During yeast chronological aging resveratrol supplementation results in a short-lived phenotype Sir2-dependent

Abstract

Resveratrol (RSV) is a naturally occurring polyphenolic compound endowed with interesting biological properties/functions amongst which are its activity as an antioxidant and as Sirtuin activating compound towards SIRT1 in mammals. Sirtuins comprise a family of NAD+-dependent protein deacetylases that are involved in many physiological and pathological processes including aging and age-related diseases. These enzymes are conserved across species and SIRT1 is the closest mammalian orthologue of Sir2 of Saccharomyces cerevisiae. In the field of aging researches, it is well known that Sir2 is a positive regulator of replicative lifespan and, in this context, the RSV effects have been already examined. Here, we analyzed RSV effects during chronological aging, in which Sir2 acts as a negative regulator of chronological lifespan (CLS). Chronological aging refers to quiescent cells in stationary phase; these cells display a survival-based metabolism characterized by an increase in oxidative stress. We found that RSV supplementation at the onset of chronological aging, namely at the diauxic shift, increases oxidative stress and significantly reduces CLS. CLS reduction is dependent on Sir2 presence both in expired medium and in extreme Calorie Restriction. In addition, all data point to an enhancement of Sir2 activity, in particular Sir2-mediated deacetylation of the key gluconeogenic enzyme phosphoenolpyruvate carboxykinase (Pck1). This leads to a reduction in the amount of the acetylated active form of Pck1, whose enzymatic activity is essential for gluconeogenesis and CLS extension.

Nicotinamide, Nicotinamide Riboside and Nicotinic Acid—Emerging Roles in Replicative and Chronological Aging in Yeast

“…NAM-supplemented cells also phenocopy the CLS of sir2∆ cells in such an extreme CR condition [62]. This CLS-extending effect takes place in concert with an increase of the acetylated Pck1 level [83], further supporting the importance of Sir2 activity on its cellular target Pck1 during chronological aging.…”

“…Referring to gluconeogenesis, the first irreversible reaction is catalyzed by phosphoenolpyruvate carboxykinase (Pck1). Pck1 enzymatic activity is regulated by its de/acetylation state: an increase in the acetylated (active) form enhances gluconeogenesis and extends CLS [62,[81][82][83]. The enzyme responsible for Pck1 deacetylation is Sir2 [81,82].…”

“…The enzyme responsible for Pck1 deacetylation is Sir2 [81,82]. Consequently, during chronological aging, the negative control of Sir2 activity on the gluconeogenic activity of Pck1 leads to a negative effect also on CLS [83]. Indeed, unlike RLS, Sir2 does not promote CLS [62,81,84,85].…”

Natural products against renin-angiotensin system for antifibrosis therapy

“…Fortunately, newly emerging anti-sclerostin therapies (romosozumab and blosozumab) and several natural small molecules have shown a beneficial effect on the treatment of rheumatoid arthritis through targeting the Wnt/β-catenin pathway. Resveratrol, a natural polyphenolic compound isolated from plants, has various physiological effects, including anticancer and anti-cardiovascular, and is expected to become a promising natural product for clinical use, despite most related studies being performed in animal models [150][151][152][153]. In collagen-induced arthritis mice, levels of Wnt5a protein are decreased and the Wnt/β-catenin pathway is suppressed by resveratrol [154].…”

Biological Effects and Properties of Eukaryotic Sirtuins

“…Основні успіхи досягнуті у з'ясуванні функцій цих білків на молекулярному рівні. Встановлено механізми реакції на кількість енергії, що надходить до організму після споживання їжі, та такі фактори навколишнього середовища, як тривалість світлового дня, температурні коливання, індукуючи при цьому зміни, що сприяють виживанню організму за несприят-ливих умов [3,6,7].…”