Molecular mechanisms underlying genotype-dependent responses to dietary restriction

Jennifer Schleit; Simon C Johnson; Christopher F Bennett; Marissa Simko; Natalie Trongtham; Anthony Castanza; Edward J Hsieh; Richard M Moller; Brian M Wasko; Joe R Delaney; George L Sutphin; Daniel Carr; Christopher J Murakami; Autumn Tocchi; Bo Xian; Weiyang Chen; Tao Yu; Sarani Goswami; Sean Higgins; Mollie Holmberg; Ki-Soo Jeong; Jin R Kim; Shannon Klum; Eric Liao; Michael S Lin; Winston Lo; Hillary Miller; Brady Olsen; Zhao J Peng; Tom Pollard; Prarthana Pradeep; Dillon Pruett; Dilreet Rai; Vanessa Ros; Minnie Singh; Benjamin L Spector; Helen Vander Wende; Elroy H An; Marissa Fletcher; Monika Jelic; Peter S Rabinovitch; Michael J MacCoss; Jing-Dong J Han; Brian K Kennedy; Matt Kaeberlein

doi:10.1111/acel.12130

Molecular mechanisms underlying genotype-dependent responses to dietary restriction

Jennifer Schleit, Simon C Johnson, Christopher F Bennett, Marissa Simko, Natalie Trongtham, Anthony Castanza, Edward J Hsieh, Richard M Moller, Brian M Wasko, Joe R Delaney, George L Sutphin, Daniel Carr, Christopher J Murakami, Autumn Tocchi, Bo Xian, Weiyang Chen, Tao Yu, Sarani Goswami, Sean Higgins, Mollie HolmbergKi-Soo Jeong, Jin R Kim, Shannon Klum, Eric Liao, Michael S Lin, Winston Lo, Hillary Miller, Brady Olsen, Zhao J Peng, Tom Pollard, Prarthana Pradeep, Dillon Pruett, Dilreet Rai, Vanessa Ros, Minnie Singh, Benjamin L Spector, Helen Vander Wende, Elroy H An, Marissa Fletcher, Monika Jelic, Peter S Rabinovitch, Michael J MacCoss, Jing-Dong J Han, Brian K Kennedy, Matt Kaeberlein

Applied Sciences Department

Research output: Contribution to journal › Article › peer-review

121 Citations (Scopus)

Abstract

Dietary restriction (DR) increases lifespan and attenuates age-related phenotypes in many organisms; however, the effect of DR on longevity of individuals in genetically heterogeneous populations is not well characterized. Here, we describe a large-scale effort to define molecular mechanisms that underlie genotype-specific responses to DR. The effect of DR on lifespan was determined for 166 single gene deletion strains in Saccharomyces cerevisiae. Resulting changes in mean lifespan ranged from a reduction of 79% to an increase of 103%. Vacuolar pH homeostasis, superoxide dismutase activity, and mitochondrial proteostasis were found to be strong determinants of the response to DR. Proteomic analysis of cells deficient in prohibitins revealed induction of a mitochondrial unfolded protein response (mtUPR), which has not previously been described in yeast. Mitochondrial proteotoxic stress in prohibitin mutants was suppressed by DR via reduced cytoplasmic mRNA translation. A similar relationship between prohibitins, the mtUPR, and longevity was also observed in Caenorhabditis elegans. These observations define conserved molecular processes that underlie genotype-dependent effects of DR that may be important modulators of DR in higher organisms.

Original language	English
Pages (from-to)	1050-61
Number of pages	12
Journal	Aging Cell
Volume	12
Issue number	6
DOIs	https://doi.org/10.1111/acel.12130
Publication status	Published - Dec 2013

Keywords

Aerobiosis
Animals
Autophagy
Caenorhabditis elegans/cytology
Caenorhabditis elegans Proteins/metabolism
Caloric Restriction
Diet
Genotype
Prohibitins
Saccharomyces cerevisiae/cytology
Unfolded Protein Response/genetics

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10.1111/acel.12130

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Schleit, J., Johnson, S. C., Bennett, C. F., Simko, M., Trongtham, N., Castanza, A., Hsieh, E. J., Moller, R. M., Wasko, B. M., Delaney, J. R., Sutphin, G. L., Carr, D., Murakami, C. J., Tocchi, A., Xian, B., Chen, W., Yu, T., Goswami, S., Higgins, S., ... Kaeberlein, M. (2013). Molecular mechanisms underlying genotype-dependent responses to dietary restriction. Aging Cell, 12(6), 1050-61. https://doi.org/10.1111/acel.12130

@article{15e725c2d0c1402f98bd9ee44a22cf5f,

title = "Molecular mechanisms underlying genotype-dependent responses to dietary restriction",

abstract = "Dietary restriction (DR) increases lifespan and attenuates age-related phenotypes in many organisms; however, the effect of DR on longevity of individuals in genetically heterogeneous populations is not well characterized. Here, we describe a large-scale effort to define molecular mechanisms that underlie genotype-specific responses to DR. The effect of DR on lifespan was determined for 166 single gene deletion strains in Saccharomyces cerevisiae. Resulting changes in mean lifespan ranged from a reduction of 79% to an increase of 103%. Vacuolar pH homeostasis, superoxide dismutase activity, and mitochondrial proteostasis were found to be strong determinants of the response to DR. Proteomic analysis of cells deficient in prohibitins revealed induction of a mitochondrial unfolded protein response (mtUPR), which has not previously been described in yeast. Mitochondrial proteotoxic stress in prohibitin mutants was suppressed by DR via reduced cytoplasmic mRNA translation. A similar relationship between prohibitins, the mtUPR, and longevity was also observed in Caenorhabditis elegans. These observations define conserved molecular processes that underlie genotype-dependent effects of DR that may be important modulators of DR in higher organisms. ",

keywords = "Aerobiosis, Animals, Autophagy, Caenorhabditis elegans/cytology, Caenorhabditis elegans Proteins/metabolism, Caloric Restriction, Diet, Genotype, Prohibitins, Saccharomyces cerevisiae/cytology, Unfolded Protein Response/genetics",

author = "Jennifer Schleit and Johnson, {Simon C} and Bennett, {Christopher F} and Marissa Simko and Natalie Trongtham and Anthony Castanza and Hsieh, {Edward J} and Moller, {Richard M} and Wasko, {Brian M} and Delaney, {Joe R} and Sutphin, {George L} and Daniel Carr and Murakami, {Christopher J} and Autumn Tocchi and Bo Xian and Weiyang Chen and Tao Yu and Sarani Goswami and Sean Higgins and Mollie Holmberg and Ki-Soo Jeong and Kim, {Jin R} and Shannon Klum and Eric Liao and Lin, {Michael S} and Winston Lo and Hillary Miller and Brady Olsen and Peng, {Zhao J} and Tom Pollard and Prarthana Pradeep and Dillon Pruett and Dilreet Rai and Vanessa Ros and Minnie Singh and Spector, {Benjamin L} and {Vander Wende}, Helen and An, {Elroy H} and Marissa Fletcher and Monika Jelic and Rabinovitch, {Peter S} and MacCoss, {Michael J} and Han, {Jing-Dong J} and Kennedy, {Brian K} and Matt Kaeberlein",

note = "{\textcopyright} 2013 the Anatomical Society and John Wiley & Sons Ltd.",

year = "2013",

month = dec,

doi = "10.1111/acel.12130",

language = "English",

volume = "12",

pages = "1050--61",

journal = "Aging Cell",

issn = "1474-9718",

publisher = "Blackwell Publishing",

number = "6",

}

Schleit, J, Johnson, SC, Bennett, CF, Simko, M, Trongtham, N, Castanza, A, Hsieh, EJ, Moller, RM, Wasko, BM, Delaney, JR, Sutphin, GL, Carr, D, Murakami, CJ, Tocchi, A, Xian, B, Chen, W, Yu, T, Goswami, S, Higgins, S, Holmberg, M, Jeong, K-S, Kim, JR, Klum, S, Liao, E, Lin, MS, Lo, W, Miller, H, Olsen, B, Peng, ZJ, Pollard, T, Pradeep, P, Pruett, D, Rai, D, Ros, V, Singh, M, Spector, BL, Vander Wende, H, An, EH, Fletcher, M, Jelic, M, Rabinovitch, PS, MacCoss, MJ, Han, J-DJ, Kennedy, BK & Kaeberlein, M 2013, 'Molecular mechanisms underlying genotype-dependent responses to dietary restriction', Aging Cell, vol. 12, no. 6, pp. 1050-61. https://doi.org/10.1111/acel.12130

TY - JOUR

T1 - Molecular mechanisms underlying genotype-dependent responses to dietary restriction

AU - Schleit, Jennifer

AU - Johnson, Simon C

AU - Bennett, Christopher F

AU - Simko, Marissa

AU - Trongtham, Natalie

AU - Castanza, Anthony

AU - Hsieh, Edward J

AU - Moller, Richard M

AU - Wasko, Brian M

AU - Delaney, Joe R

AU - Sutphin, George L

AU - Carr, Daniel

AU - Murakami, Christopher J

AU - Tocchi, Autumn

AU - Xian, Bo

AU - Chen, Weiyang

AU - Yu, Tao

AU - Goswami, Sarani

AU - Higgins, Sean

AU - Holmberg, Mollie

AU - Jeong, Ki-Soo

AU - Kim, Jin R

AU - Klum, Shannon

AU - Liao, Eric

AU - Lin, Michael S

AU - Lo, Winston

AU - Miller, Hillary

AU - Olsen, Brady

AU - Peng, Zhao J

AU - Pollard, Tom

AU - Pradeep, Prarthana

AU - Pruett, Dillon

AU - Rai, Dilreet

AU - Ros, Vanessa

AU - Singh, Minnie

AU - Spector, Benjamin L

AU - Vander Wende, Helen

AU - An, Elroy H

AU - Fletcher, Marissa

AU - Jelic, Monika

AU - Rabinovitch, Peter S

AU - MacCoss, Michael J

AU - Han, Jing-Dong J

AU - Kennedy, Brian K

AU - Kaeberlein, Matt

PY - 2013/12

Y1 - 2013/12

N2 - Dietary restriction (DR) increases lifespan and attenuates age-related phenotypes in many organisms; however, the effect of DR on longevity of individuals in genetically heterogeneous populations is not well characterized. Here, we describe a large-scale effort to define molecular mechanisms that underlie genotype-specific responses to DR. The effect of DR on lifespan was determined for 166 single gene deletion strains in Saccharomyces cerevisiae. Resulting changes in mean lifespan ranged from a reduction of 79% to an increase of 103%. Vacuolar pH homeostasis, superoxide dismutase activity, and mitochondrial proteostasis were found to be strong determinants of the response to DR. Proteomic analysis of cells deficient in prohibitins revealed induction of a mitochondrial unfolded protein response (mtUPR), which has not previously been described in yeast. Mitochondrial proteotoxic stress in prohibitin mutants was suppressed by DR via reduced cytoplasmic mRNA translation. A similar relationship between prohibitins, the mtUPR, and longevity was also observed in Caenorhabditis elegans. These observations define conserved molecular processes that underlie genotype-dependent effects of DR that may be important modulators of DR in higher organisms.

AB - Dietary restriction (DR) increases lifespan and attenuates age-related phenotypes in many organisms; however, the effect of DR on longevity of individuals in genetically heterogeneous populations is not well characterized. Here, we describe a large-scale effort to define molecular mechanisms that underlie genotype-specific responses to DR. The effect of DR on lifespan was determined for 166 single gene deletion strains in Saccharomyces cerevisiae. Resulting changes in mean lifespan ranged from a reduction of 79% to an increase of 103%. Vacuolar pH homeostasis, superoxide dismutase activity, and mitochondrial proteostasis were found to be strong determinants of the response to DR. Proteomic analysis of cells deficient in prohibitins revealed induction of a mitochondrial unfolded protein response (mtUPR), which has not previously been described in yeast. Mitochondrial proteotoxic stress in prohibitin mutants was suppressed by DR via reduced cytoplasmic mRNA translation. A similar relationship between prohibitins, the mtUPR, and longevity was also observed in Caenorhabditis elegans. These observations define conserved molecular processes that underlie genotype-dependent effects of DR that may be important modulators of DR in higher organisms.

KW - Aerobiosis

KW - Animals

KW - Autophagy

KW - Caenorhabditis elegans/cytology

KW - Caenorhabditis elegans Proteins/metabolism

KW - Caloric Restriction

KW - Diet

KW - Genotype

KW - Prohibitins

KW - Saccharomyces cerevisiae/cytology

KW - Unfolded Protein Response/genetics

U2 - 10.1111/acel.12130

DO - 10.1111/acel.12130

M3 - Article

C2 - 23837470

SN - 1474-9718

VL - 12

SP - 1050

EP - 1061

JO - Aging Cell

JF - Aging Cell

IS - 6

ER -

Molecular mechanisms underlying genotype-dependent responses to dietary restriction

Abstract

Keywords

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