infoaging guides

BIOLOGY OF AGING

CELLULAR 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 —normal SENESCENCE? called “senescent.” Cells taken cellular genes that, when mutated, from older generally have contribute to the development is a process shorter than cells from of . 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 from cancer. replicative senescence. Forty years tively senescent. ago, Dr. and his Scientists have also noted that colleague, Dr. Paul Moorhead, Critically short telomeres, which senescent cells are different from discovered that many resemble broken , their younger counterparts. Like cells—particularly 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 that maintain tissues in other normal human cells derived a healthy state, cells approaching from fetal, embryonic, or newborn senescence release that tissue can undergo between 40 break down these proteins. and 60 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 , but may also be a direct in a second report that there are reflection of the aging and two classes of cells: normal cells, determination process in humans which do not divide indefinitely and . Even cells from the and therefore are sometimes 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 and 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 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 , the 60 population doublings in young ­possibility of genetic can also be triggered by any type ­exists. Some of those human cells, the cell can no longer of severe damage to the genome replicate its chromosomes and can make cells cancerous. A finite or epigenome (the packaging and span for cells would reduce thus will stop dividing. These cells organization of the genome). It can with shortened telomeres that can the likelihood that potentially 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 ­ 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 ­. 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 . Thus, and is thought to interact with . 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 -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. published a ­contribute to the aging process. cellular senescence evolved ­review of cellular senescence For example, certain cells as a mechanism to prevent the in the journal Current Opinion produce during their ­incidence of cancer, a disease that in ­ & Development in younger, reproductive years. increases in frequency with aging. 2011. She noted that 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 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 and older persons show that both groups of cells have a ­limited ­ability to reproduce further. Both cell types also go on to form abnormal extracellular matrixes, the frameworks that hold cells together as tissues. This observa- tion suggests that a small ­number of senescent cells can affect neighboring cells and tissues and perhaps contribute to age-related declines in the function of those cells and tissues.

Some scientists also speculate that the growth arrest ­associated with replicative or ­reproductive senescence may retard the ­ or repair of damaged tissue, which could play a role in the aging of the body.

Understanding cellular senescence could result in an increase in human and more disease-free years at the end of life.

Infoaging Guide to Cellular Senescence | 5 of stimuli. One such stimulus is at senescent cells that seem to that is possible. And because the oxidative damage, and turning promote cancer. The ­researchers determinants of our longevity are to a senescent phase can help studied senescent human fibro- driven indirectly by most, if not all, cells that are suffering ­oxidative blasts, which are a variety of skin of our genes, it is also very unlikely ­damage to avoid becoming cells. They have found that these that tampering with that process is ­cancerous. senescent have the either probable or even desirable. ­effect of stimulating other skin Because the very pathways that cells that are precancerous or Instead, our goal in this research protect us from cancer, such as already cancerous to ­proliferate. and other research in the field of p53, also drive the aging process, They do not stimulate normal aging should first be to understand it seems that it might be dif- cells to proliferate. These ­studies why old cells are more ­vulnerable ficult, if not impossible, to im- ­suggested that while ­cellular to disease than are young cells. prove ­cellular tumor-suppression senescence suppresses the Once accomplished, those mechanisms without accelerating formation of tumors in early life, ­differences, if exploitable, could aging or to delay aging without senescent cells might promote the result in an increase in human life causing cancer. However, recent formation of in aging cells. expectancy and more disease-free ­studies with transgenic mice years at the end of life. have shown that this might not RESEARCH INTO CELLULAR be an ­inevitable conclusion. For SENESCENCE AND AGING example, mice were created that carried extra copies of a normally The goal of research on the regulated p53 gene. These mice ­phenomenon of cellular senes- displayed ­significant resistance to cence is not unlike the goal of all cancer without showing signs of research on the biology of aging. ­premature aging. It is not to make us all immortal; that is not only impossible but On the other hand, work done at also undesirable. Nor is it to stop the Lawrence Berkeley National or slow down the processes of Laboratory in California has looked aging, because we do not know if

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