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Article ; Online: Correction to: Higher testosterone and testosterone/estradiol ratio in men are associated with decreased Pheno‑/GrimAge and DNA‑methylation based PAI1.

Kusters, Cynthia D J / Paul, Kimberly C / Lu, Ake T / Ferrucci, Luigi / Ritz, Beate R / Binder, Alexandra M / Horvath, Steve

GeroScience

2023 Volume 46, Issue 2, Page(s) 2791–2792

Language	English
Publishing date	2023-11-02
Publishing country	Switzerland
Document type	Published Erratum
ZDB-ID	2886586-8
ISSN	2509-2723 ; 2509-2715
ISSN (online)	2509-2723
ISSN	2509-2715
DOI	10.1007/s11357-023-00995-z
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Article ; Online: Assessment of variability in the plasma 7k SomaScan proteomics assay.

Candia, Julián / Daya, Gulzar N / Tanaka, Toshiko / Ferrucci, Luigi / Walker, Keenan A

Scientific reports

2022 Volume 12, Issue 1, Page(s) 17147

Abstract: SomaScan is a high-throughput, aptamer-based proteomics assay designed for the simultaneous measurement of thousands of proteins with a broad range of endogenous concentrations. In its most current version, the 7k SomaScan assay v4.1 is capable of ... ...

Abstract	SomaScan is a high-throughput, aptamer-based proteomics assay designed for the simultaneous measurement of thousands of proteins with a broad range of endogenous concentrations. In its most current version, the 7k SomaScan assay v4.1 is capable of measuring 7288 human proteins. In this work, we present an extensive technical assessment of this platform based on a study of 2050 samples across 22 plates. Included in the study design were inter-plate technical duplicates from 102 human subjects, which allowed us to characterize different normalization procedures, evaluate assay variability by multiple analytical approaches, present signal-over-background metrics, and discuss potential specificity issues. By providing detailed performance assessments on this wide range of technical aspects, we aim for this work to serve as a valuable resource for the growing community of SomaScan users.
MeSH term(s)	Biomarkers/metabolism ; Humans ; Proteomics/methods
Chemical Substances	Biomarkers
Language	English
Publishing date	2022-10-13
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-22116-0
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Article ; Online: Proteomic Mediators of Overall Cardiovascular Health on All-Cause Mortality.

Tanaka, Toshiko / Talegawkar, Sameera A / Jin, Yichen / Candia, Julián / Fantoni, Giovanna / Bandinelli, Stefania / Ferrucci, Luigi

Nutrients

2023 Volume 15, Issue 3

Abstract: Measures of cardiovascular health (CVH) assessed by a combination of behavioral and biological factors has shown protective associations with all-cause mortality. The mechanisms underlying these associations have not been fully elucidated. In this study, ...

Abstract	Measures of cardiovascular health (CVH) assessed by a combination of behavioral and biological factors has shown protective associations with all-cause mortality. The mechanisms underlying these associations have not been fully elucidated. In this study, we characterized the plasma proteomics profile of CVH and tested whether specific proteins mediated the associations between CVH and all-cause mortality in participants of the InCHIANTI study. Of the 1301 proteins tested, 92 proteins were associated with CVH (22 positively, 70 negatively). Proteins most strongly associated with CVH included leptin (LEP), fatty acid binding protein 3 (FABP3), Angiopoietin-2 (ANGPT2), and growth-differential factor 15 (GDF15). Of the 92 CVH-associated proteins, 33 proteins significantly mediated the associations between CVH and all-cause mortality, with percent mediation ranging from 5 to 30%. The most significant mediating proteins were GDF15 and insulin-like growth factor 2 (IGFBP2). Proteins associated with better CVH were enriched for proteins that reflect the suppression of the complement coagulation and GH/IGF pathways.
MeSH term(s)	Humans ; Cardiovascular Diseases ; Cardiovascular System ; Health Status ; Proteomics ; Risk Factors ; Mortality
Language	English
Publishing date	2023-02-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu15030781
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Article ; Online: Proteomic Analysis of the Senescence-Associated Secretory Phenotype: GDF-15, IGFBP-2, and Cystatin-C Are Associated With Multiple Aging Traits.

Evans, Daniel S / Young, Danielle / Tanaka, Toshiko / Basisty, Nathan / Bandinelli, Stefania / Ferrucci, Luigi / Campisi, Judith / Schilling, Birgit

The journals of gerontology. Series A, Biological sciences and medical sciences

2023 Volume 79, Issue 3

Abstract: Cellular senescence, a hallmark of aging, results in a senescence-associated secretory phenotype (SASP) with an increased production of proinflammatory cytokines, growth factors, and proteases. Evidence from nonhuman models demonstrates that SASP ... ...

Abstract	Cellular senescence, a hallmark of aging, results in a senescence-associated secretory phenotype (SASP) with an increased production of proinflammatory cytokines, growth factors, and proteases. Evidence from nonhuman models demonstrates that SASP contributes to tissue dysfunction and pathological effects of aging. However, there are relatively few human studies on the relationship between SASP and aging-related health outcomes. Proteins from the SASP Atlas were measured in plasma using aptamer-based proteomics (SomaLogic). Regression models were used to identify SASP protein associations with aging-related traits representing multiple aspects of physiology in 1 201 participants from 2 human cohort studies (BLSA/GESTALT and InCHIANTI). Traits examined were fasting glucose, C-reactive protein, interleukin-6, alkaline phosphatase, blood urea nitrogen, albumin, red blood cell distribution width, waist circumference, systolic and diastolic blood pressure, gait speed, and grip strength. Study results were combined with a fixed-effect inverse-variance weighted meta-analysis. In the meta-analysis, 28 of 77 SASP proteins were significantly associated with age. Of the 28 age-associated SASP proteins, 18 were significantly associated with 1 or more clinical traits, and 7 SASP proteins were significantly associated with 3 or more traits. Growth/differentiation factor 15, Insulin-like growth factor-binding protein 2, and Cystatin-C showed significant associations with inflammatory markers and measures of physical function (grip strength or gait speed). These results support the relevance of SASP proteins to human aging, identify specific traits that are potentially affected by SASP, and prioritize specific SASP proteins for their utility as biomarkers of human aging.
MeSH term(s)	Humans ; Senescence-Associated Secretory Phenotype ; Growth Differentiation Factor 15/metabolism ; Insulin-Like Growth Factor Binding Protein 2 ; Proteomics ; Aging/metabolism ; Cellular Senescence/physiology ; Phenotype ; Cystatins/metabolism
Chemical Substances	Growth Differentiation Factor 15 ; Insulin-Like Growth Factor Binding Protein 2 ; Cystatins
Language	English
Publishing date	2023-11-14
Publishing country	United States
Document type	Meta-Analysis ; Journal Article
ZDB-ID	1223643-3
ISSN	1758-535X ; 1079-5006
ISSN (online)	1758-535X
ISSN	1079-5006
DOI	10.1093/gerona/glad265
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Article ; Online: Unbiased proteomics and multivariable regularized regression techniques identify SMOC1, NOG, APCS, and NTN1 in an Alzheimer's disease brain proteomic signature.

Roberts, Jackson A / Varma, Vijay R / Candia, Julián / Tanaka, Toshiko / Ferrucci, Luigi / Bennett, David A / Thambisetty, Madhav

npj aging

2023 Volume 9, Issue 1, Page(s) 18

Abstract: Advancements in omics methodologies have generated a wealth of high-dimensional Alzheimer's disease (AD) datasets, creating significant opportunities and challenges for data interpretation. In this study, we utilized multivariable regularized regression ... ...

Abstract	Advancements in omics methodologies have generated a wealth of high-dimensional Alzheimer's disease (AD) datasets, creating significant opportunities and challenges for data interpretation. In this study, we utilized multivariable regularized regression techniques to identify a reduced set of proteins that could discriminate between AD and cognitively normal (CN) brain samples. Utilizing eNetXplorer, an R package that tests the accuracy and significance of a family of elastic net generalized linear models, we identified 4 proteins (SMOC1, NOG, APCS, NTN1) that accurately discriminated between AD (n = 31) and CN (n = 22) middle frontal gyrus (MFG) tissue samples from Religious Orders Study participants with 83 percent accuracy. We then validated this signature in MFG samples from Baltimore Longitudinal Study of Aging participants using leave-one-out logistic regression cross-validation, finding that the signature again accurately discriminated AD (n = 31) and CN (n = 19) participants with a receiver operating characteristic curve area under the curve of 0.863. These proteins were strongly correlated with the burden of neurofibrillary tangle and amyloid pathology in both study cohorts. We additionally tested whether these proteins differed between AD and CN inferior temporal gyrus (ITG) samples and blood serum samples at the time of AD diagnosis in ROS and BLSA, finding that the proteins differed between AD and CN ITG samples but not in blood serum samples. The identified proteins may provide mechanistic insights into the pathophysiology of AD, and the methods utilized in this study may serve as the basis for further work with additional high-dimensional datasets in AD.
Language	English
Publishing date	2023-07-06
Publishing country	England
Document type	Journal Article
ISSN	2731-6068
ISSN (online)	2731-6068
DOI	10.1038/s41514-023-00112-6
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Article ; Online: Serum Proteomic Signatures of Common Health Outcomes among Older Adults.

Roberts, Jackson A / Basu-Roy, Sayantani / Shin, Jong / Varma, Vijay R / Williamson, Andrew / Blackshear, Chad / Griswold, Michael E / Candia, Julián / Elango, Palchamy / Karikkineth, Ajoy C / Tanaka, Toshiko / Ferrucci, Luigi / Thambisetty, Madhav

Gerontology

2024 Volume 70, Issue 3, Page(s) 269–278

Abstract: Introduction: In aging populations, the coexistence of multiple health comorbidities represents a significant challenge for clinicians and researchers. Leveraging advances in omics techniques to characterize these health conditions may provide insight ... ...

Abstract	Introduction: In aging populations, the coexistence of multiple health comorbidities represents a significant challenge for clinicians and researchers. Leveraging advances in omics techniques to characterize these health conditions may provide insight into disease pathogenesis as well as reveal biomarkers for monitoring, prognostication, and diagnosis. Researchers have previously established the utility of big data approaches with respect to comprehensive health outcome measurements in younger populations, identifying protein markers that may provide significant health information with a single blood sample. Methods: Here, we employed a similar approach in two cohorts of older adults, the Baltimore Longitudinal Study of Aging (mean age = 76.12 years) and InCHIANTI Study (mean age = 66.05 years), examining the relationship between levels of serum proteins and 5 key health outcomes: kidney function, fasting glucose, physical activity, lean body mass, and percent body fat. Results: Correlations between proteins and health outcomes were primarily shared across both older adult cohorts. We further identified that most proteins associated with health outcomes in the older adult cohorts were not associated with the same outcomes in a prior study of a younger population. A subset of proteins, adiponectin, MIC-1, and NCAM-120, were associated with at least three health outcomes in both older adult cohorts but not in the previously published younger cohort, suggesting that they may represent plausible markers of general health in older adult populations. Conclusion: Taken together, these findings suggest that comprehensive protein health markers have utility in aging populations and are distinct from those identified in younger adults, indicating unique mechanisms of disease with aging.
MeSH term(s)	Humans ; Aged ; Longitudinal Studies ; Proteomics ; Aging ; Body Composition ; Outcome Assessment, Health Care
Language	English
Publishing date	2024-01-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	193798-4
ISSN	1423-0003 ; 0304-324X
ISSN (online)	1423-0003
ISSN	0304-324X
DOI	10.1159/000534753
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Article ; Online: Plasma Growth and Differentiation Factor 15 Predict Longitudinal Changes in Bone Parameters in Women, but Not in Men.

Osawa, Yusuke / Tanaka, Toshiko / Semba, Richard D / Fantoni, Giovanna / Moaddel, Ruin / Candia, Julián / Simonsick, Eleanor M / Bandinelli, Stefania / Ferrucci, Luigi

The journals of gerontology. Series A, Biological sciences and medical sciences

2022 Volume 77, Issue 10, Page(s) 1951–1958

Abstract: Bone fragility can progress with aging, but biomarkers to detect emerging osteopenia have not been fully elucidated. Growth/differentiation factor 15 (GDF-15) has pleiotropic roles in a broad range of age-related conditions, but its association with ... ...

Abstract	Bone fragility can progress with aging, but biomarkers to detect emerging osteopenia have not been fully elucidated. Growth/differentiation factor 15 (GDF-15) has pleiotropic roles in a broad range of age-related conditions, but its association with osteopenia is unknown. We examined the relationship between plasma GDF-15 levels and rate of change in bone parameters over 9 years of follow-up in 596 adults in the InCHIANTI study (baseline age, 65-94 years; women, 52.4%; mean follow-up, 7.0 ± 3.0 years). Plasma GDF-15 concentrations were measured using the 1.3k HTS SOMAscan assay. Eight bone parameters were measured in the right tibia by peripheral quantitative computed tomography; total bone density, trabecular bone density, medullary plus trabecular bone density, cortical bone density, total bone area, cortical bone area, medullary bone area, and minimum moment of inertia (mMOI). We ran sex-specific linear mixed-effect models with random intercepts and slopes adjusted for age, age-squared, education, body mass index, the rate of change in weight, smoking, sedentary behavior, cross-sectional areas of calf muscles and fat, 25-hydroxyvitamin D, parathyroid hormone, calcium, diabetes mellitus, and follow-up time. We found a significant association of "baseline GDF-15 × time" in models predicting cortical bone density and the mMOI in women, suggesting that the rates of decline in these bone parameters increased with higher GDF-15 (false discovery rate <0.05). Higher plasma levels GDF-15 predicted an accelerated decline in bone parameters in women, but was less associated in men. Furthermore studies are needed to understand the mechanisms underlying these sex differences.
MeSH term(s)	Aged ; Aged, 80 and over ; Bone Density/physiology ; Bone Diseases, Metabolic ; Calcium ; Female ; Growth Differentiation Factor 15 ; Humans ; Male ; Parathyroid Hormone ; Radius/physiology ; Tibia/diagnostic imaging ; Tibia/physiology
Chemical Substances	GDF15 protein, human ; Growth Differentiation Factor 15 ; Parathyroid Hormone ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2022-04-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Intramural
ZDB-ID	1223643-3
ISSN	1758-535X ; 1079-5006
ISSN (online)	1758-535X
ISSN	1079-5006
DOI	10.1093/gerona/glac079
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Article ; Online: Proteins in the pathway from high red blood cell width distribution to all-cause mortality.

Osawa, Yusuke / Tanaka, Toshiko / Semba, Richard D / Fantoni, Giovanna / Moaddel, Ruin / Candia, Julián / Simonsick, Eleanor M / Bandinelli, Stefania / Ferrucci, Luigi

EBioMedicine

2022 Volume 76, Page(s) 103816

Abstract: Background: The pathophysiological mechanisms underlying the association between red blood cell distribution width (RDW) and all-cause mortality are unknown. We conducted a data-driven discovery investigation to identify plasma proteins that mediate the ...

Abstract	Background: The pathophysiological mechanisms underlying the association between red blood cell distribution width (RDW) and all-cause mortality are unknown. We conducted a data-driven discovery investigation to identify plasma proteins that mediate the association between RDW and time to death in community-dwelling adults. Methods: At baseline, 962 adults (women, 54·4%; age range, 21-98 years) participated in the InCHIANTI, "Aging in the Chianti Area" study, and proteomics data were generated from their plasma specimens. Of these, 623 participants had proteomics data available at the 9-year follow-up. For each visit, a total of 1301 plasma proteins were measured using SOMAscan technology. Complete data on vital status were available up to the 15-year follow-up period. Protein-specific exponential distribution accelerated failure time, and linear regression analyses adjusted for possible covariates were used for mortality and mediation analyses, respectively (survival data analysis). Findings: Baseline values of EGFR, GHR, NTRK3, SOD2, KLRF1, THBS2, TIMP1, IGFBP2, C9, APOB, and LRP1B mediated the association between baseline RDW and all-cause mortality. Changes in IGFBP2 and C7 over 9 years mediated the association between changes in RDW and 6-year all-cause mortality. Interpretation: Cellular senescence may contribute to the association between RDW and mortality. Funding: This study was funded by grants from the National Institutes of Health (NIH) and the National Institute on Aging (NIA) contract and was supported by the Intramural Research Program of the NIA, NIH. The InCHIANTI study was supported as a 'targeted project' by the Italian Ministry of Health and in part by the U.S. NIA.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Aging ; Erythrocyte Indices ; Erythrocytes ; Female ; Humans ; Middle Aged ; Prognosis ; Proteomics ; Risk Factors ; Young Adult
Language	English
Publishing date	2022-01-19
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2022.103816
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Article ; Online: Metabolomic Profile of Different Dietary Patterns and Their Association with Frailty Index in Community-Dwelling Older Men and Women.

Tanaka, Toshiko / Talegawkar, Sameera A / Jin, Yichen / Candia, Julián / Tian, Qu / Moaddel, Ruin / Simonsick, Eleanor M / Ferrucci, Luigi

Nutrients

2022 Volume 14, Issue 11

Abstract: Diet quality has been associated with slower rates of aging; however, the mechanisms underlying the role of a healthy diet in aging are not fully understood. To address this question, we aimed to identify plasma metabolomic biomarkers of dietary patterns ...

Abstract	Diet quality has been associated with slower rates of aging; however, the mechanisms underlying the role of a healthy diet in aging are not fully understood. To address this question, we aimed to identify plasma metabolomic biomarkers of dietary patterns and explored whether these metabolites mediate the relationship between diet and healthy aging, as assessed by the frailty index (FI) in 806 participants of the Baltimore Longitudinal Study of Aging. Adherence to different dietary patterns was evaluated using the Mediterranean diet score (MDS), Mediterranean-DASH Diet Intervention for Neurodegenerative Delay (MIND) score, and Alternate Healthy Eating Index-2010 (AHEI). Associations between diet, FI, and metabolites were assessed using linear regression models. Higher adherence to these dietary patterns was associated with lower FI. We found 236, 218, and 278 metabolites associated with the MDS, MIND, and AHEI, respectively, with 127 common metabolites, which included lipids, tri/di-glycerides, lyso/phosphatidylcholine, amino acids, bile acids, ceramides, cholesterol esters, fatty acids and acylcarnitines, indoles, and sphingomyelins. Metabolomic signatures of diet explained 28%, 37%, and 38% of the variance of the MDS, MIND, and AHEI, respectively. Signatures of MIND and AHEI mediated 55% and 61% of the association between each dietary pattern with FI, while the mediating effect of MDS signature was not statistically significant. The high number of metabolites associated with the different dietary patterns supports the notion of common mechanisms that underly the relationship between diet and frailty. The identification of multiple metabolite classes suggests that the effect of diet is complex and not mediated by any specific biomarkers. Furthermore, these metabolites may serve as biomarkers for poor diet quality to identify individuals for targeted dietary interventions.
MeSH term(s)	Aged ; Biomarkers ; Diet, Mediterranean ; Female ; Frailty ; Humans ; Independent Living ; Longitudinal Studies ; Male
Chemical Substances	Biomarkers
Language	English
Publishing date	2022-05-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu14112237
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Article: Proteomic Signature of HIV-Associated Subclinical Left Atrial Remodeling and Incident Heart Failure.

medRxiv : the preprint server for health sciences

2024

Abstract: Background: People living with HIV (PLWH) are at higher risk of heart failure (HF) and preceding subclinical cardiac abnormalities, including left atrial dilation, compared to people without HIV (PWOH). Hypothesized mechanisms include premature aging ... ...

Abstract	Background: People living with HIV (PLWH) are at higher risk of heart failure (HF) and preceding subclinical cardiac abnormalities, including left atrial dilation, compared to people without HIV (PWOH). Hypothesized mechanisms include premature aging linked to chronic immune activation. We leveraged plasma proteomics to identify potential novel contributors to HIV-associated differences in indexed left atrial volume (LAVi) among PLWH and PWOH and externally validated identified proteomic signatures with incident HF among a cohort of older PWOH. Methods: We performed proteomics (Olink Explore 3072) on plasma obtained concurrently with cardiac magnetic resonance imaging among PLWH and PWOH in the United States. Proteins were analyzed individually and as agnostically defined clusters. Cross-sectional associations with HIV and LAVi were estimated using multivariable regression with robust variance. Among an independent general population cohort, we estimated associations between identified signatures and LAVi using linear regression and incident HF using Cox regression. Results: Among 352 participants (age 55±6 years; 25% female), 61% were PLWH (88% on ART; 73% with undetectable HIV RNA) and mean LAVi was 29±9 mL/m Conclusion: Proteomic signatures that may contribute to HIV-associated LA remodeling were enriched in immune checkpoint proteins, cytokine signaling, and ECM organization. These signatures were also associated with incident HF among older PWOH, suggesting specific markers of chronic immune activation, systemic inflammation, and fibrosis may identify shared pathways in HIV and aging that contribute to risk of HF.
Language	English
Publishing date	2024-02-14
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.02.13.24302797
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