Heath and Aging

Biology of Aging

What happens when DNA becomes damaged?

The impact of age, of course, is not limited to organisms. You drive a brand new car off the lot, and ideally it’s in perfect working condition. But by the time it reaches the 100,000 mile mark, the car doesn’t run quite like it used to. Or, that lovely walking path you discovered when you first moved into your home has now become weathered, the weeds are overgrown, and some of the asphalt has buckled.

Like the car and the walking path, over time your DNA accumulates damage. That’s normal. Our DNA suffers millions of damaging events each day. Fortunately, our cells have powerful mechanisms to repair damage and, by and large, these mechanisms remain active and functional through old age. However, over time, some damage will fail to be repaired and will stay in our DNA. Scientists think this damage—and a decrease in the body’s ability to fix itself—may be an important component of aging. Most DNA damage is harmless—for example, small errors in DNA code, called mutations, are harmless. Other types of DNA damage, for example, when a DNA strand breaks, can have more serious ramifications. Fixing a break in a DNA strand is a complex operation and it is more likely the body will make mistakes when attempting this repair—mistakes that could shorten lifespan.

Another kind of DNA damage build-up occurs when a cell divides and passes its genetic information on to its two daughter cells. During cell division, the telomere, a stretch of DNA at each end of a chromosome that doesn’t encode any proteins but instead protects the protein-encoding part of the DNA, becomes shorter. When the telomere becomes too short, it can no longer protect the cell’s DNA, leaving the cell at risk for serious damage. In most cells, telomere length cannot be restored. Extreme telomere shortening triggers an SOS response, and the cell will do one of three things: stop replicating by turning itself off, becoming what is known as senescent; stop replicating by dying, called apoptosis; or continue to divide, becoming abnormal and potentially dangerous (for example, leading to cancer).

Telomerase

Telomeres shorten each time a cell divides. In most cells, the telomeres eventually reach a critical length when the cells stop proliferating and become senescent.

But, in certain cells, like sperm and egg cells, the enzyme telomerase restores telomeres to the ends of chromosomes. This telomere lengthening insures that the cells can continue to safely divide and multiply. Investigators have shown that telomerase is activated in most immortal cancer cells, since telomeres do not shorten when cancer cells divide.

A chromosome of an adult cell with the telomere labeled
'Telomere shortens after multiple replications'
'Telomere at senescence'
'Chromosome of immortal cell' with telomerase restoring telomeres

Telomere Length: Health Span vs. Lifespan?

Aging biologists are investigating whether humans' telomere length is associated with lifespan, health span, or both. In one study of people age 85 years and older, researchers found telomere length was not associated with longevity, at least not in the oldest-old. In another study, researchers analyzing DNA samples from centenarians found that telomeres of healthy centenarians were significantly longer than those of unhealthy centenarians, suggesting that telomere length may be associated with health span.

Scientists are interested in senescent cells because, although they are turned off, they still work on many levels. For instance, they continue to interact with other cells by both sending and receiving signals. However, senescent cells are different from their earlier selves. They cannot die, and they release molecules that lead to an increased risk for diseases, particularly cancer.

The relationship among cell senescence, cancer, and aging is an area of ongoing investigation. When we are young, cell senescence may be critical in helping to suppress cancer. Senescence makes the cell stop replicating when its telomeres become too short, or when the cell cannot repair other damage to its DNA. Thus, senescence prevents severely damaged cells from producing abnormal and perhaps cancerous daughter cells. However, later in life, cell senescence may actually raise the risk of cancer by releasing certain molecules that make the cells more vulnerable to abnormal function.

Young fibroblasts
orderly-appearing cells
 
 
Old fibroblasts, nearing senescence
cells with a more randomly-appearing organization
Courtesy of Leonard Hayflick, Ph.D.,
Univ. of California, San Diego

Consider fibroblasts, cells that divide about 60 times before turning off. Normally, fibroblasts hold skin and other tissues together via an underlying structure, a scaffold outside the cell, called the extracellular matrix. The extracellular matrix also helps to control the growth of other cells. When fibroblasts turn off, they emit molecules that can change the extracellular matrix and cause inflammation. This disturbs the tissue’s function and contributes to aging. At the same time, the breakdown of the extracellular matrix may contribute to increased risk of cancer with age.

Learning why—on a biological level—cell senescence goes from being beneficial early in life to having detrimental effects later in life may reveal some important clues about aging.

 

The Future of Aging Research: Stem Cells & Regenerative Medicine 

Imagine if doctors were able to reverse age-related, chronic degeneration and bring the body back to its original health and vigor. While far too early to know if regenerative medicine will ever be a reality, research on stem cells opens up the possibility.

Stem cells can come from a variety of sources. Adult stem cells are candidates for regenerative medicine approaches for several reasons—doctors can use the patient’s own stem cells; stem cells can develop into nearly any type of cell based on where they are inserted and other factors; and stem cells continue to function normally during an almost infinite number of cell divisions, making them essentially immortal. Therefore, in theory, if stem cells were inserted in a damaged part of the body, they could develop into area-specific cells that could potentially restore function. But does that work? That’s what researchers are trying to find out.

Findings from early research on regenerative medicine, primarily in animal models, show potential for stem cell treatment. For example, inserting mouse ovarian cells created from a female donor’s stem cells into infertile mice restored the mice’s ability to reproduce. Another study in mice found that function could be restored to injured muscle tissue by reactivating existing stem cells rather than transplanting new ones. The ability to reactivate dormant adult stem cells continues to be investigated. In a 2010 Italian study with human participants, researchers restored vision to some people with severe burns on the outmost layer of their eyes (the cornea) by using stem cells grown in the laboratory.

Researchers are also looking for alternatives to stem cells that have similar healing abilities and can be used in regenerative medicine. It appears that certain cells, like skin cells, can be reprogrammed to act as artificial stem cells, called induced pluripotent cells.

Many questions about stem cell (and induced pluripotent cell) therapy need to be answered: Do older adults have enough stem cells for this type of therapy or do they need to be donated from someone else? Would creating stem cells from an older person’s skin cells work? Would stem cell therapy restore health and vigor to an older person or only work in a younger person? How would stem cell therapy work on the cellular level—would stem cells replace the non-functioning cells or would they reactivate and repair the damaged cells? Would stem cell therapy work in all areas of the body, or only in some areas?

While many questions remain, the prospect of regenerative medicine could have important implications for the treatment of many degenerative diseases.

Publication Date: November 2011
Page Last Updated: January 19, 2012