating further research in thatarea _ the role of cell replication and replicativepotential in the pathogenic process of atherosclerosis.
Hodes concluded, "The value of such measurements inimmediate diagnosis is not at present a practical reality.
"The basis questions still remaining to be answered," theNIA director indicated, "have to do with directdemonstrations of the role of telomere length, and itsregulation, in normal aging as well as in pathologicprocesses." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.