Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Mar 29;7(13):16542-66.
doi: 10.18632/oncotarget.7665.

Discovery of Plant Extracts That Greatly Delay Yeast Chronological Aging and Have Different Effects on Longevity-Defining Cellular Processes

Affiliations
Free PMC article

Discovery of Plant Extracts That Greatly Delay Yeast Chronological Aging and Have Different Effects on Longevity-Defining Cellular Processes

Vicky Lutchman et al. Oncotarget. .
Free PMC article

Abstract

We discovered six plant extracts that increase yeast chronological lifespan to a significantly greater extent than any of the presently known longevity-extending chemical compounds. One of these extracts is the most potent longevity-extending pharmacological intervention yet described. We show that each of the six plant extracts is a geroprotector which delays the onset and decreases the rate of yeast chronological aging by eliciting a hormetic stress response. We also show that each of these extracts has different effects on cellular processes that define longevity in organisms across phyla. These effects include the following: 1) increased mitochondrial respiration and membrane potential; 2) augmented or reduced concentrations of reactive oxygen species; 3) decreased oxidative damage to cellular proteins, membrane lipids, and mitochondrial and nuclear genomes; 4) enhanced cell resistance to oxidative and thermal stresses; and 5) accelerated degradation of neutral lipids deposited in lipid droplets. Our findings provide new insights into mechanisms through which chemicals extracted from certain plants can slow biological aging.

Keywords: aging-delaying chemical compounds; cellular aging; longevity; plant extracts; yeast.

Conflict of interest statement

CONFLICTS OF INTEREST

Vicky Lutchman, Younes Medkour, Eugenie Samson, Anthony Arlia-Ciommo, Pamela Dakik, Berly Cortes, Rachel Feldman, Sadaf Mohtashami, Mélissa McAuley Marisa Chancharoen, Belise Rukundo and Vladimir I. Titorenko have no conflicts of interest to declare. Éric Simard is the president of Idunn Technologies Inc.

Figures

Figure 1
Figure 1. PE4, PE5, PE6, PE8, PE12 and PE21 extend the chronological lifespan (CLS) of yeast grown under non-caloric restriction (non-CR) conditions
Wild-type (WT) cells were grown in the synthetic minimal YNB medium (0.67% Yeast Nitrogen Base without amino acids) initially containing 2% glucose, in the presence of a PE or in its absence. Survival curves of chronologically aging WT strain cultured with or without 0.5% PE4 (A), 0.5% PE5 (B), 1% PE6 (C), 0.3% PE8 (D), 0.1% PE12 (E) or 0.1% PE21 (F) are shown. Data are presented as means ± SEM (n = 21–35). CLS extension was significant for each of the PEs tested (p < 0.05; the p values for comparing survival curves were calculated with the help of the GraphPad Prism statistics software). Abbreviations: Logarithmic (L), post-diauxic (PD) or stationary (ST) growth phase.
Figure 2
Figure 2. PE5 and PE21, but not PE4, PE6, PE8 or PE12, extend the CLS of yeast grown under CR conditions
WT cells were grown in the synthetic minimal YNB medium initially containing 0.5% glucose (CR conditions) or 2% glucose (non-CR conditions), in the presence of a PE or in its absence. Survival curves (A), the mean (B) and maximum (C) lifespans of chronologically aging WT strain cultured under CR or non-CR conditions in the absence of a PE are shown; data are presented as means ± SEM (n = 5–7). CR caused significant extension of CLS (A) (p < 0.05; the p values for comparing survival curves were calculated with the help of the GraphPad Prism statistics software). CR extended both the mean (B) and maximum (C) lifespans (*p < 0.05; the p values for comparing the means of two groups were calculated with the help of the GraphPad Prism statistics software using an unpaired two-tailed t test). Survival curves of chronologically aging WT strain cultured under CR on 0.5% glucose with or without 0.5% PE4 (D), 0.5% PE5 (E), 1% PE6 (F), 0.3% PE8 (G), 0.1% PE12 (H) or 0.1% PE21 (I) are shown; data are presented as means ± SEM (n = 5–7). CLS extension under CR on 0.5% glucose was significant for PE5 and PE21 (p < 0.05; the p values for comparing survival curves were calculated with the help of the GraphPad Prism statistics software). CLS extension under CR on 0.5% glucose was not significant for PE4, PE6, PE8 and PE12. Abbreviations: Logarithmic (L), post-diauxic (PD) or stationary (ST) growth phase.
Figure 3
Figure 3. The longevity-extending efficacy under non-CR conditions significantly exceeds that under CR conditions for each of the six lifespan-prolonging PEs
WT cells were grown in the synthetic minimal YNB medium initially containing 0.5% glucose (CR conditions) or 2% glucose (non-CR conditions), in the presence of a PE or in its absence. The mean (A, C and E) and maximum (B, D and F) lifespans of chronologically aging WT strain cultured under CR (C, D, E and F) or non-CR (A, B, E and F) conditions in the absence of a PE or in the presence of 0.5% PE4, 0.5% PE5, 1% PE6, 0.3% PE8, 0.1% PE12 or 0.1% PE21 are shown; data are presented as means ± SEM (n = 5–7; *p < 0.05). The extent to which each of the PE tested increases the mean and maximum lifespans under non-CR conditions exceeds that under CR conditions (*p < 0.05; the p values for comparing the means of two groups were calculated with the help of the GraphPad Prism statistics software using an unpaired two-tailed t test).
Figure 4
Figure 4. Analysis of the Gompertz mortality function indicates that PE4, PE5, PE6, PE8, PE12 and PE21 significantly decrease the rate of chronological aging in yeast
WT cells were grown in the synthetic minimal YNB medium initially containing 2% glucose, in the presence of a PE or in its absence. Survival curves shown in Figure 1A–1F were used to calculate the age-specific mortality rates (qx) of chronologically aging WT yeast populations cultured with or without 0.5% PE4 (A), 0.5% PE5 (B), 1% PE6 (C), 0.3% PE8 (D), 0.1% PE12 (E) or 0.1% PE21 (F). Each of these longevity-extending PEs caused a substantial decrease in slope of the Gompertz mortality rate (also known as mortality rate coefficient α) and a considerable increase in the mortality rate doubling time (MRDT) (G). The values of qx, α and MRDT were calculated as described in Materials and methods. Abbreviations: Logarithmic (L), post-diauxic (PD) or stationary (ST) growth phase.
Figure 5
Figure 5. PE4, PE5, PE6, PE8, PE12 and PE21 alter the age-related chronology of mitochondrial oxygen consumption by yeast grown under non-CR conditions
WT cells were grown in the synthetic minimal YNB medium initially containing 2% glucose, in the presence of a PE or in its absence. A polarographic assay was used to measure oxygen uptake by live yeast cells, as described in Materials and methods. Age-dependent changes in the rate of mitochondrial oxygen consumption by chronologically aging WT strain cultured under non-CR conditions on 2% glucose with or without 0.5% PE4 (A), 0.5% PE5 (B), 1% PE6 (C), 0.3% PE8 (D), 0.1% PE12 (E) or 0.1% PE21 (F) are shown; data are presented as means ± SEM (n = 7–9; *p < 0.05; the p values for comparing the means of two groups were calculated with the help of the GraphPad Prism statistics software using an unpaired two-tailed t test). Abbreviations: Logarithmic (L), post-diauxic (PD) or stationary (ST) growth phase.
Figure 6
Figure 6. PE4, PE5, PE6, PE8, PE12 and PE21 sustain healthy populations of functional mitochondria that exhibit high mitochondrial membrane potential (ΔΨm) in chronologically aging yeast grown under non-CR conditions
WT cells were grown in the synthetic minimal YNB medium initially containing 2% glucose, in the presence of a PE or in its absence. ΔΨm was measured in live yeast by fluorescence microscopy of Rhodamine 123 staining, as described in Materials and methods. Age-dependent changes in the percentage of WT cells displaying high ΔΨm in chronologically aging yeast cultures under non-CR conditions on 2% glucose with or without 0.5% PE4 (A), 0.5% PE5 (B), 1% PE6 (C), 0.3% PE8 (D), 0.1% PE12 (E) or 0.1% PE21 (F) are shown; data are presented as means ± SEM (n = 3–4; *p < 0.05; the p values for comparing the means of two groups were calculated with the help of the GraphPad Prism statistics software using an unpaired two-tailed t test). Abbreviations: Logarithmic (L), post-diauxic (PD) or stationary (ST) growth phase.
Figure 7
Figure 7. In yeast grown under non-CR conditions, PE4, PE5, PE6, PE8, PE12 and PE21 alter the patterns of age-related changes in intracellular reactive oxygen species (ROS) known to be generated mainly as by-products of mitochondrial respiration
WT cells were grown in the synthetic minimal YNB medium initially containing 2% glucose, in the presence of a PE or in its absence. The intracellular concentrations of ROS were measured in live yeast by fluorescence microscopy of dihydrorhodamine 123 staining, as described in Materials and methods. Age-dependent changes in ROS concentrations within chronologically aging WT cells cultured under non-CR conditions on 2% glucose with or without 0.5% PE4 (A), 0.5% PE5 (B), 1% PE6 (C), 0.3% PE8 (D), 0.1% PE12 (E) or 0.1% PE21 (F) are shown; data are presented as means ± SEM (n = 3–4; *p < 0.05; the p values for comparing the means of two groups were calculated with the help of the GraphPad Prism statistics software using an unpaired two-tailed t test). Abbreviations: Logarithmic (L), post-diauxic (PD) or stationary (ST) growth phase.
Figure 8
Figure 8. PE4, PE5, PE6, PE8, PE12 and PE21 delay an age-dependent rise in the extent of oxidative damage to cellular proteins in chronologically aging yeast grown under non-CR conditions. PE5, PE6, PE8, PE12 and PE21, but not PE4, have similar effects on the extent of oxidative damage to membrane lipids
WT cells were grown in the synthetic minimal YNB medium initially containing 2% glucose, in the presence of a PE or in its absence. Carbonylated cellular proteins (A–F) and oxidatively damaged membrane lipids (G–L) were determined as described in Materials and methods. Age-dependent changes in the concentrations of these oxidatively damaged macromolecules within chronologically aging WT cells cultured under non-CR conditions on 2% glucose with or without 0.5% PE4 (A and G), 0.5% PE5 (B and H), 1% PE6 (C and I), 0.3% PE8 (D and J), 0.1% PE12 (E and K) or 0.1% PE21 (F and L) are shown; data are presented as means ± SEM (n = 2–4; *p < 0.05; the p values for comparing the means of two groups were calculated with the help of the GraphPad Prism statistics software using an unpaired two-tailed t test). Abbreviations: Logarithmic (L), post-diauxic (PD) or stationary (ST) growth phase.
Figure 9
Figure 9. PE4, PE5, PE6, PE8, PE12 and PE21 slow down an age-dependent rise in the frequency of spontaneous point mutations in the rib2 and rib3 loci of mitochondrial DNA (mtDNA) in chronologically aging yeast grown under non-CR conditions. PE12 and PE21, but not PE4, PE5, PE6 or PE8, have similar effects on the frequency of spontaneous point mutations in the CAN1 gene of nuclear DNA (nDNA)
WT cells were grown in the synthetic minimal YNB medium initially containing 2% glucose, in the presence of a PE or in its absence. The frequency of spontaneous point mutations in the rib2 and rib3 loci of mtDNA (A–F), as well as the frequency of spontaneous point mutations in the CAN1 gene of nDNA (G–L), were measured as described in Materials and methods. Age-dependent changes in the frequencies of these mtDNA and nDNA mutations in chronologically aging WT cells cultured under non-CR conditions on 2% glucose with or without 0.5% PE4 (A and G), 0.5% PE5 (B and H), 1% PE6 (C and I), 0.3% PE8 (D and J), 0.1% PE12 (E and K) or 0.1% PE21 (F and L) are shown; data are presented as means ± SEM (n = 3–5; *p < 0.05; the p values for comparing the means of two groups were calculated with the help of the GraphPad Prism statistics software using an unpaired two-tailed t test). Abbreviations: Logarithmic (L), post-diauxic (PD) or stationary (ST) growth phase.
Figure 10
Figure 10. PE4, PE5, PE6, PE8, PE12 and PE21 enhance the ability of chronologically aging yeast grown under non-CR conditions to resist chronic oxidative stress
WT cells were grown in the synthetic minimal YNB medium initially containing 2% glucose, in the presence of a PE or in its absence. (A) Spot assays for monitoring oxidative stress resistance were performed as described in Materials and methods. Serial 10-fold dilutions of cells recovered at different days of culturing were spotted on plates with solid YEP medium containing 2% glucose as carbon source, with or without 5 mM hydrogen peroxide. All pictures were taken after a 3-d incubation at 30°C. (B) A model for how 0.5% PE4, 0.5% PE5, 1% PE6, 0.3% PE8, 0.1% PE12 and 0.1% PE21 influence the resistance of yeast to chronic oxidative stress during logarithmic (L), post-diauxic (PD) or stationary (ST) phases of growth. formula image or formula image Denote unaltered or enhanced, respectively, cell resistance to chronic oxidative stress during a particular phase of growth. Abbreviations: Logarithmic (L), post-diauxic (PD) or stationary (ST) growth phase.
Figure 11
Figure 11. PE4, PE5, PE6, PE8, PE12 and PE21 exhibit different effects on the ability of chronologically aging yeast grown under non-CR conditions to resist chronic thermal stress
WT cells were grown in the synthetic minimal YNB medium initially containing 2% glucose, in the presence of a PE or in its absence. (A) Spot assays for monitoring thermal stress resistance were performed as described in Materials and methods. Serial 10-fold dilutions of cells recovered at different days of culturing were spotted on plates with solid YEP medium containing 2% glucose as carbon source. Plates were initially incubated at 30°C (control) or 60°C for 60 min, and were then transferred to 30°C. All pictures were taken after a 3-d incubation at 30°C. (B) A model for how 0.5% PE4, 0.5% PE5, 1% PE6, 0.3% PE8, 0.1% PE12 and 0.1% PE21 influence the resistance of yeast to chronic thermal stress during logarithmic (L), post-diauxic (PD) or stationary (ST) phases of growth. formula image, formula image or formula image Denote unaltered, reduced or enhanced, respectively, cell resistance to chronic thermal stress during a particular phase of growth. Abbreviations: Logarithmic (L), post-diauxic (PD) or stationary (ST) growth phase.
Figure 12
Figure 12. PE4, PE5, PE6, PE8, PE12 and PE21 induce rapid consumption of neutral lipids deposited in lipid droplets (LDs) of chronologically aging yeast grown under non-CR conditions
WT cells were grown in the synthetic minimal YNB medium initially containing 2% glucose, in the presence of a PE or in its absence. Neutral lipids deposited in LDs were measured in live yeast by fluorescence microscopy of BODIPY 493/503 staining, as described in Materials and methods. Age-dependent changes in the percentage of WT cells exhibiting LDs in chronologically aging yeast cultures under non-CR conditions on 2% glucose with or without 0.5% PE4 (A), 0.5% PE5 (B), 1% PE6 (C), 0.3% PE8 (D), 0.1% PE12 (E) or 0.1% PE21 (F) are shown; data are presented as means ± SEM (n = 3–4; *p < 0.05; the p values for comparing the means of two groups were calculated with the help of the GraphPad Prism statistics software using an unpaired two-tailed t test). Abbreviations: Logarithmic (L), post-diauxic (PD) or stationary (ST) growth phase.
Figure 13
Figure 13. PE4, PE5, PE6, PE8, PE12 and PE21 delay yeast chronological aging and have different effects on several longevity-defining cellular processes
Arrows pointing at boxes with the terms of longevity-defining cellular processes denote activation of these processes, T bars denote inhibition of these processes, whereas lines with filled circles denote change in the age-related chronology of intracellular ROS. The thickness of such arrows, T bars and lines with filled circles correlates with the extent to which a PE activates, inhibits or alters the age-related chronology (respectively) of a particular longevity-defining cellular process. Arrows and T bars pointing at boxes with the term “AGING” denote acceleration or deceleration (respectively) of yeast chronological aging.

Similar articles

See all similar articles

Cited by 9 articles

See all "Cited by" articles

References

    1. Botstein D, Fink GR. Yeast: an experimental organism for 21st Century biology. Genetics. 2011;189:695–704. - PMC - PubMed
    1. Feldmann H, editor. Yeast: Molecular and Cell Biology. 2. Wiley-Blackwell; Weinheim, Germany: 2012. p. 464.
    1. Lachance M-A. eLS. Chichester, West Sussex, UK: John Wiley & Sons; 2010. Yeasts; pp. 1–12.
    1. Smith JS, Burke DJ, editors. Springer; New York, USA: 2014. Yeast Genetics: Methods and Protocols; p. 378.
    1. Weissman J, Guthrie C, Fink GR, editors. Guide to Yeast Genetics: Functional Genomics, Proteomics, and Other Systems Analysis. Academic Press; Burlington, USA: 2010. p. 892.

MeSH terms

LinkOut - more resources

Feedback