The integrity of the intestinal epithelium is essential for the well-being of the organism throughout life. Alterations in the composition of the intestina microbiota have been implicated in various human disorders and are significantly correlated with measures of frailty, co-morbidity and inflammation in the elderly. However, fundamental questions remain regarding the relationships between intestinal integrity, aging, microbiome dynamics and organismal health and longevity. In preliminary work, we have shown that intestinal barrier dysfunction accompanies aging across a range of Drosophila genotypes and environmental conditions. Moreover, the age-dependent loss of intestinal integrity is tightly linked to dysbiosis of the intestinal microbiota as well as multiple markers of organismal aging, including systemic metabolic dysfunction, increased expression of immunity-related genes, and, critically, is a harbinger of death. These findings provide an important first step towards understanding the causal relationships between intestinal dysbiosis, intestinal barrier dysfunction, and organismal aging. AMP-activated protein kinase (AMPK) and the cellular recycling process of autophagy have each been linked to aging in diverse species; however, the tissue-specific mechanisms involved are poorly understood. Recently, we have shown that AMPK induces autophagy to delay the onset of intestinal barrier failure and promote longevity. These findings provide a framework to investigate how a key aging pathway (AMPK/autophagy) modulates pathophysiology to prolong healthy lifespan. Here, we propose to build upon these groundbreaking findings by exploring three broad questions: 1) What are the causal relationships between intestinal barrier dysfunction, intestinal dysbiosis, immunity gene activation and aging? 2) What are the causal relationships between intestinal barrier dysfunction, intestinal dysbiosis, systemic metabolic dysfunction and aging? 3) What are the causal relationships between AMPK/autophagy activation, microbiome dynamics, intestinal homeostasis and aging? The work described in this grant proposal will bring about fundamental knowledge towards our understanding of the molecular and cellular mechanisms of aging. At the same time, our findings may lead to new therapeutic approaches to treat age-related diseases in humans.

Public Health Relevance

Advanced age is the greatest risk factor for the prevalent diseases of developed countries: cancer, cardiovascular disease and neurodegeneration. We are using the powerful genetics of the fruit fly Drosophila to better understand the biological mechanisms of aging. The long-term goal of this research is to provide novel therapeutic targets to counteract age-related human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG049157-01A1
Application #
8963343
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Williams, John
Project Start
2015-08-01
Project End
2020-03-31
Budget Start
2015-08-01
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
$331,100
Indirect Cost
$116,100
Name
University of California Los Angeles
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Resnik-Docampo, Martin; Sauer, Vivien; Schinaman, Joseph M et al. (2018) Keeping it tight: The relationship between bacterial dysbiosis, septate junctions, and the intestinal barrier in Drosophila. Fly (Austin) 12:34-40
Clark, Rebecca I; Walker, David W (2018) Role of gut microbiota in aging-related health decline: insights from invertebrate models. Cell Mol Life Sci 75:93-101
Salazar, Anna M; Resnik-Docampo, Martin; Ulgherait, Matthew et al. (2018) Intestinal Snakeskin Limits Microbial Dysbiosis during Aging and Promotes Longevity. iScience 9:229-243
Resnik-Docampo, Martin; Koehler, Christopher L; Clark, Rebecca I et al. (2017) Tricellular junctions regulate intestinal stem cell behaviour to maintain homeostasis. Nat Cell Biol 19:52-59
Rana, Anil; Oliveira, Matheus P; Khamoui, Andy V et al. (2017) Promoting Drp1-mediated mitochondrial fission in midlife prolongs healthy lifespan of Drosophila melanogaster. Nat Commun 8:448
Clark, Rebecca I; Salazar, Anna; Yamada, Ryuichi et al. (2015) Distinct Shifts in Microbiota Composition during Drosophila Aging Impair Intestinal Function and Drive Mortality. Cell Rep 12:1656-67