Hematopoietic progenitor cell liabilities and alarmins S100A8/A9-related inflammaging associate with frailty and predict poor cardiovascular outcomes in older adults

Benedetta Maria  Bonora; Maria Teresa Palano; Gian Luca Testa; Gian Paolo Fadini; Elena Sangalli; Fabia Madotto; Giuseppe Persico; Francesca Casciaro; Rosa Vono; Ornella Colpani; Francesco Scavello; Roberta Capellari; Pasquale Abete; Patrizia Orlando; Franco Carnelli; Andrea Giovanni Berardi; Stefano De Servi; Angela RAucci; Marco Giorgio; Paolo R Madeddu; Gaia Spinetti

doi:10.1111/acel.13545

Hematopoietic progenitor cell liabilities and alarmins S100A8/A9-related inflammaging associate with frailty and predict poor cardiovascular outcomes in older adults

Benedetta Maria Bonora, Maria Teresa Palano, Gian Luca Testa, Gian Paolo Fadini, Elena Sangalli, Fabia Madotto, Giuseppe Persico, Francesca Casciaro, Rosa Vono, Ornella Colpani, Francesco Scavello, Roberta Capellari, Pasquale Abete, Patrizia Orlando, Franco Carnelli, Andrea Giovanni Berardi, Stefano De Servi, Angela RAucci, Marco Giorgio, Paolo R Madeddu^*Gaia Spinetti^*

^*Corresponding author for this work

Bristol Medical School (THS)

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Abstract

Frailty affects the physical, cognitive, and social domains exposing older adults to an increased risk of cardiovascular disease and death. The mechanisms linking frailty and cardiovascular outcomes are mostly unknown. Here, we studied the association of abundance (flow cytometry) and gene expression profile (RNAseq) of stem/progenitor cells (HSPCs) and molecular markers of inflammaging (ELISA) with the cardiorespiratory phenotype and prospective adverse events of individuals classified according to levels of frailty. Two cohorts of older adults were enrolled in the study. In a cohort of pre-frail 35 individuals (average age: 75 years), a physical frailty score above the median identified subjects with initial alterations in cardiorespiratory function. RNA sequencing revealed S100A8/A9 upregulation in HSPCs from the bone marrow (>10-fold) and peripheral blood (>200-fold) of individuals with greater physical frailty. Moreover higher frailty was associated with increased alarmins S100A8/A9 and inflammatory cytokines in peripheral blood. We then studied a cohort of 104 more frail individuals (average age: 81 years) with multidomain health deficits. Reduced levels of circulating HSPCs and increased S100A8/A9 concentrations were independently associated with the frailty index. Remarkably, low HSPCs and high S100A8/A9 simultaneously predicted major adverse cardiovascular events at 1-year follow-up after adjustment for age and frailty index. In conclusion, inflammaging characterized by alarmin and pro-inflammatory cytokines in pre-frail individuals is mirrored by the pauperization of HSPCs in frail older people with comorbidities. S100A8/A9 is upregulated within HSPCs, identifying a phenotype that associates with poor cardiovascular outcomes.

Original language	English
Article number	e13545
Number of pages	13
Journal	Aging Cell
Volume	21
Issue number	3
DOIs	https://doi.org/10.1111/acel.13545
Publication status	Published - 15 Feb 2022

Bibliographical note

Funding Information:
This work was supported by the Italian Ministry of Health (Ricerca Corrente to the IRCCS MultiMedica and Centro Cardiologico Monzino‐IRCCS) and British Heart Foundation grant RG/13/17/30545, “Unravelling mechanisms of stem cell depletion for the preservation of regenerative fitness in patients with diabetes.” F.S. was supported by Fondazione Veronesi Fellowship 2020

Funding Information:
This work was supported by the Italian Ministry of Health (Ricerca Corrente to the IRCCS MultiMedica and Centro Cardiologico Monzino-IRCCS) and British Heart Foundation grant RG/13/17/30545, “Unravelling mechanisms of stem cell depletion for the preservation of regenerative fitness in patients with diabetes.” F.S. was supported by Fondazione Veronesi Fellowship 2020 The authors wish to thank Dr. Tharita Ferrari from the Functional Rehabilitation Unit of the IRCCS MultiMedica for conducting the 6MWT in subject referring to the pre-frail cohort; the staff of the Cardiology and the Pneumology Units for echocardiography and spirometry analyses, and Mrs Barbara Paludo for the help in patient recruitment.

Publisher Copyright:
© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.

Keywords

alarmins
cardiovascular outcomes
frailty
hematopoietic stem/progenitor cell
inflammaging

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Bonora, B. M., Palano, M. T., Testa, G. L., Fadini, G. P., Sangalli, E., Madotto, F., Persico, G., Casciaro, F., Vono, R., Colpani, O., Scavello, F., Capellari, R., Abete, P., Orlando, P., Carnelli, F., Berardi, A. G., De Servi, S., RAucci, A., Giorgio, M., ... Spinetti, G. (2022). Hematopoietic progenitor cell liabilities and alarmins S100A8/A9-related inflammaging associate with frailty and predict poor cardiovascular outcomes in older adults. Aging Cell, 21(3), Article e13545. https://doi.org/10.1111/acel.13545

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title = "Hematopoietic progenitor cell liabilities and alarmins S100A8/A9-related inflammaging associate with frailty and predict poor cardiovascular outcomes in older adults",

abstract = "Frailty affects the physical, cognitive, and social domains exposing older adults to an increased risk of cardiovascular disease and death. The mechanisms linking frailty and cardiovascular outcomes are mostly unknown. Here, we studied the association of abundance (flow cytometry) and gene expression profile (RNAseq) of stem/progenitor cells (HSPCs) and molecular markers of inflammaging (ELISA) with the cardiorespiratory phenotype and prospective adverse events of individuals classified according to levels of frailty. Two cohorts of older adults were enrolled in the study. In a cohort of pre-frail 35 individuals (average age: 75 years), a physical frailty score above the median identified subjects with initial alterations in cardiorespiratory function. RNA sequencing revealed S100A8/A9 upregulation in HSPCs from the bone marrow (>10-fold) and peripheral blood (>200-fold) of individuals with greater physical frailty. Moreover higher frailty was associated with increased alarmins S100A8/A9 and inflammatory cytokines in peripheral blood. We then studied a cohort of 104 more frail individuals (average age: 81 years) with multidomain health deficits. Reduced levels of circulating HSPCs and increased S100A8/A9 concentrations were independently associated with the frailty index. Remarkably, low HSPCs and high S100A8/A9 simultaneously predicted major adverse cardiovascular events at 1-year follow-up after adjustment for age and frailty index. In conclusion, inflammaging characterized by alarmin and pro-inflammatory cytokines in pre-frail individuals is mirrored by the pauperization of HSPCs in frail older people with comorbidities. S100A8/A9 is upregulated within HSPCs, identifying a phenotype that associates with poor cardiovascular outcomes.",

keywords = "alarmins, cardiovascular outcomes, frailty, hematopoietic stem/progenitor cell, inflammaging",

author = "Bonora, {Benedetta Maria} and Palano, {Maria Teresa} and Testa, {Gian Luca} and Fadini, {Gian Paolo} and Elena Sangalli and Fabia Madotto and Giuseppe Persico and Francesca Casciaro and Rosa Vono and Ornella Colpani and Francesco Scavello and Roberta Capellari and Pasquale Abete and Patrizia Orlando and Franco Carnelli and Berardi, {Andrea Giovanni} and {De Servi}, Stefano and Angela RAucci and Marco Giorgio and Madeddu, {Paolo R} and Gaia Spinetti",

note = "Funding Information: This work was supported by the Italian Ministry of Health (Ricerca Corrente to the IRCCS MultiMedica and Centro Cardiologico Monzino‐IRCCS) and British Heart Foundation grant RG/13/17/30545, “Unravelling mechanisms of stem cell depletion for the preservation of regenerative fitness in patients with diabetes.” F.S. was supported by Fondazione Veronesi Fellowship 2020 Funding Information: This work was supported by the Italian Ministry of Health (Ricerca Corrente to the IRCCS MultiMedica and Centro Cardiologico Monzino-IRCCS) and British Heart Foundation grant RG/13/17/30545, “Unravelling mechanisms of stem cell depletion for the preservation of regenerative fitness in patients with diabetes.” F.S. was supported by Fondazione Veronesi Fellowship 2020 The authors wish to thank Dr. Tharita Ferrari from the Functional Rehabilitation Unit of the IRCCS MultiMedica for conducting the 6MWT in subject referring to the pre-frail cohort; the staff of the Cardiology and the Pneumology Units for echocardiography and spirometry analyses, and Mrs Barbara Paludo for the help in patient recruitment. Publisher Copyright: {\textcopyright} 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.",

year = "2022",

month = feb,

day = "15",

doi = "10.1111/acel.13545",

language = "English",

volume = "21",

journal = "Aging Cell",

issn = "1474-9718",

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Bonora, BM, Palano, MT, Testa, GL, Fadini, GP, Sangalli, E, Madotto, F, Persico, G, Casciaro, F, Vono, R, Colpani, O, Scavello, F, Capellari, R, Abete, P, Orlando, P, Carnelli, F, Berardi, AG, De Servi, S, RAucci, A, Giorgio, M, Madeddu, PR & Spinetti, G 2022, 'Hematopoietic progenitor cell liabilities and alarmins S100A8/A9-related inflammaging associate with frailty and predict poor cardiovascular outcomes in older adults', Aging Cell, vol. 21, no. 3, e13545. https://doi.org/10.1111/acel.13545

Hematopoietic progenitor cell liabilities and alarmins S100A8/A9-related inflammaging associate with frailty and predict poor cardiovascular outcomes in older adults. / Bonora, Benedetta Maria; Palano, Maria Teresa; Testa, Gian Luca et al.
In: Aging Cell, Vol. 21, No. 3, e13545, 15.02.2022.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

TY - JOUR

T1 - Hematopoietic progenitor cell liabilities and alarmins S100A8/A9-related inflammaging associate with frailty and predict poor cardiovascular outcomes in older adults

AU - Bonora, Benedetta Maria

AU - Palano, Maria Teresa

AU - Testa, Gian Luca

AU - Fadini, Gian Paolo

AU - Sangalli, Elena

AU - Madotto, Fabia

AU - Persico, Giuseppe

AU - Casciaro, Francesca

AU - Vono, Rosa

AU - Colpani, Ornella

AU - Scavello, Francesco

AU - Capellari, Roberta

AU - Abete, Pasquale

AU - Orlando, Patrizia

AU - Carnelli, Franco

AU - Berardi, Andrea Giovanni

AU - De Servi, Stefano

AU - RAucci, Angela

AU - Giorgio, Marco

AU - Madeddu, Paolo R

AU - Spinetti, Gaia

N1 - Funding Information: This work was supported by the Italian Ministry of Health (Ricerca Corrente to the IRCCS MultiMedica and Centro Cardiologico Monzino‐IRCCS) and British Heart Foundation grant RG/13/17/30545, “Unravelling mechanisms of stem cell depletion for the preservation of regenerative fitness in patients with diabetes.” F.S. was supported by Fondazione Veronesi Fellowship 2020 Funding Information: This work was supported by the Italian Ministry of Health (Ricerca Corrente to the IRCCS MultiMedica and Centro Cardiologico Monzino-IRCCS) and British Heart Foundation grant RG/13/17/30545, “Unravelling mechanisms of stem cell depletion for the preservation of regenerative fitness in patients with diabetes.” F.S. was supported by Fondazione Veronesi Fellowship 2020 The authors wish to thank Dr. Tharita Ferrari from the Functional Rehabilitation Unit of the IRCCS MultiMedica for conducting the 6MWT in subject referring to the pre-frail cohort; the staff of the Cardiology and the Pneumology Units for echocardiography and spirometry analyses, and Mrs Barbara Paludo for the help in patient recruitment. Publisher Copyright: © 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.

PY - 2022/2/15

Y1 - 2022/2/15

N2 - Frailty affects the physical, cognitive, and social domains exposing older adults to an increased risk of cardiovascular disease and death. The mechanisms linking frailty and cardiovascular outcomes are mostly unknown. Here, we studied the association of abundance (flow cytometry) and gene expression profile (RNAseq) of stem/progenitor cells (HSPCs) and molecular markers of inflammaging (ELISA) with the cardiorespiratory phenotype and prospective adverse events of individuals classified according to levels of frailty. Two cohorts of older adults were enrolled in the study. In a cohort of pre-frail 35 individuals (average age: 75 years), a physical frailty score above the median identified subjects with initial alterations in cardiorespiratory function. RNA sequencing revealed S100A8/A9 upregulation in HSPCs from the bone marrow (>10-fold) and peripheral blood (>200-fold) of individuals with greater physical frailty. Moreover higher frailty was associated with increased alarmins S100A8/A9 and inflammatory cytokines in peripheral blood. We then studied a cohort of 104 more frail individuals (average age: 81 years) with multidomain health deficits. Reduced levels of circulating HSPCs and increased S100A8/A9 concentrations were independently associated with the frailty index. Remarkably, low HSPCs and high S100A8/A9 simultaneously predicted major adverse cardiovascular events at 1-year follow-up after adjustment for age and frailty index. In conclusion, inflammaging characterized by alarmin and pro-inflammatory cytokines in pre-frail individuals is mirrored by the pauperization of HSPCs in frail older people with comorbidities. S100A8/A9 is upregulated within HSPCs, identifying a phenotype that associates with poor cardiovascular outcomes.

AB - Frailty affects the physical, cognitive, and social domains exposing older adults to an increased risk of cardiovascular disease and death. The mechanisms linking frailty and cardiovascular outcomes are mostly unknown. Here, we studied the association of abundance (flow cytometry) and gene expression profile (RNAseq) of stem/progenitor cells (HSPCs) and molecular markers of inflammaging (ELISA) with the cardiorespiratory phenotype and prospective adverse events of individuals classified according to levels of frailty. Two cohorts of older adults were enrolled in the study. In a cohort of pre-frail 35 individuals (average age: 75 years), a physical frailty score above the median identified subjects with initial alterations in cardiorespiratory function. RNA sequencing revealed S100A8/A9 upregulation in HSPCs from the bone marrow (>10-fold) and peripheral blood (>200-fold) of individuals with greater physical frailty. Moreover higher frailty was associated with increased alarmins S100A8/A9 and inflammatory cytokines in peripheral blood. We then studied a cohort of 104 more frail individuals (average age: 81 years) with multidomain health deficits. Reduced levels of circulating HSPCs and increased S100A8/A9 concentrations were independently associated with the frailty index. Remarkably, low HSPCs and high S100A8/A9 simultaneously predicted major adverse cardiovascular events at 1-year follow-up after adjustment for age and frailty index. In conclusion, inflammaging characterized by alarmin and pro-inflammatory cytokines in pre-frail individuals is mirrored by the pauperization of HSPCs in frail older people with comorbidities. S100A8/A9 is upregulated within HSPCs, identifying a phenotype that associates with poor cardiovascular outcomes.

KW - alarmins

KW - cardiovascular outcomes

KW - frailty

KW - hematopoietic stem/progenitor cell

KW - inflammaging

U2 - 10.1111/acel.13545

DO - 10.1111/acel.13545

M3 - Article (Academic Journal)

C2 - 35166014

SN - 1474-9718

VL - 21

JO - Aging Cell

JF - Aging Cell

IS - 3

M1 - e13545

ER -

Hematopoietic progenitor cell liabilities and alarmins S100A8/A9-related inflammaging associate with frailty and predict poor cardiovascular outcomes in older adults

Abstract

Bibliographical note

Keywords

UN SDGs

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