Humans began seeking out ways to stave off the decrepitude of aginglong before Ponce de Leon set off on his famed search for thefountain of youth. Unfortunately, science has yet to concoct an elixirthat will cure all age-related ills.
Now researchers at the Picower Institute for Medical Research inManhasset, N.Y., report that it might be possible, in many cases, toprotect the cardiovascular system and kidneys from the ravages ofaging well into the last decades of life.
The answer appears to lie in aminoguanidine, a substance thatneutralizes a common chemical reaction, called glycation, whichleads over time to the accumulation of damaging protein deposits inblood vessels through the body.
Glycation is complex and its evolution is poorly understood, saidmolecular biologist Yong Ming Li, a member of the research team.Researchers have found, however, that it results from the unhealthymatrimony of proteins with such sugars as glucose.
When the two marry in the cardiovascular system and kidney, theysnag other proteins _ albumen, antibodies and collagen, amongothers _ and form deposits which harden blood vessels and limittheir exquisite physiologic responsiveness to the changing dynamicsof blood pressure and flow.
Protein deposits in blood vessels leading to the heart can causehypertrophy, which weakens the heart muscle and limits its pumpingpower. Deposits in the kidney interfere with a person's ability toexcrete metabolic waste.
"This leads to the accumulation of bioproducts that might otherwisehave been cleared from the bloodstream," Li said.
In essence, the new research suggests that age-related deterioration ofheart and kidney function may share at least one common cause,which may contribute to progressive tissue damage and organ failure,Li and his coworkers' report in the April 29, 1996, Proceedings ofthe National Academy of Sciences (PNAS).
The impetus for the work was research into heart and kidneycomplications in diabetes, showing that the higher the blood sugarlevel of an uncontrolled diabetic, the greater the risk of vascular andkidney damage.
Previous studies have linked the cause of this damage to byproductsof glycation _ called advanced glycation end products, or AGEs.Several AGEs have been identified. Among them are compoundsnamed carboxymetholysine, pyrroline, and pentizidone. Resear-chersbelieve that many others have not been discovered yet, Li said.
The Tie That Binds
Despite these research efforts, no one fully understands the tie thatbinds glucose and protein. But the linkage is so pronounced that akitchen experimenter who marinated beef in sugar could glycate thebeef proteins _ so long as the combination remained free of bacteria.
Aminoguanadine appears to disrupt this tie by binding with bloodsugars so that they can no longer interact with proteins.
The Picower team used two groups of rats, one more susceptible toage-related kidney damage than the other, to demonstrate that earlyintervention with aminoguanadine "may impart significant protectionagainst the progressive cardiovascular and renal decline afflicting thelast decades of life," according to the PNAS article.
As expected, normal aging increased the burden of AGEs in olderrats' hearts and tissues to a level much higher than is seen in youngerrats. In the untreated rats, this build-up could be detected, in part, byweighing the body, heart and kidneys of sacrificed research animals.In contrast, the organs of treated rats did not show any weight gain.
So promising is this potential treatment that Alteon Inc., of Ramsey,N.J., was founded in 1986 to develop aminoguanadine as a potentialtreatment for diabetes-related complications in man.
The firm has since won authorization of a generic name _pimagedine _ for the chemical, which it is developing in partnershipwith Hoechst Marion Roussel, in Frankfurt, and YamanouchiPharmaceuticals, in Tokyo.
A Potential Blockbuster
"It has potential to be a blockbuster drug eventually," said JereGoyan, Alteon's chief operating officer and president. "It works inanimal models. Let's hope it extrapolates to man."
The company currently is recruiting subjects for two Phase III trialsof the drug. One, which is expected to be closed to recruitment inJuly, will examine pimagedine's effectiveness in more than 560people with Type I diabetes. The second will examine the drug'seffectiveness in more than 900 people with Type II diabetes.Recruitment will end sometime next year, Goyan said. The studieswill take three or four years.
Li asserted that many other researchers are working in this area aswell. Several papers are scheduled for release at the AmericanDiabetes Association meeting in San Francisco in June. Many of theresearchers are trying to develop new inhibitors for AGE; others aretrying to devise tests that will pinpoint those who would benefit fromtreatment, Li said. n
-- Steve Sternberg Special To BioWorld Today
(c) 1997 American Health Consultants. All rights reserved.