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this site is maintained by Nona Poulton under the supervision of Dr. A. Malcolm Campbell as part of the course requirements of Genomics at Davidson College, Davidson NC

Fountain of Youth or Just another Gene?

p21 implicated in senescence and age-related diseases

What does it mean to age?

Aging can bring changes in perspective, both good and bad, knowledge and, hopefully, a little wisdom. It does seem a little strange that our culture celebrates the arrival of a birthday of a younger person with great fanfare, but past a certain age, a birthday is looked upon with sadness, dread, and is sometimes flat ignored. Perhaps in the future with developing technologies and movement toward an aging baby boomer society, our culture can start to consider aging in a more positive light.

Until the fourth or fifth decade of life, the finality of aging oftentimes is irrelevant even though it is a lifelong process. Childhood, adolescence and young adulthood are typically filled with feelings of immortality. It's often only when physical changes arise that one accepts that aging has consequences.

Every living thing dies in one way or another, a mysterious occurrence that is dreaded in much of western society. The causes of aging are not fully understood, but most scientists theorize that aging is probably the result of a combination of factors including your genes, your environment and your lifestyle. According to the National Institute on Aging, theories of aging are generally grouped into two categories: genetically programmed theories, and environmental damage theories.

Genetic theories: These theories suggest that biological agendas in your body cause aging to occur on a set timeline. For example, one theory suggests that your immune system is responsible; it is programmed to decline, leading to disease and therefore aging and death. Another points to your hormones, proposing that throughout your life programmed changes in the production of hormones regulate your aging.

Environmental theories: Aging also results from environmental factors that gradually damage your body and interfere with its normal function. For example, the wear-and-tear theory suggests that the cells and tissues in your body have essential parts that simply wear out over time. Another theory indicates that byproducts of your cells' normal metabolism (free radicals) damage the ability of your cells to work normally until eventually your organs no longer work. Environmental factors such as sunlight and toxins can also cause free radicals that trigger wear. Other theories suggest that genetic mutations or impaired protein synthesis - the process by which your cells produce protein - are behind damaged cells. For more information on particular theories, refer to http://www.infoaging.org/bio-h.html

How long can you live?

One hundred twenty-two years is the longest documented human life span. Though a life span this long is rare, improvements in medicine, science and technology in the last century have helped more people live longer, healthier lives. In the early 1900s the average life expectancy in the United States at birth was only about 50 years. Today, it's close to 77.

What is more, the 85-plus bracket is the fastest-growing demographic segment in the United States, although the number of people 100 and older has exploded as well. The U.S. Census Bureau projects that the number of people age 85 and older could increase from 4 million in 2000 to 19 million by 2050, probably due to more than 70 million baby boomers reaching this age.One hundred twenty-two years is the longest documented human life span. Though a life span this long is rare, improvements in medicine, science and technology in the last century have helped more people live longer, healthier lives. In the early 1900s the average life expectancy in the United States at birth was only about 50 years. Today, it's close to 77.
What is more, the 85-plus bracket is the fastest-growing demographic segment in the United States, although the number of people 100 and older has exploded as well. The U.S. Census Bureau projects that the number of people age 85 and older could increase from 4 million in 2000 to 19 million by 2050, probably due to more than 70 million baby boomers reaching this age. For more information, please refer to http://www.infoaging.org/bio-h.html.

The Aging Gene

The p21 protein has been implicated in the aging process. Before the publication of splash paper relating it to cancer, arthritis, heart disease, and other age-related events, it was already known to have the ability to cause cells to stop dividing. This simple mechanism seems to be a big cause of the aging process.
CDKN1A is the gene that encodes p21, a 21-kd protein (where p21 gets its name) that is found in immunoprecipitates of cyclin A, cyclin D1, cyclin E, and CDK2. From this data, it was inferred that it was indeed cylcin-dependent and is involved with many known ‘aging’ genes. p21 can interact with proliferating cell nuclear antigen (PCNA), a DNA polymerase accessory factor, meaning it plays a regulatory role in S phase DNA replication and DNA damage repair (as well as the G1 phase discussed later). The protein is specifically cleaved by CASP3 and CASP3-like caspases, leading to activation of CDK2, and may be instrumental in the execution of apoptosis following caspase activation. NCBI search shows that there are two alternatively spliced variants, which encode an identical protein. To see the map of the chromosome with surrounding proteins go here.

Chime image of p21

p21 is a potent inhibitor of cyclin-dependent kinase activities that are required for the progression of cell division from the G1 phase to S phase of mitosis. Overexpression causes growth-arrest in many cell types. Transcription of p21 is induced following DNA damage (oxidative damage), oftentimes resulting from the accumulation of p53, a tumor suppressor gene, which is mutated in many tumors. It is also thought to be responsible for activating p53in some situations. These findings provide a model in which it may be possible to help influence the growth of cancer cells, even with a mutated p53 gene.

Expression of p21 has been shown to be sufficient to upregulate genes implicated in atherosclerosis, Alzheimer's disease, amyloidosis, and arthritis, all key players in senescence. On a cellular level, many markers of cell aging are expressed after the transcription of p21.

The Aging Gene: Fact and Fiction

The popular press jumped on the discovery of p21 function due to the vested interest in staying ‘forever young’. p21 was always known to be a cyclin-dependent kinase inhibitor, but a PNAS paper presented data that implicated it in many age-related diseases. The popular press was vested in the PNAS article because of the number and variety of senescence-related genes that are affected by p21. A quick fix to death was implied in both the cnn and bbc articles (http://www.cnn.com/HEALTH/library/HA/00040.html and http://news.bbc.co.uk/1/hi/health/708540.stm respectively), although each article is reasonable in its claims.
In the article entitled “Scientists target a master gene linked to cancer, arthritis, and other age-related diseases” published on CNN.com, authors write, “Most scientists do not believe it possible to ‘cure’ old age. They say too many processes underlie aging, including the workings of genes and the damage done by radiation and chemicals. But scientists also know that young cells of the body repair themselves better than old cells do, and understanding how this occurs could help people stay healthier as they age.” This reporting is accurate in that curing old age is a somewhat farfetched idea. The fountain of youth will never truly be found. The article in PNAS merely alluded to the fact that these findings may be able to provide a basis for gene therapy for age-related disorders. Although accurate, the CNN article implies impossible science with its title and undertones.

The British article, published one day later, entitled “Key old-age gene found” provides nearly the same information. It provides a brief overview of how p21 can be related to many diseases. It focuses on p21s link to heart disease and arthritis, presumably because they are the most widespread and cause the biggest problems on a large scale. They also mention at the end that the gene is not really a cure for old age, but merely a next step in understanding it.

The PNAS article’s main claims about p21 as presented in the abstract are:
1. Induction of p21 triggers growth arrest in cells associated with senescence and response to injury. Over expression of p21 from an inducible promoter in a human cell line induces growth arrest and phenotypic senescence.
2. p21 expression selectively inhibits a set of genes involved in mitosis, DNA replication, segregation, and repair.
4. The kinetics of inhibition of these genes on p21 induction parallels the onset of growth arrest, and their re-expression on release from p21 precedes the reentry of cells into cell cycle, indicating that inhibition of cell-cycle progression genes is a mechanism of p21-induced growth arrest.
5. p21 also up-regulates multiple genes that have been associated with senescence or implicated in age-related diseases, including atherosclerosis, Alzheimer's disease, amyloidosis, and arthritis.
6. Several p21-induced genes encode secreted proteins with effects on cell growth and apoptosis, and media from p21-induced cells were found to have antiapoptotic and mitogenic activity.
8. The effects of p21 induction on gene expression in senescent cells may contribute to the pathogenesis of cancer and age-related diseases.

Thus, the primary research article focuses more on the actual function of the protein in a detailed way rather than the widespread effect it may have on aging in general. For example, the scientific article states that p21 up-regulates genes that have been associated with arthritis, while the BBC reports that, “Other p21-activated genes produce various proteins and enzymes that contribute to heart disease and arthritis”. The language of the two articles is such that even though they say the same thing logically, they present the information in a different way. The popular press article is surer sounding about its statement even though it is based on the findings of the PNAS article.

Even though the popular press articles sited most things very accurately, the end sentiment a reader gets after reading the article is very different. The PNAS paper focuses on the biology behind p21 and only suggests the age-related functions, whereas the popular press articles were very bold in their assumptions that the age-link was found in p21. The popular press articles leave out important details like p53s involvement in the process and the fact that the protein was only shown to be able to bind to some proteins, without evidence of functional changes that come about due to this binding activity.

References:

Chime image from: http://www.rcsb.org/pdb

Information on p21: http://www.ncbi.nih.gov/ and http://www3.ncbi.nlm.nih.gov/Omim/

Statistics from: http://www.infoaging.org/bio-h.html

Chang B, K Watanabe, E V Broude, J Fang, J C Poole, T V Kalinichenko, and IB Roninson. (2000) Effects of p21Waf1/Cip1/Sdi1 on cellular gene expression: Implications for carcinogenesis, senescence, and age-related diseases Proc. Natl. Acad. Sci. USA. 97 (8): 4291-4296. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=18232

Hollingham, Richard. “Key old-age gene found.” http://news.bbc.co.uk. Posted April 11, 2002.

Rowland R. and Reuters. “Scientists target a master gene linked to cancer, arthritis andother age-related diseases.” http://www.cnn.com Posted April 10, 2002.