By David N. Leff

While more and more people are living happily past the century mark, many of these codgers, geezers and gaffers pay a price for their advanced years. The wages of longevity are paid for in cancers, cardiovascular ailments and neurodegenerative diseases ¿ to mention the main penalties of codging, geezing and gaffing.

Why the aging and aged population is singled out to pay these taxes of advanced years has been puzzling biomedical researchers for the past 50 years. Their controversial culprit is, ironically, oxygen ¿ more properly, reactive oxygen species (ROS) ¿ perpetrator of oxidative damage in cellular DNA.

¿There was a long-standing question,¿ observed molecular biologist Arlan Richardson, ¿as to whether or not oxidative damage increased with age.¿ Richardson is director of the Longevity and Aging Center at the University of Texas, San Antonio. ¿Part of the problem,¿ he continued, ¿was that in the past there were about as many studies that said ROS increased with age as claimed the contrary.

¿ROS impacts on the human condition in two ways,¿ he explained. ¿First, people encounter ROS from the external environment ¿ ultraviolet or other types of radiation, different kinds of chemicals. But an important component, which I think we have ignored, is that cells during normal endogenous metabolism generate ROS by a variety of pathways. One of the main sources is mitochondria from the electron transport to oxygen. So I think a large amount of this ROS oxidative damage occurs with normal metabolism, and will increase with age.

¿We don¿t know whether more such DNA lesions are being produced as the cells get older,¿ Richardson said, ¿or that the cells are more sensitive, and the ROS that are normally produced are not removed efficiently, or are more prone to damage DNA. And this damage is primarily if not totally from endogenous sources. We know that age is the No. 1 risk factor for cancers, and this could be related to the fact that there is a greater accumulation of oxidative damage to DNA, which could potentially lead to mutations, chromosomal rearrangements and genomic instability, which are the first steps in cancer.¿

He surmised that it might also apply to neurodegenerative diseases, such as Alzheimer¿s and Parkinson¿s. ¿There is a general feeling that a buildup of oxidative damage would lead to the death of the cells, and if these are neurons, they are not going to be replaced,¿ he observed.

Findings Refute Long-Held ROS Dogmas

Richardson is senior author of a paper in the current Proceedings of the National Academy of Sciences (PNAS), dated Aug. 28, 2001, but released electronically Tuesday. Its title poses the blunt question: ¿Does oxidative damage to DNA increase with age?¿

¿We report two major findings,¿ he told BioWorld Today. ¿The first is the fact that there was this universal increase in oxidative damage to DNA. So using a new methodology in which we could accurately measure DNA damage, we did an in vivo study and were able to show that in essentially all cases that we looked at ¿ many strains of male and female rodents ¿ we saw this increase in oxidative damage.

¿Our second conclusion was that the increase of oxidative damage with age doesn¿t appear to be due to the ability of cells to remove the damaged DNA. Somehow our older experimental animals were less able to take care of the ROS that cause those oxidative lesions. So this increase in damage that people had thought before was because cells just didn¿t have the ability to repair the DNA doesn¿t appear to be the case at all. The rate of removal of this type of damage was no different. It appeared that the older animals, in some way that we don¿t know exactly how, are more sensitive. There¿s more damage that occurs to these cells, and we think that probably their antioxidant system is compromised in such a way where there¿s just more ROS generated.

¿We looked at a variety of tissues in a variety of animals,¿ Richardson recounted. ¿Oftentimes, people would report they had seen this increase in rat liver, and no change in mouse heart, so you didn¿t know if the difference was a technical problem, or inherent in the animal model. We saw oxidative damage in every tissue that we looked at, in every rodent strain. It varied from a 20 percent increase over life span to almost 200 percent, depending on the tissue that we examined ¿ liver, heart, brain, kidney, skeletal muscle and mitochondrial DNA.¿

Besides the ravages of ROS, a separate determinant of aging is caloric intake.

¿When you talked about aging,¿ Richardson recalled, ¿up until a few years ago, the only way you could extend the life span was by dietary restrictions. Rodent studies in the ¿60s, ¿70s and ¿80s showed that animals on low-calorie regimens were living longer, or aging more slowly. They had less pathology. Physiological functions that declined with age were improved by dietary restrictions. In this PNAS paper we were asking: If the age-related increase in oxidative damage played a role in aging, then we should reverse this by dietary restriction, which has an anti-aging effect.¿

Back To Basics With Ticking Cancer Clock

¿Certainly in mouse tissues we did see a significant reduction in oxidative damage in every case that we looked at. In the rat tissues it wasn¿t quite as clean-cut. If oxidative damage can accumulate at the same rate in the diet-restricted rats as in the ad-libidum rats, we would say it had nothing to do with aging or age-related disease because we know that we can alter them with dietary restriction. I would say that almost 90 percent of the things that change with age are improved by dietary restrictions. It¿s a nice method of retarding age, but it¿s a difficult system to ask how it¿s working at the molecular level.¿

Reverting to cancer as a time clock punch card of superannuation, Richardson observed: ¿When most people think of cancer, they say. Well, what was in the drinking water? Am I living close to power lines? Yeah, I shouldn¿t have overdone my sunbathing.¿ But probably the major player in this,¿ he concluded, ¿is just normal metabolism, which technically we can¿t do much about ¿ yet. Controlling that is what I see as the big payoff in the future.¿