Tyler JK, Johnson JE
Ann. N. Y. Acad. Sci. 2018 Jan;
The goal of the aging field is to develop novel therapeutic interventions that extend human health span and reduce the burden of age-related disease. While organismal aging is a complex, multifactorial process, a popular theory is that cellular aging is a significant contributor to the progressive decline inherent to all multicellular organisms. To explore the molecular determinants that drive cellular aging, as well as how to retard them, researchers have utilized the highly genetically tractable budding yeast Saccharomyces cerevisiae. Indeed, every intervention known to extend both cellular and organismal health span was identified in yeast, underlining the power of this approach. Importantly, a growing body of work has implicated the process of autophagy as playing a critical role in the delay of aging. This review summarizes recent reports that have identified a role for autophagy, or autophagy factors in the extension of yeast life span. These studies demonstrate (1) that yeast remains an invaluable tool for the identification and characterization of conserved mechanisms that promote cellular longevity and are likely to be relevant to humans, and (2) that the process of autophagy has been implicated in nearly all known longevity-promoting manipulations and thus represents an ideal target for interventions aimed at improving human health span.
The ultimate goal of aging research is to develop therapeutic means to extend human lifespan, while reducing susceptibility to many age-related diseases including cancer, as well as metabolic, cardiovascular and neurodegenerative disorders. However, this first requires clarification of the causes of aging, which has been greatly facilitated by the use of model organisms. In particular, the budding yeast Saccharomyces cerevisiae has been vital in the identification of conserved molecular and cellular determinants of aging and for the development of approaches to manipulate these aging determinants to extend lifespan. Past studies have shown that all means to experimentally extend lifespan result in the initiation of cellular stress responses which, in turn, increases the process of autophagy.
This review describes growing evidence in yeast that activation of the integrated stress response contributes significantly to lifespan extension. Thus, therapeutics to directly activate autophagy could be another promising approach to extend lifespan and healthspan. There are many different types of autophagy, and in order to have a better understanding of the aging process, it is crucial to know the specific autophagy pathways that need to be activated in order to extend yeast lifespan. This could then lead to the discovery of pharmaceutical and physiological regulators of these processes in yeast, which will likely have biological significance to human health and aging. It should also be noted that the impressive pace of research and discoveries being made using the yeast model organism indicate that it will continue to be a central model for aging studies in the near future.
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In order to delay aging, the process of aging must first be understood; that the aging of cells is what drives the aging of an organism. Recent aging research studies have shown that cellular aging and asymmetric cell division are intimately linked. Yeast has been the ideal model for replicative aging because it undergoes asymmetric cell division. In budding yeast, asymmetric cell division yields a mother cell and a daughter cell that are easily distinguishable under a microscope, giving scientists the opportunity to compare the two cells and further understand aging at a molecular level. Tracking the fate of the mother lineage has led to the discovery that individual mother cells have a fixed replicative lifespan, defined by the number of daughters a mother cell produces before deterioration. Although mother cells age with each division, their daughters retain the same full lifespan independent of the age of the mother. Thus, the asymmetry in cell division leads to asymmetry of aging.
In this study, Jing Yang et al. took a proteome-centric approach to explore cell division asymmetry and its connection to lifespan asymmetry in budding yeast. They found that mother-enriched proteins tend to accumulate in mother cells over time using an active sorting mechanism, a process that has been linked to aging in these cells. Mother cells age because they retain damaged, or lifespan-limiting, proteins, so that their daughters start out with a younger, ‘reset’ physiology. These observations provide a consistent picture of how asymmetric dividing of the proteome influences lifespan asymmetry, and serve as a starting point for generating new hypotheses on the mechanism of asymmetry and aging.
Studying why and how these aging-related traits happen in yeast may provide interesting avenues of future research in higher organisms. Observations from this study support the general notion that mother cells retain aging factors to themselves, enabling their daughters to rejuvenate. However, a global view of the identities of asymmetrically partitioned aging factors and the mechanism through which they influence lifespan is still lacking. Clearly, there is still more to be gained from yeast for understanding human aging, what causes it, and how it can be delayed.
Our work at the Orentreich Foundation for the Advancement of Science has proven that methionine restriction (MR) extends lifespan and has many beneficial effects on various systems in animal models. Rodent MR models have shown improved cardiovascular function, bone development, insulin sensitivity, stress tolerance, and glucose metabolism, as well as a reduction in body mass and cancer development. Some of these effects have also been documented in invertebrate organisms, such as yeast, nematodes, and fruit flies.
In order for these effects to translate to humans, it is crucial to have access to the appropriate food sources. Building on their previous research, Associate Science Director Gene Ables and Senior Scientist Jay Johnson utilized information from the US National Nutrient Database to compile a list of various food sources that contain methionine content in order to give individuals an idea of what foods are best for a low-methionine diet. It was revealed that food sources for beef contained the highest content of methionine, followed by other animal-based sources such as poultry, fish, and dairy, whereas food like nuts, vegetables, cereals, and fruit contained less methionine. According to the data found, in order to achieve MR, a person has to eat more plant-based food and less animal-based food. This supports the idea that a vegan diet, which is naturally low in methionine, could be beneficial to healthspan.