Aging : Protein Crosslinking and DNA Repair

by National Institute on Aging

(Page 8 of 15)

Blood sugar - glucose - is another suspect in cellular deterioration. In a process called non-enzymatic glycosylation or glycation, glucose molecules attach themselves to proteins, setting in motion a chain of chemical reactions that ends in the proteins binding together or crosslinking, thus altering their biological and structural roles. The process is slow and complex, but crosslinked proteins accumulate with time and eventually disrupt cellular function.

Investigators suspect that glycation and oxidation are interdependent processes since free radicals and crosslinks seem to accelerate the formation of one another.

Crosslinks, also known as advanced glycation end products (AGEs), seem to "stiffen" tissues and may cause some of the deterioration associated with aging. Collagen, for instance, the most common protein molecule in our bodies, forms the connective tissue that provides structure and support for organs and joints. When glucose binds with collagen - as it tends to do as we age - this normally supple protein loses much of its flexibility. As a result, lungs, arteries, tendons, and other tissues stiffen and become less efficient. In the circulatory system, AGEs may help trap LDL (the so-called "bad") cholesterol in artery walls, and thus contribute to the development of atherosclerosis. They also have been linked to clouded lenses (cataracts), reduced kidney function (nephropathy), and age-related neurological disorders including Alzheimer's disease.

These conditions appear at younger ages in people with diabetes, who have high glucose levels (hyperglycemia). Glycosylated hemoglobin in red blood cells, for instance, is an important marker doctors use to measure hyperglycemia. While the physiological effects of glycosylated hemoglobin are unclear, the disease it helps doctors detect - diabetes - is sometimes considered an accelerated model of aging. Not only do the complications of diabetes mimic the physiologic changes that can accompany old age, but people with this condition have shorter-than-average life expectancies. As a result, much research on crosslinking has focused on its relationship to diabetes as well as aging.

Just as the body has antioxidants to fight freeradical damage, it has other guardians, immune cells called macrophages, which combat glycation. Macrophages with special receptors for AGEs seek out and engulf them. Once AGEs are broken down, they are ejected into the blood stream where they are filtered out by the kidneys and eliminated in urine.

The only apparent drawback to this defense system is that it is not complete and levels of AGEs increase steadily with age. One reason is that kidney function tends to decline with advancing age. Another is that macrophages, like certain other components of the immune system, become less active.

Why this happens is not known, but immunologists are beginning to learn more about how the immune system affects, and is affected by aging. And in the meantime, diabetes researchers are investigating drugs that could supplement the body's natural defenses by blocking AGEs formation.

Crosslinking interests gerontologists for several reasons. It is associated with disorders that are common among older people, such as diabetes and heart disease; it progresses with age; and AGEs are potential targets for drugs. In addition, cross-linking may play a role in damage to DNA, which is another important focus for research on aging.

DNA Repair and Synthesis

In the normal wear and tear of cellular life, DNA undergoes continual damage. Attacked by oxygen radicals, ultraviolet light, and other toxic agents, it suffers damage in the form of deletions, or deleted sections, and mutations, or changes in the sequence of DNA bases that make up the genetic code. In addition, sometimes the DNA replication machinery makes an error.

Biologists theorize that this DNA damage, which gradually accumulates, leads to malfunctioning genes, proteins, cells, and, as the years go by, deteriorating tissues and organs.

Not surprisingly, numerous enzyme systems in the cell have evolved to detect and repair damaged DNA. For repair, transcription, and replication to occur, the double-helical structure that makes up DNA must be partially unwound. Enzymes called helicases do the unwinding. Investigators have found that people who have Werner's syndrome (WS), a rare disease with several features of premature aging, have a defect in one of their helicases. George Martin, M.D., of the University of Washington and other investigators are exploring the mechanisms involved in DNA repair in WS and similar disorders, collectively known as progeroid syndromes. This research could help explain why DNA repair becomes less efficient during normal human aging.

The repair process interests gerontologists for many reasons. It is known that an animal's ability to repair certain types of DNA damage is directly related to the lifespan of its species. Humans repair DNA, for example, more quickly and efficiently than mice or other animals with shorter lifespans. This suggests that DNA damage and repair are in some way part of the aging puzzle.

In addition, researchers have found defects in DNA repair in people with a genetic or familial susceptibility to cancer. If DNA repair processes decline with age while damage accumulates as scientists hypothesize, it could help explain why cancer is more common among older people.

Gerontologists who study DNA damage and repair have begun to uncover numerous complexities. Even within a single organism, repair rates can vary among cells, with the most efficient repair going on in germ (sperm and egg) cells. Moreover, certain genes are repaired more quickly than others, including those that regulate cell proliferation.

Especially intriguing is repair to a kind of DNA that resides not in the cell's nucleus but in its mitochondria. These small organelles are the principal sites of metabolism and energy production, and cells have hundreds of them. Investigators suspect mitochondrial DNA is injured at a much greater rate than nuclear DNA, possibly because the mitochondria produce a stream of damaging oxygen radicals during metabolism. Adding to its vulnerability, mitochondrial DNA is unprotected by the protein coat that helps shield DNA in the nucleus from damage.

Research has shown that mitochondrial DNA damage increases exponentially with age, and as a result, energy production in cells diminishes over time. These changes may cause declines in physiological performance, and may play a role in the development of age-related diseases. Investigators are examining how much mitochondrial DNA damage occurs in specific parts of the body such as the brain, what causes the damage, and whether it can be prevented.

About the Author

www.nia.nih.gov
NIA, one of the 27 Institutes and Centers of NIH, leads a broad scientific effort to understand the nature of aging and to extend the healthy, active years of life. In 1974, Congress granted authority to form NIA to provide leadership in aging research, training, health information dissemination, and other programs relevant to aging and older people.