|Utz Herbig, PhD, assistant professor, Department of Microbiology and Molecular Genetics, UMDNJ-New Jersey Medical School and New Jersey Medical School - University Hospital Cancer Center|
With the exception of stem cells and cells from the germ line, all human somatic cells have a limited lifespan and eventually will become senescent. Similar to apoptosis, cellular senescence has been demonstrated to function as a potent tumor suppressor mechanism, preventing the accumulation of cells that encountered signaling imbalances and other transforming events. As senescent cells accumulate in living organisms, however, they potentially contribute to organismal aging by depleting various organ systems of functional cells required to maintain organ homeostasis. Although cellular senescence will likely protect us from neoplasia, it might also reduce our lifespan by contributing to biological aging of organisms with renewable tissues.
We were never meant to live as long as we do today. With a current average life expectancy of 78 years in the U.S., most would agree that lifestyle, technology and modern medicine have allowed us to escape the force of natural selection during evolution and live far beyond the point that nature intended.
Cheating evolution, however, has its tradeoffs. Instead of being eaten by predators, starving to death or dying of infection at a relatively young age, modern humans now succumb to aging-associated diseases such as diabetes, cardiovascular diseases and cancer much later in life. The dramatic increase in the incidence of these diseases during the final decades of life is inarguably the consequence of a variety of factors and could be explained by a number of theories. However, one theory, that of evolutionary antagonistic pleiotropy, has recently been put to the test and passed.
The concept of evolutionary antagonistic pleiotropy predicts that processes that are beneficial to a young organism, such as ones that suppress cancer growth, are detrimental to the same organism later in life. The reasoning behind this theory is that in hazardous environments, which have existed throughout the majority of human evolution, most organisms never reach “old age.” In these environments, traits that would promote a long life and prevent disease after the reproductive potential has declined would not emerge. The lack of natural selection late in life would then allow mechanisms that protect the young organism to potentially exert deleterious effects on the old organism. One such mechanism, called cellular senescence, is the research focus of my laboratory.
Cellular senescence is an irreversible growth arrest that limits the replicative potential of virtually all human somatic cells. This growth arrest was initially described in 1965 by Leonard Hayflick who observed that human cells grown in culture dishes did not have the capability to divide indefinitely. Instead, they eventually stopped growing after a certain number of cell divisions. The cells, however, remained attached to the culture dishes, were metabolically active and “alive” but never started to divide again. The reproducibility of these results led to the hypothesis that cells possess an internal clock that counts how many times a cell divides and stops growth once the cell has reached a predetermined limit. Could this be the reason why humans age and succumb to aging associated diseases? Scientists immediately began speculating that the limited ability of cells to divide would contribute to aging of organisms with renewable tissues, such as humans, simply because these organisms ran out of cells capable of dividing and repairing aged tissue. Although this cannot explain all the pathophysiological changes that we observe in aging humans, our recent results suggest that these speculations were not far from the truth.
As we found out many years later, telomeres —highly repetitive DNA sequences at the tips of linear chromosomes — are the internal clock that limits the growth of human cells. With every cell division, telomeres progressively shorten until they reach a critical length that prevents further cell growth. Rather than keeping track of time like a finely tuned Swiss watch, however, the clocking mechanism of telomeres not only counts cell divisions, but also appears to monitor the cellular environment for various stresses in order to stop cell growth prematurely if these stresses compromise cellular integrity. Telomeres should therefore be considered as sentinels of stress rather than countdown timers.
How does telomere shortening trigger cellular senescence? In an attempt to answer this question, we focused on the DNA damage repair machinery, since it had previously been demonstrated that telomeres become dysfunctional and are recognized as double stranded DNA breaks when their structural integrity is compromised. When cellular surveillance mechanisms discover a break in the DNA, cell growth immediately stops to prevent the accumulation of DNA mutations. Usually these breaks can be repaired by the cell, allowing proliferation to continue. We found that aging cells accumulated double stranded DNA breaks that were not repaired, keeping these cells in a constant growth arrested state. These breaks were localized at telomeric sequences suggesting that telomere shortening, either by progressive cell divisions or cellular stresses, leads to irreparable telomere damage and consequently permanent
|1B: Short and damaged telomeres (TTAGGG) in old and/or stressed cells trigger a stable growth arrest called cellular senescence. This response is a highly effective tumor suppressor mechanism preventing the growth of cells that have acquired potentially hazardous mutations. However, an aging-associated increase of senescent cells in tissues of long lived organisms likely contributes to the functional decline that is observed in old age.|
growth arrest. Not only did we discover telomere dysfunction induced senescence in old cell cultures, but we also observed an exponential increase of these senescent cells in skin tissues of aging primates, reaching a level that would likely impact the structure and regenerative capacity of aged skin (Figure 1A). Forty-one years after Hayflick first documented cellular senescence in cultured cells, we were able to show that this terminal growth arrest also occurs in living organisms and potentially contributes to aging of organisms with renewable tissues. Whether telomere damage induced senescence also affects other organ systems of aging organisms or whether it is limited to sun exposed skin tissue is currently under investigation in our laboratory.
Although our results suggest that cellular senescence is an unfavorable molecular event that might contribute to organismal aging, we probably would not live long enough to experience its “side effects” if our cells lacked this response. Studies from a number of laboratories have recently demonstrated that oncogene induced senescence, a similar growth arrest to telomere damage induced senescence, is a highly effective tumor suppressing mechanism that stops the growth of cancers at a pre-malignant stage. Could cellular senescence induced by telomere damage also be a tumor suppressing mechanism? Since critically short telomeres place a cell at risk for acquiring additional potentially cancer promoting mutations by facilitating genomic instability, the growth arrest induced by short and damaged telomeres certainly would be beneficial for the organism. Although direct evidence is still lacking, the available data from a large number of studies strongly suggest that telomeres play a critical role in suppressing tumorigenesis. It is therefore likely that the beneficial tumor suppressing properties of cellular senescence early in life contribute to the functional decline of various organ systems later in life by slowly depleting our tissues of functional cells required to maintain organ homeostasis (Figure 1B).
Our current studies center around understanding the various causes and consequences of telomere damage induced senescence. Not only would these studies improve our understanding of the molecular changes associated with tumor suppression and organismal aging, but they may also pave a path for developing novel therapies that target cancer cells and treat aging associated diseases. Perhaps some day we will be able to manipulate the senescence response in such a manner that would protect us from developing cancer without accelerating the rate at which we age.
Utz Herbig received his PhD in molecular biology from Vanderbilt University in 1999, studying initiation of DNA replication in human cells. In 2000, he joined the team of Dr. John Sedivy at Brown University to study cellular senescence on an NIH funded fellowship. In August 2006, he became a faculty member at UMDNJ-New Jersey Medical School and the NJMS-UH Cancer Center. His academic appointment is in the Department of Microbiology and Molecular Genetics.