Wholemount immunostaining for a Keratin-15-GFP transgenic reporter (green) on mouse tail epidermis labels a population of stem cells that undergoes age-associated changes. Co-stained with keratin 15-protein (red) and DAPI (blue).
Credit: Image courtesy of Centre for Genomic Regulation
Aging is a complex biological process whereby the functional capacity of the body diminishes with time, ultimately leading to the death of the individual. However, aging is also associated with the onset of many diseases, including cancer, which is often called a “disease of aging.” While aging has major effects on the individual, it also represents a significant burden on society as a major healthcare cost. Therefore, it is of chief importance to understand the normal process of aging to help improve not only the lifespan of individuals, but also their healthspan; in other words, to enable people to live longer, healthier lives.
Despite significant worldwide research, the causes of aging remain poorly understood. In particular, why the body undergoes a functional decline over the course of time is not entirely clear. Now, a new study from researchers at the CRG has uncovered a significant clue in understanding how aging may occur, and how this may promote the development of diseases such as cancer.
In this study, the researchers studied the skin of young and old mice, as the skin is one of the most obvious tissues to undergo aging. Indeed many of the visible features of aging are the result of skin aging, including loss of hair growth, wrinkling and thinning of the skin and a reduced wound-healing ability.
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In the skin, as in the rest of the body, the tissue is constantly in a state of turnover, replenishing itself by replacing dead and damaged cells with new healthy ones. To achieve this, each tissue relies on populations of specialized cells known as stem cells. “These cells are unique in their ability, as they are able to grow and differentiate into all the other different cells types in the tissue, as well as tolerating stress and damage better than non-stem cells. This process of rejuvenation and renewal is something that was thought to occur all throughout life” says Jason Doles, the first author on the study and a postdoctoral researcher at the CRG.
In this work, the researchers have studied skin stem cells during the aging process to see if changes in stem cell function might contribute to aging. Their major finding is that during the aging process, skin stem cells actually lose their ability to function properly. “We have discovered that major changes occur in these stem cells during aging, whereby stem cells exhibit impaired growth in older animals as compared to their more youthful counterparts. We also found that the aged stem cells are not able to tolerate stress as well as young stem cells, strongly supporting the idea that changes in stem cell function might actually drive the aging process” says Bill Keyes, group leader of the Mechanisms of Cancer and Aging lab at the CRG and lead author of the study.
The report goes further, uncovering novel processes driving skin stem cell aging, and linking the aging process with diseases such as cancer. In fact, a recent study from the same group, demonstrated that these same stem cells become deregulated during the development of squamous cell carcinoma, a deadly type of skin cancer. The current study performed high-throughput profiling of the aging stem cells and identified a likely cause of the loss of function during aging. They demonstrated that during normal aging, the entire skin changes and produces many different proteins that mediate inflammation, and that it is the abnormal production of these inflammatory-mediators that contributes to the decline of stem cell function. Given that the link between inflammation and the development of cancer has been long known, the current study uncovers important findings on how the two might be linked.
Altogether, these findings help to explain what is likely a major cause of the aging process and how this develops, opening the door for future studies that may help to alleviate aspects of the aging process. But in addition, with the identification of inflammation as a cause of stem cell dysfunction, the study also uncovers likely causes in the development of cancer.
The research has been funded by the Spanish Ministry for Science and Innovation and the Centre for Genomic Regulation (CRG).
J. Doles, M. Storer, L. Cozzuto, G. Roma, W. M. Keyes. Age-associated inflammation inhibits epidermal stem cell function. Genes & Development, 2012, DOI: 10.1101/gad.192294.112