MARK-AGE: European study to establish biomarkers of human ageing

Beschreibung

The rate of ageing in humans is not uniform, due to genetic heterogeneity and the influence of environmental factors. Age-related changes in body function or composition that could serve as a measure of “biological” age and predict the onset of age-related diseases and/or residual lifetime are termed “biomarkers of ageing”. Many candidate biomarkers have been proposed but in all cases their variability in cross-sectional studies is considerable, and therefore no single measurement has so far proven to yield a useful biomarker of ageing on its own, probably due to the multi-causal and multi-system nature of ageing. We propose to conduct a population study (3,700 probands) to identify a set biomarkers of ageing which, as a combination of parameters with appropriate weighting, would measure biological age better than any marker in isolation. Two large groups of subjects will be recruited, i.e. (1) randomly recruited age-stratified individuals from the general population covering the age range 35-74 years and (2) subjects born from a long-living parent belonging to a family with long living sibling(s) already recruited in the framework of the GEHA project. For genetic reasons such individuals (“GEHA offspring”) are expected to age at a slower rate. They will be recruited together with their spouses as controls, thus allowing initial validation of the biomarkers identified. (3) A small number of patients with progeroid syndromes will also be included in the study. A wide range of candidate biomarkers will be tested, including (a) “classical” ones for which data from several smaller studies have been published; (b) “new” ones, based on recent preliminary data, as well as (c) “novel” ones, based on recent research on mechanistic aspects of ageing, conducted by project participants. Bioinformatics will be used in order to extract a robust set of biomarkers of human ageing from the large amounts of data to be generated and to derive a model for healthy ageing.

Institutionen
  • FB Biologie
Publikationen
  Giacconi, Robertina; D'Aquila, Patrizia; Malavolta, Marco; Piacenza, Francesco; Bürkle, Alexander; Moreno-Villanueva, Maria; Dollé, Martijn E T; Jansen, Eugène; Bellizzi, Dina; Provinciali, Mauro (2023): Bacterial DNAemia in older subjects and nonagenarian offspring and association with redox biomarkers : results from MARK-AGE Study Journals of Gerontology Series A: Biological Sciences and Medical Sciences. Oxford University Press (OUP). 2023, 78(1), pp. 42-50. ISSN 1079-5006. eISSN 1758-535X. Available under: doi: 10.1093/gerona/glac154

Bacterial DNAemia in older subjects and nonagenarian offspring and association with redox biomarkers : results from MARK-AGE Study

×

Aging and age-related diseases have been linked to microbial dysbiosis with changes in blood bacterial DNA concentration. This condition may promote chronic low-grade inflammation, which can be further aggravated by antioxidant nutrient deficiency. Low plasma carotenoids are associated with an increased risk of inflammation and cellular damage and predict mortality. However, no evidence is yet available on the relationship between antioxidants and the blood bacterial DNA (BB-DNA). Therefore, this study aimed to compare BB-DNA from (i) GO (nonagenarian offspring), (ii) age matched controls [(Randomly recruited Age-Stratified Individuals from the General population (RASIG)] and (iii) Spouses of GO (SGO) recruited in the MARK-AGE project, as well as to investigate the association between BB-DNA, behavior habits, Charlson comorbidity index (CCI), leucocyte subsets, and the circulating levels of some antioxidants and oxidative stress markers.

BB-DNA was higher in RASIG than GO and SGO, while GO and SGO participants showed similar values. BB-DNA increased in smokers and in males with CCI≥2 compared to those with CCI≤1 within RASIG. Moreover, BB-DNA was positively associated with lymphocyte, neutrophil and monocyte counts, but not with self-reported dietary habits. Higher quartiles of BB-DNA were associated with low lutein and zeaxanthin and elevated malondialdehyde plasma concentrations in RASIG. BB-DNA was also positively correlated with nitric oxide levels.

Herein, we provide evidence of a reduced BB-DNA in individuals from long-living families and their spouses, suggesting a decreased microbial dysbiosis and bacterial systemic translocation. BB-DNA was also associated with smoking, CCI, leukocyte subsets and some redox biomarkers in older subjects.

Forschungszusammenhang (Projekte)

  Giacconi, Robertina; Laffon, Blanca; Costa, Solange; Teixeira-Gomes, Armanda; Maggi, Fabrizio; Macera, Lisa; Spezia, Pietro Giorgio; Piacenza, Francesco; Bürkle, Alexander; Moreno-Villanueva, Maria (2023): Association of Torquetenovirus viremia with physical frailty and cognitive impairment in three independent European cohorts Gerontology. Karger. ISSN 0304-324X. eISSN 1423-0003. Available under: doi: 10.1159/000528169

Association of Torquetenovirus viremia with physical frailty and cognitive impairment in three independent European cohorts

×

Introduction: Immunosenescence and inflammaging have been implicated in the pathophysiology of frailty. Torquetenovirus (TTV), a single-stranded DNA anellovirus, the major component of the human blood virome, shows an increased replication rate with advancing age. An elevated TTV viremia has been associated with an impaired immune function and an increased risk of mortality in the older population. The objective of this study was to analyze the relation between TTV viremia, physical frailty and cognitive impairment Methods: TTV viremia was measured in 1131 nonfrail, 45 physically frail, and 113 cognitively impaired older adults recruited in the MARK-AGE study (overall mean age 64.7±5.9 years), then the results were checked in two other independent cohorts from Spain and Portugal, including 126 frail, 252 prefrail and 141 nonfrail individuals (overall mean age: 77.5±8.3 years). Results: TTV viremia ≥4log was associated with physical frailty (OR: 4.69; 95% CI: 2.06-10.67, p<0.0001) and cognitive impairment (OR: 3.49, 95% CI : 2.14-5.69, p<0.0001) in the MARK-AGE population. The association between TTV DNA load and frailty status was confirmed in the Spanish cohort, while a slight association with cognitive impairment was observed (OR: 1.33; 95% CI: 1.000-1.773), only in the unadjusted model. No association between TTV load and frailty or cognitive impairment was found in the Portuguese sample, although a negative association between TTV viremia and MMSE score was observed in Spanish and Portuguese females. Conclusions: These findings demonstrate an association between TTV viremia and physical frailty, while the association with cognitive impairment was observed only in the younger population from the MARK-AGE study. Further research is necessary to clarify TTV's clinical relevance in the onset and progression of frailty and cognitive decline in older individuals.

Forschungszusammenhang (Projekte)

  Kananen, Laura; Hurme, Mikko; Bürkle, Alexander; Moreno-Villanueva, Maria; Bernhardt, Jürgen; Debacq-Chainiaux, Florence; Grubeck-Loebenstein, Beatrix; Malavolta, Marco; Basso, Andrea; Piacenza, Francesco (2022): Circulating cell-free DNA in health and disease : the relationship to health behaviours, ageing phenotypes and metabolomics GeroScience. Springer. ISSN 2509-2715. eISSN 2509-2723. Available under: doi: 10.1007/s11357-022-00590-8

Circulating cell-free DNA in health and disease : the relationship to health behaviours, ageing phenotypes and metabolomics

×

Circulating cell-free DNA (cf-DNA) has emerged as a promising biomarker of ageing, tissue damage and cellular stress. However, less is known about health behaviours, ageing phenotypes and metabolic processes that lead to elevated cf-DNA levels. We sought to analyse the relationship of circulating cf-DNA level to age, sex, smoking, physical activity, vegetable consumption, ageing phenotypes (physical functioning, the number of diseases, frailty) and an extensive panel of biomarkers including blood and urine metabolites and inflammatory markers in three human cohorts (N = 5385; 17-82 years). The relationships were assessed using correlation statistics, and linear and penalised regressions (the Lasso), also stratified by sex.

cf-DNA levels were significantly higher in men than in women, and especially in middle-aged men and women who smoke, and in older more frail individuals. Correlation statistics of biomarker data showed that cf-DNA level was higher with elevated inflammation (C-reactive protein, interleukin-6), and higher levels of homocysteine, and proportion of red blood cells and lower levels of ascorbic acid. Inflammation (C-reactive protein, glycoprotein acetylation), amino acids (isoleucine, leucine, tyrosine), and ketogenesis (3-hydroxybutyrate) were included in the cf-DNA level-related biomarker profiles in at least two of the cohorts.

In conclusion, circulating cf-DNA level is different by sex, and related to health behaviour, health decline and metabolic processes common in health and disease. These results can inform future studies where epidemiological and biological pathways of cf-DNA are to be analysed in details, and for studies evaluating cf-DNA as a potential clinical marker.

Forschungszusammenhang (Projekte)

Baur, Jennifer (2015): Biomathematical exploration of the MARK-AGE database

Biomathematical exploration of the MARK-AGE database

×

dc.title:


dc.contributor.author: Baur, Jennifer

Forschungszusammenhang (Projekte)

  Jansen, Eugène; Beekhof, Piet; Cremers, Johannes; Weinberger, Birgit; Fiegl, Simone; Toussaint, Olivier; Bernhard, Jürgen; Gonos, Efstathios; Capri, Miriam; Franceschi, Claudio; Sikora, Ewa; Moreno-Villanueva, Maria; Breusing, Nicolle; Grune, Tilman; Bürkle, Alexander; Dollé, Martijn E. T. (2015): Quality control data of physiological and immunological biomarkers measured in serum and plasma Mechanisms of Ageing and Development. 2015, 151, pp. 54-59. ISSN 0047-6374. eISSN 1872-6216. Available under: doi: 10.1016/j.mad.2015.06.004

Quality control data of physiological and immunological biomarkers measured in serum and plasma

×

In two work packages of the MARK-AGE project, 37 immunological and physiological biomarkers were measured in 3637 serum, plasma or blood samples in five batches during a period of 4 years.
The quality of the serum and plasma samples was very good as judged by the low number of biomarker measurements (only 0.2%) that were rejected because of a high hemolysis, icteria or lipemia of the samples.
Using quality control samples, day-to-day and batch variations were determined. The mean inter-assay variation of the five batches were all below 8%, with an average inter-assay coefficient of variation of all biomarkers of 4.0%. Also the precision of the measurements was very good, because all measurements were between 90% and 115% of the defined target values.
A possible mix-up of samples was determined by comparison of the extreme testosterone levels of men and women. It was concluded that 3% of the sample identification could be mixed-up.
Considering the complex procedure from collection to analysis, including preparation, handling, shipment and storage, of the samples in the MARK-AGE project, both the quality of the samples and the quality of the measurements are very good.

Forschungszusammenhang (Projekte)

Mittelgeber
Name Kennziffer Beschreibung Laufzeit
Kooperation570/08
Weitere Informationen
Laufzeit: 01.04.2008 – 31.03.2013
Link: Projekthomepage