Xenohormetic and anti-aging activity of secoiridoid polyphenols present in extra virgin olive oil: a new family of gerosuppressant agents.

Aging can be viewed as a quasi-programmed phenomenon driven by the overactivation of the nutrient-sensing mTOR gerogene. mTOR-driven aging can be triggered or accelerated by a decline or loss of responsiveness to activation of the energy-sensing protein AMPK, a critical gerosuppressor of mTOR. The occurrence of age-related diseases, therefore, reflects the synergistic interaction between our evolutionary path to sedentarism, which chronically increases a number of mTOR activating gero-promoters (e.g., food, growth factors, cytokines and insulin) and the "defective design" of central metabolic integrators such as mTOR and AMPK. Our laboratories at the Bioactive Food Component Platform in Spain have initiated a systematic approach to molecularly elucidate and clinically explore whether the "xenohormesis hypothesis," which states that stress-induced synthesis of plant polyphenols and many other phytochemicals provides an environmental chemical signature that upregulates stress-resistance pathways in plant consumers, can be explained in terms of the reactivity of the AMPK/mTOR-axis to so-called xenohormetins. Here, we explore the AMPK/mTOR-xenohormetic nature of complex polyphenols naturally present in extra virgin olive oil (EVOO), a pivotal component of the Mediterranean style diet that has been repeatedly associated with a reduction in age-related morbid conditions and longer life expectancy. Using crude EVOO phenolic extracts highly enriched in the secoiridoids oleuropein aglycon and decarboxymethyl oleuropein aglycon, we show for the first time that (1) the anticancer activity of EVOO secoiridoids is related to the activation of anti-aging/cellular stress-like gene signatures, including endoplasmic reticulum (ER) stress and the unfolded protein response, spermidine and polyamine metabolism, sirtuin-1 (SIRT1) and NRF2 signaling; (2) EVOO secoiridoids activate AMPK and suppress crucial genes involved in the Warburg effect and the self-renewal capacity of "immortal" cancer stem cells; (3) EVOO secoiridoids prevent age-related changes in the cell size, morphological heterogeneity, arrayed cell arrangement and senescence-associated β-galactosidase staining of normal diploid human fibroblasts at the end of their proliferative lifespans. EVOO secoiridoids, which provide an effective defense against plant attack by herbivores and pathogens, are bona fide xenohormetins that are able to activate the gerosuppressor AMPK and trigger numerous resveratrol-like anti-aging transcriptomic signatures. As such, EVOO secoiridoids constitute a new family of plant-produced gerosuppressant agents that molecularly "repair" the aimless (and harmful) AMPK/mTOR-driven quasi-program that leads to aging and aging-related diseases, including cancer.
AuthorsJavier A Menendez, Jorge Joven, Gerard Aragonès, Enrique Barrajón-Catalán, Raúl Beltrán-Debón, Isabel Borrás-Linares, Jordi Camps, Bruna Corominas-Faja, Sílvia Cufí, Salvador Fernández-Arroyo, Anabel Garcia-Heredia, Anna Hernández-Aguilera, María Herranz-López, Cecilia Jiménez-Sánchez, Eugeni López-Bonet, Jesús Lozano-Sánchez, Fedra Luciano-Mateo, Begoña Martin-Castillo, Vicente Martin-Paredero, Almudena Pérez-Sánchez, Cristina Oliveras-Ferraros, Marta Riera-Borrull, Esther Rodríguez-Gallego, Rosa Quirantes-Piné, Anna Rull, Laura Tomás-Menor, Alejandro Vazquez-Martin, Carlos Alonso-Villaverde, Vicente Micol, Antonio Segura-Carretero
JournalCell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 12 Issue 4 Pg. 555-78 (Feb 15 2013) ISSN: 1551-4005 [Electronic] United States
PMID23370395 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Iridoids
  • Olive Oil
  • Plant Oils
  • Polyphenols
  • Protein Kinases
  • AMP-activated protein kinase kinase
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • beta-Galactosidase
  • SIRT1 protein, human
  • Sirtuin 1
  • Aging (drug effects, genetics)
  • Animals
  • Cell Transformation, Neoplastic (drug effects, genetics)
  • Diet, Mediterranean
  • Endoplasmic Reticulum Stress (drug effects)
  • Fibroblasts (cytology, drug effects, metabolism)
  • Gene Expression Regulation (drug effects)
  • Hormesis
  • Humans
  • Iridoids (isolation & purification, pharmacology)
  • Longevity (drug effects, genetics)
  • Olive Oil
  • Plant Oils (chemistry)
  • Polyphenols (isolation & purification, pharmacology)
  • Protein Kinases (genetics, metabolism)
  • Sirtuin 1 (genetics, metabolism)
  • TOR Serine-Threonine Kinases (genetics, metabolism)
  • Unfolded Protein Response (drug effects)
  • beta-Galactosidase (genetics, metabolism)

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