TY - JOUR
T1 - Lifelong reduction in complex IV induces tissue-specific metabolic effects but does not reduce lifespan or healthspan in mice
AU - Deepa, Sathyaseelan S.
AU - Pharaoh, Gavin
AU - Kinter, Michael
AU - Diaz, Vivian
AU - Fok, Wilson C.
AU - Riddle, Kaitlyn
AU - Pulliam, Daniel
AU - Hill, Shauna
AU - Fischer, Kathleen E.
AU - Soto, Vanessa
AU - Georgescu, Constantin
AU - Wren, Jonathan D.
AU - Viscomi, Carlo
AU - Richardson, Arlan
AU - Van Remmen, Holly
N1 - Funding Information:
National Institute on Aging, Grant/Award Number: AG046803, T32 AG021890; U.S. Department of Veterans Affairs; Ellison Medical Foundation, Grant/Award Number: Senior Scholar award
Funding Information:
We wish to thank Massimo Zeviani, MRC-MBU, University of Cambridge, Cambridge, UK for the kind gift of Surf1−/− mice, Kevin Becker of the IRP Core (Gene Expression and Genomics Unit at NIA) for performing microarray, and Metabolon Inc. (Durham, USA) for generating the metabolomics data. We also thank Merry Lindsey for assistance in measuring cardiac function and the San Antonio Nathan Shock Center Core for assistance with the lifespan studies. This work was supported by an Ellison Medical Foundation Senior Scholar award to H.V.R. and an NIA funded R21 (AG046803) to H.V.R. H.V.R and A.R. are supported by Senior VA Research Career Scientist awards from the Department of Veterans Affairs. C.V. is supported by a MRC core grant to MBU and D.P. was supported by the training grant (T32 AG021890).
PY - 2018/8
Y1 - 2018/8
N2 - Loss of SURF1, a Complex IV assembly protein, was reported to increase lifespan in mice despite dramatically lower cytochrome oxidase (COX) activity. Consistent with this, our previous studies found advantageous changes in metabolism (reduced adiposity, increased insulin sensitivity, and mitochondrial biogenesis) in Surf1 −/− mice. The lack of deleterious phenotypes in Surf1 −/− mice is contrary to the hypothesis that mitochondrial dysfunction contributes to aging. We found only a modest (nonsignificant) extension of lifespan (7% median, 16% maximum) and no change in healthspan indices in Surf1 −/− vs. Surf1 +/+ mice despite substantial decreases in COX activity (22%–87% across tissues). Dietary restriction (DR) increased median lifespan in both Surf1 +/+ and Surf1 −/− mice (36% and 19%, respectively). We measured gene expression, metabolites, and targeted expression of key metabolic proteins in adipose tissue, liver, and brain in Surf1 +/+ and Surf1 −/− mice. Gene expression was differentially regulated in a tissue-specific manner. Many proteins and metabolites are downregulated in Surf1 −/− adipose tissue and reversed by DR, while in brain, most metabolites that changed were elevated in Surf1 −/− mice. Finally, mitochondrial unfolded protein response (UPR mt )-associated proteins were not uniformly altered by age or genotype, suggesting the UPR mt is not a key player in aging or in response to reduced COX activity. While the changes in gene expression and metabolism may represent compensatory responses to mitochondrial stress, the important outcome of this study is that lifespan and healthspan are not compromised in Surf1 −/− mice, suggesting that not all mitochondrial deficiencies are a critical determinant of lifespan.
AB - Loss of SURF1, a Complex IV assembly protein, was reported to increase lifespan in mice despite dramatically lower cytochrome oxidase (COX) activity. Consistent with this, our previous studies found advantageous changes in metabolism (reduced adiposity, increased insulin sensitivity, and mitochondrial biogenesis) in Surf1 −/− mice. The lack of deleterious phenotypes in Surf1 −/− mice is contrary to the hypothesis that mitochondrial dysfunction contributes to aging. We found only a modest (nonsignificant) extension of lifespan (7% median, 16% maximum) and no change in healthspan indices in Surf1 −/− vs. Surf1 +/+ mice despite substantial decreases in COX activity (22%–87% across tissues). Dietary restriction (DR) increased median lifespan in both Surf1 +/+ and Surf1 −/− mice (36% and 19%, respectively). We measured gene expression, metabolites, and targeted expression of key metabolic proteins in adipose tissue, liver, and brain in Surf1 +/+ and Surf1 −/− mice. Gene expression was differentially regulated in a tissue-specific manner. Many proteins and metabolites are downregulated in Surf1 −/− adipose tissue and reversed by DR, while in brain, most metabolites that changed were elevated in Surf1 −/− mice. Finally, mitochondrial unfolded protein response (UPR mt )-associated proteins were not uniformly altered by age or genotype, suggesting the UPR mt is not a key player in aging or in response to reduced COX activity. While the changes in gene expression and metabolism may represent compensatory responses to mitochondrial stress, the important outcome of this study is that lifespan and healthspan are not compromised in Surf1 −/− mice, suggesting that not all mitochondrial deficiencies are a critical determinant of lifespan.
KW - SURF1
KW - cytochrome c oxidase
KW - dietary restriction
KW - lifespan
KW - mitochondria
KW - mitochondrial unfolded protein response
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U2 - 10.1111/acel.12769
DO - 10.1111/acel.12769
M3 - Article
AN - SCOPUS:85045927087
VL - 17
JO - Aging Cell
JF - Aging Cell
SN - 1474-9718
IS - 4
M1 - e12769
ER -