Regulation of aging in yeast by glycation inhibitors

Abstract

Aging is an irreversible degenerative process characterized by a general decline in cellular metabolic activity accompanied with progressive deterioration of cellular components resulting in enhanced mortality. Although, average life expectancy has increased, it is associated with different aging related diseases such as cardiovascular diseases, cancer, diabetes and so on. Hence, there is demand of active research on aging process and aging associated diseases to make added years of older people healthy. Short lived organisms, such as yeast are excellent model for aging research, as longevity-defining genes and signaling pathways discovered in yeast have been shown to define cellular and organismal longevity in eukaryotes across phyla. Yeast displays two distinct lifespan, namely, replicative lifespan (RLS) and chronological lifespan (CLS), which serve as models for proliferating (mitotic) and non-proliferating (post-mitotic) tissues in higher eukaryotes, respectively. RLS is defined as the number of daughter cells produced by a mother cell before cell division ceases; whereas CLS is the duration of cell survival in the stationary phase. Nutrients play important role in chronological aging of yeast. Calorie restriction is associated with lifespan extension in yeast and other higher organism including C elegans, drosophila, and mouse. While, non calorie restriction in terms of glucose (2%) leads to activation of various signaling pathways such as TOR/Sch9 and RAS/AC/PKA, which stimulate cellular senescence in yeast. In addition to these factors, non calorie restriction in terms of glucose can promote formation of advanced glycation reaction products (AGEs). AGEs are formed as a result of series of non-enzymatic reactions between protein and reducing sugars. AGEs are known to affect functions of many intracellular proteins and also AGE modification of proteins results in protease resistance, which affect the protein homeostasis. Glycated proteins and aggregates are responsible for several age associated diseases like Alzheimer‘s disease, Parkinson‘s disease, familial amyloidotic polyneuropathy, amyloidotic lateral sclerosis and diabetic complications. Thus, targeting AGE formation could be a rational approach to extend the lifespan and delay aging. Therefore, thesis deals with the development of yeast as a model system to study glycation induced aging and targeting AGEs by glycation inhibitors. For that, we have studied the effect of glycation and glycation inhibitors on yeast chronological lifespan. Further, we explored the effect of presence of glycation inhibitors on AGE modification and on global proteome through proteomics approach. Lastly, we have investigated the effect of glycation inhibitors on aging responsive genes using microarray and real time PCR.