This is the revised version of the first competing renewal of a Program Project (PP) focused on investigating the role that age-related changes in autophagy play in the functional alterations and inefficient response to immunological challenges and to stress of old organisms. Autophagy is a basic catabolic pathway essential for the maintenance of cellular homeostasis, regulation of the cellular energetic balance and an integral part of the response to stress. The components of the PP are four Projects involving 6 faculty members from 5 academic departments and three Cores that provide support to the research activities of the four projects. The projects share ideas, techniques and experimental models. Completion of aims requires participation of members from several of the projects. The PPG activities are reviewed periodically by a 6-member Scientific Advisory Committee. The long-term goal of the PP remains testing the overall hypothesis that impairment in autophagy mediates the functional deterioration and the inability to orchestrate an efficient response to stressors and to immunological challenges in old organisms. Building on the novel findings of the previous period, we propose now the following specific aims: 1) to characterize the involvement of different autophagic pathways, including endosomal-microautophagy (eMI), in the cellular response to stress with the focus now on proteotoxicity, lipotoxicity and genotoxicity in liver, brain (P1), adipose tissue (P4) and immune system (P2, P3);2) to determine the impact of age-related changes in the different autophagic pathways on the immune response (P2, P3), adipose tissue homeostasis and remodeling (P4) and in the organismal resistance to stress (P1);3) to analyze the effect of different interventions that modulate the activity of different autophagic pathways on the metabolic changes associated with aging (P1, P4) and on the failure of two essential immune functions, antigen processing and presentation (P2) and T cell activation (P3). These studies will require the synergistic cooperation of groups with expertise in autophagy, dendritic cell function, T cell biology, lipid metabolism, medicinal chemistry and oxidative cellular injury. Relevance: This PP explores the novel concepts that: 1. defective autophagic function is behind the higher vulnerability to stressors of old organisms and that 2. interventions aimed at restoring or enhancing autophagy could be implemented as anti-aging strategies to prolong health-span. Our studies may ultimately lead to fundamental insights in understanding, treating or preventing the metabolic alterations and declined cognitive and immune function of elders through manipulations of the autophagic system.
This Program Project benefits from the expertise in biology of aging, immunology, metabolism, cell biology and medical chemistry contributed by the different members of the program to explore the contribution of defects in autophagy to the higher vulnerability to stressors of old organisms. We intend to perform interventions to restore or enhance autophagy in mouse models that we propose could be implemented as anti-aging strategies to prolong health-span in humans. Our studies may ultimately lead to fundamental insights in understanding, treating or preventing common diseases that affect our elders such as diabetes, dementia and opportunistic infectious diseases.
| Kaushik, Susmita; Cuervo, Ana Maria (2018) The coming of age of chaperone-mediated autophagy. Nat Rev Mol Cell Biol 19:365-381 |
| Amengual, Jaume; Guo, Liang; Strong, Alanna et al. (2018) Autophagy Is Required for Sortilin-Mediated Degradation of Apolipoprotein B100. Circ Res 122:568-582 |
| Bejarano, Eloy; Murray, John W; Wang, Xintao et al. (2018) Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging. Aging Cell :e12777 |
| Gong, Zhenwei; Tasset, Inmaculada; Diaz, Antonio et al. (2018) Humanin is an endogenous activator of chaperone-mediated autophagy. J Cell Biol 217:635-647 |
| Dowling, Samuel D; Macian, Fernando (2018) Autophagy and T cell metabolism. Cancer Lett 419:20-26 |
| Caballero, Benjamin; Wang, Yipeng; Diaz, Antonio et al. (2018) Interplay of pathogenic forms of human tau with different autophagic pathways. Aging Cell 17: |
| Toledo, Miriam; Batista-Gonzalez, Ana; Merheb, Emilio et al. (2018) Autophagy Regulates the Liver Clock and Glucose Metabolism by Degrading CRY1. Cell Metab 28:268-281.e4 |
| Walters, Ryan O; Arias, Esperanza; Diaz, Antonio et al. (2018) Sarcosine Is Uniquely Modulated by Aging and Dietary Restriction in Rodents and Humans. Cell Rep 25:663-676.e6 |
| Mocholi, Enric; Dowling, Samuel D; Botbol, Yair et al. (2018) Autophagy Is a Tolerance-Avoidance Mechanism that Modulates TCR-Mediated Signaling and Cell Metabolism to Prevent Induction of T Cell Anergy. Cell Rep 24:1136-1150 |
| Rodriguez-Muela, Natalia; Parkhitko, Andrey; Grass, Tobias et al. (2018) Blocking p62-dependent SMN degradation ameliorates spinal muscular atrophy disease phenotypes. J Clin Invest 128:3008-3023 |
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