In S. cerevisiae hydroxycitric acid antagonizes chronological aging and apoptosis regardless of citrate lyase

Abstract

Caloric restriction mimetics (CRMs) are promising molecules to prevent age-related diseases as they activate pathways driven by a true caloric restriction. Hydroxycitric acid (HCA) is considered a bona fide CRM since it depletes acetyl-CoA pools by acting as a competitive inhibitor of ATP citrate lyase (ACLY), ultimately repressing protein acetylation and promoting autophagy. Importantly, it can reduce inflammation and tumour development. In order to identify phenotypically relevant new HCA targets we have investigated HCA effects in Saccharomyces cerevisiae, where ACLY is lacking. Strikingly, the drug revealed a powerful anti-aging effect, another property proposed to mark bona fide CRMs. Chronological life span (CLS) extension but also resistance to acetic acid of HCA treated cells were associated to repression of cell apoptosis and necrosis. HCA also largely prevented cell deaths caused by a severe oxidative stress. The molecule could act widely by negatively modulating cell metabolism, similarly to citrate. Indeed, it inhibited both growth reactivation and the oxygen consumption rate of yeast cells in stationary phase. Genetic analyses on yeast CLS mutants indicated that part of the HCA effects can be sensed by Sch9 and Ras2, two conserved key regulators of nutritional and stress signal pathways of primary importance. Our data together with published biochemical analyses indicate that HCA may act with multiple mechanisms together with ACLY repression and allowed us to propose an integrated mechanistic model as a basis for future investigations.

Unraveling the Anti-Aging Properties of Phycocyanin from the Cyanobacterium Spirulina (Arthrospira platensis)

“…These data suggest that the addition of phycocyanin at the end of the growth phase might favour survival through a mechanism other than hormesis, previously proposed to explain how an increase in ROS might, in the case of phycocyanin added at the time of inoculation, favour survival. It might be that phycocyanin added on day 0 of CLS (when maximum cell density is reached) acts on signalling mechanisms, as observed for hydroxycitric acid, a caloric restriction mimetic we previously investigated [37]. Genetic analysis on yeast CLS mutants indicated that part of the powerful anti-aging effects of hydroxycitrate can be sensed by Sch9 and Ras2, two conserved key regulators of nutritional and stress signal pathways of primary importance in S. cerevisiae [37].…”

“…It might be that phycocyanin added on day 0 of CLS (when maximum cell density is reached) acts on signalling mechanisms, as observed for hydroxycitric acid, a caloric restriction mimetic we previously investigated [37]. Genetic analysis on yeast CLS mutants indicated that part of the powerful anti-aging effects of hydroxycitrate can be sensed by Sch9 and Ras2, two conserved key regulators of nutritional and stress signal pathways of primary importance in S. cerevisiae [37]. However, it could not be excluded that the reduced ROS level observed when PC was added at the end of the growth phase could be simply explained by the lower concentration of PC present in the medium.…”

ATP-Citrate Lyase (ACLY): An Extensive Investigation from Molecular Insight to Therapeutic implications

“…In addition, HCA seems to upregulate the genes encoding serotonin receptors and raise endogenous serotonin concentrations. These actions promote oxidation of fullness fat and lower de novo lipogenesis (Baroni et al, 2020).…”

The role of NAD and NAD precursors on longevity and lifespan modulation in the budding yeast, Saccharomyces cerevisiae

“…Interestingly, there is interplay between aging progression and secretion of secondary metabolites. These metabolites modulate the rate of aging, and may include sphingolipids (Ren and Hannun 2016 ), NADPH (Mohammad et al 2020 ), hydrogen peroxide (Dakik and Titorenko et al 2016 ), ethanol (Mohammad et al 2018 ), acetic acid (Baroni et al 2020 ), and hydrogen sulfide (Huang et al 2017 ), among others.…”

“…It is a model organism of choice due to its relatively short lifespan, well-characterized genome, and easy genetic engineering with myriad protocols readily available (Dakik et al 2020 ; Kaeberlein 2010 ). S. cerevisiae has become the most extensively used eukaryote in the study of aging (Arlia-Ciommo et al 2014 ; Bilinski et al 2017 ), cell cycle (Musa, et al 2018 ; Leonov et al 2017 ), gene expression (Postnikoff et al 2017 ; Ksiazek 2010 ), metabolism (Baccolo et al 2018 ; Croft et al 2020 ), signal transduction (Hohmann et al 2007 ; Babazadeh et al 2014 ), and apoptosis (Baroni et al 2020 ; Owsianowski et al 2008 ). Hence, to understand the complexity of organismal lifespan in a model organism (e.g., yeast S. cerevisiae ), aging studies are often designed to; (i) identify underlying causes of aging and in extension the associated physiological cellular damage it causes (ii) to devise strategies for the delay and possible reversal of aging development, (iii) and thirdly, to limit cell vulnerability to a wide range of aging inducing conditions.…”