Sex-specific Transcriptome Differences in a Middle-aged Frailty Cohort

Overview

Journal BMC Geriatr

Publisher Biomed Central

Specialty Geriatrics

Date 2022 Aug 9

PMID 35945487

Authors

Natasha L Pacheco

Nicole Noren Hooten

Yongqing Zhang

Calais S Prince

Nicolle A Mode

Ngozi Ezike

Kevin G Becker

Alan B Zonderman

Michele K Evans

Affiliations

Soon will be listed here.

Abstract

Background: Frailty is a clinical syndrome described as reduced physiological reserve and increased vulnerability. Typically examined in older adults, recent work shows frailty occurs in middle-aged individuals and is associated with increased mortality. Previous investigation of global transcriptome changes in a middle-aged cohort from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study demonstrated inflammatory genes and pathways were significantly altered by frailty status and race. Transcriptome differences in frailty by sex remain unclear. We sought to discover novel genes and pathways associated with sex and frailty in a diverse middle-aged cohort using RNA-Sequencing.

Methods: Differential gene expression and pathway analyses were performed in peripheral blood mononuclear cells for 1) frail females (FRAF, n = 4) vs non-frail females (NORF, n = 4), 2) frail males (FRAM, n = 4) vs non-frail males (NORM, n = 4), 3) FRAM vs FRAF, and 4) NORM vs NORF. We evaluated exclusive significant genes and pathways, as well as overlaps, between the comparison groups.

Results: Over 80% of the significant genes exclusive to FRAF vs NORF, FRAM vs NORM, and FRAM vs FRAF, respectively, were novel and associated with various biological functions. Pathways exclusive to FRAF vs NORF were associated with reduced inflammation, while FRAM vs NORM exclusive pathways were related to aberrant musculoskeletal physiology. Pathways exclusive to FRAM vs FRAF were associated with reduced cell cycle regulation and activated catabolism and Coronavirus pathogenesis.

Conclusions: Our results indicate sex-specific transcriptional changes occur in middle-aged frailty, enhancing knowledge on frailty progression and potential therapeutic targets to prevent frailty.

Citing Articles

Metallothionein-1A (MT1A) Gene Variability May Play a Role in Female Frailty: A Preliminary Study.

Crocco P, De Rango F, La Grotta R, Passarino G, Rose G, Dato S Genes (Basel). 2025; 16(1).

PMID: 39858562 PMC: 11765288. DOI: 10.3390/genes16010015.

Growth Differentiation Factor 15 and Diet Quality Trajectory Interact to Determine Frailty Incidence among Middle-Aged Urban Adults.

Beydoun M, Noren Hooten N, Fanelli-Kuczmaski M, Maino Vieytes C, Georgescu M, Beydoun H J Nutr. 2024; 154(5):1652-1664.

PMID: 38479650 PMC: 11130674. DOI: 10.1016/j.tjnut.2024.03.006.

Frailty, sex, and poverty are associated with DNA damage and repair in frail, middle-aged urban adults.

Smith J, Noren Hooten N, Mode N, Zonderman A, Ezike N, Kaushal S DNA Repair (Amst). 2023; 129:103530.

PMID: 37437502 PMC: 10807508. DOI: 10.1016/j.dnarep.2023.103530.

Physical activity plays a crucial role in multidomain intervention for frailty prevention.

Huang T, Chou M, Liang C, Lin Y, Chen R, Wu P Aging Clin Exp Res. 2023; 35(6):1283-1292.

PMID: 37101084 PMC: 10132799. DOI: 10.1007/s40520-023-02412-z.

Mitochondrial DNA and inflammatory proteins are higher in extracellular vesicles from frail individuals.

Byappanahalli A, Noren Hooten N, Vannoy M, Mode N, Ezike N, Zonderman A Immun Ageing. 2023; 20(1):6.

PMID: 36710345 PMC: 9885591. DOI: 10.1186/s12979-023-00330-2.

References

Griffin F, Mode N, Ejiogu N, Zonderman A, Evans M . Frailty in a racially and socioeconomically diverse sample of middle-aged Americans in Baltimore. PLoS One. 2018; 13(4):e0195637. PMC: 5892911. DOI: 10.1371/journal.pone.0195637. View

Arlt A, Schafer H . Role of the immediate early response 3 (IER3) gene in cellular stress response, inflammation and tumorigenesis. Eur J Cell Biol. 2010; 90(6-7):545-52. DOI: 10.1016/j.ejcb.2010.10.002. View

Qu T, Walston J, Yang H, Fedarko N, Xue Q, Beamer B . Upregulated ex vivo expression of stress-responsive inflammatory pathway genes by LPS-challenged CD14(+) monocytes in frail older adults. Mech Ageing Dev. 2008; 130(3):161-6. PMC: 2673566. DOI: 10.1016/j.mad.2008.10.005. View

Zampino M, Ferrucci L, Semba R . Biomarkers in the path from cellular senescence to frailty. Exp Gerontol. 2019; 129:110750. DOI: 10.1016/j.exger.2019.110750. View

Ipson B, Fletcher M, Espinoza S, Fisher A . Identifying Exosome-Derived MicroRNAs as Candidate Biomarkers of Frailty. J Frailty Aging. 2018; 7(2):100-103. PMC: 6384524. DOI: 10.14283/jfa.2017.45. View

Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N . The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009; 25(16):2078-9. PMC: 2723002. DOI: 10.1093/bioinformatics/btp352. View

Cardoso A, Fernandes A, Aguilar-Pimentel J, de Angelis M, Guedes J, Brito M . Towards frailty biomarkers: Candidates from genes and pathways regulated in aging and age-related diseases. Ageing Res Rev. 2018; 47:214-277. DOI: 10.1016/j.arr.2018.07.004. View

Sathyan S, Ayers E, Gao T, Milman S, Barzilai N, Verghese J . Plasma proteomic profile of frailty. Aging Cell. 2020; 19(9):e13193. PMC: 7511877. DOI: 10.1111/acel.13193. View

Brunner E, Shipley M, Ahmadi-Abhari S, Valencia Hernandez C, Abell J, Singh-Manoux A . Midlife contributors to socioeconomic differences in frailty during later life: a prospective cohort study. Lancet Public Health. 2018; 3(7):e313-e322. PMC: 6120440. DOI: 10.1016/S2468-2667(18)30079-3. View

10.

Prince C, Noren Hooten N, Mode N, Zhang Y, Ejiogu N, Becker K . Frailty in middle age is associated with frailty status and race-specific changes to the transcriptome. Aging (Albany NY). 2019; 11(15):5518-5534. PMC: 6710041. DOI: 10.18632/aging.102135. View

11.

Kim S, Volsky D . PAGE: parametric analysis of gene set enrichment. BMC Bioinformatics. 2005; 6:144. PMC: 1183189. DOI: 10.1186/1471-2105-6-144. View

12.

Liao Y, Smyth G, Shi W . featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2013; 30(7):923-30. DOI: 10.1093/bioinformatics/btt656. View

13.

Evans M, Lepkowski J, Powe N, LaVeist T, Fanelli Kuczmarski M, Zonderman A . Healthy aging in neighborhoods of diversity across the life span (HANDLS): overcoming barriers to implementing a longitudinal, epidemiologic, urban study of health, race, and socioeconomic status. Ethn Dis. 2010; 20(3):267-75. PMC: 3040595. View

14.

Bolger A, Lohse M, Usadel B . Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014; 30(15):2114-20. PMC: 4103590. DOI: 10.1093/bioinformatics/btu170. View

15.

Love M, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15(12):550. PMC: 4302049. DOI: 10.1186/s13059-014-0550-8. View

16.

Sheng X, Fan T, Jin X . Identification of Key Genes Involved in Acute Myocardial Infarction by Comparative Transcriptome Analysis. Biomed Res Int. 2020; 2020:1470867. PMC: 7559508. DOI: 10.1155/2020/1470867. View

17.

Gordon E, Hubbard R . Do sex differences in chronic disease underpin the sex-frailty paradox?. Mech Ageing Dev. 2019; 179:44-50. DOI: 10.1016/j.mad.2019.02.004. View

18.

Noren Hooten N, Pacheco N, Smith J, Evans M . The accelerated aging phenotype: The role of race and social determinants of health on aging. Ageing Res Rev. 2021; 73:101536. PMC: 10862389. DOI: 10.1016/j.arr.2021.101536. View

19.

Bandeen-Roche K, Seplaki C, Huang J, Buta B, Kalyani R, Varadhan R . Frailty in Older Adults: A Nationally Representative Profile in the United States. J Gerontol A Biol Sci Med Sci. 2015; 70(11):1427-34. PMC: 4723664. DOI: 10.1093/gerona/glv133. View

20.

Kim D, Paggi J, Park C, Bennett C, Salzberg S . Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype. Nat Biotechnol. 2019; 37(8):907-915. PMC: 7605509. DOI: 10.1038/s41587-019-0201-4. View