Lifespan of mice and primates correlates with immunoproteasome expression
Andrew M. Pickering, … , Marcus Lehr, Richard A. Miller
Andrew M. Pickering, … , Marcus Lehr, Richard A. Miller
Published April 13, 2015
Citation Information: J Clin Invest. 2015;125(5):2059-2068. https://doi.org/10.1172/JCI80514.
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Research Article Aging

Lifespan of mice and primates correlates with immunoproteasome expression

Abstract

There is large variation in lifespan among different species, and there is evidence that modulation of proteasome function may contribute to longevity determination. Comparative biology provides a powerful tool for identifying genes and pathways that control the rate of aging. 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, including β-2 microglobulin, (TAP1), and TAP2. 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.

Authors

Andrew M. Pickering, Marcus Lehr, Richard A. Miller

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Figure 3

Fibroblasts from longer-lived species of primates have increased mRNA expression of PSMB8 compared with those from shorter-lived species but no significant change in mRNA for PSMB5; fibroblasts from long-lived primates are also more responsive to IFN-γ signaling and have elevated expression of IFNGR2, relative to those from short-lived species.

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Fibroblasts from longer-lived species of primates have increased mRNA ex...
(A) Scatter plot of relative PSMB8 mRNA levels. (B) Scatter plot of relative PSMB5 mRNA levels. (C) Scatter plot of PSMB8 mRNA levels following 24 hours exposure to 40 ng/ml of IFN-γ, as a percentage of PSMB8 mRNA in cells incubated without IFN-γ. (D) Plot of L’Hoest’s monkey (MLS 24.1 yr) cell viability, following exposure to a range of doses of H2O2, with or without a 24-hour incubation with 40 ng/ml of IFN-γ. (E) Plot of gorilla (MLS 55.4 yr) cell viability, following exposure to a range of doses of H2O2, with or without 24-hour incubation with 40 ng/ml IFN-γ. Error bars represent SEM of 6 replicate wells at each H2O2 concentration. (F) Scatter plot of the change in H2O2 dose required to reduce cell viability to 50% under incubation for 24 hours with 40 ng/ml of IFN-γ. Raw values are shown in Supplemental Figure 6. Statistical significance was established using simple linear regression analysis.