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Sex-specific transcriptome differences in a middle-aged frailty cohort.

Natasha L Pacheco1, Nicole Noren Hooten1, Yongqing Zhang2

  • 1Laboratory of Epidemiology and Population Sciences, National Institute On Aging, National Institutes of Health, Baltimore, MD, USA.

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Middle-aged frailty shows distinct gene expression patterns between sexes. RNA sequencing reveals novel sex-specific pathways, offering insights into frailty progression and potential therapeutic targets.

Keywords:
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Area of Science:

  • Genomics
  • Aging Research
  • Sex Differences in Health

Background:

  • Frailty, a syndrome of reduced physiological reserve, is increasingly recognized in middle-aged individuals.
  • Previous studies in the HANDLS cohort highlighted inflammatory gene alterations linked to frailty and race.
  • The impact of sex on transcriptome changes in middle-aged frailty remains largely unexplored.

Purpose of the Study:

  • To identify novel genes and pathways associated with sex and frailty in a diverse middle-aged population.
  • To investigate sex-specific transcriptional differences in the context of frailty.
  • To lay the groundwork for understanding frailty progression and developing targeted interventions.

Main Methods:

  • RNA sequencing was employed to analyze peripheral blood mononuclear cells.
  • Differential gene expression and pathway analyses were conducted comparing frail and non-frail individuals across sexes.
  • Exclusive and overlapping genes and pathways between comparison groups were evaluated.

Main Results:

  • Over 80% of significant genes identified were novel, linked to diverse biological functions.
  • Female-specific pathways (FRAF vs NORF) indicated reduced inflammation.
  • Male-specific pathways (FRAM vs NORM) were associated with musculoskeletal abnormalities; (FRAM vs FRAF) pathways showed altered cell cycle regulation and catabolism.

Conclusions:

  • Sex-specific transcriptional alterations are evident in middle-aged frailty.
  • These findings advance the understanding of frailty's molecular underpinnings.
  • The study identifies potential targets for frailty prevention and treatment strategies.