EP2281202A1 - Marker zur bestimmung der biologischen alterung - Google Patents
Marker zur bestimmung der biologischen alterungInfo
- Publication number
- EP2281202A1 EP2281202A1 EP09734665A EP09734665A EP2281202A1 EP 2281202 A1 EP2281202 A1 EP 2281202A1 EP 09734665 A EP09734665 A EP 09734665A EP 09734665 A EP09734665 A EP 09734665A EP 2281202 A1 EP2281202 A1 EP 2281202A1
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- EP
- European Patent Office
- Prior art keywords
- protein
- activity
- aging
- age
- measurement
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
Definitions
- the present invention relates to markers which can be used for the determination of biological aging, regenerative capacity and prognosis in age-associated and chronic diseases, in particular markers which can be determined from blood or serum.
- telomere shortening occurs in human cells with each cell division (3). This limits the proliferation capacity of human cells to 50-70 divisions (3). In humans, telomere shortening occurs as part of aging in almost all tissues (4). Shortening of telomeres correlates with the survival of 60-75 year olds (5). Accelerated shortening of telomeres has been associated with age-associated diseases such as Alzheimer's disease (6), diabetes mellitus (7), cardiovascular disease (8), and tumor development (9). In addition, shortening of telomeres correlates with disease progression and organ failure in chronic diseases such as hepatitis (10) and myelodysplastic syndromes (11).
- telomere length has not been successful in the clinic so far, since technically complex methods such as Southern blot, quantitative fluorescence in situ hybridization or quantitative PCR must be used for this purpose. In addition, sample collection is often difficult. Telomere shortening in liver tissue correlates with the progression of chronic liver disease to liver cirrhosis (10). It would therefore be necessary to carry out liver biopsies in order to be able to estimate the prognosis and disease progression.
- telomere length per se has only limited power over cell function and regenerative capacity.
- Animal experiments have shown that it is not the average telomere length that is decisive, but the number of critically short, dysfunctional telomeres (12). So it comes in the mouse model to a premature Aging and a reduction in organ preservation when the number of dysfunctional telomeres is increased, although the median telomere length may still be relatively long (12).
- These results are also important for the proliferation capacity of human cells. This leads to the induction of senescence and thus to the irreversible proliferation loss of the cells when the number of dysfunctional telomeres per cell exceeds a certain level (13).
- telomere dysfunction appears to be an indication of aging, age-associated diseases, as well as chronic diseases.
- the determination of telomere dysfunction as a clinical marker was not successful because telomere dysfunction is difficult to determine methodologically and biopsies from the affected organs are often not available.
- telomere dysfunction A group of four proteins secreted by cells in response to telomere dysfunction or DNA damage has been identified (Jiang, Rudolph, Schiffer, Mischak et al., 2008 and unpublished data). These proteins have been identified in the culture supernatant of bone marrow cells from telomerase knockout (Terc " ⁇ ) mice with dysfunctional telomeres, and it has been shown in advance that Terc " ⁇ mice develop telomere dysfunction in bone marrow cells and thereby the function of hematopoietic cells Strain and progenitor cells is restricted. To identify marker proteins of telomere dysfunction, bone marrow cells from these mice were cultured (4 hrs). Proteome analysis of the secreted proteins in the cell culture supernatant was then performed by CE-TOF-MS. In this method, four proteins were identified that are specifically associated with the aging of telomere dysfunctional mice.
- Elongation Factor 1 alpha (EF-lalpha): This protein controls transcriptional protein synthesis and is up-regulated in human cells in response to proliferation loss (senescence) (18,19).
- Chitinase 3 like protein 3 (Chi3L3): This protein belongs to the family of chitinases, which are also activated in response to activation of the innate immune system (15, 16). Upregulation of a member of the chitinase family has been associated with the aging of human cartilage cells (17). Subsequent studies have shown that the determination of the enzyme activity of chitobiosidases, chitinases, chitibiases and / or N-acetyl-glucosaminidases can be used to determine the age and risk of developing age-associated diseases and cancer in humans. All or individual activities of chitobiosidases, chitinases, chitibiases and N-acetyl-glucosaminidases are measured.
- CRAMP Catelcidino-Related Anti-Microbial Protein
- Stathmin This protein controls microtubule stability, cell motility and mitosis (20).
- the determination preferably takes place from blood or serum samples. It turns out that these four protein markers are upregulated in different organs of telomere dysfunctional mice (kidney, liver, lung, brain, spleen and heart). In addition, protein expression of these marker proteins in the blood serum of aging mice with dysfunctional telomeres is increased. These markers appear to be specific for aging in telomere dysfunction because upregulation of these marker proteins does not occur in wild-type mice with long telomeres. The work also shows that the same marker proteins in aging human cells (fibroblasts) are upregulated as part of aging and in response to radiation-induced DNA damage in young human cells.
- Orthologous proteins of the marker proteins identified in the mouse system are known in humans for three of the four proteins: EF-lalpha, stathmin, CRAMP.
- An orthologue for Chi3L3 is currently unknown in humans.
- telomere dysfunction An essential feature of aging is the accumulation of DNA damage.
- telomere dysfunction is also to be understood, since in response to telomere dysfunction, activation of DNA damage signaling pathways occurs in cells (21).
- a number of premature aging syndromes in humans are associated with the mutation of genes necessary for the maintenance of DNA stability.
- Our own investigations show that the identified marker proteins are also up-regulated in human cells in response to irradiation-induced DNA damage.
- the marker proteins at the RNA and protein level there is a significant upregulation of the marker proteins at the RNA and protein level.
- an upregulation of the marker proteins in the cell culture medium of irradiated human cells is detectable in comparison with unirradiated human cells.
- Further methods for detecting the marker proteins are quantitative PCRs for the marker proteins.
- antibodies were additionally defined which can be used for immunohistochemical detection of the marker proteins in human tissue samples.
- the identified proteins are biomarkers of DNA damage, telomere dysfunction and can be used to determine the biological age, regenerative capacity, risk of cancer, the risk of developing age-associated diseases and the prognosis of chronic human and animal diseases.
- the methods relate to ex vivo examinations of body fluids or biopsies.
- the method is applicable to mammals and especially humans.
- the determination ex-vivo is preferred.
- DNA damage and telomere dysfunction are fundamental mechanisms that can prevent the development of age-associated diseases, aging, regeneration capacity, and cancer formation are underlying.
- the detection of DNA damage and telomere dysfunction is difficult.
- serum markers that can be determined in the blood or body fluids that indicate the presence of DNA breaks or telomere dysfunction.
- the defined markers can be used for this application.
- the studies show for the first time that the identified markers increase in response to telomere dysfunction or DNA damage in the blood serum. Due to the increasing recognition that DNA damage and telomere dysfunction are fundamentally underlying the development of age-associated diseases and cancer, the invention represents a significant advance in medicine and can be used as a novel biomarker.
- the biological age of an individual may differ from the chronological age. It is well known that genetic factors, living conditions, lifestyle habits, eating habits, external factors and many other factors have an influence on the aging of the organism. The biological age determines the life expectancy and fitness of the aging individual in some cases more than the chronological age. Slow-aged, 60-year-old people can be fitter and have a longer life expectancy than aged 50 years old.
- Measurement of the expression of the biomarkers defined herein can determine the presence and extent of DNA damage and telomere dysfunction. There is increasing evidence that these two parameters correlate with the biological age of an individual and their expected life expectancy.
- the measurement can be carried out in body fluids (eg serum, blood, urine, saliva, cerebrospinal fluid) or in tissue and organ biopsies and samples.
- the markers can also be determined with modern imaging techniques (molecular imaging). These methods are suitable for determining the state of aging of organs or for identifying aged cell clones with increased risk of degeneration.
- a) Personal life planning For individual life planning, it is important to be able to estimate how long you are expected to be fit and able to work and what your own, probable life expectancy is. The determination of the biomarkers defined here can be used to determine the biological age and life expectancy of the individual. This can help the individual with their personal life planning.
- Forensic / criminalistics The determination of markers defined here can be used to determine the biological age of victims of violent crimes and accidents.
- the trade in livestock, domestic animals and animals used in sport is often accompanied by medical reports on the fitness and the expected useful life of the animals.
- the measurement of the markers defined here can be used determine the biological age and the expected fitness span and life expectancy of animals.
- Occupational / Environmental Medicine The determination of the markers defined here can be used to determine the influence of certain activities and the influence of environmental factors on the biological aging and fitness of individuals.
- the biomarkers defined here can therefore be used to determine the regeneration capacity of tissues and organs.
- the measurement may be in body fluids (e.g., serum, blood, urine, saliva, cerebrospinal fluid) or in tissue and organ biopsies / samples.
- body fluids e.g., serum, blood, urine, saliva, cerebrospinal fluid
- tissue and organ biopsies / samples e.g., in tissue and organ biopsies / samples.
- a) Determination of prognosis and treatment planning in chronic diseases A number of chronic diseases lead to failure of the affected organs in the final stage. Interindividual profiles can be very different. The prediction of individual history is clinically meaningful to better plan the timing of invasive therapies (eg, organ transplants). The determination of the markers defined here can be used to predict the individual case of chronic Diseases (eg: hepatitis, pulmonary fibrosis, anemia, chronic inflammatory diseases) to determine.
- chronic Diseases eg: hepatitis, pulmonary fibrosis, anemia, chronic inflammatory diseases
- a number of acute illnesses and injuries can lead to failure of the affected organs and death of the patient. Interindividual profiles can be very different. The prediction of individual history is clinically meaningful to estimate the timing and benefits of invasive therapies (eg: surgery, intensive care). The determination of the markers defined here can be used to determine the individual prognosis for acute illnesses and injuries.
- the determination of the markers defined here can therefore be used to determine the risk of the occurrence and prognosis of age-associated diseases.
- the measurement may be in body fluids (e.g., serum, blood, urine, saliva, cerebrospinal fluid) or in tissue and organ biopsies / samples.
- the determination of the risk of occurrence and prognosis of age-associated diseases using the markers defined here is suitable for the following areas:
- a) Determination of the risk of the occurrence of age-associated diseases A variety of diseases are associated with aging (vascular disease, diabetes mellitus, dementia, strokes, etc.). It would be of clinical importance to be able to estimate the risk of the occurrence of such diseases in order, if necessary, to start early with preventive or therapeutic measures. see countermeasures begin. The determination of the markers defined here can be used to determine the individual risk of developing diseases associated with aging.
- b) Determination of the prognosis of age-associated diseases A variety of diseases are associated with aging (vascular disease, diabetes mellitus, dementia, strokes, etc.). It would be of clinical importance to be able to estimate the prognosis of such diseases in order to take therapy measures adapted to the individual course. The determination of the markers defined here can be used to determine the individual course and prognosis in age-associated diseases.
- the determination of the markers defined here can therefore be used to determine the risk of cancer in chronic diseases and in the context of aging.
- the measurement may be in body fluids (e.g., serum, blood, urine, saliva, cerebrospinal fluid) or in tissue and organ biopsies / samples.
- Many chronic diseases eg hepatitis, inflammatory bowel disease
- the defined markers show the individual Ie cancer risk in chronic diseases.
- a cancer risk assessment can be used to tailor cancer screening to individual cancer risk.
- the timing of preventative measures can be improved.
- Many genetic diseases for example, LiFraumatici syndrome, Adenomatosis poplyposis coli
- the determination of the markers defined here may indicate the individual cancer risk of genetic predisposition and thus be used to improve cancer screening and improve the timing of preventative measures in these diseases.
- General Cancer Screening The "General Cancer Screening" is recommended for many cancers (e.g., colon carcinoma, prostate carcinoma, breast carcinoma) as part of aging, following general medical guidelines at the time and frequency of screening. The individual risk of developing cancer is not included in these measures. The determination of the markers defined here can indicate the individual cancer risk and can be used for an improved "general cancer screening" adapted to the individual risk.
- cancers e.g., colon carcinoma, prostate carcinoma, breast carcinoma
- Figure 1 The markers of telomere dysfunction and DNA damage are detectable in the blood and indicate the risk of tumors in the context of aging and chronic liver disease.
- A) Serum levels of EFlalpha are significantly elevated in the blood of hepatitis C virus infected patients who developed liver cancer during the course of the disease (group 1) compared to patients who did not develop liver cancer in the same observation period (group 2, p 0.02).
- Figure 2 The markers of telomere dysfunction and DNA damage are detectable in the blood and are influenced by the lifestyle (smoking, exercise, obesity).
- EF-lalpha The up-regulation of this protein has been linked to the proliferation loss (senescence) of human cells in culture (18,19). A link with human aging and age-associated diseases has not been described. Furthermore, it has not been shown that eflalpha is up-regulated by DNA damage and telomere dysfunction. Furthermore, it has not been shown that eflalpha is up-regulated by DNA damage and telomere dysfunction.
- the marker also showed increased end-stage expression of chronic diseases (e.g., cirrhosis and myelodysplastic syndromes) in both the blood serum and the affected tissues.
- the studies show for the first time that the serum protein levels of the marker indicate the risk of cancer in old age and in chronic diseases (FIG. 1A).
- serum EF-lalpha levels were significantly higher in liver cirrhotic patients who developed liver cancer during the disease than in cirrhotic patients who did not develop liver cancer (Figure IB).
- CRAMP also referred to as LL-37 in humans
- the studies show for the first time that this protein in blood serum response to telomere dysfunction increases (22).
- our studies show for the first time that this protein increases in human blood in the context of human aging and in the context of age-associated diseases (22).
- the marker also shows increased end-stage expression of chronic diseases (e.g., cirrhosis and myelodysplastic syndromes) in both the blood serum and the affected tissues.
- chronic diseases e.g., cirrhosis and myelodysplastic syndromes
- Stathmin The studies show for the first time that this protein in blood serum increases in response to telomere dysfunction (22). In addition, the studies show for the first time that this protein increases in human blood in the context of human aging and in age-associated diseases (22).
- the marker also showed increased end-stage expression of chronic diseases (e.g., liver cirrhosis and myelodysplastic syndromes) in both the blood serum and the affected tissues.
- the marker indicates the risk of cancer in old age and chronic diseases.
- Stathmin serum levels are significantly higher in cirrhotic liver cancer patients than in liver cirrhotic patients without liver cancer.
- Enzyme activity of chitinases, chitibiases and N-acetylglucosaminidases An increase in the secretion of chitinase-like protein is described in the cell culture of aged human cartilage cells and in arthritis patients been (17). An increase in the enzyme activity of chitinases, chitibiases and N-acetylglucosaminidases in human blood or in human tissues / organs as a result of DNA damage, telomere dysfunction, aging or diseases has not previously been described.
- the investigations show for the first time that the enzyme activity of chitobiosidases, chitinases, chitibiases and N-acetylglucosaminidases increases in the blood serum in response to telomere dysfunction (22).
- the studies show for the first time that these enzyme activities in human blood increase in the context of human aging and in age-associated diseases (22).
- chitinases e.g., chitibiases and N-acetylglucosaminidases
- chronic diseases e.g., liver cirrhosis and myelodysplastic syndromes
- the investigations show for the first time that the enzyme activity of chitobiosidases, chitinases, chitibiases and N-acetylglucosaminidases measured in the blood serum indicates the risk of cancer in chronic diseases.
- the enzyme activity of chitobiosidases, chitinases, chitibiases and N-acetylglucosaminidases is significantly higher in liver cirrhosis patients with liver cancer than in cirrhotic patients, who developed liver cancer in the course of disease significantly higher than in cirrhotic patients who did not develop liver cancer in the same follow-up period (Figure ID).
- the studies show for the first time that chitinase enzyme activity is significantly influenced by lifestyle habits (sport and smoking, Figure 2C, D).
- telomere length is critical for cell viability and chromosomal stability. Cell. 2001 Oct 5; 107 (1): 67-77.
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| EP3712616A4 (en) * | 2017-11-14 | 2021-08-25 | Hiroshima University | AGING STATE ASSESSMENT PROCESS, INFORMATION PRESENTATION PROCESS AND SCREENING PROCESS FOR A SUBSTANCE TO IMPROVE OR PREVENT AN AGING STATE |
| EP3674418A1 (en) * | 2018-12-26 | 2020-07-01 | Life Length S.L. | Method for measuring telomere associated variables and uses thereof for the diagnosis and/or prognosis of telomeric-associated diseases |
| CN111333713B (zh) * | 2020-03-27 | 2021-06-25 | 江南大学 | 一种表达抗菌肽基因的植物乳杆菌 |
| CN111398456A (zh) * | 2020-03-31 | 2020-07-10 | 中国科学院昆明动物研究所 | 指征健康老龄关键通路的内源性代谢小分子标志物及应用 |
| DE112021001866T5 (de) * | 2020-06-16 | 2023-01-12 | Fanuc Corporation | Steuervorrichtung mit Werkzeugeinstellverwaltungsfunktion, Steuersystem und Werkzeug |
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| JPH08319298A (ja) * | 1995-05-25 | 1996-12-03 | Fujirebio Inc | 抗ヒト老化マーカータンパク質モノクローナル抗体及びそれを用いる測定方法 |
| JP3754611B2 (ja) * | 2000-10-03 | 2006-03-15 | 旭テクノグラス株式会社 | ヒト老化マーカー及びストレスマーカーの検定方法 |
| JP2005528581A (ja) * | 2001-02-21 | 2005-09-22 | ストライカー コーポレイション | 骨形態形成タンパク質を使用する、軟骨変性および老化の測定 |
| US7041449B2 (en) * | 2001-03-19 | 2006-05-09 | Wisconsin Alumni Research Foundation | Methods of screening for compounds that inhibit expression of biomarker sequences differentially expressed with age in mice |
| US20060099586A1 (en) * | 2002-06-07 | 2006-05-11 | Lee Jonathan M | Eef1a2 for use in the prognosis, diagnosis, and treatment of cancer |
| US7588895B2 (en) * | 2006-01-11 | 2009-09-15 | The Regents Of The University Of California | Biomarkers for oral tongue cancer metastasis and extracapsular spread (ECS) |
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