Epigenetic scores for the circulating proteome as tools for disease prediction

Protein biomarkers have been identified across many age-related morbidities. However, characterising epigenetic influences could further inform disease predictions. Here, we leverage epigenome-wide data to study links between the DNAm signatures of the circulating proteome and incident diseases. Using data from four cohorts, we trained and tested epigenetic scores (EpiScores) for 953 plasma proteins, identifying 109 scores that explained between 1% and 58% of the variance in protein levels after adjusting for known protein quantitative trait loci (pQTL) genetic effects. By projecting these EpiScores into an independent sample, (Generation Scotland; n=9,537) and relating them to incident morbidities over a follow-up of 14 years, we uncovered 137 EpiScore – disease associations. These associations were largely independent of immune cell proportions, common lifestyle and health factors and biological aging. Notably, we found that our diabetes-associated EpiScores highlighted previous top biomarker associations from proteome-wide assessments of diabetes. These EpiScores for protein levels can therefore be a valuable resource for disease prediction and risk stratification.

Download Full-text

DNA methylation proxies for 16 plasma proteins predict the incidence of 7 leading causes of morbidity

10.1101/2020.12.01.404681 ◽

2020 ◽

Author(s):

Danni A Gadd ◽

Robert F Hillary ◽

Daniel L McCartney ◽

Anna J Stevenson ◽

Cliff Nangle ◽

...

Keyword(s):

Dna Methylation ◽

Plasma Proteins ◽

Multiple Testing ◽

Disease Risk ◽

Common Disease ◽

Protein Biomarkers ◽

Inflammatory Protein ◽

Generation Scotland ◽

Lothian Birth Cohort

AbstractChronic morbidities place longstanding burdens on our health as we age. Although protein biomarkers are critical for the early detection of such diseases, current studies are limited by low sample sizes, variability in proteomics methods and fluctuations in inflammatory protein expression. Here, we present a novel framework for protein-by-proxy analysis of incident disease. We show that DNA methylation proxies for nine inflammatory and seven neurology plasma proteins (generated in up to 875 individuals in the Lothian Birth Cohort 1936) predict the incidence of seven leading causes of morbidity in the Generation Scotland cohort (n=9,537), ascertained via electronic health data linkage over a follow-up period of up to 14 years. After correction for multiple testing and adjustment for common disease risk factors, these included proxy associations between CCL11 and depression (Hazard Ratio: HR = 1.45, P = 1.8 x 10-4), VEGFA and ischaemic heart disease (HR = 1.16, P = 0.02) and associations between incident diabetes and FGF-21 (HR = 1.39, P = 9.7 x 10-7), NEP (HR = 1.32, P = 2.8 x 10-6) and N-CDase (HR = 1.16, P = 0.02). Several of the protein-proxy associations with disease pinpoint proteins that are already therapeutic targets for the diseases in question. These results provide new opportunities to identify circulating biomarkers for disease detection and candidate pathways for drug targeting.

Download Full-text

The INSPIRE Bio-resource Research Platform for Healthy Aging and Geroscience: Focus on the Human Translational Research Cohort (The INSPIRE-T Cohort)

Journal of Frailty & Aging ◽

10.14283/jfa.2020.38 ◽

2020 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

S. Guyonnet ◽

Y. Rolland ◽

C. Takeda ◽

P.-J. Ousset ◽

I. Ader ◽

...

Keyword(s):

Health Care ◽

Translational Research ◽

Healthy Aging ◽

Care Pathway ◽

Integrative Approach ◽

Biological Aging ◽

Imaging Data ◽

Aging Research ◽

Age Related

Background: The Geroscience field focuses on the core biological mechanisms of aging, which are involved in the onset of age-related diseases, as well as declines in intrinsic capacity (IC) (body functions) leading to dependency. A better understanding on how to measure the true age of an individual or biological aging is an essential step that may lead to the definition of putative markers capable of predicting healthy aging. Objectives: The main objective of the INStitute for Prevention healthy agIng and medicine Rejuvenative (INSPIRE) Platform initiative is to build a program for Geroscience and healthy aging research going from animal models to humans and the health care system. The specific aim of the INSPIRE human translational cohort (INSPIRE-T cohort) is to gather clinical, digital and imaging data, and perform relevant and extensive biobanking to allow basic and translational research on humans. Methods: The INSPIRE-T cohort consists in a population study comprising 1000 individuals in Toulouse and surrounding areas (France) of different ages (20 years or over - no upper limit for age) and functional capacity levels (from robustness to frailty, and even dependency) with follow-up over 10 years. Diversified data are collected annually in research facilities or at home according to standardized procedures. Between two annual visits, IC domains are monitored every 4-month by using the ICOPE Monitor app developed in collaboration with WHO. Once IC decline is confirmed, participants will have a clinical assessment and blood sampling to investigate markers of aging at the time IC declines are detected. Biospecimens include blood, urine, saliva, and dental plaque that are collected from all subjects at baseline and then, annually. Nasopharyngeal swabs and cutaneous surface samples are collected in a large subgroup of subjects every two years. Feces, hair bulb and skin biopsy are collected optionally at the baseline visit and will be performed again during the longitudinal follow up. Expected Results: Recruitment started on October 2019 and is expected to last for two years. Bio-resources collected and explored in the INSPIRE-T cohort will be available for academic and industry partners aiming to identify robust (set of) markers of aging, age-related diseases and IC evolution that could be pharmacologically or non-pharmacologically targetable. The INSPIRE-T will also aim to develop an integrative approach to explore the use of innovative technologies and a new, function and person-centered health care pathway that will promote a healthy aging.

Download Full-text

Association of macular disease with long-term use of pentosan polysulfate sodium: findings from a US cohort

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2019-314765 ◽

2019 ◽

Vol 104 (8) ◽

pp. 1093-1097 ◽

Cited By ~ 12

Author(s):

Nieraj Jain ◽

Alexa L Li ◽

Yinxi Yu ◽

Brian L VanderBeek

Keyword(s):

Age Related Macular Degeneration ◽

Pentosan Polysulfate ◽

Macular Disease ◽

Age Related ◽

National Cohort ◽

Using Data ◽

New Diagnosis ◽

Medical Claims Database

Background/AimsA series at a single clinical centre recently demonstrated an association between the interstitial cystitis drug pentosan polysulfate sodium (PPS) and a vision-threatening pigmentary maculopathy. The aim of this study was to determine if an association exists between PPS use and macular disease in a large national cohort.MethodsA retrospective, matched cohort study using data from a large US medical claims database from 2002 to 2016 was performed. A total of 3012 and 1604 PPS users were compared with 15 060 and 8017 matched controls at 5 and 7 years, respectively. The primary outcome measures included (1) any new diagnosis of a hereditary or secondary pigmentary maculopathy (atypical maculopathy outcome), and (2) any new diagnosis of dry age-related macular degeneration (AMD) or drusen in addition to the aforementioned diagnoses (atypical maculopathy+AMD outcome).ResultsAt the 5-year and 7-year follow-up, 9 (0.3%) and 10 (0.6%) PPS patients progressed to the atypical maculopathy outcome compared with 32 (0.2%) and 25 (0.3%) control patients, respectively. 103 (3.4%) and 87 (5.4%) PPS patients developed the atypical maculopathy+AMD outcome compared with 440 (2.9%) and 328 (4.1%) control patients at 5 and 7 years, respectively. At 5 years, multivariate analysis showed no significant association (p>0.13). At 7 years, PPS users had significantly increased odds of having the atypical maculopathy+AMD outcome (OR=1.41, 95% CI 1.09 to 1.83, p=0.009).ConclusionsPPS exposure was associated with a new diagnosis of macular disease at the 7-year follow-up in a large national cohort.

Download Full-text

Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial

GeroScience ◽

10.1007/s11357-019-00113-y ◽

2019 ◽

Vol 41 (6) ◽

pp. 861-869 ◽

Cited By ~ 24

Author(s):

Christina Lee Chung ◽

Ibiyonu Lawrence ◽

Melissa Hoffman ◽

Dareen Elgindi ◽

Kumar Nadhan ◽

...

Keyword(s):

Human Skin ◽

Immunohistochemical Analysis ◽

Intrinsic Rate ◽

Skin Aging ◽

Clinical Appearance ◽

Protein Levels ◽

Age Related ◽

Lost To Follow Up ◽

Collagen Vii

AbstractAging is a major risk factor for the majority of human diseases, and the development of interventions to reduce the intrinsic rate of aging is expected to reduce the risk for age-related diseases including cardiovascular disease, cancer, and dementia. In the skin, aging manifests itself in photodamage and dermal atrophy, with underlying tissue reduction and impaired barrier function. To determine whether rapamycin, an FDA-approved drug targeting the mechanistic target of rapamycin (mTOR) complex, can reduce senescence and markers of aging in human skin, an exploratory, placebo-controlled, interventional trial was conducted in a clinical dermatology setting. Participants were greater than 40 years of age with evidence of age-related photoaging and dermal volume loss and no major morbidities. Thirty-six participants were enrolled in the study, and nineteen discontinued or were lost to follow-up. A significant (P = 0.008) reduction in p16INK4A protein levels and an increase in collagen VII protein levels (P = 0.0077) were observed among participants at the end of the study. Clinical improvement in skin appearance was noted in multiple participants, and immunohistochemical analysis revealed improvement in histological appearance of skin tissue. Topical rapamycin reduced the expression of the p16INK4A protein consistent with a reduction in cellular senescence. This change was accompanied by relative improvement in clinical appearance of the skin and histological markers of aging and by an increase in collagen VII, which is critical to the integrity of the basement membrane. These results indicate that rapamycin treatment is a potential anti-aging therapy with efficacy in humans.Trial registration ClinicalTrials.gov Identifier: NCT03103893.

Download Full-text

A multiple sclerosis disease progression measure based on cumulative disability

Multiple Sclerosis Journal ◽

10.1177/1352458520988632 ◽

2021 ◽

pp. 135245852098863

Author(s):

Ali Manouchehrinia ◽

Elaine Kingwell ◽

Feng Zhu ◽

Helen Tremlett ◽

Jan Hillert ◽

...

Keyword(s):

Multiple Sclerosis ◽

Severe Disease ◽

Area Under The Curve ◽

Disease Course ◽

Cross Sectional ◽

Age Related ◽

Similar Disease ◽

Longitudinal Comparison ◽

Using Data

Background: Existing severity measurements in multiple sclerosis (MS) are often cross-sectional, making longitudinal comparisons of disease course between individuals difficult. Objective: The objective of this study is to create a severity metric that can reliably summarize a patient’s disease course. Methods: We developed the nARMSS – normalized ARMSS (age-related MS severity score) over follow-up, using the deviation of individual ARMSS scores from the expected value and integrated over the corresponding time period. The nARMSS scales from −5 to +5; a positive value indicates a more severe disease course for a patient when compared to other patients with similar disease timings. Results: Using Swedish MS registry data, the nARMSS was tested using data at 2 and 4 years of follow-up to predict the most severe quartile during the subsequent period up to 10 years total follow-up. The metric used was area under the curve of the receiver operating characteristic (AUC-ROC). This resulted in measurements of 0.929 and 0.941. In an external Canadian validation cohort, the equivalent AUC-ROCs were 0.901 and 0.908. Conclusion: The nARMSS provides a reliable, generalizable and easily measurable metric which makes longitudinal comparison of disease course between individuals feasible.

Download Full-text

Exploring biomarkers of age in routine diagnostics for the risk stratification of older patients in the emergency department

European Heart Journal ◽

10.1093/eurheartj/ehab724.2808 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

P Bahrmann ◽

A L Kunz ◽

A Schoenstein ◽

E Giannitsis ◽

H.-W Wahl ◽

...

Keyword(s):

Emergency Department ◽

Risk Stratification ◽

Older Patients ◽

University Hospital ◽

Biological Aging ◽

Kaplan Meier ◽

Age Related ◽

Increased Risk ◽

All Cause Mortality

Abstract Objectives To estimate the association of the routinely applied biological age-related biomarkers hs-TnT, CRP and Hemoglobin (Hb) with mortality for the purpose of older patient's risk stratification in the emergency department (ED). Design Exploratory, prospective cohort study with a follow-up at 2.5 years after recruitment start. Setting and participants A cardiological emergency department (ED), chest pain unit, of our University Hospital. N=256 cardiological ED patients with a minimum age of 70 years and with an expected life-expectancy above 24h. Methods Data from the hospital files were supplemented by a questionnaire. Patients were followed-up for mortality by requesting registry office information. Results Among N=256 patients 63 died over the follow-up period. Positive results in each of the three biomarkers alone as well as the combination were associated with increased all-cause mortality at follow-up. The number of positive age-related biomarkers appeared to be strongly indicative of the risk of mortality, even when controlled for major confounders (age, sex, BMI, creatinine clearance, and comorbidity). Conclusion and implications In older ED patients, biomarkers explicitly related to biological aging processes such as hs-TnT, CRP and Hb were independently of each other as well as combined associated with an increased risk of all-cause mortality. Thus, they may have the potential to be used to supplement the general risk stratification of older patients in the ED. Validation of the results in a large dataset is needed. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Robert Bosch Foundation, Stuttgart, Germany Kaplan-Meier curves with 95% CI Kaplan-Meier curves for patients grouped

Download Full-text

Biological age is a universal marker of aging, stress, and frailty

10.1101/578245 ◽

2019 ◽

Cited By ~ 1

Author(s):

Timothy V. Pyrkov ◽

Peter O. Fedichev

Keyword(s):

Large Scale ◽

Systematic Investigation ◽

Biological Age ◽

Biological Aging ◽

Physical And Mental Health ◽

Mortality And Morbidity ◽

Markers Of Inflammation ◽

Biomarkers Of Aging ◽

Age Related

SummaryWe carried out a systematic investigation of supervised learning techniques for biological age modeling. The biological aging acceleration is associated with the remaining health- and life-span. Artificial Deep Neural Networks (DNN) could be used to reduce the error of chronological age predictors, though often at the expense of the ability to distinguish health conditions. Mortality and morbidity hazards models based on survival follow-up data showed the best performance. Alternatively, logistic regression trained to identify chronic diseases was shown to be a good approximation of hazards models when data on survival follow-up times were unavailable. In all models, the biological aging acceleration was associated with disease burden in persons with diagnosed chronic age-related conditions. For healthy individuals, the same quantity was associated with molecular markers of inflammation (such as C-reactive protein), smoking, current physical, and mental health (including sleeping troubles, feeling tired or little interest in doing things). The biological age thus emerged as a universal biomarker of age, frailty and stress for applications involving large scale studies of the effects of longevity drugs on risks of diseases and quality of life.To be published as Chapter 2 in “Biomarkers of aging”, ed. A. Moskalev, Springer, 2019.

Download Full-text

Macrophage multinucleated giant cells: hallmarks of the aging ovary

Reproduction ◽

10.1530/rep-20-0489 ◽

2020 ◽

Author(s):

K. Grace Foley ◽

Michele T. Pritchard ◽

Francesca E. Duncan

Keyword(s):

Immune Cell ◽

Giant Cells ◽

Point Of View ◽

Biological Aging ◽

Low Grade ◽

Multinucleated Giant Cells ◽

Ovarian Aging ◽

Age Related ◽

Low Grade Inflammation ◽

Cell Profile

Inflammaging is a state of chronic, low grade inflammation associated with biological aging which contributes to age-related diseases. Recently, an age-associated increase in inflammation has been documented in the mammalian ovary, which is accompanied by a shift in the immune cell profile. In this Point of View article, we consider a unique population of macrophage-derived multinucleated giant cells, found in all reproductively old mouse ovaries, as potential markers or functional drivers of inflammation in ovarian aging.

Download Full-text