Longevity-related molecular pathways are subject to midlife “switch” in humans

James A. Timmons, Claude Henry Volmar, Hannah Crossland, Bethan E. Phillips, Sanjana Sood, Karolina J. Janczura, Timo Törmäkangas, Urho M. Kujala, William E. Kraus, Philip J. Atherton, Claes R Wahlestedt

Research output: Contribution to journalArticle

Abstract

Emerging evidence indicates that molecular aging may follow nonlinear or discontinuous trajectories. Whether this occurs in human neuromuscular tissue, particularly for the noncoding transcriptome, and independent of metabolic and aerobic capacities, is unknown. Applying our novel RNA method to quantify tissue coding and long noncoding RNA (lncRNA), we identified ~800 transcripts tracking with age up to ~60 years in human muscle and brain. In silico analysis demonstrated that this temporary linear “signature” was regulated by drugs, which reduce mortality or extend life span in model organisms, including 24 inhibitors of the IGF-1/PI3K/mTOR pathway that mimicked, and 5 activators that opposed, the signature. We profiled Rapamycin in nondividing primary human myotubes (n = 32 HTA 2.0 arrays) and determined the transcript signature for reactive oxygen species in neurons, confirming that our age signature was largely regulated in the “pro-longevity” direction. Quantitative network modeling demonstrated that age-regulated ncRNA equaled the contribution of protein-coding RNA within structures, but tended to have a lower heritability, implying lncRNA may better reflect environmental influences. Genes ECSIT, UNC13, and SKAP2 contributed to a network that did not respond to Rapamycin, and was associated with “neuron apoptotic processes” in protein–protein interaction analysis (FDR = 2.4%). ECSIT links inflammation with the continued age-related downwards trajectory of mitochondrial complex I gene expression (FDR < 0.01%), implying that sustained inhibition of ECSIT may be maladaptive. The present observations link, for the first time, model organism longevity programs with the endogenous but temporary genome-wide responses to aging in humans, revealing a pattern that may ultimately underpin personalized rates of health span.

Original languageEnglish (US)
Article numbere12970
JournalAging Cell
Volume18
Issue number4
DOIs
StatePublished - Aug 1 2019

Fingerprint

Long Noncoding RNA
Sirolimus
RNA
Neurons
Skeletal Muscle Fibers
Phosphatidylinositol 3-Kinases
Insulin-Like Growth Factor I
Transcriptome
Computer Simulation
Reactive Oxygen Species
Genome
Inflammation
Gene Expression
Muscles
Mortality
Health
Brain
Pharmaceutical Preparations
Genes
Proteins

Keywords

  • aging
  • Alzheimer's
  • Brain
  • ECSIT
  • long noncoding RNA
  • mitochondrial complex 1
  • mTOR
  • reactive oxygen species
  • skeletal muscle
  • skin

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Cite this

Timmons, J. A., Volmar, C. H., Crossland, H., Phillips, B. E., Sood, S., Janczura, K. J., ... Wahlestedt, C. R. (2019). Longevity-related molecular pathways are subject to midlife “switch” in humans. Aging Cell, 18(4), [e12970]. https://doi.org/10.1111/acel.12970

Longevity-related molecular pathways are subject to midlife “switch” in humans. / Timmons, James A.; Volmar, Claude Henry; Crossland, Hannah; Phillips, Bethan E.; Sood, Sanjana; Janczura, Karolina J.; Törmäkangas, Timo; Kujala, Urho M.; Kraus, William E.; Atherton, Philip J.; Wahlestedt, Claes R.

In: Aging Cell, Vol. 18, No. 4, e12970, 01.08.2019.

Research output: Contribution to journalArticle

Timmons, JA, Volmar, CH, Crossland, H, Phillips, BE, Sood, S, Janczura, KJ, Törmäkangas, T, Kujala, UM, Kraus, WE, Atherton, PJ & Wahlestedt, CR 2019, 'Longevity-related molecular pathways are subject to midlife “switch” in humans', Aging Cell, vol. 18, no. 4, e12970. https://doi.org/10.1111/acel.12970
Timmons JA, Volmar CH, Crossland H, Phillips BE, Sood S, Janczura KJ et al. Longevity-related molecular pathways are subject to midlife “switch” in humans. Aging Cell. 2019 Aug 1;18(4). e12970. https://doi.org/10.1111/acel.12970
Timmons, James A. ; Volmar, Claude Henry ; Crossland, Hannah ; Phillips, Bethan E. ; Sood, Sanjana ; Janczura, Karolina J. ; Törmäkangas, Timo ; Kujala, Urho M. ; Kraus, William E. ; Atherton, Philip J. ; Wahlestedt, Claes R. / Longevity-related molecular pathways are subject to midlife “switch” in humans. In: Aging Cell. 2019 ; Vol. 18, No. 4.
@article{cf7044204300489a9887b5771f21e42b,
title = "Longevity-related molecular pathways are subject to midlife “switch” in humans",
abstract = "Emerging evidence indicates that molecular aging may follow nonlinear or discontinuous trajectories. Whether this occurs in human neuromuscular tissue, particularly for the noncoding transcriptome, and independent of metabolic and aerobic capacities, is unknown. Applying our novel RNA method to quantify tissue coding and long noncoding RNA (lncRNA), we identified ~800 transcripts tracking with age up to ~60 years in human muscle and brain. In silico analysis demonstrated that this temporary linear “signature” was regulated by drugs, which reduce mortality or extend life span in model organisms, including 24 inhibitors of the IGF-1/PI3K/mTOR pathway that mimicked, and 5 activators that opposed, the signature. We profiled Rapamycin in nondividing primary human myotubes (n = 32 HTA 2.0 arrays) and determined the transcript signature for reactive oxygen species in neurons, confirming that our age signature was largely regulated in the “pro-longevity” direction. Quantitative network modeling demonstrated that age-regulated ncRNA equaled the contribution of protein-coding RNA within structures, but tended to have a lower heritability, implying lncRNA may better reflect environmental influences. Genes ECSIT, UNC13, and SKAP2 contributed to a network that did not respond to Rapamycin, and was associated with “neuron apoptotic processes” in protein–protein interaction analysis (FDR = 2.4{\%}). ECSIT links inflammation with the continued age-related downwards trajectory of mitochondrial complex I gene expression (FDR < 0.01{\%}), implying that sustained inhibition of ECSIT may be maladaptive. The present observations link, for the first time, model organism longevity programs with the endogenous but temporary genome-wide responses to aging in humans, revealing a pattern that may ultimately underpin personalized rates of health span.",
keywords = "aging, Alzheimer's, Brain, ECSIT, long noncoding RNA, mitochondrial complex 1, mTOR, reactive oxygen species, skeletal muscle, skin",
author = "Timmons, {James A.} and Volmar, {Claude Henry} and Hannah Crossland and Phillips, {Bethan E.} and Sanjana Sood and Janczura, {Karolina J.} and Timo T{\"o}rm{\"a}kangas and Kujala, {Urho M.} and Kraus, {William E.} and Atherton, {Philip J.} and Wahlestedt, {Claes R}",
year = "2019",
month = "8",
day = "1",
doi = "10.1111/acel.12970",
language = "English (US)",
volume = "18",
journal = "Aging Cell",
issn = "1474-9718",
publisher = "Wiley-Blackwell",
number = "4",

}

TY - JOUR

T1 - Longevity-related molecular pathways are subject to midlife “switch” in humans

AU - Timmons, James A.

AU - Volmar, Claude Henry

AU - Crossland, Hannah

AU - Phillips, Bethan E.

AU - Sood, Sanjana

AU - Janczura, Karolina J.

AU - Törmäkangas, Timo

AU - Kujala, Urho M.

AU - Kraus, William E.

AU - Atherton, Philip J.

AU - Wahlestedt, Claes R

PY - 2019/8/1

Y1 - 2019/8/1

N2 - Emerging evidence indicates that molecular aging may follow nonlinear or discontinuous trajectories. Whether this occurs in human neuromuscular tissue, particularly for the noncoding transcriptome, and independent of metabolic and aerobic capacities, is unknown. Applying our novel RNA method to quantify tissue coding and long noncoding RNA (lncRNA), we identified ~800 transcripts tracking with age up to ~60 years in human muscle and brain. In silico analysis demonstrated that this temporary linear “signature” was regulated by drugs, which reduce mortality or extend life span in model organisms, including 24 inhibitors of the IGF-1/PI3K/mTOR pathway that mimicked, and 5 activators that opposed, the signature. We profiled Rapamycin in nondividing primary human myotubes (n = 32 HTA 2.0 arrays) and determined the transcript signature for reactive oxygen species in neurons, confirming that our age signature was largely regulated in the “pro-longevity” direction. Quantitative network modeling demonstrated that age-regulated ncRNA equaled the contribution of protein-coding RNA within structures, but tended to have a lower heritability, implying lncRNA may better reflect environmental influences. Genes ECSIT, UNC13, and SKAP2 contributed to a network that did not respond to Rapamycin, and was associated with “neuron apoptotic processes” in protein–protein interaction analysis (FDR = 2.4%). ECSIT links inflammation with the continued age-related downwards trajectory of mitochondrial complex I gene expression (FDR < 0.01%), implying that sustained inhibition of ECSIT may be maladaptive. The present observations link, for the first time, model organism longevity programs with the endogenous but temporary genome-wide responses to aging in humans, revealing a pattern that may ultimately underpin personalized rates of health span.

AB - Emerging evidence indicates that molecular aging may follow nonlinear or discontinuous trajectories. Whether this occurs in human neuromuscular tissue, particularly for the noncoding transcriptome, and independent of metabolic and aerobic capacities, is unknown. Applying our novel RNA method to quantify tissue coding and long noncoding RNA (lncRNA), we identified ~800 transcripts tracking with age up to ~60 years in human muscle and brain. In silico analysis demonstrated that this temporary linear “signature” was regulated by drugs, which reduce mortality or extend life span in model organisms, including 24 inhibitors of the IGF-1/PI3K/mTOR pathway that mimicked, and 5 activators that opposed, the signature. We profiled Rapamycin in nondividing primary human myotubes (n = 32 HTA 2.0 arrays) and determined the transcript signature for reactive oxygen species in neurons, confirming that our age signature was largely regulated in the “pro-longevity” direction. Quantitative network modeling demonstrated that age-regulated ncRNA equaled the contribution of protein-coding RNA within structures, but tended to have a lower heritability, implying lncRNA may better reflect environmental influences. Genes ECSIT, UNC13, and SKAP2 contributed to a network that did not respond to Rapamycin, and was associated with “neuron apoptotic processes” in protein–protein interaction analysis (FDR = 2.4%). ECSIT links inflammation with the continued age-related downwards trajectory of mitochondrial complex I gene expression (FDR < 0.01%), implying that sustained inhibition of ECSIT may be maladaptive. The present observations link, for the first time, model organism longevity programs with the endogenous but temporary genome-wide responses to aging in humans, revealing a pattern that may ultimately underpin personalized rates of health span.

KW - aging

KW - Alzheimer's

KW - Brain

KW - ECSIT

KW - long noncoding RNA

KW - mitochondrial complex 1

KW - mTOR

KW - reactive oxygen species

KW - skeletal muscle

KW - skin

UR - http://www.scopus.com/inward/record.url?scp=85068796043&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85068796043&partnerID=8YFLogxK

U2 - 10.1111/acel.12970

DO - 10.1111/acel.12970

M3 - Article

VL - 18

JO - Aging Cell

JF - Aging Cell

SN - 1474-9718

IS - 4

M1 - e12970

ER -