Aging is associated with a systemic length-associated transcriptome imbalance

Thomas Stoeger; Rogan A. Grant; Alexandra C. McQuattie-Pimentel; Kishore R. Anekalla; Sophia S. Liu; Heliodoro Tejedor-Navarro; Benjamin D. Singer; Hiam Abdala-Valencia; Michael Schwake; Marie Pier Tetreault; Harris Perlman; William E. Balch; Navdeep S. Chandel; Karen M. Ridge; Jacob I. Sznajder; Richard I. Morimoto; Alexander V. Misharin; G. R.Scott Budinger; Luis A. Nunes Amaral

doi:10.1038/s43587-022-00317-6

Aging is associated with a systemic length-associated transcriptome imbalance

Thomas Stoeger^*, Rogan A. Grant, Alexandra C. McQuattie-Pimentel, Kishore R. Anekalla, Sophia S. Liu, Heliodoro Tejedor-Navarro, Benjamin D. Singer, Hiam Abdala-Valencia, Michael Schwake, Marie Pier Tetreault, Harris Perlman, William E. Balch, Navdeep S. Chandel, Karen M. Ridge, Jacob I. Sznajder, Richard I. Morimoto^*, Alexander V. Misharin^*, G. R.Scott Budinger^*, Luis A. Nunes Amaral^*

^*Corresponding author for this work

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

41 Scopus citations

Abstract

Aging is among the most important risk factors for morbidity and mortality. To contribute toward a molecular understanding of aging, we analyzed age-resolved transcriptomic data from multiple studies. Here, we show that transcript length alone explains most transcriptional changes observed with aging in mice and humans. We present three lines of evidence supporting the biological importance of the uncovered transcriptome imbalance. First, in vertebrates the length association primarily displays a lower relative abundance of long transcripts in aging. Second, eight antiaging interventions of the Interventions Testing Program of the National Institute on Aging can counter this length association. Third, we find that in humans and mice the genes with the longest transcripts enrich for genes reported to extend lifespan, whereas those with the shortest transcripts enrich for genes reported to shorten lifespan. Our study opens fundamental questions on aging and the organization of transcriptomes.

Original language	English (US)
Pages (from-to)	1191-1206
Number of pages	16
Journal	Nature Aging
Volume	2
Issue number	12
DOIs	https://doi.org/10.1038/s43587-022-00317-6
State	Published - Dec 2022

Funding

This work was supported by NIH AG068544 (to T.S.), NSF 1956338 (to T.S. and N.A.N.A.), AG071225 (to R.A.G.), NIH HL128867 (to B.D.S.), Parker B. Francis Research Opportunity Award (to B.D.S.), NIH AI135964 (to B.D.S., A.V.M., G.R.S.B. and N.A.N.A.), Heisenberg Fellowship from the Deutsche Forschungsgemeinschaft (to M.S.), NIH DK116988 (to M.P.T.), NIH DK117824 (to M.P.T.), NIH AR064546 (to H.P.), NIH HL134375 (to H.P.), NIH AG049665 (to H.P., W.E.B., N.C., J.I.S., A.V.M. and G.R.S.B.), NIH UH2AR067687 (to H.P.), Rheumatology Research Foundation Agmt 05/06/14 (to H.P.), United States-Israel Binational Science Foundation no. 2013247 (to H.P.), Mabel Greene Myers Professorship of Medicine, generous donations to the Rheumatology Precision Medicine Fund (to H.P.), NIH DK051870 (to W.E.B.), NIH HL141810 (to W.E.B.), NIH HL079190 (to K.R.), NIH HL124664 (to K.R.), NIH HL048129 (to J.I.S.), NIH HL071643 (to J.I.S. and G.R.S.B.), NIH HL085534 (to J.I.S.), NIH AG054407 (to R.I.M.), NIH AG026647 (to R.I.M.), NIH AG057296 (to R.I.M.), NIH AG059579 (to R.I.M.), a gift of the Daniel F. and Ada L. Rice Foundation (to R.I.M.), NIH HL135124 (to A.V.M.), Department of Defense grant PR141319 (to A.V.M.), Office of the Assistant Secretary of Defense for Health Affairs W81XWH-15-1-0215 (to G.R.S.B. and A.V.M.), NIH ES013995 (to G.R.S.B.), The Veterans Administration BX000201 (to G.R.S.B.), Department of Defense grant PR141319 (to G.R.S.B.), NSF 1764421-01 (to N.A.N.A.) and a gift of John and Leslie McQuown (to N.A.N.A.). Additional support is from NCI Cancer Center Support Grant P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center (Northwestern University Flow Cytometry Facility), computational resources and staff contributions provided by the Genomics Computing Cluster (Genomic Nodes on Quest), which is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine and Feinberg’s Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research and Northwestern Information Technology. We thank E. Ceco, C. -I. Chen, C. Chen, Y. Cheng, M. Chi, S. Chiu, C. Cuda, A. Flozak, F. Gonzales, K. Helmin, E. Hogan, P. Homan, D. Kimelman, E. Lecuona, N. Mangani, V. Morgan, T. Nicholson, R. Ratsimandresy, C. Runyan, R. Saber and S. Soberanes for sample preparation; E. Bartom for the template of bioinformatic processing of the RNA sequences toward counts; P. A. Reyman and R. Verma for creating the template for differential gene expression; M. Sun, J. Davis, C. Wang and S. Loguerico for comments on the paper; and Northwestern University IT and Genomics Nodes for infrastructural support. We thank N. Schaum and T. Wyss-Coray for sharing the results of their differential gene expression analysis before publication, and for creating a FigShare entry to make this analysis publicly available. This work was supported by NIH AG068544 (to T.S.), NSF 1956338 (to T.S. and N.A.N.A.), AG071225 (to R.A.G.), NIH HL128867 (to B.D.S.), Parker B. Francis Research Opportunity Award (to B.D.S.), NIH AI135964 (to B.D.S., A.V.M., G.R.S.B. and N.A.N.A.), Heisenberg Fellowship from the Deutsche Forschungsgemeinschaft (to M.S.), NIH DK116988 (to M.P.T.), NIH DK117824 (to M.P.T.), NIH AR064546 (to H.P.), NIH HL134375 (to H.P.), NIH AG049665 (to H.P., W.E.B., N.C., J.I.S., A.V.M. and G.R.S.B.), NIH UH2AR067687 (to H.P.), Rheumatology Research Foundation Agmt 05/06/14 (to H.P.), United States-Israel Binational Science Foundation no. 2013247 (to H.P.), Mabel Greene Myers Professorship of Medicine, generous donations to the Rheumatology Precision Medicine Fund (to H.P.), NIH DK051870 (to W.E.B.), NIH HL141810 (to W.E.B.), NIH HL079190 (to K.R.), NIH HL124664 (to K.R.), NIH HL048129 (to J.I.S.), NIH HL071643 (to J.I.S. and G.R.S.B.), NIH HL085534 (to J.I.S.), NIH AG054407 (to R.I.M.), NIH AG026647 (to R.I.M.), NIH AG057296 (to R.I.M.), NIH AG059579 (to R.I.M.), a gift of the Daniel F. and Ada L. Rice Foundation (to R.I.M.), NIH HL135124 (to A.V.M.), Department of Defense grant PR141319 (to A.V.M.), Office of the Assistant Secretary of Defense for Health Affairs W81XWH-15-1-0215 (to G.R.S.B. and A.V.M.), NIH ES013995 (to G.R.S.B.), The Veterans Administration BX000201 (to G.R.S.B.), Department of Defense grant PR141319 (to G.R.S.B.), NSF 1764421-01 (to N.A.N.A.) and a gift of John and Leslie McQuown (to N.A.N.A.). Additional support is from NCI Cancer Center Support Grant P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center (Northwestern University Flow Cytometry Facility), computational resources and staff contributions provided by the Genomics Computing Cluster (Genomic Nodes on Quest), which is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine and Feinberg’s Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research and Northwestern Information Technology. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense.

ASJC Scopus subject areas

Neuroscience (miscellaneous)
Aging
Geriatrics and Gerontology

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10.1038/s43587-022-00317-6

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Stoeger, T., Grant, R. A., McQuattie-Pimentel, A. C., Anekalla, K. R., Liu, S. S., Tejedor-Navarro, H., Singer, B. D., Abdala-Valencia, H., Schwake, M., Tetreault, M. P., Perlman, H., Balch, W. E., Chandel, N. S., Ridge, K. M., Sznajder, J. I., Morimoto, R. I., Misharin, A. V., Budinger, G. R. S., & Nunes Amaral, L. A. (2022). Aging is associated with a systemic length-associated transcriptome imbalance. Nature Aging, 2(12), 1191-1206. https://doi.org/10.1038/s43587-022-00317-6

@article{188c9bdde79f4556a99dba4e584e5c47,

title = "Aging is associated with a systemic length-associated transcriptome imbalance",

abstract = "Aging is among the most important risk factors for morbidity and mortality. To contribute toward a molecular understanding of aging, we analyzed age-resolved transcriptomic data from multiple studies. Here, we show that transcript length alone explains most transcriptional changes observed with aging in mice and humans. We present three lines of evidence supporting the biological importance of the uncovered transcriptome imbalance. First, in vertebrates the length association primarily displays a lower relative abundance of long transcripts in aging. Second, eight antiaging interventions of the Interventions Testing Program of the National Institute on Aging can counter this length association. Third, we find that in humans and mice the genes with the longest transcripts enrich for genes reported to extend lifespan, whereas those with the shortest transcripts enrich for genes reported to shorten lifespan. Our study opens fundamental questions on aging and the organization of transcriptomes.",

author = "Thomas Stoeger and Grant, {Rogan A.} and McQuattie-Pimentel, {Alexandra C.} and Anekalla, {Kishore R.} and Liu, {Sophia S.} and Heliodoro Tejedor-Navarro and Singer, {Benjamin D.} and Hiam Abdala-Valencia and Michael Schwake and Tetreault, {Marie Pier} and Harris Perlman and Balch, {William E.} and Chandel, {Navdeep S.} and Ridge, {Karen M.} and Sznajder, {Jacob I.} and Morimoto, {Richard I.} and Misharin, {Alexander V.} and Budinger, {G. R.Scott} and {Nunes Amaral}, {Luis A.}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s43587-022-00317-6",

language = "English (US)",

volume = "2",

pages = "1191--1206",

journal = "Nature Aging",

issn = "2662-8465",

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Stoeger, T, Grant, RA, McQuattie-Pimentel, AC, Anekalla, KR, Liu, SS, Tejedor-Navarro, H, Singer, BD , Abdala-Valencia, H, Schwake, M, Tetreault, MP, Perlman, H, Balch, WE, Chandel, NS , Ridge, KM , Sznajder, JI , Morimoto, RI , Misharin, AV , Budinger, GRS & Nunes Amaral, LA 2022, 'Aging is associated with a systemic length-associated transcriptome imbalance', Nature Aging, vol. 2, no. 12, pp. 1191-1206. https://doi.org/10.1038/s43587-022-00317-6

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AU - Stoeger, Thomas

AU - Grant, Rogan A.

AU - McQuattie-Pimentel, Alexandra C.

AU - Anekalla, Kishore R.

AU - Liu, Sophia S.

AU - Tejedor-Navarro, Heliodoro

AU - Singer, Benjamin D.

AU - Abdala-Valencia, Hiam

AU - Schwake, Michael

AU - Tetreault, Marie Pier

AU - Perlman, Harris

AU - Balch, William E.

AU - Chandel, Navdeep S.

AU - Ridge, Karen M.

AU - Sznajder, Jacob I.

AU - Morimoto, Richard I.

AU - Misharin, Alexander V.

AU - Budinger, G. R.Scott

AU - Nunes Amaral, Luis A.

PY - 2022/12

Y1 - 2022/12

N2 - Aging is among the most important risk factors for morbidity and mortality. To contribute toward a molecular understanding of aging, we analyzed age-resolved transcriptomic data from multiple studies. Here, we show that transcript length alone explains most transcriptional changes observed with aging in mice and humans. We present three lines of evidence supporting the biological importance of the uncovered transcriptome imbalance. First, in vertebrates the length association primarily displays a lower relative abundance of long transcripts in aging. Second, eight antiaging interventions of the Interventions Testing Program of the National Institute on Aging can counter this length association. Third, we find that in humans and mice the genes with the longest transcripts enrich for genes reported to extend lifespan, whereas those with the shortest transcripts enrich for genes reported to shorten lifespan. Our study opens fundamental questions on aging and the organization of transcriptomes.

AB - Aging is among the most important risk factors for morbidity and mortality. To contribute toward a molecular understanding of aging, we analyzed age-resolved transcriptomic data from multiple studies. Here, we show that transcript length alone explains most transcriptional changes observed with aging in mice and humans. We present three lines of evidence supporting the biological importance of the uncovered transcriptome imbalance. First, in vertebrates the length association primarily displays a lower relative abundance of long transcripts in aging. Second, eight antiaging interventions of the Interventions Testing Program of the National Institute on Aging can counter this length association. Third, we find that in humans and mice the genes with the longest transcripts enrich for genes reported to extend lifespan, whereas those with the shortest transcripts enrich for genes reported to shorten lifespan. Our study opens fundamental questions on aging and the organization of transcriptomes.

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JO - Nature Aging

JF - Nature Aging

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Aging is associated with a systemic length-associated transcriptome imbalance

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