MnSOD activity regulates hydroxytyrosol-induced extension of chronological lifespan

Abstract

Chronological lifespan (CLS) is defined as the duration of quiescence in which normal cells retain the capacity to reenter the proliferative cycle. This study investigates whether hydroxytyrosol (HT), a naturally occurring polyphenol found in olives, extends CLS in normal human fibroblasts (NHFs). Quiescent NHFs cultured for a long duration (30-60 days) lose their capacity to repopulate. Approximately 60% of these cells exit the cell cycle permanently; a significant increase in the doubling time of the cell population was observed. CLS was extended in quiescent NHFs that were cultured in the presence of HT for 30-60 days. HT-induced extension of CLS was associated with an approximately 3-fold increase in manganese superoxide dismutase (MnSOD) activity while there was no change in copper-zinc superoxide dismutase, catalase, or glutathione peroxidase protein levels. Quiescent NHFs overexpressing a dominant-negative mutant form of MnSOD failed to extend CLS. HT suppressed ageassociated increase in mitochondrial ROS levels. Results from spectroscopy assays indicate that HT in the presence of peroxidases can undergo catechol-semiquinone-quinone redox cycling generating superoxide, which in a cellular context can activate the antioxidant system, e.g., MnSOD expression. These results demonstrate that HT extends CLS by increasing MnSOD activity and decreasing age-associated mitochondrial reactive oxygen species accumulation.

Manganese Superoxide Dismutase Regulates a Redox Cycle Within the Cell Cycle

“…A regulatory role of MnSOD during the cell cycle is also evident from our studies using both genetic and pharmacological manipulations of MnSOD expression (72,73,76,77). MEFs with wild-type MnSOD showed a typical growth curve consisting of a lag, exponential, and plateau phase (77).…”

Use of Topical Small Molecule Technology to Improve Patient Outcomes in the Diabetic Wound Care Setting

“…6,8,9 In addition, Hydroxytyrosol, a potent antioxidant that results from the hydrolysis of Oleuropein, was found to increase the activity of the oxidative defense enzyme, manganese superoxide dismutase (MnSOD), three-fold in studies where Hydroxytyrosol also extended the chronological lifespan of skin cells. 10 In a model of wound healing that included glucose impaired wound healing, similar to diabetic conditions, Hydroxytyrosol and Oleuropein were shown to increase endothelial cell migration and decrease wound healing times by 50%. 6 ViniferamineÔ products represent a new advancedstandard of care that combines advanced technologies in easy-to use products.…”

“…ViniferamineÔ products contain potent antioxidants with molecular weights that easily penetrate the stratum corneum by passive diffusion and have been proven to improve viability of endothelial cells by 50%. 7 Endothelial cells are the cells that line the vital capillaries that are required to deliver nourishment to the dermal-epidermal junction. The small molecules in ViniferamineÔ include transresveratrol from grapes, Oleuropein from olives and Epigallocatechin gallate (EGCG) from green tea.…”

Neuroinflammation and Mitochondrial Dysfunction in the Pathogenesis of Alzheimer?s Disease: Modulation by Coriolus Versicolor (Yun-Zhi) Nutritional Mushroom

“…Pharmacological manipulation of cellular stress pathways is emerging as a viable approach to treating certain neurologic diseases, such as Alzheimer's disease and psychiatric disorders, such as schizophrenia 51 . Specifically, small redox active molecules, such as the phytochemicals sulforaphane and hydroxytyrosol, or nutritional mushrooms may be potential candidates to modulate physiological pathways associated with cellular stress response and vitagene networks 52 56 and synaptic dysfunction 57 . Conceivably, such therapeutic tactics may be of value in mitigating or perhaps preventing signs and symptoms of neurodegeneration.…”