Extension of lifespan by reducing ill-folded proteins to be aggregated.

Robert Hughes' group at Buck Institute found recently that aggregation of
specific proteins (mostly due to their misfolding) contributes to the normal
aging process, and blocking such an aggregation by RNAi indeed extends the
lifespan of C. elegans (1).

Misfolding of specific proteins can cause late-onset diseases such as AD
and HD. However, the contribution of protein aggregation to the normal aging
process is less well understood. To address this issue, they performed a
mass spectrometry-based proteomic analysis to identify proteins that adopt
SDS-insoluble conformations during aging in C. elegans. SDS Insoluble proteins
extracted from young and aged C. elegans were chemically labelled by isobaric
tagging for relative and absolute quantification (iTRAQ) and identified
by liquid chromatography and mass spectrometry.

They identified more than 200 distinct proteins significantly enriched in
an SDS-insoluble fraction of aged nematodes and largely absent from that
of young nematodes. The SDS-insoluble fraction in aged animals contains
a diverse range of proteins including a large number of ribosomal proteins.
Gene Ontology analysis revealed highly significant enrichments for energy
production and protein synthesis.

Using RNAi, they silenced each of genes encoding proteins remaining insoluble
in aged nematodes, to see the effect on lifespan. Around 40% of genes tested
were shown to extend lifespan after RNAi treatment, compared to only 20%
in a control group of genes. These data strongly indicate that the age-associated
protein misfolding/aggregation is among time-bombs (shorteners) of lifespan.

In support of this notion, CA (caffeic acid) or its derivatives, curcumin,
and trehalose, which prevent the heat/stress-induced protein aggregation
by activating heat-shock genes, indeed extend lifespan of nematodes and
fruit flies at least.

Reference:

1. Reis-Rodrigues, P., Czerwieniec, G., Peters,T., Evani, U. et al.
Proteomic Analysis of Age-dependent Changes in Protein Solubility Identifies
Genes that Modulate Lifespan. Aging Cell, 2011, in press.