Over the past ten years, understanding of the physiological changes that occur as people age has greatly improved. Common mechanisms seem to support several age-related diseases, including diabetes, Parkinson’s disease and Alzheimer’s. A review of more than 400 studies of people and animal models indicates that similar processes are the basis of DNA damage, cellular senescence, or inflammation and autophagy. Over the years, studies have shown that one age-related disease can accelerate the onset of others. Until now, aging research has focused mainly on single diseases or on delaying death, meaning that the fundamental mechanisms of aging are being missed as targets for the treatment or prevention of several age-related conditions. What’s more, patients multiple diseases are being exposed to many drugs at once, often with adverse effects.
A class of drugs called geroprotectors might be able to delay the onset of concurrent age-related diseases (multimorbidity) and boost resilience. In various animal models, these drugs can ward off problems of the heart, muscles, immune system and more. However, there are various factors, such as agreeance on definitions and desired metrics, preventing these drugs from reaching the clinic. With an ever-increasing aging population and the social and health-care systems of many nations close to a crisis point, we must take a different approach. Proof-of-concept clinical studies could demonstrate the value of geroprotectors as boosters of resilience in frail patients within the next decade. If successful, such studies could catalyze efforts to advance definitions, animal models, and the characterization of measurable outcomes against which to test the drugs.
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Optimal maintenance of protein quality is critical for proper cellular functions. Protein turnover (PT) is a critical contributor to protein integrity and serves other functions, such as providing amino acids during starvation or dietary deficiency. By controlling the rates of synthesis and degradation of specific proteins, PT can also help regulate a number of physiological processes, including inflammation, immunity, cholesterol metabolism, and gene transcription. Thus, a decline in PT results not just in the accumulation of damaged and nonfunctional proteins but also has wider implications for overall healthspan and lifespan.
The mechanisms underlying lifespan extension by sulfur amino acid restriction (SAAR) are still unclear. Caloric restriction and SAAR are the two dietary interventions that have shown to extend lifespan in rodent models. A significant number of mechanistic studies suggest that caloric restriction increases PT by increasing autophagy and proteasomal functions. However, some recent studies in C. elegans suggest that lower rates of protein synthesis are associated with lifespan extension. Depending on the biological context, both an increase and a decrease in protein synthesis rates could lead to increased protein quality and contribute to lifespan extension. An increase in protein synthesis would result in less damage under conditions of oxidative stress, but would also cause energy usage. Slower protein synthesis, as a result of SAAR, would lead to a decrease of energy usage. This saved energy could then be used for other cellular functions.
Restriction of protein synthesis not only minimizes cell senescence but also increases the resistance to environmental damage, including UV radiation, oxidative stress, and starvation. These advantages, when coupled with reduced oxidative insult, as shown in previous studies, might lead to a significant improvement in hepatic proteostasis. Additional studies are required to confirm whether slower rates of protein synthesis result in improved proteostasis and whether it is a contributing factor in SAAR-induced lifespan extension.
Aging is a complex, multifactorial process that is driven by the progressive accumulation of several types of cellular damage. Functional impairment at the cellular level causes a multitude of pathologies and disorders in aged individuals. The goal of the aging field is to develop novel therapeutic interventions that extend human health span and reduce the burden of age-related disorders. To explore the molecular determinants that drive cellular aging, as well as how to slow them, researchers have utilized the highly genetically tractable budding yeast S. 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 lifespan. These studies demonstrate that yeast remains an invaluable tool for the identification and characterization of conserved mechanisms that promote cellular longevity for a number of reasons. Principal among them is the facility with which yeast can be genetically manipulated, as well as the fact that its genome has been well characterized. These features, combined with ease of growth and a short doubling time, conspire to make yeast highly amenable to a variety of high-throughput screening procedures. The use of yeast as an experimental system also allows for incomparably rapid lifespan experiments. Perhaps most importantly, since many of the pathways regulating longevity are conserved from yeast to more complex eukaryotes, including mammals, novel pharmaceutical or nutritional regulators of these processes that are identified in yeast will likely be translatable to the ultimate goal of delaying aging and improving the health span of humans. These studies also demonstrate that the process of autophagy has been implicated in nearly all known longevity-promoting manipulations and thus represent an ideal target for interventions aimed at improving human health span.
As we begin the new year, we at the Orentreich Foundation for the Advancement of Science (OFAS) are reminded of how grateful we are for our friends around the globe. We are pleased with the advances in our research this past year and for the success of our symposia series in gathering fellow scientists to share progress and ideas. We are confident that our gatherings will continue support advancement in the field of aging.
We hope you will consider investing in OFAS’s research efforts with a donation. With each day that passes, advancements are made toward the goal of extending healthy lifespan, and each day OFAS is able to be a part of this work because of friends like you.
To view our recently published 2017 Report of Directors, click here.
Thank you for your part in making OFAS’s 2017 such a success!
Norman Orentreich, MD, FACP David S. Orentreich, MD
Founder and Co-Director Co-Director
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.
You can find the full paper here.
Did you know that kidney disease is one of the major causes of early mortality, morbidity, and rising medical costs in the United States? Now, more than ever, it is crucial to find a way to delay or avoid this devastating disease. OFAS and other researchers have proven that methionine restriction extends the lifespan of several species, and although studies have been conducted on various rodent organs, the effects of MR on kidneys are not well known. A study conducted by the Orentreich Foundation’s Associate Science Director, Dr. Gene Ables, has shown that MR reduced the effects of kidney injury by suppressing inflammation and fibrosis mechanisms. This, in turn, delays the progression of kidney disease.
When protein is ingested, protein waste products are created. Healthy kidneys have millions of nephrons that filter this waste, which then leaves the body in urine. Unhealthy kidneys lose the ability to remove protein waste, and it starts to build up in the blood. One way to prevent this is by putting patients with chronic kidney disease on low-protein diets. Methionine restrictive diets offer the alternative of simulating a low-protein diet without actually reducing overall protein intake, which is done through the increased consumption of plant-based foods instead of animal-based foods. It is recommended that future studies that investigate the effects of MR on kidney function should be done with older mice in order to include the effects of age and provide more insight.