NOVEL METHIONINE-RELATED INTERVENTIONS THAT CONFER HEALTHSPAN BENEFITS TO YEAST AND RODENTS

Abstract Methionine restriction (MR) is one of only a few dietary manipulations known to robustly extend healthspan in mammals. Methionine-restricted rodents are up to 45% longer-lived than control-fed littermates and a number of studies suggest that humans may also benefit from MR. While a methionine-restricted human diet is technically feasible, compliance to such a regimen might not be practical or desirable. Therefore, an important goal is to identify and/or develop more facile dietary interventions, or preferably, pharmacological agents that mimic MR. Towards this end, we have made use of the yeast chronological lifespan and replicative lifespan assays, which serve as models of aging in quiescent and mitotic cells, respectively. Importantly, our lab and others have demonstrated that MR dramatically extends yeast lifespan. Here we show work aimed at developing novel MR-like interventions that extend yeast lifespan, as well as preliminary data demonstrating that such interventions significantly improve the healthspan of mice.


OLDER ADULT MALNUTRITION: A GROWING CRISIS
Meredith Whitmire 1 , 1. Matz, Blancato and Associates, Washington, District of Columbia, United States Malnutrition, a caloric or nutrient imbalance, is particularly common in the older adult population, and food insecurity is a rising concern. This paper will discuss the incidence of malnutrition and food insecurity in the older adult population. It will also discuss federal and state programs in place that work to prevent and combat malnutrition. It will provide strategies for aging network members to engage in these policy discussions.

Robert Blancato 1 , 1. Matz, Blancato & Associates, Washington, District of Columbia, United States
This paper will discuss the Older Americans Act nutrition programs and their reauthorization progress, older adult programs under the US Department of Agriculture, and advances in nutrition services being made in healthcare programs such as Medicare Advantage and managed long-term care services and supports. It will also discuss funding for federal older adult nutrition programs and their sustainability moving forward.

PROBING THE COMPLEX INTERACTIONS BETWEEN DIET, DISEASE, AND AGING Chair: Rozalyn Anderson, University of Wisconsin Madison, Madison, United States
Nutrient response pathways are conserved modifiers of longevity, and dietary restriction is the most studied intervention for slowing aging in laboratory animals. For many years it was believed that lifespan extension from dietary restriction was tightly linked to total caloric intake. Recent evidence suggests that the interaction between diet and aging is more complex than this, however, with nutrient sensing, dietary composition, and circadian components all playing a role. This symposium will delve into some of the complex biological interactions linking food intake, lifespan, and diseases of aging.

Rozalyn Anderson 1 , 1. University of Wisconsin Madison, Madison, United States
An emerging paradigm in aging research identifies metabolic dysfunction as a root cause in age-related disease vulnerability. Several diseases of aging, including diabetes, cancer, and neurodegeneration, have an established metabolic component. Our studies have focused on links between metabolic status and disease vulnerability. Caloric restriction (CR) delays aging and the onset of age-related disease in diverse species, including nonhuman primates. Molecular profiling identifies CR responsive elements in the transcriptome, proteome, and metabolome that are highly enriched for metabolic pathways and in particular mitochondrial processes. These data show that improvements in health and survival are associated with maintenance of system wide metabolic homeostasis and preserved energy metabolism among tissues. Metabolic biomarkers identified in these studies may be clinically relevant for the early identification of elevated disease risk in humans and could even be potential targets for the development of novel strategies to lower disease vulnerability as a function of age.

NOVEL METHIONINE-RELATED INTERVENTIONS THAT CONFER HEALTHSPAN BENEFITS TO YEAST AND RODENTS
Jay E. Johnson, 1 Jason D. Plummer, 1 Spike D. Postnikoff, 2 Jessica K. Tyler, 2 and Jay E. Johnson 1 , 1. Orentreich Foundation for the Advancement of Science,Cold Spring,New York,United States,2. Weill Cornell Medicine,New York,New York,United States Methionine restriction (MR) is one of only a few dietary manipulations known to robustly extend healthspan in mammals. Methionine-restricted rodents are up to 45% longer-lived than control-fed littermates and a number of studies suggest that humans may also benefit from MR. While a methionine-restricted human diet is technically Innovation in Aging, 2019, Vol. 3, No. S1 feasible, compliance to such a regimen might not be practical or desirable. Therefore, an important goal is to identify and/ or develop more facile dietary interventions, or preferably, pharmacological agents that mimic MR. Towards this end, we have made use of the yeast chronological lifespan and replicative lifespan assays, which serve as models of aging in quiescent and mitotic cells, respectively. Importantly, our lab and others have demonstrated that MR dramatically extends yeast lifespan. Here we show work aimed at developing novel MR-like interventions that extend yeast lifespan, as well as preliminary data demonstrating that such interventions significantly improve the healthspan of mice. Diet modifications are some of the most well-established aging interventions. For decades we have known that caloric restriction can dramatically increase lifespan and healthspan in organisms ranging from yeast to primates. More recently, other dietary modifications, including varying nutrient composition, have been experimentally shown to alter healthspan and lifespan. However, limitations inherent in human trials, such as diet adherence and heterogeneity of other lifestyle factors, mitigate our ability to identify the mechanisms through which diet alters healthspan and lifespan. Here, we conducted a randomized, long-term, whole-diet manipulation in a nonhuman primate, where cynomolgus macaques consumed either a Mediterranean or Western diet for 15 months. We hypothesized that individuals fed a Western diet would exhibit accelerated rates of cellular and physiological aging relative to their Mediterranean-fed counterparts. Indeed, we found that Western diet-fed animals exhibited increases in physiological measures that also increase with age, including body weight, fasting insulin, and triglycerides. Animals eating a Mediterranean diet, on the other hand, had a more sensitive and tuned autonomic response, and reduced HPA responses to an acute stress challenge. Probing further, we found that diet strongly affected monocyte function, altering the expression of 40% of expressed genes, leading to a more proinflammatory monocyte phenotype in Western diet fed animals. Experiments are underway to explore effects of diet on other markers of biological aging. Together, these data provide the first controlled evidence that Western and Mediterranean diets can alter aging-associated function in a species with clear biological similarity and relevance to humans.

Rachel Brem 1 , 1. Buck Institute for Research on Aging, Novato, California, United States
Dietary restriction (DR) extends lifespan and healthspan, by mechanisms that remain incompletely understood. To identify new genes with a role in dietary response, we developed a screening strategy harnessing genetic variation among wild fruit flies. We quantified the lifespan of lines of the Drosophila Genetic Reference Panel on protein-rich and DR diets, and mapped polymorphisms associated with diet-dependent longevity. Among the hits was CG34351/ decima, an ortholog of the mammalian GABA-receptor regulator RGS7BP. In validation experiments, pan-neuronal knockdown of decima extended lifespan and elicited repression of Drosophila insulin-like peptides, in flies on the rich diet but not on DR. Knockdown of decima in GABA neurons rescued fat storage and energy availability defects that derive from overnutrition. We propose that decima tunes signaling in these neurons upstream of the insulin pathway to rewire metabolism. These results establish decima as a determinant of the toxic effects of the rich diet in the fly. Persistent chronic conditions are among the top leading causes of death in the U.S. The majority of older adults live with two or more chronic conditions. When poorly managed, chronic conditions can result in negative psychosocial and health outcomes such as low quality of life, diminished mood, workforce withdrawal, high healthcare utilization, and disability. Fortunately, chronic disease self-management interventions show promise in reducing the negative impact of chronic conditions on health status. This symposium will highlight formative work and recent findings of community-based interventions that promote successful self-management. To start, presenter one will describe findings from four studies that constitute the formative work necessary to inform implementation of self-management interventions in community and healthcare settings. Next, presenter two will report findings from an effectiveness trial of a technology-based intervention to support hypertension self-management. Then, presenter three will describe findings on the feasibility of a Health Passport tool to promote