Mechanisms by which PE21, an extract from the white willow Salix alba, delays chronological aging in budding yeast.
Journal: 2019/October - Oncotarget
ISSN: 1949-2553
Abstract:
We have recently found that PE21, an extract from the white willow Salix alba, slows chronological aging and prolongs longevity of the yeast Saccharomyces cerevisiae more efficiently than any of the previously known pharmacological interventions. Here, we investigated mechanisms through which PE21 delays yeast chronological aging and extends yeast longevity. We show that PE21 causes a remodeling of lipid metabolism in chronologically aging yeast, thereby instigating changes in the concentrations of several lipid classes. We demonstrate that such changes in the cellular lipidome initiate three mechanisms of aging delay and longevity extension. The first mechanism through which PE21 slows aging and prolongs longevity consists in its ability to decrease the intracellular concentration of free fatty acids. This postpones an age-related onset of liponecrotic cell death promoted by excessive concentrations of free fatty acids. The second mechanism of aging delay and longevity extension by PE21 consists in its ability to decrease the concentrations of triacylglycerols and to increase the concentrations of glycerophospholipids within the endoplasmic reticulum membrane. This activates the unfolded protein response system in the endoplasmic reticulum, which then decelerates an age-related decline in protein and lipid homeostasis and slows down an aging-associated deterioration of cell resistance to stress. The third mechanisms underlying aging delay and longevity extension by PE21 consists in its ability to change lipid concentrations in the mitochondrial membranes. This alters certain catabolic and anabolic processes in mitochondria, thus amending the pattern of aging-associated changes in several key aspects of mitochondrial functionality.
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Oncotarget 10(56): 5780-5816

Mechanisms by which PE21, an extract from the white willow <em>Salix alba</em>, delays chronological aging in budding yeast

+6 authors
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Department of Biology, Concordia University, Montreal, Quebec H4B 1R6, Canada
Idunn Technologies Inc., Rosemere, Quebec J7A 4A5, Canada
Correspondence to:Vladimir I. Titorenko, ac.aidrocnoc@oknerotit.rimidalv
Received 2019 Jul 19; Accepted 2019 Aug 27.
This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

We have recently found that PE21, an extract from the white willow Salix alba, slows chronological aging and prolongs longevity of the yeast Saccharomyces cerevisiae more efficiently than any of the previously known pharmacological interventions. Here, we investigated mechanisms through which PE21 delays yeast chronological aging and extends yeast longevity. We show that PE21 causes a remodeling of lipid metabolism in chronologically aging yeast, thereby instigating changes in the concentrations of several lipid classes. We demonstrate that such changes in the cellular lipidome initiate three mechanisms of aging delay and longevity extension. The first mechanism through which PE21 slows aging and prolongs longevity consists in its ability to decrease the intracellular concentration of free fatty acids. This postpones an age-related onset of liponecrotic cell death promoted by excessive concentrations of free fatty acids. The second mechanism of aging delay and longevity extension by PE21 consists in its ability to decrease the concentrations of triacylglycerols and to increase the concentrations of glycerophospholipids within the endoplasmic reticulum membrane. This activates the unfolded protein response system in the endoplasmic reticulum, which then decelerates an age-related decline in protein and lipid homeostasis and slows down an aging-associated deterioration of cell resistance to stress. The third mechanisms underlying aging delay and longevity extension by PE21 consists in its ability to change lipid concentrations in the mitochondrial membranes. This alters certain catabolic and anabolic processes in mitochondria, thus amending the pattern of aging-associated changes in several key aspects of mitochondrial functionality.

Keywords: cellular aging, geroprotectors, lipid metabolism, necrotic cell death, mitochondria
Abstract

ACKNOWLEDGMENTS

We are grateful to current and former members of the Titorenko laboratory for discussions. We acknowledge the Centre for Biological Applications of Mass Spectrometry, the Centre for Structural and Functional Genomics and the Centre for Microscopy and Cellular Imaging (all at Concordia University) for outstanding services.

ACKNOWLEDGMENTS

Abbreviations

Ac-CoAacetyl-CoA
ACNacetonitrile
ADHAPacyl-dihydroxyacetone phosphate
AMPKAMP-dependent protein kinase
ATGautophagy
CDPcytidine diphosphate
CFUcolony forming units
CLcardiolipin
CLSchronological lifespan
CRcaloric restriction
DAGdiacylglycerols
DTTdithiothreitol
emPAIexponentially modified protein abundance index
ERendoplasmic reticulum
ETCelectron transport chain
FA-CoAfatty acyl-CoA esters
FFAfree (unesterified) fatty acids
IAAiodoacetamide
IGF-1insulin/insulin-like growth factor 1
IMMinner mitochondrial membrane
IMSintermediate space
Llogarithmic growth phase
LDlipid droplets
LPAlysophosphatidic acid
MAGmonoacylglycerols
MSmass spectrometry
mTORC1mammalian target of rapamycin complex 1
OMMouter mitochondrial membrane
OXPHOSoxidative phosphorylation
PAphosphatidic acid
PCphosphatidylcholine
PCAprincipal component analysis
PDpost-diauxic growth phase
PEphosphatidylethanolamine
PGphosphatidylglycerol
PIphosphatidylinositol
PKAprotein kinase A
PKH1/2Pkb-activating kinase homolog
PMplasma membrane
POApalmitoleic acid
PSphosphatidylserine
RCDregulated cell death
ROSreactive oxygen species
RP-HPLC/MSreverse phase high performance liquid chromatography coupled to mass spectrometry
SNFsucrose non-fermenting
STstationary growth phase
TAGtriacylglycerols
TCAtricarboxylic acid
UPRERunfolded protein response in the endoplasmic reticulum
WTwild type
YNByeast nitrogen base
Abbreviations

Footnotes

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

FUNDING

We are grateful to current and former members of the Titorenko laboratory for discussions. This study was supported by grants from the Natural Sciences and Engineering Research Council (NSERC) of Canada (RGPIN 2014-04482 and CRDPJ 515900 - 17), and Concordia University Chair Fund (CC0113). Y.M. was supported by the Concordia University Public Scholars Program Award. K.M. and P.D. were supported by the Concordia University Graduate Fellowship Awards. A.A.-C. was supported by the NSERC Postgraduate Doctoral Scholarship Award. V.S. was supported by the Harriet and Abe Gold Entrance Bursary Award. J.A.B.J. was supported by the Concordia University Merit Award.

Footnotes

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