Lifespan of Mice and Primates Correlates with Immunoproteasome Expression

It is known that cellular repair processes are important in the determination of life span. Many of the methods of modestly slowing aging in laboratory species are accompanied by increased rates of cellular housekeeping, the recycling of damaged proteins and cell components. One set of these processes is centered around the proteasome, responsible for breaking down unneeded or damaged proteins, and here researchers demonstrate a correlation between proteasomal activity and species longevity in mammals:

Within the animal kingdom there is extraordinary variation in lifespan. Members of some species only live a few days or weeks, while others live tens, if not hundreds, of years. This large variation in species lifespan found in nature provides a powerful tool for the identification of factors that regulate the rate of aging. There is now a body of evidence to suggest that primary skin-derived fibroblasts can be used to evaluate aspects of cell biology that may differ between long-lived and short-lived species. This approach is not based on any assumption that changes in fibroblast properties would significantly affect organismal lifespan, but rather on the notion that evolutionary changes that produce slow aging might affect multiple cell types, including some that contribute to long-lasting resistance to disease and disability, as well as others, like fibroblasts, that are easy to cultivate and expand under standardized conditions for scores of species in parallel.

Here, we evaluated skin-derived fibroblasts and demonstrate that among primate species, longevity correlated with an elevation in proteasomal activity as well as immunoproteasome expression at both the mRNA and protein levels. Immunoproteasome enhancement occurred with a concurrent increase in other elements involved in MHC class I antigen presentation. Fibroblasts from long-lived primates also appeared more responsive to IFN-γ than cells from short-lived primate species, and this increase in IFN-γ responsiveness correlated with elevated expression of the IFN-γ receptor protein IFNGR2. Elevation of immunoproteasome and proteasome activity was also observed in the livers of long-lived Snell dwarf mice and in mice exposed to drugs that have been shown to extend lifespan, including rapamycin, 17-α-estradiol, and nordihydroguaiaretic acid. This work suggests that augmented immunoproteasome function may contribute to lifespan differences in mice and among primate species.



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