· Web viewKDM Biologic Age, CALERIE (Belsky et al. 2017) 7 Homeostatic Dysregulation (Li et al....

SUPPLEMENTAL MATERIALJustice et al. A Framework for Selection of Blood-Based Biomarkers for Geroscience-Guided Clinical Trials: Report from the TAME Biomarkers Workgroup

Guide to Supplemental Material 1 Numbered References1 Frailty Index – LAB (FI-LAB) (Howlett et al. 2014); 2 Biomarker-based Frailty Index (FI-B) (Mitnitski et al. 2015)3 Newcastle 85+ Study (Martin-Ruiz et al. 2011); 4 Biomarker Signature (Sebastiani et al. 2017)5 Biological Aging (Belsky et al. 2015) 6 KDM Biologic Age, CALERIE (Belsky et al. 2017)7 Homeostatic Dysregulation (Li et al. 2015) 8 Healthy Aging Index (HAI) (Sanders et al. 2014)9 Fried Frailty Phenotype (Fried et al. 2001) 10 Composite Biological Age Score (Khan et al. 2017)11 Biochemical Markers Aging (Engelfriet et al. 2013) 12 Biological Age Predictors (Jylhava et al. 2017)13 Molecular & Phenotypic Biomarkers (Xia et al. 2017) 14 Panel Biomarkers of Healthy Ageing (Lara et al. 2015)15 MARK-AGE Biomarkers (Burkle et al. 2015) 16 CALERIE (Rochon et al. 2011)17 Biomarkers of Aging: Function to Molecular (Wagner et al. 2016)

Colors: Orange = included as routine clinical chemistry or safety panel specific to trial (excluded from biomarker selection); Green = prioritized based on frequency, utility as marker of clinical disease outcome, or strength of expert opinion; Gray text = potential biomarker of aging, but not blood-based (excluded from biomarker selection); Asterisks:** indicates non-blood based biomarkers that will be included in all 3,000 trial participants as functional or clinical measure; * denotes potential substudy or ancillary to be performed in n < 3,000.Abbreviations (“Omit” Column): NB = Not Blood; CMP = Comprehensive Metabolic Panel; CBC = Complete Blood Count; Glyc = Glucose/A1c; Safety = clinical safety labs

Supplemental Table 1 Index or Composite Review / Consensus Panels Prioritization

Candidate Biomarker of Aging 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Freq Omit Dis

.Expr

t8-Hydroxy/deoxyguanosine X 1Adiponectin X X X X X 5 + +Advanced glycation endproducts X X X X 4Akt 0Alanine aminotransferase (ALT) X X X 3 CMPAlbumin X X X X X X X 7 CMPAlkaline phosphatase, bone-specific X X X X 4AMPK activation 0Amyloid A (acute phase protein) X X 2Ankle-Brachial Index (ABI) 0 NBAortic valve calcification X 1 NBAPOE genotype X 1Apolipoproteins (ApoA1, ApoB) X X 2



.Expr

tAspartate aminotransferase (AST) X X X 3 CMPAtg (autophagy) 0 NBAuditory test X 1 NBAugmentation index/pressure (AI,AG) X 1 NBB cells, Memory / naïve ratio X X 2Basophils X X X 3 CBCBeck Depression Inventory** 0 NB**Beta 2 microglobulin X 1Beta-amyloid X 1Bicarbonate X 1Bilirubin, total X X X 3 CMPBlood pressure, diastolic** X X X 3 NB**Blood pressure, systolic** X X X X X 5 NB**Body Fat (DEXA) X 1 NB*Body Mass Index** X X X X X 5 NB**Body weight** 0 NB**Bone mineral density X 1 NB*C- Reactive Protein (CRP) X X X X X X X X X 9 ++ ++Calcium, adjusted X 1 CMPCalcium, total X X X 3 CMPCalifornia Verbal Learning Test X 1 NBCANTAB (neuropsych battery) 0 NBCarbon Dioxide 0 CMPCarbonyls X 1Cardiorespiratory fitness X X X 3 NB*Caveolin-1 X 1CCL11 (eotaxin) X 1 ++Cellular immunity, influenza virus X X 2Chloride X 1 LPCholesterol, HDL X X X X X X X 7 LPCholesterol, LDL X X X X X 5 LPCholesterol, Total X X X X X X X X X 9 LPCholesterol, Total / HDL ratio X X X X 4 LPCirculating anti-DNA antibodies X 1Collagen turnover X 1 NBCollagen, procollagen type1 X 1Cortisol X X 2CPG island DNA methylation X 1Creatinine X X X X X X X X 8 Safty



.Expr

tCystatin C X X X X X 5 + +++Cytomegalovirus antibody (IgG) X X X X 4 +Dehydroepiandrosterone (DHEA-S) X X X X X X 6 +Depression** 0 NB**Diet (appetite, eating, eating disorder) 0 NBDigit Symbol Substitution Test (DSST)** X X X 3

NB**

DNA damage, post irradiation (PBMCs) X X X 3DNA methylation patterns, global X X X X X 5 +++DNA repair, post-irradiation (PBMCs) X X X X 4Doubly labeled water 0 NBEchocardiographic parameters X 1 NBEndothelial progenitor cells X 1Eosinophils X X 2 RCEotaxin (CCL11) X 1 ++Epigenetic (see DNA methylation) X X X X X 5 +++Ext matrix remodeling (MMP9) X 1 +++Facial features X 1 NBFalls (LIFE questionnaire)** 0 NB**Fatigue / Exhaustion** X 1 NB**Ferritin X X X 3Fibrinogen X X 2 +Fibroblast growth factor 23 X 1Folate X X 2Folate, RBC X X 2Forced expiratory volume, 1s (FEV1) X X X X X 5 NB*Forced vital capacity (FVC) X X X X X 5 NB*Free fatty acids X X 2Functional MRI X 1 NBg-H2A.X X 1 NBGait speed** X X X X X X 6 NB**Gamma-glutamyl transpeptidase X 1Glomerular Filtration Rate (eGFR) X 1 CMPGlucose tolerance (oral) 0Glucose, fasting X X X X X X X 7 GlycGlutathione, glutat. reductase/peroxidase X 1Glycated hemoglobin (HbA1c) X X X X X X X X X X X 11 GlycGrowth Differentiating Factor 11/8 X 1

Growth Differentiating Factor 15 0 +++ +++Supplemental Table 1 Index or Composite Review / Consensus Panels Prioritization


.Expr

tGrowth hormone X X X 3H4K16 acetylation X 1Hand grip strength** X X X X X X X 7 NB**Heart rate variability X X 2 NBHeat shock proteins 0Hematocrit X X X 3 CBCHemoglobin X X X X X X X 7 CBCHomocysteine, total X X X 3ICAM-1 or 2 0 + +Insulin-like growth factor -1 (IGF-1) X X X X X X 6 +++Insulin-like growth factor BP-1 X X 2 ++Insulin-like growth factor BP3 X X X X 4 ++ ++Insulin, fasting X X X 3 +++Interferon gamma (IFN-γ) 0Interleukin 1β (Il-1β) X X 2Interleukin-2 (Il-2) 0Interleukin 8 (IL-8) 0 +Interleukin-6 (IL-6), basal X X X X X X X X X 9 ++ +++Interleukin-6 (IL-6), post-stimulation X 1Iron, refrigerated X X 2Isoprostanes (iPF2alpha - III, VI) X X X X 4 NB ++ ++Klotho X 1Knee extensor strength 0 NB*Lactate dehydrogenase, LDH X X 2Lactate levels 0LC3 (autophagy) 0 NBLean Mass X X X 3 NB*Left ventricular mass (LV mass) X 1 NBLeptin X X X 3 +Line 1 DNA methylation X 1Lipid peroxidation products X 1Lymphyocytes X X X 3 CBCMagnesium X 1Mean Arterial Pressure** X X 2 NB**Mean corpuscular hemoglobin (MCH) X 1

CBC

Mean corpuscular hemoglobin conc. X 1 CBCMean corpuscular volume X X X 3 CBC

Metabolomics X X X 3 +++Metallothioneins (MTs) X 1Supplemental Table 1 Index or Composite Review / Consensus Panels Prioritization


.Expr

tMetformin levels 0 MetMethylation (H4K20, H3K4, H3K9, etc) X 1Microbiome** 0 NB* +++Mitochondrial DNA copy number X 1Mitochondrial DNA haplotype X 1Mitochondrial protein levels X 1Mitochondrial respiration (OXPHOS) 0 +++Mobility Assessment Tool (MATsf)** 0 NB**Mini Mental State (3MS), MOCA** X X 2 NB**Monocyte chemoattractant protein 1 0 ++Monocytes X X X X X 5 CBCN-glycan profile X X 2Natriuretic peptides, NT-pro BNP X X X X 4 +++ +++Neutrophils X X X X X 5 CBCNicotinamide phosphoribosyltransferase (visfatin) X X 2NIH Toolbox – cognitive battery X 1 NBNitric oxide (NO) metabolic pathway X 1Noncoding RNA patterns (miRNA) X X 2 ++Norepinephrine 0Number of mitochondria X 1Oxidized low-density lipoprotein X X 2 +p16INK4a X X 2 ++p19ARF X 1 NBp53, p21 X X 2 NBp62 (autophagy) 0 NBPain** 0 NB**PARP-1 X 1Pegboard test, manual dexterity X X 2 NBPentraxin-3 X X 2PGC-1a NBPhosphate X 1Phosphorus, inorganic X X 2Physical activity* X 1 NB*Plasminogen activator inhibitor1 X X 2Platelets X X X 3 CBCPotassium X X 2 CMP

Proinsulin 0 +Prostate specific antigen X 1 *Supplemental Table 1 Index or Composite Review / Consensus Panels Prioritization


.Expr

tProtein, total X X X 3 CMPProteomics X X X 3 +++Pulse** X 1 NB**Pulse pressure** X X 2 NB**Pulse wave velocity (PWV) X 1 NBReceptor for advanced glycation endproducts X X X X 4Red blood cell count X X 2 CBCRed blood cell distribution width, RDW X X 2 CBCRelative left ventricular wall thickness X 1 NBResting metabolic rate (RMR) 0 NBRetinal microvascular damage X 1 NBSenescence Assoc. β-Galactosidase X X 2 NBSex hormone-binding globulin (SHBG) X 1Sex hormones (LH, FSH) X X X X X 5SF-36 physical functioning scale** X 1 NB**Short Physical Performance Battery** X X 2 NB**Sirtuin-1, sirtuin-2 X X 2Skin elasticity X 1 NBSkin Thickness X 1 NBSodium X X X 3 CMPStanding balance test (part of SPPB)** X X X X 4 NB**Superoxide dismutase X 1 NBT cells, CD4 X X X X 4 ++T cells, CD4/CD8 ratio X X X X X 5 +++T cells, CD8 X X X X 4 ++T cells, Memory CD4 X X X 3T cells, Memory/naïve CD4 ratio X X X X 4T cells, Memory/naïve CD8 ratio X X X X 4T cells, Senescent memory CD4 X X 2Telomerase; reverse transcriptase X 1Telomere length X X X X X X X 7 -Temperature, resting** 0 NB**Thioredoxin reductase-1 X 1Thyroid biochemical tests (T4, TSH) X X X X 4 +Timed up & go (TUG) X X 2 NBTranscriptomics X X X 3 +++

Transferrin receptor (Transf. R) X 1Transforming growth factor β (TGF β) X X X 3Supplemental Table 1 Index or Composite Review / Consensus Panels Prioritization


.Expr

tTriglycedride X X X X X X 6 LPTroponin X 1Tumor Necrosis Factor α (TNFα) X X X X X X X 7 ++ **Tumor Necrosis Factor post-stim. X 1Tumor Necrosis Factor Receptors 0 +++Urate X 1 NBUrea nitrogen (blood) X X X X X 5 CMPUric Acid X X X 3Vascular endothelial growth factor 0VDRL X 1Visual acuity X 1 NBVitamin A, alpha-carotene X X 2Vitamin A, beta-cryptoxanthin X X 2Vitamin A, retinol X 1Vitamin B12 X X X 3Vitamin B2 X 1Vitamin B6 X 1Vitamin C X 1Vitamin D (25(OH)D) X X X X X 5Vitamin E, gamma-tocopherol X 1Vitamin K-dependent clotting factors X 1Waist:Hip; Waist Circumference X X X X X 5 NBWeight loss, unintentional** X 1 NB**White blood cells X X X X X X X 7 CBC

Additional Blood-Based Biomarkers of Clinical Disease CategoryAssymetric dimethylarginine (AD-MA) CVDvon Willebrand factor CVDS100beta CVDLipoprotein-associated phospholipase A2 (Lp-PLA2) CVDVascular cell adhesion molecule (VCAM) CVDD-Dimer CVDCopeptin (c-terminal provasopressin) CVDCardiac troponin CVDCreatine-Kinase-MB CVDMyeloperoxidase CVDHeart-type fatty acid binding protein CVD

Endothelin-1 (ET1) or C-terminal pro-Endothelin-1 (CTproET1) CVDSupressor of tumorgenecity 2 (ST2) CVDGalectin-3 (gal-3) CVD +CancerTissue inhibitors of metalloproteinases (TIMPs) CVDplasma T-tau MCI / AD / Dementiaserum neurofilament light chain MCI / AD / DementiaHER-2 (ERBB2) overexpression / amplification Cancerα-fetoprotein ( AFP ) CancerHuman chorionic gonadotropin-β (β- hGC ) CancerCarbohydrate antigen 19–9 ( CA 19–9 ) CancerCarbohydrate antigen 125 ( CA 125 ) CancerCarbohydrate antigen 15.3 ( CA 15.3 ) CancerCarbohydrate antigen 27.29 ( CA 27.29) CancerCarcinoembryonic antigen ( CEA ) CancerFibrin/fibrinogen degradation products (FDP) CancerHuman epidermidis protein 4 ( HE4 ) CancerProstate specifi c antigen ( PSA ) CancerThyroglobulin ( TG ) CancerColors: Orange = included as routine clinical chemistry or safety panel specific to trial (excluded from biomarker selection); Green = prioritized based on frequency, utility as marker of clinical disease outcome, or strength of expert opinion; Gray text = potential biomarker of aging, but not blood-based (excluded from biomarker selection); Asterisks:** indicates non-blood based biomarkers that will be included in all 3,000 trial participants as functional or clinical measure; * denotes potential substudy or ancillary to be performed in n < 3,000.Abbreviations (“Omit” Column): NB=Not Blood; CMP=Comprehensive Metabolic Panel; CBC= Complete Blood Count; Glyc=Glucose/A1c; Saft = safety labs.

Supplemental Material 2. Candidate biomarkers excluded due to concerns for assay reliability or feasibility for large, multi-center clinical trials.Excluded Biomarker Low Reliability or Feasibility for

Large Multi-Center Trial? Details

AKT Reliability & feasibility cells needed; Plasma assay unknownAMPK activation Feasibility cells neededB cells, Memory / naïve ratio Feasibility cells neededCellular immunity, influenza virus Feasibility clinic follow-up, cells neededCPG island DNA methylation Feasibility resource burdenDNA damage, post irradiation (PBMCs) Feasibility cells needed; lab tech & resource burdenDNA methylation patterns, global Feasibility resource burdenDNA repair, post-irradiation (PBMCs) Feasibility cells needed; lab tech & resource burdenEndothelial progenitor cells Feasibility cells neededGlucose tolerance (oral) Feasibility resource and clinic burdenGrowth Differentiating Factor 11/8 Low reliability / assay specificity antibody not-specific; resource LC-MS/MSH4K16 acetylation Feasibility cells neededInterferon gamma (IFN-γ) Reliability test-retest reliability (vs. other cytokines)Interleukin 1β (Il-1β) Reliability test-retest reliability (vs. other cytokines)Interleukin-2 (Il-2) Reliability test-retest reliability (vs. other cytokines)Interleukin 8 (IL-8) Reliability test-retest reliability (vs. other cytokines)Interleukin-6 (IL-6), post-stimulation Feasibility cells neededLactate levels Reliability (without experimental control) cells needed; lab tech & resource burdenLine 1 DNA methylation Feasibility resource burdenMetabolomics Feasibility resource burdenMethylation (H4K20, H3K4, H3K9, etc) Feasibility resource burdenMitochondrial DNA copy number Feasibility resource burdenMitochondrial DNA haplotype Feasibility resource burdenMitochondrial respirometry (OX PHOS) Feasibility cells needed; lab tech & resource burdenMitochondrial protein levels Reliability cells needed; lab tech & resource burdenNitric oxide (NO) metabolic pathway Reliability (without experimental control) resource burdenNoncoding RNA patterns (miRNA) Feasibility resource burdenNumber of mitochondria Feasibility cells needed; lab tech & resource burdenp16INK4a Feasibility cells needed; lab tech & resource burdenProteomics Feasibility resource burdenT cells, CD4 Feasibility cells neededT cells, CD4/CD8 ratio Feasibility cells neededT cells, CD8 Feasibility cells neededT cells, Memory CD4 Feasibility cells needed

T cells, Memory/naïve CD4 ratio Feasibility cells neededT cells, Memory/naïve CD8 ratio Feasibility cells neededT cells, Senescent memory CD4 Feasibility cells neededTranscriptomics Feasibility resource burdenTumor Necrosis Factor post-stim. Feasibility cells needed; lab tech & resource burdenVascular endothelial growth factor Reliability Plasma assay variability less established

Supplemental Material 3. Evidence supporting biomarker association with risk of all-cause mortality or risk of chronic disease or functional decline

Reference Population Age Range

Follow-Up (yr)

Sample Size

HR Mortalty

95% CI Mortalty

Risk Disease or Function

Interleukin-6 (IL-6)

(Adriaensen et al. 2015) BEFRAIL 80+ years 2.83 415 2.83 1.53, 5.22 CVD mort.

(Baune et al. 2011) MEMO study, community dwelling 65-83 9 385 2.47 1.3, 4.7(Baylis et al. 2013) Community dwelling older adults 10 254 0.96 0.77, 0.91 Frailty(Bruunsgaard et al. 2003b) Healthy octogenarians 80+ 6 333 1.13(Cappola et al. 2003) Women's Health & Aging study 3 718 2.1 Disability(Cesari et al. 2012) Health ABC 74 11 2234 1.25 1.17, 1.33 Disability

(Cohen et al. 2003) Establ Populations Epidemiologic Stud. Elderly (EPESE) 71+ 5 1723 1.28 0.98,1.69 Functional

decline(Gallucci et al. 2007) Treviso Longeva (Trelong) study 84 1.7 668 1.3 Disability(Giovannini et al. 2011) Aging & Longevity Study, Sirente 80+ 4 362 2.18 1.29, 3.69 Disability(Harris et al. 1999) Iowa 65+ Rural Health Study 4.6 1293 1.9 1.2, 3.1(Jylha et al. 2007) Vitality 90+ study 90+ 4 285 1.24, 3.62(Maurel et al. 2007) Long term geriatric unit 2 249 2.28 1.04, 4.95

(Reuben et al. 2002) High functioning older adults 70-79 3 870 1.5 Functional decline

7 1.3(Roberts et al. 2010) SALSA study 60-101 9 1468 1.73 1.5, 2.0

(Roubenoff et al. 2003) Framingham Heart Study; ambulatory free living 72-92 4 525 1.3 1.04, 1.63

(Schnabel et al. 2013) Community dwelling older adults 9 3035 1.41 1.28, 1.55 CVD event(Wassel et al. 2010) Rancho Bernardo Study 80-99 23 1354 1.15C Reactive Protein (CRP)


Follow-Up (yr)

Sample Size HR Mort 95% CI,

MortRisk Disease or Function

(Baylis et al. 2013) Community dwelling older adults 10 254 0.98 0.8, 1.21(Carriere et al. 2008) Men 60+ 9 553 2.15 1.14, 4.04

Women 60+ 9 888 1.32 0.55, 2.59(Eugen-Olsen et al. 2010) MONICA10 56 13.6 2602 2.1 1.25, 1.52 Cancer, CVD(Giovannini et al. 2011) Aging & Longevity Study, Sirente 80+ 4 362 2.58 1.52, 4.4(Harris et al. 1999) Iowa 65+ Rural Health Study 4.6 1293 1.6 1.0, 2.6(Kabagambe et al. 2011) REGARDS 45+ 4.5 17845 1.33 1.21, 1.46(Kistorp et al. 2005) Denmark 50-89 5 626 1.45 0.92, 2.32 CVD event(Koenig et al. 2008) MONICA cohort, men 45-74 7.1 3620 1.88 1.41,2.51 Cancer, CVD,

CHD(Makita et al. 2009) Japanese men 40-80 2.7 7901 2.25 1.49, 3.42(Schnabel et al. 2013) Framingham Heart Study 62 8.9 3035 1.32 1.18, 1.48 CVD event(Wannamethee et al. 2011a) Men with / without CVD CVD, CHD(Wu et al. 2011) NHANES III: men 13 4873 1.51 1.21, 1.88

NHNES III: women 13 5372 1.1 0.81, 1.49(Zacho et al. 2010) Copenhagen City Heart Study 16 10388 1.25 1.21-1.29Tumor Necrosis Factor α (TNFα); TNF-receptors (I or II)


Follow-Up (yr)



(Arai et al. 2008) Centenarians 100+ 6 252 TBD(Baune et al. 2011) MEMO study, community dwelling 65-83 9 385 TBD(Bruunsgaard et al. 2003a) Centenarians 100+ 5 126 1.34 1.12, 1.6 Dementia, CVD

(Carlsson et al. 2014) Vasculature in Uppsala Seniors 70+ 8 1005 1.37 1.17-1.60 CVD, Cancer mort

Uppsala Longitud Study Adult Men 70+ 8 775 1.22 1.10-1.37(Luna et al. 2013) Northern Manhattan Study 1862 1.8 1.4, 2.4(Roberts et al. 2010) SALSA 60-101 9 1468 2.47 2.03, 2.99(Roubenoff et al. 2003) Framingham Heart Study 72-92 4 525 1.27 1, 1.6(Schnabel et al. 2013) Framingham Heart Study 62 8.9 3035 1.33 1.19, 1.49Cystatin-C


Follow-Up (yr)



(Astor et al. 2012) US 45-64 10.2 9988 1.49 1.14, 1.95(Deo et al. 2008) US 8.2 3044 CVD mort

(Emberson et al. 2010) UK, men 40-69 11 5371 1.83 1.58, 2.12 Atherosclerotic events

(Luo et al. 2015) Meta-analysis, 9 studies 45+ 1.32 1.12, 1.55 CVD mort(Shastri et al. 2012) CHS All Stars 80's 2.6 1053 2.04 1.12-3.71

(Shlipak et al. 2005) older adults, general population 80’s 7.4 4637 2.05 1.74, 2.4 CVD mort,CVD events

(Shlipak et al. 2006) older adults, general population 1.74 1.74 (1.21 to 2.50)

CVD events, CKD

(Shinkai et al. 2008) Japan 65+ 7.9 1034 2.05 1.74, 2.4(Svensson-Farbom et al. 2014) Sweden 57.5 13.9 4650 171 1.32, 2.22 CVD risk

(Toft et al. 2012) women 60+/-10 12 3153 1.38 1.04-1.84(Wu et al. 2011) Men; NHANES III - low risk 13 5372 1.44 1.1, 1.88 CVD events

Women; NHANES III 13 5372 1.315 1.08, 1.64

(Wu et al. 2010) 40+ 11 2990 4.36 2.52, 7.82 CVD, Cancer mort

(Zethelius et al. 2008) Sweden, men 71 10 1135 1.31 1.18, 1.46 CVD mortIGF-1


Follow-Up (yr)



(Andreassen et al. 2009) Community dwelling 50-89 5 642 1.52 (High) 1.01, 2.28

(Arai et al. 2008) Centenarians 100-108 6.17260274 252 1.35, Lo 1.03, 1.76

1.5, Hi 0.72, 1.54(Brugts et al. 2008) Community dwelling 73-94 8.6 376 1.29, Lo 0.76, 2.18

1.42, Hi 1.0, 2.0

(Burgers et al. 2011) Meta-Analysis, 12 studies 14,906 1.27, Lo 1.10, 1.46 U: Cancer, CVD mort

1.18, Hi 1.04, 1.34(Cappola et al. 2003) Women 65+ 5 718 1.29, Lo 0.94, 1.78 Disability

(Friedrich et al. 2009) Study of Health in Pomerania (SHIP), men 20-79 8.5 1988 1.92, Lo 1.35, 2.73 Cancer, CVD

mort (men)1.24, Hi 0.81, 1.89

SHIP, women 20-79 8.5 2069 0.76, Lo 0.4, 1.470.57, Hi 0.25, 1.31

(Kaplan et al. 2008) CHS study 64-92 8 1122 1.18, Lo 0.89, 1.540.99, Hi 0.67, 1.47

(Maggio et al. 2007) InCHIANTI, men 65-92 6 410 1.36, Lo 0.78, 2.38(Roubenoff et al. 2003) Framingham Heart Study 72-92 4 525 0.7 0.49-0.99(Schneider et al. 2012) Community dwelling 10 3967 1.6 CVD mort

(Svensson et al. 2012) Sweden, Osteoporotic Fractures in Men Study 69-81 6 2901 1.67

(van Bunderen et al. 2010) Longitudinal Aging Study Amsterdam (LASA) 64-88 11.6 1273 1.28, Lo 1.01, 1.63 Cancer, CVD

1.17, Hi 0.90, 1.53NT-proBNP


Follow-Up (yr)



(Kistorp et al. 2005) Denmark 50-89 5 626 1.43 1.1, 1.86 CVD(McKie et al. 2006) Rochester Epidemiology Project 45+ 5.6 1991 1.44 1.07, 1.93 CVD(Welsh et al. 2013) West of Scotland Coronary 45-65 14.7 6595 1.26 CVD

Prevention Study, menFasting Insulin


Follow-Up (yr)



(Ausk et al. 2010) NHANES III, nondiabetic 40+ 8.5 5511 1.48 0.9, 1.25(de Boer et al. 2012) CHS 65+ 14.5 3138 1.22 0.89, 1.25(Group 2004) Meta-analysis, men 8.8 CVD

Meta-analysis, women 8.8 CVD(Nilsson et al. 2003) Malmo Preventive Project (Sweden) 47 19 6074 1.17 0.96, 1.41(Welsh et al. 2014) PROSPER, high CVD risk 75 3.2 4,923 1.03 0.91, 1.17(Zhang et al. 2017a) Meta-analysis, non-diabetics 26976 1.13 1.0, 1.27 CVDGrowth Differentiation Factor 15 (GDF15) / Macrophage Inhibitory Cytokine-1 (MIC-1)


Follow-Up (yr)



(Hagstrom et al. 2017) Stable Coronary Heart Disease (KAROLA study) 10 1073 1.68 1.08, 2.62 CV events

(Daniels et al. 2011) Rancho Bernardo study 11 1391 1.5 1.3, 1.8 CVD & non-CVD mort

(Doerstling et al. 2018) VaMIS (Vastmanland Myocardial Infarction Study)

68 (mean) 8 806 1.8 1.48, 2.20

(Eggers et al. 2013) PIVUS (prospective investigation of the vasculature in Uppsala Seniors) 70, 75 8 1817 4 2.7, 6.0

(Frimodt-Moller et al. 2018) Type 2 Diabetes, Copenhagen 59 (mean) 6.1 200 1.9 1.2, 2.9 CVD, CKD

(Fujita et al. 2017) Japanese community dwelling 65+ 4.7 1832 2.33 1.06, 5.12(Jiang et al. 2016) MCI, dementia(Rohatgi et al. 2012) Dallas Heart Study 30-65 7.3 3219 3.5 2.1-5.9

(Wallentin et al. 2013) ULSAM, men 71 9.8 940 1.48 1.33, 1.67 CVD mort & events, Cancer

(Wang et al. 2012) Framingham Offspring Study 50-70 11.3 3428 1.66 1.51–1.81 CVD events, HF

(Wiklund et al. 2010) Swedish population registry, men 30-85 14 876 2.61 1.53, 4.45 CVD, cancer, other

Swedish twin registry (same sex twins) 30-85 324 2.2 1.47, 3.42

DHEAS


Follow-Up (yr)



(Baylis et al. 2013) community dwelling 10 254 1.18 0.97, 1.43 Frailty

(Ohlsson et al. 2010) MrOS Sweden study, men 69-81 4.5 2,644 1.54 1.21, 1.96 CVDTelomere Length


Follow-Up (yr)



(Arai et al. 2015) Tokyo Oldest Old Survey on Total Health (TOOTH) 85+ 4-7 1,220

NOT: physical, cognitive function,

multimorbidity(Fitzpatrick et al. 2011) CHS 65+ 1,136 1.34 1.11, 1.63

(Glei et al. 2015) Taiwanese, Social Environment and Biomarkers of Aging Study 54+ 10 942 0.89 0.81, 0.98

(Houben et al. 2011) Zutphen Elderly Study 78 7 203 0.86 0.53, 1.40(Loprinzi and Loenneke 2018) NHANES 20-85 5 6,611 0.76 0.50, 1.14

(Martin-Ruiz et al. 2005) Leiden 85+ Study 85+ 3 598 1.0 0.82, 1.21

NOT: dementia, CVD, cancer,

infectious disease

(Mons et al. 2017) Meta-Analysis of: Nurse’s Health Study &ESTHER 43-75 >10 12,199 1.23 1.04, 1.46

(Needham et al. 2015) NHANES 50-84 9.5 3,091 1.1 0.9, 1.4

(Rode et al. 2015)Copenhagen City Heart Study;

Copenhagen General Population Study

50-60 64,637 1.4 1.25, 1.57

(Svensson et al. 2014) MrOS-Sweden study, men 60-81 6 2,744 1.05 0.85, 1.28(Zhang et al. 2017b) Meta-analysis, non-diabetics Cancer riskAdiponectin


Follow-Up (yr)



(Choi et al. 2015)Korean Longitudinal Study on Health and Aging (KLoSHA) 65+ 6.2 1000 1.38 1.17, 1.64 CVD mort

(Dekker et al. 2008)General population, Hoorn

Netherlands 50-75 15 1886 0.92 0.64, 1.31 CVD

(Dekker et al. 2008)

Ludwigshafen Risk and Cardiovascular Health (LURIC)

Study, smokers 10 777 1.83 1.28, 2.62LURIC, non-smokers 1178 1.56 1.15, 2.11

(Hascoet et al. 2013) Genetique et ENvironnement en Europe du Sud (GENES) study: no

45-74 8.1 782 2.2 1.15, 4.22 CVD mort

CAD at entryCAD + Non-CAD 1497 2.07 1.48, 2.90

(Kizer et al. 2011) CHS All Stars 65+ 8.9 840 1.91 1.61, 3.448.9 840 0.72 0.52, 0.99

(Kizer et al. 2012) CHS Study 3272 1.19 1.12, 1.27 CVD mort0.81 0.65, 0.95

(Laughlin et al. 2007)San Bernardo Study: community-

dwelling men and women 50-91 20 1361 1.22 0.99, 1.51Coronary heart

disease

(Lindberg et al. 2013)Copenhagen City Heart Study: men

and women without CV 7.8 5624 1.2 1.14, 1.27 CV events

(Pilz et al. 2006)Persons with/without angiographic

CA 5.45 3146 1.22 1.12, 1.34(Poehls et al. 2009) Well-functioning adults 69-79 6.6 3075 1.26 1.15, 1.37 CVD Mort

(Uetani et al. 2014) British men62.4 +/-

12.3 6.5 2020 1.92(Wannamethee et al. 2007) Community dwelling men 60-79 6 3099 1.55 1.19-2.02 CVD Mort

(Wannamethee et al. 2011b) Men without history of CVD 60-79 9 2879 1.41 1.13, 1.95CVD, heart

failure

(Witberg et al. 2016) Dallas Heart Study 45 10.4 3263 2.27 1.47, 3.50CVD mort &

events

(Yoon et al. 2012)Lung Health Study: general

population (smokers) 4686 1.1 0.93, 1.29COPD

outcomesIsoprostanes

(Cesari et al. 2012) Health ABC 74 11 2234 1.12 1.04, 1.2 NOT: Disability (HR 0.99)

IGF Binding Proteins (IGFBPs)


Follow-Up (yr)

Sample Size

HR, Mort.

95% CI, Mort.


(Arai et al. 2008) Centenarians 100-108 6 252 1.19, Lo 0.71, 1.990.96, Hi 0.67, 1.38

(Friedrich et al. 2009) Study of Health in Pomerania (SHIP), men 20-79 8.5 1988 1.87, Lo 1.31, 2.67 CVD & Cancer

mort1.04, Hi 0.66, 1.64

SHIP, women 20-79 8.5 2069 1.63, Lo 0.96, 2.27 Cancer & CVD mort

8.5 0.63, Hi 0.27, 1.47

(Hu et al. 2009) Health ABC study 70+ 6.2 625 1.48, IGFBP1 1.14, 1.92 Metabolic

health1.34, 1.01, 1.76

IGFBP2

(Kaplan et al. 2008) CHS study 64-92 8 1122 1.23, Lo 0.94, 1.61 Function status (IGFBP1)

1.02, Hi 0.69, 1.51(Nolte et al. 2015) Women: PRIMOS 68-79 9.9 338 1.98, Hi 1.03-3.81CMV Antibody


Follow-Up (yr)



(Gkrania-Klotsas et al. 2013) European Prospective Investigation of Cancer-Norfolk 40-79 14 13,090 1.16 1.07, 1.26 CVD, cancer

(Roberts et al. 2010) SALSA study 60-101 10 1468 1.43 1.14, 1.79(Simanek et al. 2011) NHANES III 14 14153 1.19 1.01, 1.41 CVDLeptin(Batsis et al. 2015) NHANES III, men 70 12 1.23

NHANES III, women 70 12 0.97(Mishra et al. 2015) Health ABC, men 70-79 8.4 2919 0.88 0.61, 1.01

Health ABC, women 70-79 8.4 0.82 0.55, 0.98Fibrinogen


Follow-Up (yr)

Sample Size HR Mort 95% CI


(Schnabel et al. 2013) Framingham Heart Study 62 8.9 3035 1.15 1.03, 1.29 CVD(Wu et al. 2011) NHANES III, men 13 4873 1.43 1.1, 1.88 CVD

NHANES III, men + women 13 5372 1.15 1.13, 1.29 CVDAdvanced Glycation End products(Semba et al. 2009) Nondiabetic, InCHIANTI 65+ 6 1013 1.68 1.27, 3.49 CVDHemoglobin A1c


Follow-Up (yr)



(Blaum et al. 2005) Disabled, mild hyperglycemia, women 65-101 6 576 1.81 1.03, 3.17

Disabled, moderate hyperglycemia, women 65-101 6 2.02 1.34, 3.57

(Brown et al. 2014) NHANES III 64 9.2 438 1.15 0.88, 1.5(Chonchol et al. 2010) nondiabetics in CHS aged 65+ 65+ 14.2 810 1.16 0.91, 1.47 CVD

(Eskesen et al. 2013) Nondiabetic; Copenhagen Heart Study 10 5127 1.21 0.99, 1.47 CVD

(Grossman et al. 2016) Nondiabetics 65+ 12937 1.17 1.04, 1.32(Khaw et al. 2004) Residents of Norfolk, men 45-79 6 4662 1.22 1.14, 1.34 CVD

Residents of Norfolk, women 6 5570 1.28 1.06, 1.32 CVD

(Kim et al. 2016) Community dwelling nondiabetics Disability(Lauritzen et al. 2012) Normal glucose, A1c 6-6.5% 40-69 6.6 16355 1.3 1.02, 1.75

Impaired fasting glucose, A1c>6.5% 875 2.5 1.49, 4.02(Reddigan et al. 2012) NHANES III 64 13.4 10352 1.54 1.3,1.82 CVD(Schottker et al. 2016) Meta-Analysis, nondiabetic 65+ 10.7 28681 1.14 1.03, 1.27Epigenetic Clock


Follow-Up (yr)

Sample Size

HR Mort

95% CI, Mort


(Perna et al. 2016), Hannum German case-cohort, ESTHER 50-75 Per 5 yr 1548 1.21 1.14, 1.29 Cancer, CVD(Perna et al. 2016), Horvath 1.11 1.05, 1.18(Chen et al. 2016), EEAA Meta-Analysis, 13 cohorts 13089 1.04 1.03, 1.05(Zhang et al. 2017c), DNAm score (10 CpG) German case-cohort, ESTHER 50-75 14 954 2.16 1.1, 4.24

(Quach et al. 2017), EEAA WHI 50-82 4173InCHIANTI 71 ± 16 -- 402

(Zhang et al. 2018), AgeAccel Subset of population-based cohort 62.1 ±

6.5 14 858 1.37 1.25,1.51

(Zhang et al. 2018), Methylation risk (MR) score Subset of population-based cohort 62.9 ±

6.7 14 993 1.91 1.63, 2.22

(Levine et al. 2018), PhenoAge

5 studies: women’s health (WHI), Framingham Heart (FHS),

Normative Aging (NAS), Jackson Heart (JHS)

10

WHI: 2191FHS: 2553NAS: 657JHS: 1747

Meta: 1.045

Healthspan; CVD, cancer,

AD, T2D, respiratory

(Starnawska et al. 2017), DNAm score Middle-aged twins 10 486 NOT Cognitive

function

(Marioni et al. 2015), Hannum

5 cohorts: Lothian Birth cohorts (1921, 1936), Framingham Heat (FHS), Normative Aging (NAS

~60-80 Per 5 yr

1921: 4461936: 920FHS: 2635NAS 657

1.21 1.14, 1.29

(Marioni et al. 2015), Horvath 1.11 1.05, 1.19*Effect sizes are for highest levels compared with lowest levels unless otherwise specified (e.g. for U-shaped associations middle tertile often comparator). HRs adjusted for age and sex (minimum) and population or biomarker specific confounds

Supplemental Material 4. Biomarker Responsiveness to Geroscience-Guided Interventions

Inflammation (IL-6, hs-CRP, TNFα)Intervention Study / Population Design Duration Biomarker Change ReferenceMetformin LANCET: diabetics with elevated

CRP, aged 53.9 ± 11.5 yrs2x2 open label factorial trial: metformin (2000mg/d) vs. Placebo, ± insulin glargine

< 1 yr Lower IL-6 (-10%) (Pradhan et al. 2009)

Metformin Mild metabolic syndrome (n=41) RCT: Metformin v. Simvastatin

16 weeks Lower Il-6, CRP; No change TNFα

(Bulcao et al. 2007)

Metformin DPP: high risk for diabetes (n=3.234)

RCT: metformin vs. lifestyle vs. placebo

1 yrs Lower hsCRP & tPA (Goldberg et al. 2014)

3.4 yrs Lower hsCRP & tPA (Goldberg et al. 2014)

Metformin T2DM (n=208) RCT: Metformin vs. Placebo Lower CRP (Chakraborty et al. 2011)

Metformin DPP: Impaired glucose tolerance Metformin vs. Intensive Lifestyle Intervention (ILI)

12 mo Lower CRP (women) –greater effect in ILI

(Haffner et al. 2005)

Metformin Carotid artery atherosclerosis (n=43)

RCT: Metformin (1000mg) v. placebo

12 weeks Lower IL-6, CRP, TNFα (Xu et al. 2015)

Metformin T2DM Metformin vs. pioglitazone 16 week No change CRP (Genovese et al. 2013)

Metformin T2DM + subclinical atherosclerosis (n=92)

Metformin (1700mg/d) vs. rosiglitazone

24 weeks No change hsCRP (-4%)

(Stocker et al. 2007)

Metformin Nondiabetic heart failure (TAYSIDE trial; n=62)

RCT: metformin vs. placebo 4-mo Lower IL6 (and CCL11) (Cameron et al. 2016)

Metformin Impaired glucose tolerance (N=55) aged 48.4 ± 9.6 yr

RCT: Metformin (2000mg/d) 16 week No Change: TNFα, CRP, tPA

(Caballero et al. 2004)

Glucose lowering (with Metformin)

VA Diabetes Trial (VADT) (n=266) Intensive glucose lowering therapy vs. standard

9 mo No change IL-6, CRP, PAI-1, fibrinogen,

(Koska et al. 2013)

Acarbose Obesity + T2DM treated with metformin (n=36)

RCT: acarbose vs. exenatide

3 mo No changeIL-6, TNFα

(Shi et al. 2017)

Acarbose T2DM treated with sulphonylurea or metformin (n=274)

RCT: Acarbose vs. pioglitazone

12 mo No change IL-6, CRP or TNFα

(Derosa et al. 2010)

Caloric Restriction CALERIE, nonobese (n=218) aged 21-51 years

Hypocaloric diet designed for -25% kCal/d vs. Ad libitum

2 yr Lower TNFα, CRP (Ravussin et al. 2015)

Caloric Restriction (weight loss)

Overweight/Obese Postmenopausal women (n=400+)

RCT: CR weight loss + exercise

12 mo Lower IL-6, hs-CRP (Imayama et al. 2012)

Caloric Restriction + Low-Protein (weight loss)

RESMENA project (Obesity), n=96

RT: hypocaloric diet w varying protein type

8 week Lower Il-6, hs-CRP, TNFα, PAI-1 in low protein group

(Lopez-Legarrea et al. 2014)


Nondiabetic overweight / obese (n=28) aged 39 ± 5yrs


12 mo Lower Il-6, hs-CRP (Ho et al. 2015)


Obese women (n=29) aged 21-54 yrs

Single-arm hypocaloric diet (-500-1000 kCal/d)

12 weeks Lower Il-6, Il-18, no change IL-10

(Tajik et al. 2013)

Caloric Restriction Obese women (n=84) aged 25-50 yrs

RCT: Caloric Restriction ± Nigella Sativa Oil

No change with diet alone Il-6, hs-CRP, TNFα

(Mahdavi et al. 2016)

Resveratrol Metabolic syndrome (n=74) aged 49.5 ± 0.8 yrs

RCT: resveratrol (1000mg/d) vs. 150mg/d vs. placebo

16 weeks No change Il-6, hs-CRP, inflammatory gene expression

(Kjaer et al. 2017)

Resveratrol Older adults with stable angina pectoris (n=87)

Double blind RCT: calcium fructoborate, resveratrol, or combo.

60 day Combo: Lower hsCRP (-30.3%)

(Militaru et al. 2013)

Resveratrol Overweight/obese adults (n=45) aged 61 ± 7 yrs.

Randomized X-over trial: resveratrol (150mg) v. placebo

4 weeks No change (van der Made et al. 2015)

Summary: potentially responsive to interventionImproved inflammatory profile: 14 (out of 23 studies)No change: 9 (out of 23 studies)GDF15Intervention Study / Population Design Duration Biomarker Change ReferenceMetformin Outcome Reduction with Initial

Glargine Intervention (ORIGIN) trial (n=8,401; 2,317 metformin)

Metformin use Cross-Sectional

OR of metformin use per SD increase GDF15 level: 3.73 to 3.94

(Gerstein et al. 2017)

Summary: limited clinical trial evidence; GDF15 levels highly sensitive to metforminFasting InsulinIntervention Study / Population Design Duration Biomarker Change ReferenceMetformin DPP: high risk for diabetes

(n=2,155)RCT: metformin vs. lifestyle vs. placebo

1 yr Lower (Laughlin et al. 2007)

Caloric Restriction CALERIE, nonobese (n=218) aged 21-51 years

Hypocaloric diet designed for -25% kCal/d vs. Ad libitum

2 yr Lower (Ravussin et al. 2015)

Resveratrol T2DM, Meta-Analysis of 9 trials Lower (Zhu et al.

(n=283) 2017)Resveratrol Meta-Analysis of 11 trials (n=388) Lower (T2DM only) (Liu et al. 2014)Resveratrol Obese but healthy men (n=24) Double blind RCT:

Resveratrol vs placebo4 weeks No change (Poulsen et al.

2013)Resveratrol Well-controlled T2DM (n=17) Randomized X-over trial:

resveratrol (150mg) v. placebo

30 days No change (Timmers et al. 2016)

Resveratrol Diet controlled T2DM RC X-over Trial: resveratrol (1000mg/d) vs placebo

5 week No change (Thazhath et al. 2016)

Resveratrol Overweight/obese adults (n=45) aged 61 ± 7 yrs.

Randomized X-over trial: resveratrol (150mg) v. placebo

4 weeks No change (van der Made et al. 2015)

Resveratrol / Rpapmycin

Mice: high fat diet (HFD) HFD ± resveratrol, rapamyin, or combo

13 weeks Lower (rapa, combo) (Leontieva et al. 2013)

Summary:Improved (lower) fasting insulin: 4 (out of 8 studies)No change: 4 (out of 8 studies)Preclinical evidence suggests fasting insulin improved by geroscience-guided interventions (example above).IGF-1 (& IGFBPs)Intervention Study / Population Design Duration Biomarker Change ReferenceMetformin Polycystic ovarian syndrome

(n=17)Single-arm, open label: Metformin (1500mg)

30 days Increase IGFBP1; IGF1 non-significant increase

(De Leo et al. 2000)

Metformin Polycystic ovarian syndrome with hyperinsulinemia (n=27)

Single-arm, open label: Metformin (1500mg)

12 week No change IGF1; Increase IGFBP1

(Pawelczyk et al. 2004)

Caloric Restriction CALERIE, normal weight adults (n=), aged 38±7 yrs

RCT: Hypocaloric diet vs. (n=143)Ad libitum (n=75)

2 yr No change IGF-1; Increase IGFBP1 (+21%)

(Fontana et al. 2016)

Summary:IGF-1 is generally unchanged in clinical trials of geroscience-guided intervention, whereas IGFPB1 may be sensitive to treatments.Cystatin CIntervention Study / Population Design Duration Biomarker Change ReferenceCaloric Restriction Obese, pharmacologically treated

adults (n=23), aged 52 ± 7.5 yrsSingle-arm weight loss trial: Mediterranean hypocaloric diet (1400-1600 kCal/day)

4 mo No change (Greco et al. 2014)


Medifast for Seniors: older adults with obesity (n=82), aged 70±3.7 years

Hypocaloric diet (1100-1300 kCal/d;) vs.weight stable controls

12 week Lower (-21%) (Shaver et al. 2018)

Summary:Cystatin C more often used for eligibility and safety screening; limited evidence exists to document change with interventions.NT-proBNPIntervention Study / Population Design Duration Biomarker Change ReferenceResveratrol Older adults with stable angina

pectoris (n=87)Double blind RCT: calcium fructoborate, resveratrol, or combo.

60 day Lower NT-proBNP. Resv. Only: -59.7% Combo: (-65.5%)

(Militaru et al. 2013)

Summary:NT-proBNP used as index of cardiovascular health; limited evidence in geroscience-context.

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