This is the revised second 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 stress response of old organisms. The programmatic approach has allowed us to establish previously unknown connections between autophagy, an essential component of the proteostasis network, and key cellular processes in biology of aging such as metabolism, immune response/inflammation and the stress response. The expansion of our team of experts and the conceptual and technical maturation of the program have placed us in an ideal position to contribute to test the Geroscience hypothesis that aging is the major risk factor for common chronic diseases and that modulating processes that contribute to aging could set the basis for new interventions to ameliorate aging-related disorders. We propose to use modulation of autophagy as a way to prevent or delay proteotoxicity and proteostasis loss associated with Alzheimer?s disease and related dementias (AD/ADRD). The components of the PP are four Projects involving 8 faculty members from 6 academic departments and four Cores that provide support to the research activities of the four projects. The projects share ideas, techniques and experimental models. Completion of aims in each project requires participation of members from several of the Projects and Cores. The PP activities are reviewed periodically by the executive committee, and an internal (Einstein Faculty) and external (faculty at other institutions) Scientific Advisory Committee. The long-term goal of the PP remains testing the overall hypothesis that impairment in autophagy in elders mediates the functional deterioration and increases vulnerability to proteotoxicity associated with diseases, in this case AD. Building on the novel findings of the previous period, we propose now the following specific aims: 1) to determine the impact of AD-associated proteotoxicity on proteostasis and activity of three main autophagic pathways CMA (P1, P3), MA (P4, P3) and eMI (P1, P2, P3) in peripheral tissues (liver, adipose tissue, pancreas, skeletal muscle) (P1, P4) and the immune and hematopoietic systems (P2, P3). 2) to determine the contribution of lymph in the transference of the aging and AD-related signature of brain proteotoxicity to peripheral tissues (P1, P2, P4); 3) to determine the impact of loss of autophagy-dependent proteostasis in peripheral tissues (P1, P4) and the immune system (P3) on AD-related proteotoxicity progression and 4) to analyze the effect on AD- related proteotoxicity of genetic (P1, P3), chemical (P1, P3, P4) and dietary (P2, P3, P4) interventions that enhance/restore normal autophagy in old organisms. These studies will require the synergistic cooperation of groups with expertise in aging, AD-related proteotoxicity, autophagy, proteostasis, dendritic cell function, T cell biology, hematopoiesis, lymph, lipid and glucose metabolism, nutrient sensing, medicinal chemistry, advanced high-resolution and in vivo imaging, drug development, and data analysis and integration. Relevance: We explore the novel concept that interventions to restore/enhance autophagy could be applied as anti-aging strategies to prolong health-span and ameliorate AD-related proteotoxicity. Our studies may ultimately provide pre-clinical evidence of the value of autophagy targeting in the treatment of AD/ADRD.

Public Health Relevance

Aging has been known to be a common risk factor to the large group of age-related disorders, including Alzheimer?s disease and related dementias (AD/ADRD). However, the mechanisms by which aging increases vulnerability to the toxicity of proteins related with AD remain unknown. This Program Project aims at answering this question building in the multidisciplinary team assembled (with expertise in biology of aging, neurodegeneration, lysosomal biology, metabolism, nutrient sensing, immunology, stem cells, medicinal chemistry, drug development and advance imaging procedures), the programmatic approach and the series of tools, resources and models developed by the team in previous periods. We will analyze if the age- dependent changes in autophagy are behind the aggravating effect of aging in AD-related proteotoxicity and test if preventing autophagy deterioration with genetical, chemical and dietary intervention is beneficial in this context. Our studies may ultimately lead to fundamental insights in understanding, treating or preventing AD and other common diseases related with loss of proteostasis that affect our elders.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1)
Program Officer
Guo, Max
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Albert Einstein College of Medicine
United States
Zip Code
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
Tekirdag, Kumsal; Cuervo, Ana Maria (2018) Chaperone-mediated autophagy and endosomal microautophagy: Joint by a chaperone. J Biol Chem 293:5414-5424
Theofilas, Panos; Ehrenberg, Alexander J; Nguy, Austin et al. (2018) Probing the correlation of neuronal loss, neurofibrillary tangles, and cell death markers across the Alzheimer's disease Braak stages: a quantitative study in humans. Neurobiol Aging 61:1-12
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:

Showing the most recent 10 out of 147 publications