Higher levels of heat shock proteins in longer-lived mammals and birds

Cellular stress resistance is generally associated with longevity, but the mechanisms underlying this phenotype are not clear. In invertebrate models there is a clear role for heat shock proteins (Hsps) and organelle-specific unfolded protein responses (UPR) in longevity. However, this has not been demonstrated in vertebrates. Some Hsp amino acid sequences are highly conserved amongst mammals and birds. We used antibodies recognizing conserved regions of Hsp60 (primarily mitochondrial), Hsp70 (primarily cytosolic), GRP78 (Bip) and GRP94 (endoplasmic reticulum) to measure constitutive levels of these proteins in brain, heart and liver of 13 mammalian and avian species ranging in maximum lifespan from 3 to 30 years. In all three tissues, the expression of these proteins was highly correlated with MLSP, indicating higher basal levels of Hsp expression are characteristic of longer-lived species. We also quantified the levels of Hsp60, Hsp70 and GRP78 in brain and heart tissue of young adult (6–7 month old) Snell dwarf mice and normal littermates. Snell dwarf mice are characterized by a single gene mutation that is associated with an ∼50% increase in lifespan. However, neither Hsp60, nor Hsp70, nor GRP78 levels were elevated in brain or heart tissue from Snell dwarf mice compared to normal littermates.

► We used a comparative approach to analyze the correlation of four heat shock proteins (mitochondrial, cytosolic and endoplasmic reticular) with vertebrate species lifespan. Conserved regions within the amino acid sequences of these heat shock proteins were identified and used to quantify constitutive expression levels in 13 species of mammals and birds by immunoblotting.
► Heat shock protein expression is highly correlated with maximum lifespan (MLSP). Hsp60, Hsp70, GRP78 and GRP94 protein levels in liver, heart and brain were all quantified and found to positively correlate with MLSP. This suggests Hsps have co-evolved with longevity in endothermic vertebrates.
► Surprisingly, however, Hsp60, Hsp70 and GRP78 levels in heart and brain of young adult Snell dwarf mice did not differ from their normal littermates, indicating that heat shock proteins are not upregulated in this model of mouse longevity.