Genetic signature of human longevity in PKC and NF-κB signaling

Seungjin Ryu; Jeehae Han; Trina M. Norden-Krichmar; Quanwei Zhang; Seunggeun Lee; Zhengdong Zhang; Gil Atzmon; Laura J. Niedernhofer; Paul D. Robbins; Nir Barzilai; Nicholas J. Schork; Yousin Suh

doi:10.1111/acel.13362

Genetic signature of human longevity in PKC and NF-κB signaling

Seungjin Ryu, Jeehae Han, Trina M. Norden-Krichmar, Quanwei Zhang, Seunggeun Lee, Zhengdong Zhang, Gil Atzmon, Laura J. Niedernhofer, Paul D. Robbins, Nir Barzilai, Nicholas J. Schork, Yousin Suh

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

17 Scopus citations

Abstract

Gene variants associated with longevity are also associated with protection against cognitive decline, dementia and Alzheimer's disease, suggesting that common physiologic pathways act at the interface of longevity and cognitive function. To test the hypothesis that variants in genes implicated in cognitive function may promote exceptional longevity, we performed a comprehensive 3-stage study to identify functional longevity-associated variants in ~700 candidate genes in up to 450 centenarians and 500 controls by target capture sequencing analysis. We found an enrichment of longevity-associated genes in the nPKC and NF-κB signaling pathways by gene-based association analyses. Functional analysis of the top three gene variants (NFKBIA, CLU, PRKCH) suggests that non-coding variants modulate the expression of cognate genes, thereby reducing signaling through the nPKC and NF-κB. This matches genetic studies in multiple model organisms, suggesting that the evolutionary conservation of reduced PKC and NF-κB signaling pathways in exceptional longevity may include humans.

Original language	English (US)
Article number	e13362
Journal	Aging cell
Volume	20
Issue number	7
DOIs	https://doi.org/10.1111/acel.13362
State	Published - Jul 1 2021

Bibliographical note

Funding Information:
We would like to thank Genomics Shared Facility at Albert Einstein College of Medicine for their assistance with the iPLEX MassArray assay. All the Illumina sequencings were performed in Axeq Technologies and we would like to thank Dr. Jennifer Bae for the assistance. This work was supported by NIH grants AG069750, DK127778, AG057433, AG061521, HL150521, AG055501, AG057341, AG057706, AG057909, and AG17242 (Y.S.), a grant from The Paul F. Glenn Center for the Biology of Human Aging (Y.S.), a grant GCRLE-1320 (Y.S.) from the Global Consortium for Reproductive Longevity and Equality at the Buck Institute, made possible by the Bia-Echo Foundation, and a grant from The Simons Foundation (Y.S.). S. R. is the recipient of a Glenn/AFAR Scholarships for Research in the Biology of Aging. The work was also supported by NIH grant U19 AG056278 to Z. Z., L.J.N., P.D.R., N.B. and Y.S.

Funding Information:
We would like to thank Genomics Shared Facility at Albert Einstein College of Medicine for their assistance with the iPLEX MassArray assay. All the Illumina sequencings were performed in Axeq Technologies and we would like to thank Dr. Jennifer Bae for the assistance. This work was supported by NIH grants AG069750, DK127778, AG057433, AG061521, HL150521, AG055501, AG057341, AG057706, AG057909, and AG17242 (Y.S.), a grant from The Paul F. Glenn Center for the Biology of Human Aging (Y.S.), a grant GCRLE‐1320 (Y.S.) from the Global Consortium for Reproductive Longevity and Equality at the Buck Institute, made possible by the Bia‐Echo Foundation, and a grant from The Simons Foundation (Y.S.). S. R. is the recipient of a Glenn/AFAR Scholarships for Research in the Biology of Aging. The work was also supported by NIH grant U19 AG056278 to Z. Z., L.J.N., P.D.R., N.B. and Y.S.

Publisher Copyright:
© 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.

Keywords

NF-κB
PKC
centenarian
genetic variant
longevity
rare variant

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10.1111/acel.13362

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title = "Genetic signature of human longevity in PKC and NF-κB signaling",

abstract = "Gene variants associated with longevity are also associated with protection against cognitive decline, dementia and Alzheimer's disease, suggesting that common physiologic pathways act at the interface of longevity and cognitive function. To test the hypothesis that variants in genes implicated in cognitive function may promote exceptional longevity, we performed a comprehensive 3-stage study to identify functional longevity-associated variants in ~700 candidate genes in up to 450 centenarians and 500 controls by target capture sequencing analysis. We found an enrichment of longevity-associated genes in the nPKC and NF-κB signaling pathways by gene-based association analyses. Functional analysis of the top three gene variants (NFKBIA, CLU, PRKCH) suggests that non-coding variants modulate the expression of cognate genes, thereby reducing signaling through the nPKC and NF-κB. This matches genetic studies in multiple model organisms, suggesting that the evolutionary conservation of reduced PKC and NF-κB signaling pathways in exceptional longevity may include humans.",

keywords = "NF-κB, PKC, centenarian, genetic variant, longevity, rare variant",

author = "Seungjin Ryu and Jeehae Han and Norden-Krichmar, {Trina M.} and Quanwei Zhang and Seunggeun Lee and Zhengdong Zhang and Gil Atzmon and Niedernhofer, {Laura J.} and Robbins, {Paul D.} and Nir Barzilai and Schork, {Nicholas J.} and Yousin Suh",

note = "Funding Information: We would like to thank Genomics Shared Facility at Albert Einstein College of Medicine for their assistance with the iPLEX MassArray assay. All the Illumina sequencings were performed in Axeq Technologies and we would like to thank Dr. Jennifer Bae for the assistance. This work was supported by NIH grants AG069750, DK127778, AG057433, AG061521, HL150521, AG055501, AG057341, AG057706, AG057909, and AG17242 (Y.S.), a grant from The Paul F. Glenn Center for the Biology of Human Aging (Y.S.), a grant GCRLE-1320 (Y.S.) from the Global Consortium for Reproductive Longevity and Equality at the Buck Institute, made possible by the Bia-Echo Foundation, and a grant from The Simons Foundation (Y.S.). S. R. is the recipient of a Glenn/AFAR Scholarships for Research in the Biology of Aging. The work was also supported by NIH grant U19 AG056278 to Z. Z., L.J.N., P.D.R., N.B. and Y.S. Funding Information: We would like to thank Genomics Shared Facility at Albert Einstein College of Medicine for their assistance with the iPLEX MassArray assay. All the Illumina sequencings were performed in Axeq Technologies and we would like to thank Dr. Jennifer Bae for the assistance. This work was supported by NIH grants AG069750, DK127778, AG057433, AG061521, HL150521, AG055501, AG057341, AG057706, AG057909, and AG17242 (Y.S.), a grant from The Paul F. Glenn Center for the Biology of Human Aging (Y.S.), a grant GCRLE‐1320 (Y.S.) from the Global Consortium for Reproductive Longevity and Equality at the Buck Institute, made possible by the Bia‐Echo Foundation, and a grant from The Simons Foundation (Y.S.). S. R. is the recipient of a Glenn/AFAR Scholarships for Research in the Biology of Aging. The work was also supported by NIH grant U19 AG056278 to Z. Z., L.J.N., P.D.R., N.B. and Y.S. Publisher Copyright: {\textcopyright} 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.",

year = "2021",

month = jul,

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doi = "10.1111/acel.13362",

language = "English (US)",

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T1 - Genetic signature of human longevity in PKC and NF-κB signaling

AU - Ryu, Seungjin

AU - Han, Jeehae

AU - Norden-Krichmar, Trina M.

AU - Zhang, Quanwei

AU - Lee, Seunggeun

AU - Zhang, Zhengdong

AU - Atzmon, Gil

AU - Niedernhofer, Laura J.

AU - Robbins, Paul D.

AU - Barzilai, Nir

AU - Schork, Nicholas J.

AU - Suh, Yousin

N1 - Funding Information: We would like to thank Genomics Shared Facility at Albert Einstein College of Medicine for their assistance with the iPLEX MassArray assay. All the Illumina sequencings were performed in Axeq Technologies and we would like to thank Dr. Jennifer Bae for the assistance. This work was supported by NIH grants AG069750, DK127778, AG057433, AG061521, HL150521, AG055501, AG057341, AG057706, AG057909, and AG17242 (Y.S.), a grant from The Paul F. Glenn Center for the Biology of Human Aging (Y.S.), a grant GCRLE-1320 (Y.S.) from the Global Consortium for Reproductive Longevity and Equality at the Buck Institute, made possible by the Bia-Echo Foundation, and a grant from The Simons Foundation (Y.S.). S. R. is the recipient of a Glenn/AFAR Scholarships for Research in the Biology of Aging. The work was also supported by NIH grant U19 AG056278 to Z. Z., L.J.N., P.D.R., N.B. and Y.S. Funding Information: We would like to thank Genomics Shared Facility at Albert Einstein College of Medicine for their assistance with the iPLEX MassArray assay. All the Illumina sequencings were performed in Axeq Technologies and we would like to thank Dr. Jennifer Bae for the assistance. This work was supported by NIH grants AG069750, DK127778, AG057433, AG061521, HL150521, AG055501, AG057341, AG057706, AG057909, and AG17242 (Y.S.), a grant from The Paul F. Glenn Center for the Biology of Human Aging (Y.S.), a grant GCRLE‐1320 (Y.S.) from the Global Consortium for Reproductive Longevity and Equality at the Buck Institute, made possible by the Bia‐Echo Foundation, and a grant from The Simons Foundation (Y.S.). S. R. is the recipient of a Glenn/AFAR Scholarships for Research in the Biology of Aging. The work was also supported by NIH grant U19 AG056278 to Z. Z., L.J.N., P.D.R., N.B. and Y.S. Publisher Copyright: © 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.

PY - 2021/7/1

Y1 - 2021/7/1

N2 - Gene variants associated with longevity are also associated with protection against cognitive decline, dementia and Alzheimer's disease, suggesting that common physiologic pathways act at the interface of longevity and cognitive function. To test the hypothesis that variants in genes implicated in cognitive function may promote exceptional longevity, we performed a comprehensive 3-stage study to identify functional longevity-associated variants in ~700 candidate genes in up to 450 centenarians and 500 controls by target capture sequencing analysis. We found an enrichment of longevity-associated genes in the nPKC and NF-κB signaling pathways by gene-based association analyses. Functional analysis of the top three gene variants (NFKBIA, CLU, PRKCH) suggests that non-coding variants modulate the expression of cognate genes, thereby reducing signaling through the nPKC and NF-κB. This matches genetic studies in multiple model organisms, suggesting that the evolutionary conservation of reduced PKC and NF-κB signaling pathways in exceptional longevity may include humans.

AB - Gene variants associated with longevity are also associated with protection against cognitive decline, dementia and Alzheimer's disease, suggesting that common physiologic pathways act at the interface of longevity and cognitive function. To test the hypothesis that variants in genes implicated in cognitive function may promote exceptional longevity, we performed a comprehensive 3-stage study to identify functional longevity-associated variants in ~700 candidate genes in up to 450 centenarians and 500 controls by target capture sequencing analysis. We found an enrichment of longevity-associated genes in the nPKC and NF-κB signaling pathways by gene-based association analyses. Functional analysis of the top three gene variants (NFKBIA, CLU, PRKCH) suggests that non-coding variants modulate the expression of cognate genes, thereby reducing signaling through the nPKC and NF-κB. This matches genetic studies in multiple model organisms, suggesting that the evolutionary conservation of reduced PKC and NF-κB signaling pathways in exceptional longevity may include humans.

KW - NF-κB

KW - PKC

KW - centenarian

KW - genetic variant

KW - longevity

KW - rare variant

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ER -

Genetic signature of human longevity in PKC and NF-κB signaling

Abstract

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