Tae-Won Kang, Tetyana Yevsa, Norman Woller, Lisa Hoenicke, Torsten Wuestefeld, Daniel Dauch, Anja Hohmeyer, Marcus Gereke, Ramona Rudalska, Anna Potapova, Marcus Iken, Mihael Vucur, Siegfried Weiss, Mathias Heikenwalder, Sadaf Khan, Jesus Gil, Dunja Bruder, Michael Manns, Peter Schirmacher, Frank Tacke, Michael Ott, Tom Luedde, Thomas Longerich, Stefan Kubicka & Lars Zender
Upon the aberrant activation of oncogenes, normal cells can enter the cellular senescence program, a state of stable cell-cycle arrest, which represents an important barrier against tumour development in vivo1. Senescent cells communicate with their environment by secreting various cytokines and growth factors, and it was reported that this ‘secretory phenotype’ can have pro- as well as anti-tumorigenic effects2, 3, 4, 5. Here we show that oncogene-induced senescence occurs in otherwise normal murine hepatocytes in vivo. Pre-malignant senescent hepatocytes secrete chemo- and cytokines and are subject to immune-mediated clearance (designated as ‘senescence surveillance’), which depends on an intact CD4+ T-cell-mediated adaptive immune response. Impaired immune surveillance of pre-malignant senescent hepatocytes results in the development of murine hepatocellular carcinomas (HCCs), thus showing that senescence surveillance is important for tumour suppression in vivo. In accordance with these observations, ras-specific Th1 lymphocytes could be detected in mice, in which oncogene-induced senescence had been triggered by hepatic expression of NrasG12V. We also found that CD4+ T cells require monocytes/macrophages to execute the clearance of senescent hepatocytes. Our study indicates that senescence surveillance represents an important extrinsic component of the senescence anti-tumour barrier, and illustrates how the cellular senescence program is involved in tumour immune surveillance by mounting specific immune responses against antigens expressed in pre-malignant senescent cells.
A paper worth reading. Excellent work.
Darren J. Baker, Tobias Wijshake, Tamar Tchkonia, Nathan K. LeBrasseur, Bennett G. Childs, Bart van de Sluis, James L. Kirkland & Jan M. van Deursen
Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive ageing remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells1, 2. Senescent cells accumulate in various tissues and organs with ageing3 and have been hypothesized to disrupt tissue structure and function because of the components they secrete4, 5. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16Ink4a, to design a novel transgene, INK-ATTAC, for inducible elimination of p16Ink4a-positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16Ink4a-positive senescent cells upon drug treatment. In tissues—such as adipose tissue, skeletal muscle and eye—in which p16Ink4a contributes to the acquisition of age-related pathologies, life-long removal of p16Ink4a-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.
Chronic obstructive pulmonary disease (COPD) is characterized by progressively reduced airflow within the lungs, making it difficult to breath. During normal breathing, air sacs (alveoli) (which are elastic) fill up with air and oxygen passes through the air sac walls into the blood. With COPD the air sacs can lose elasticity, the walls between air sacs are destroyed, the walls become thick and inflamed and the airways make more mucus than normal leading to clogging. All these changes contribute to reduced airflow in COPD.
COPD is predominately associated with tobacco smoking and previous studies investigating the pathophysiology of emphysema have demonstrated that cigarette smoke can cause cells to enter cellular senescence (Tsuji et al, 2004, Nyunoya et al 2006). As such, a number of studies have investigated the role of cellular senescence in the development and progression of COPD. Cigarette smoke may trigger cells to senesce directly due to DNA damage or indirectly (if apoptosis is occurring) through increasing cell turnover leading to accelerated telomere shortening.
Senescent cells secrete pro-inflammatory cytokines, growth factors and proteases (most likely for immune clearance) that can cause tissue damage, leading to loss of function of the tissue in which they reside. In the case off COPD the secretion of proteases by senescent cells could result in loss of elasticity of air sacs and destruction of air sac walls. The secretion of cytokines and chemokines by senescent cells would lead to persistent inflammation.
Tsuji et al (2009) has shown that lung tissue of COPD patients contained higher percentages of senescent alveolar cells displaying a pro-inflammatory phenotype compared with tissue from asymptomatic smokers and non-smokers. Noureddine et al (2011) has demonstrated that pulmonary artery smooth muscle cell (PA-SMC) senescence is an important contributor in the process of pulmonary vessel remodeling in COPD patients. Senescent PA-SMC were shown to stimulate cell growth and migration of normal PA-SMC through the release of paracrine soluble and insoluble factors. Dogauassat et al (2011) have shown that lung fibroblasts in smokers and ex-smokers with moderate COPD display a senescent phenotype. This study suggests that even after stopping smoking, the persistence of senescent cells may still contribute to COPD. Amsellem et al (2011) have recently showed that premature senescence in pulmonary vascular endothelial cells may contribute to inflammation in COPD.
Research also suggests that patients with COPD have a two to six times more chance of developing lung cancer compared with people of normal lung function (COPD Foundation). It could be speculated that the presence of senescent cells in COPD patients may increase the chances of lung cancer. It has been shown that the secretory phenotype of senescent cells can play a role in cancer development by stimulating growth and angiogenic activity of pre-malignant cells (reviewed in Campisi and d'Adda di Fagagna, 2007). Additionally, stochastic epigenetic/genetic alterations within senescent cells may allow them to escape the senescence growth arrest, thus becoming cancerous.
Tsuji T, Aoshiba K, Nagai A. Alveolar cell senescence exacerbates pulmonary inflammation in patients with chronic obstructive pulmonary disease. Respiration. 2010;80(1):59-70. Epub 2009 Dec 17.
The age-associated increase in the incidence of disease development and cancer occurrence is often thought to be due to the gradual accumulation of damage over the lifetime of an organism. However, an alternative opinion is that damaged cells are effectively eliminated and replaced by the immune system and regenerative cells (stem cells) and only when this “remove and replace” system failures, do organisms begin to show signs of ageing.
The presence of persistent DNA damage triggers cells to enter senescence (irreversible growth arrest) to protect the cell from becoming cancerous. The presence of the persistent DNA damage in these growth-arrested cells appears to activate pathways leading to cytokine/chemokine secretion and presentation of cell surface ligands (i.e MICA, MICB, ULBP2) which can be recognized by natural killer cells (NK) and some T-cells. This may allow damaged/senescent cells to communicate with immune cells for their removal (although more evidence of this is required).
For cells to become cancerous, they need to bypass senescence (following irreparable DNA damage), often achieved by acquiring mutations in genes associated with activation and maintenance of the senescence growth arrest. When such cells bypass senescence, the persistence of DNA damage may also activate pathways leading to cytokine/chemokine secretion and presentation of NK ligands.
It is also possible that cells can become cancerous if they instead escape senescence. “Escaping” is different from “bypassing” in that these cells were once senescent. If senescent cells persist in tissues without immune clearance, it is possible that stochastic genetic/epigenetic changes may lead to activation/inactivation of genes that allow the once senescent cell to reneter the cell cycle. A consequence of this escape may be the maintenance of the pro-survival phenotype and the pro-inflammatory phenotype associated with senescence. Escaping senescence may be more pertinent in cancer cells that have become senescent in response to therapy. Escape from senescence in this instance may lead to the progression of more aggressive cancers.
I am not aware of any studies that have investigated the similarities/differences in the secretory phenotype/NK ligand activation of senescent verses cancer cells. However, if both exist due the DNA damage response activating the immune response (DDR-AIR), then they are probably very similar.
If senescent and cancer cells were always effectively being removed then the incidence of cancer and disease would greatly be reduced. However, age-associated cancer and disease does occur and this may in part be due to a failure in the immune system to effectively remove senescent/cancer cells as we age. Additionally, cancer cells can develop various strategies for evading the immune response (i.e secretion of immunosuppressive cytokines). Whether the same strategies occur in senescent cells remains to be discovered.
Although purely speculative, it is possible that some of these strategies for evading immune surveillance is a result of pro-longed exposure to the pro-inflammatory phenotype of these cells. There may be a limited biological time frame whereby the presence of the inflammatory phenotype is beneficial for cell removal. Longer exposure may lead to an adaptive response through autocrine signalling leading to changes that evade immune surveillance. For example, the secretion of immunosuppressive cytokines may be an adaptive response for preventing detrimental damage from long exposure to pro-inflammatory cytokines.
Ongoing and future investigations should aim to provide solid evidence of whether (1) the secretory phenotype of senescent cells is for the purpose of immune clearance, (2) and if so, does immune clearance fail or become impaired with age and (3) if it does fail, what are the mechanisms?
The following is a brief article provided by Stem Cell Backup (click here), which discusses the importance of banking your cells for future therapeutic applications.
Growing replacement ears for injured soldiers. Allowing the paralyzed to walk again. Restoring sight to the blind. Curing multiple sclerosis. Growing transplantable lungs. This, and more, is being done today. The magic technology? The most basic there is, the patient's own cells. You are witnessing the dawn of a new era of medicine. Regenerative medicine—using your own stem cells to heal yourself—is no longer science fiction. The U.S. Department of Health and Human Services reports that “regenerative medicine is the vanguard of 21st century health care.” These experts estimate that half of Americans now under the age of 65 will receive regenerative therapies during their lifetime. Simultaneously, groundbreaking advances now mean scientists can use your own non-stem cells to make the stem cells used in regenerative medicine.
In 2006 a Japanese researcher did something that most researchers considered impossible, he 'reprogrammed' a normal skin cell and made it into a stem cell. The new technique was so effective and technically simple that thousands of research laboratories soon began using these 'induced' pluripotent stem cells (iPSC). Even the scientist who cloned Dolly the sheep abandoned cloning, saying "[Reprogramming is] 100 times more interesting [than cloning]…I have no doubt that in the long term, direct reprogramming will be more productive” (London Telegraph 11/10/08).
High expectations, to be sure, but iPSC are already exceeding them. Researchers have treated or even fully cured maladies like Parkinson's, heart attack damage and diabetes in test animals using iPSC. Additionally, iPSC have also been used to grow dozens of types of transplantable tissue, like retinas, and even fully-functioning organs, like livers. Medical experts expect iPSC to play a role in virtually every medical treatment of the future.
To help you take advantage of these dual advances, Stem Cell Backup banks your cells for your future use. Like many things in life, age matters. Research shows that cells taken from older patients are less effective for therapeutic use. By banking your own youngest, healthiest cells you can grow any kind of new tissue you need, whether heart, liver, or muscle.
"You are seeing the birth of a new industry," says Patrick O'Malley, president of Stem Cell Backup, "that has a strong precedent in the long-established cord blood industry. In the U.S. alone, over one million families currently bank their newborn child’s umbilical cord blood for future medical treatments. Banking your own cells is like cord blood for the rest of us." Mr. O’Malley points to the universal consensus of medical experts who expect great things from this new form of personalized medicine, "Every knowledgeable expert says that this technology is transformational. The Nobel Laureate for Medicine said, 'This is going to be the way forward. …We’ve all been waiting for this' (WSJ 11/21/07). Doctor Oz predicted on Oprah that a patient’s own cells will be used to cure Parkinson's disease in 8 or 9 years."
Stem Cell Backup was founded in 2008 to allow individuals to take advantage of new discoveries in stem cell medicine. After extensive research and testing, the company began accepting client samples in 2011. Stem Cell Backup is the first and only company to allow individuals to easily, safely, and inexpensively save their own cells for use in future medical therapies. It has a processing laboratory in the U.S. and is currently identifying local partner candidates in European and Asian markets.
For those who want to take advantage of this unique service, visit http://www.stemcellbackup.com/ for further details.
Personal genome analysis (PGA) will revolutionize how we think about our own health. Currently, whenever a symptom or illness presents itself, we see doctors and those doctors provide medicines and treatments to remove or control the problem. With PGA we can discover what diseases we may be at risk of developing and in some cases adjust our lifestyles to reduce/prevent disease occurrence/progression.
For example, my PGA suggests (based on a number of studies) that I am at risk of developing a mild form of hemochromatosis, a disorder in which the body absorbs too much iron, causing damage to tissues, specifically the liver. A fact I find rather amusing considering I nearly started a research project focused on the role of iron in ageing.
Novelli V et al. (2008) . “Lack of replication of genetic associations with human longevity.” Biogerontology 9(2):85-92.
Atzmon G et al. (2006) . “Lipoprotein genotype and conserved pathway for exceptional longevity in humans.” PLoS Biol 4(4):e113.
Willcox BJ et al. (2008) . “FOXO3A genotype is strongly associated with human longevity.” Proc Natl Acad Sci U S A 105(37):13987-92.