Cellular Senescence
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infoaging guides BIOLOGY OF AGING CELLULAR SENESCENCE An introduction to aging science brought to you by the American Federation for Aging Research WHAT IS CELLULAR no longer divide become what is that activate oncogenes—normal SENESCENCE? called “senescent.” Cells taken cellular genes that, when mutated, from older humans generally have contribute to the development Cellular senescence is a process shorter telomeres than cells from of cancer. These diverse triggers associated with aging that occurs young humans, so cells from older support the idea that cellular at the level of our cells. Cellular humans generally divide fewer senescence evolved primarily to senescence is sometimes called times before becoming replica- protect organisms from cancer. replicative senescence. Forty years tively senescent. ago, Dr. Leonard Hayflick and his Scientists have also noted that colleague, Dr. Paul Moorhead, Critically short telomeres, which senescent cells are different from discovered that many human resemble broken chromosomes, their younger counterparts. Like cells—particularly fibroblast cells, are not the only causes of ”senes- older people themselves, cells ap- which secrete substances that cence,” and so scientists often proaching senescence incur many provide structure to tissues—had use the more general term ”cellular biological losses or take on new a limited capacity to reproduce senescence.” Cellular senescence functions. Where younger cells themselves in culture by dividing. produce structural or functional They found that these and many proteins that maintain tissues in other normal human cells derived a healthy state, cells approaching from fetal, embryonic, or newborn senescence release enzymes that tissue can undergo between 40 break down these proteins. and 60 cell divisions, but then can divide no more. This number is Senescent cells are not only often referred to as the Hayflick associated with certain age-related Limit. Hayflick also pointed out diseases, but may also be a direct in a second report that there are reflection of the aging and longevity two classes of cells: normal cells, determination process in humans which do not divide indefinitely and animals. Even cells from the and therefore are sometimes oldest people may still have some termed ”mortal,” and cancer cells, divisions left. Many scientists which often can divide indefinitely therefore believe that the biological and therefore are often termed losses that precede the inability “immortal.” to replicate increase vulnerability to disease and death well before Some scientists today believe the cells are incapable of further that what determines the Hayflick division. Limit for dividing cells is the length of cells’ telomeres. Telomeres WHY IS CELLULAR can be pictured as caps on the SENESCENCE IMPORTANT? ends of chromosomes. Each time a cell divides, it must first Scientists today focus on double its chromosomes, so that several key aspects of cellular each daughter cell receives a full senescence. The first may explain complement of genetic material. Most normal human cells can why such a phenomenon would But each time a chromosome undergo between 40 and 60 exist. Scientists note that limiting the number of divisions a cell can reproduces itself, it loses a small cell divisions, but then can portion of its telomeres. When a undergo may serve to suppress cell’s telomeres have reached a divide no more. tumor formation and cancer. With critically short length, after 40 to each normal cell division, the possibility of genetic mutation 60 population doublings in young can also be triggered by any type human cells, the cell can no longer exists. Some of those mutations of severe damage to the genome can make cells cancerous. A finite replicate its chromosomes and or epigenome (the packaging and thus will stop dividing. These cells life span for cells would reduce organization of the genome). It can the likelihood that potentially with shortened telomeres that can also be triggered by mutations cancerous cells can survive. 2 | Infoaging Guide to Cellular Senescence Telomeres can be pictured as caps on the ends of chromosomes. Each time a cell divides, it loses a small portion of its telomeres. A second important phenomenon secreted proteins to communicate ensure that a proper balance is associated with cellular senescence their damaged state to the tissue maintained between circulating is the many changes in function and help prepare the tissue for white blood cells and other that occur in all cells as they repair. However, as senescent cells components of the blood. approach senescence. Many accumulate with age, the chronic senescent cells stop functioning presence of the proteins they HOW IS CELLULAR SENESCENCE as they did when they still had the secrete can eventually compro- RELATED TO AGING AND AGE- capacity to divide. These hundreds mise tissue integrity and function. RELATED DISEASES? of functional losses that precede the loss of division capacity in Replicative senescence also plays As normal cells become normal cells mimic many of the an important role in the functioning senescent—whether due to functional losses that occur in of many human systems, ongoing cell division, direct DNA humans as we age, thus making including, for example, the damage, activated oncogenes the study of these cells important immune system. When our bodies or any other cause—they incur in learning more about aging. are confronted with infection, hundreds of biological changes they produce white blood cells that affect many of their activities. A third key feature of senescent called T lymphocytes that fight the Some of these changes are similar, cells is their secretion of a large infection. Those white blood cells if not identical, to the kinds of number of proteins that can affect reproduce themselves time and changes that we see occurring neighboring cells. Many of these again in order to win this battle. in aging humans themselves. secreted proteins are associated Cellular or replicative senescence, Scientists speculate that the many with tissue repair and regenera- however, limits those lymphocytes losses in function that occur in tion. Senescent cells, particularly to a specific number of repro- cells as they approach senes- those with short telomeres or ductions. This may serve as one cence increase their vulnerability genomic damage, may use these mechanism the body uses to to the diseases or pathologies that Infoaging Guide to Cellular Senescence | 3 Our goal in this research and other research in the field of aging should first be to understand why old cells are more vulnerable to disease than are young cells. are so common in old age. Thus, and is thought to interact with p53. establish that link, revealing that the study of cellular senescence They created transgenic mice that p44-transgenic mice had higher continues to provide important overexpress p44 and discovered circulating IGF-1 levels. Thus, clues to the aging process at the that these animals showed signs hyperactivity of p53, caused by the most fundamental level—the cell of premature aging after just four overexpression of p44, increased and the pathways within the cell. months. This suggested that p44 IGF-1 levels. The new findings increased the activity of p53, trig- indicated that hyperactive p53 One of those clues came in 2004 gering senescence and aging. can drive aging, at least in some when Bernhard Maier, Heide tissues, by increasing production Scrable, and their colleagues at To find out why hyperactive p53 of IGF-1. the University of Virginia demon- promotes aging, the research team strated a direct link between p53, then looked at IGF-1 signaling. Clearly, p53 orchestrates an a tumor-suppression pathway In animals such as nematodes equilibrium between several that triggers senescence, and (roundworms), fruit flies, and mice, competing pathways that the insulin-like growth factor-1 reducing IGF-1 levels increases balance tissue renewal and tumor (IGF-1), an important pathway longevity, so finding a link be- suppression. Understanding this linked to aging in mammals. The tween p53 and IGF-1 would add balance is crucial if we hope to researchers actually focused on further clarification to the complex optimize protection from cancer p44, which is expressed at low cellular pathways associated with while minimizing aging. levels in mouse and human cells aging. The researchers did indeed 4 | Infoaging Guide to Cellular Senescence Other evidence exists to suggest HOW IS CELLULAR mechanism that stops cell division a relationship between cellular SENESCENCE RELATED TO may also serve to stop cancer senescence and aging because CANCER? before it starts. some of the senescent cells’ functional losses appear to Scientists have postulated that Dr. Judith Campisi published a contribute to the aging process. cellular senescence evolved review of cellular senescence For example, certain skin cells as a mechanism to prevent the in the journal Current Opinion produce collagen during their incidence of cancer, a disease that in Genetics & Development in younger, reproductive years. increases in frequency with aging. 2011. She noted that telomere When they reach senescence While clearly not a failsafe method, shortening induces replicative and can no longer divide, they without cellular senescence, senescence, the cessation of cell produce collagenase, an enzyme cancer could well be inevitable division. Cellular senescence, in that breaks down collagen. Some for all of us as we age. With each which the cells enter a phase in researchers suggest that this cell division, cells can potentially which they have different functions process may be responsible for acquire mutations in their genes than they have while reproducing, the thinning and wrinkling of skin that can lead to cancer, so a can come about after a variety as we age. Additional evidence comes from research on Werner syndrome, an inherited disease of premature aging, which suggests that cellular senescence can contribute to age-related diseases. Comparisons of cells in culture from younger persons with Werner syndrome and older persons show that both groups of cells have a limited ability to reproduce further.