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Transcriptome evidence reveals enhanced autophagy-lysosomal function in centenarians.

Fu-Hui Xiao1,2,3,4, Xiao-Qiong Chen1,2,3,4, Qin Yu1,2,3,5,4

  • 1State Key Laboratory of Genetic Resources and Evolution/Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.

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Centenarians exhibit an up-regulated autophagy-lysosomal pathway, crucial for cellular waste removal. This enhanced cellular cleaning mechanism may be key to human longevity and healthy aging.

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Area of Science:

  • Gerontology
  • Molecular Biology
  • Genetics

Background:

  • Centenarians (CENs) offer insights into human longevity and healthy aging mechanisms.
  • Autophagy-lysosomal pathway function typically declines with age.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying longevity in centenarians.
  • To identify genetic factors contributing to healthy aging and extended lifespan.

Main Methods:

  • RNA sequencing of transcriptomes from centenarians, their children, and spouses.
  • Gene expression analysis to identify significantly differentially expressed genes (SDEGs).
  • Functional validation of key autophagy genes in cell culture and transgenic fly models.

Main Results:

  • Centenarians show significantly up-regulated expression of autophagy-lysosomal pathway genes.
  • Overexpression of specific genes (CTSB, ATP6V0C, ATG4D, WIPI1) promoted autophagy and delayed senescence in cells.
  • Transgenic flies overexpressing a WIPI1 homolog exhibited extended lifespan.
  • Enhanced autophagy-lysosomal activity was partially heritable in offspring.

Conclusions:

  • Up-regulated autophagy-lysosomal pathway activity is a potential mechanism for longevity in centenarians.
  • Enhanced cellular waste clearance via autophagy may be a conserved longevity mechanism across species.
  • These findings suggest therapeutic targets for promoting healthy aging and extending lifespan.