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; 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, Ki Soo JeongJin 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

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

122 Scopus citations

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 (US)
Pages (from-to)	1050-1061
Number of pages	12
Journal	Aging Cell
Volume	12
Issue number	6
DOIs	https://doi.org/10.1111/acel.12130
State	Published - Dec 2013
Externally published	Yes

Keywords

Aging
Dietary restriction
Longevity
Mitochondria
Mitochondrial unfolded protein response
Replicative lifespan
Yeast

ASJC Scopus subject areas

Aging
Cell Biology

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10.1111/acel.12130

Cite this

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), 1050-1061. https://doi.org/10.1111/acel.12130

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, Jeong, KS, 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, Wende, HV, An, EH, Fletcher, M, Jelic, M, Rabinovitch, PS, Maccoss, MJ, Han, JDJ, Kennedy, BK & Kaeberlein, M 2013, 'Molecular mechanisms underlying genotype-dependent responses to dietary restriction', Aging Cell, vol. 12, no. 6, pp. 1050-1061. https://doi.org/10.1111/acel.12130

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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 = "Aging, Dietary restriction, Longevity, Mitochondria, Mitochondrial unfolded protein response, Replicative lifespan, Yeast",

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 Jeong, {Ki Soo} 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 Wende, {Helen Vander} 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",

year = "2013",

month = dec,

doi = "10.1111/acel.12130",

language = "English (US)",

volume = "12",

pages = "1050--1061",

journal = "Aging Cell",

issn = "1474-9718",

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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 - 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 - Wende, Helen Vander

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 - Aging

KW - Dietary restriction

KW - Longevity

KW - Mitochondria

KW - Mitochondrial unfolded protein response

KW - Replicative lifespan

KW - Yeast

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DO - 10.1111/acel.12130

M3 - Article

C2 - 23837470

AN - SCOPUS:84888134441

SN - 1474-9718

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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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