Transcriptome Evidence Reveals Enhanced Autophagy-Lysosomal Function in Centenarians

Genome Res. 2018 Nov;28(11):1601-1610. doi: 10.1101/gr.220780.117. Epub 2018 Oct 23.

Abstract

Centenarians (CENs) are excellent subjects to study the mechanisms of human longevity and healthy aging. Here, we analyzed the transcriptomes of 76 centenarians, 54 centenarian-children, and 41 spouses of centenarian-children by RNA sequencing and found that, among the significantly differentially expressed genes (SDEGs) exhibited by CENs, the autophagy-lysosomal pathway is significantly up-regulated. Overexpression of several genes from this pathway, CTSB, ATP6V0C, ATG4D, and WIPI1, could promote autophagy and delay senescence in cultured IMR-90 cells, while overexpression of the Drosophila homolog of WIPI1, Atg18a, extended the life span in transgenic flies. Interestingly, the enhanced autophagy-lysosomal activity could be partially passed on to their offspring, as manifested by their higher levels of both autophagy-encoding genes and serum beclin 1 (BECN1). In light of the normal age-related decline of autophagy-lysosomal functions, these findings provide a compelling explanation for achieving longevity in, at least, female CENs, given the gender bias in our collected samples, and suggest that the enhanced waste-cleaning activity via autophagy may serve as a conserved mechanism to prolong the life span from Drosophila to humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Autophagy / genetics*
  • Autophagy-Related Proteins / genetics
  • Autophagy-Related Proteins / metabolism
  • Beclin-1 / genetics
  • Beclin-1 / metabolism
  • Cathepsin B / genetics
  • Cathepsin B / metabolism
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / metabolism
  • Female
  • Humans
  • Longevity / genetics*
  • Lysosomes / metabolism
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Middle Aged
  • Transcriptome*
  • Vacuolar Proton-Translocating ATPases / genetics
  • Vacuolar Proton-Translocating ATPases / metabolism

Substances

  • ATP6V0C protein, human
  • Autophagy-Related Proteins
  • BECN1 protein, human
  • Beclin-1
  • Membrane Proteins
  • WIPI-1 protein, human
  • ATG4D protein, human
  • Cysteine Endopeptidases
  • CTSB protein, human
  • Cathepsin B
  • Vacuolar Proton-Translocating ATPases