Xenohormetic and anti-aging activity of secoiridoid polyphenols present in extra virgin olive oil

Abstract

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.

Uncovering the Geroprotective Potential of Medicinal Plants from the Judea Region of Israel

“…From this perspective, it would be of special interest to examine the fractions containing the polysaccharides, polyphenols, and flavonoids, as compounds belonging to these chemical classes have already been shown to possess geroprotective activities. Examples include myricetin found in many edible plants, 23 tyrosol, 24 and secoiridoid polyphenols 25 from olive oil, and the whole-apple extracts that are enriched in flavonoids. 26 The above compounds or extracts increased the resistance to stress and extended life span in the nematode Caenorhabditis elegans [24][25][26] or exhibited anti-cancer activity and prevented induction of cellular senescence.…”

“…Examples include myricetin found in many edible plants, 23 tyrosol, 24 and secoiridoid polyphenols 25 from olive oil, and the whole-apple extracts that are enriched in flavonoids. 26 The above compounds or extracts increased the resistance to stress and extended life span in the nematode Caenorhabditis elegans [24][25][26] or exhibited anti-cancer activity and prevented induction of cellular senescence. 26 With regard to the reported data and on the basis of results obtained in this study, the Judean plants warrant further experimental investigation for their geroprotective activity.…”

Lycopene and human health-A review

“…Although additional research to explain the causes and mechanisms of lycopene deficiency in ageing is required, it is clear now that correction of carotenoid deficiency in older individuals may have anenormous impact on their health status. Moreover, lycopene has to suppress activation of them TOR/AMPK cascade,a major metabolic pathway linked to ageing (Menendez et al 2013).There are numerous pieces of clinical evidence suggesting that lycopene supplementation prevents osteoporosis and incidence of bone fractures (Sacco et al 2013), improves pulmonary function (Samba et al 2012), delays skin ageing (Schagen et al 2012), and enhances physical performance in elderly patients (Alipanah et al 2009). The set of clinical consequences of lycopene deficiency is greatly enlightened by the solid body of clinical evidence revealing the crucial role of lycopene in maintaining prostate health and its ability to prevent prostate cancer in elderly males (Mariani et al 2014).…”

Gerometabolites: The pseudohypoxic aging side of cancer oncometabolites

“…First, the activation of metabolic gerosuppressors (e.g., the evolutionarily conserved energy-sensor AMP-activated protein kinase), which critically antagonize the mTOR gerogenic activity, [60][61][62][63][64][65][66][67][68][69][70][71]84 might exert anti-aging effects by restoring nuclear-mitochondrial communication during aging via the gerometabolite NAD + . Indeed, AMPK regulates energy expenditure by modulating NAD + metabolism and SIRT1 activity.…”