Cellular senescence in aging: Molecular basis, implications and therapeutic interventions.

Cellular senescence is an irreversible proliferation arrest in response to cellular damage and stress. Although cellular senescence is a highly stable cell cycle arrest, it can influence many physiological, pathological, and aging processes. Cellular senescence can be triggered by various intrinsic and extrinsic stimuli such as oxidative stress, mitochondrial dysfunction, genotoxic stress, oncogenic activation, irradiation and chemotherapeutic agents. Senescence is associated with several molecular and phenotypic alterations, such as senescence-associated secretory phenotype (SASP), cell cycle arrest, DNA damage response (DDR), senescence-associated ß-galactosidase, morphogenesis, and chromatin remodeling. Cellular senescence is a regular physiological event involved in tissue homeostasis, embryonic development, tissue remodeling, wound healing, and inhibition of tumor progression. Mitochondria are one of the organelles that undergo significant morphological and metabolic changes associated with senescence. Recent evidence unraveled that inter-organelle communication regulates cellular senescence, where mitochondria form a highly complex and dynamic network throughout the cytoplasm with other organelles, like the endoplasmic reticulum. An imbalance in organelle interactions may result in faulty cellular homeostasis, which contributes to cellular senescence and is associated with organ aging. Since mitochondrial dysfunction is a common characteristic of cellular senescence and age-related diseases, mitochondria-targeted senolytic or redox modulator senomorphic strategies help solve the complex problems with the detrimental consequences of cellular senescence. Understanding the regulation of mitochondrial metabolism would provide knowledge on effective therapeutic interventions for aging and age-related pathologies. This chapter focuses on the biochemical and molecular mechanisms of senescence and targeting senescence as a potential strategy to alleviate age-related pathologies and support healthy aging.

Betulinic acid mitigates oxidative stress-mediated apoptosis and enhances longevity in the yeast Saccharomyces cerevisiae model.

Betulinic acid (BA), a pentacyclic triterpenoid found in certain plant species, has been reported to have several health benefits including antioxidant and anti-apoptotic properties. However, the mechanism by which BA confers these properties is currently unknown. Saccharomyces cerevisiae, a budding yeast with a short life cycle and conserved cellular mechanism with high homology to humans, was used as a model for determining the role of BA in aging and programmed cell death (PCD). Treatment with hydrogen peroxide (H2O2) exhibited significantly increased (30-35%) survivability of antioxidant (sod1Δ, sod2Δ, cta1Δ, ctt1Δ, and tsa1Δ) and anti-apoptotic (pep4Δ and fis1Δ) mutant strains when cells were pretreated with BA (30 µM) as demonstrated in spot and CFU (Colony forming units) assays. Measurement of intracellular oxidation level using the ROS-specific dye H2DCF-DA showed that all tested BA-pretreated mutants exhibited decreased ROS than the control when exposed to H2O2. Similarly, when mutant strains were pretreated with BA and then exposed to H2O2, there was reduced lipid peroxidation as revealed by the reduced malondialdehyde content. Furthermore, BA-pretreated mutant cells showed significantly lower apoptotic activity by decreasing DNA/nuclear fragmentation and chromatin condensation under H2O2-induced stress as determined by DAPI and acridine orange/ethidium bromide staining. In addition, BA treatment also extended the life span of antioxidant and anti-apoptotic mutants by ∼10-25% by scavenging ROS and preventing apoptotic cell death. Our overall results suggest that BA extends the chronological life span of mutant strains lacking antioxidant and anti-apoptotic genes by lowering the impact of oxidative stress, ROS levels, and apoptotic activity. These properties of BA could be further explored for its use as a valuable nutraceutical.