Immunosenescence defines the changes in the immune system associated with age that are responsible for the age-dependent defects in the ability to respond to pathogens and develop effective responses to vaccination in the elderly. Both the innate and the adaptive immune system show functional defects with age, with T cells' function being specially affected. The molecular mechanisms that are responsible for defective T cell function are however not yet fully understood. Lysosomal degradation of proteins via autophagy has been shown to play a key role in maintaining normal cell homeostasis by reducing the accumulation of damaged proteins. Autophagy also plays an important role in the regulation of cell protein levels in response to extracellular signals, and has been implicated in the control of T cell homeostasis. In collaboration with P1 and P2 in this Program Project (PP), we have shown that macroautophagy and chaperone mediated autophagy are both activated in response to TCR engagement and play key roles in the regulation of the maintenance of the bioenergetics output in activated T cells and in the regulation of signaling cascades downstream of the TCR, respectively. Interestingly the activity of these pathways is reduced in T cells from aged mice and its restoration leads to improve activation-induced responses in aged T cells. Furthermore, working with P4 we have found that the activity of both pathways appears to respond to lipid and oxidative stress, both characteristic of the aging process. In this proposal we intend to elucidate the molecular mechanisms that regulate the different forms of autophagy in T cells and characterize how the age-associated decline in autophagy may determine the development of deficient T cell responses. We will also study how increased chronic pathogen, lipid and oxidative stress in aging may contribute to the decreased activity of macroautophagy and/or chaperone mediated autophagy with age. Finally, using mouse models, we will study the possibility ofrestoring autophagic activity in old rodents to improve T cell-mediated responses in vivo. Relevance: Understanding the molecular mechanism that are responsible for reduced immunity in old organisms should prove valuable in the development of new therapeutic interventions aimed at restoring normal immune function and therefore reduce morbidity and mortality in the elderly. .

Public Health Relevance

Immune system function decreases with age which translates into a reduced ability to respond to pathogens or to develop effective responses to vaccination in the elderly. The mechanisms that mediate those effects are not yet fully understood. In this proposal we will examine how the decline in the activity of autophagy with age negatively affects T cell function and will characterize the mechanism that underlie this process. We will also explore the possibility of restoring autophagy activity as a means of improving T cell function to boost immune responses to pathogens and vaccinations. These studies should be able to open new venues for the development of new therapeutic interventions aimed at restoring normal immune function and therefore reduce morbidity and mortality in the elderly.

National Institute of Health (NIH)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1)
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Albert Einstein College of Medicine
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Valdor, Rut; Mocholi, Enric; Botbol, Yair et al. (2014) Chaperone-mediated autophagy regulates T cell responses through targeted degradation of negative regulators of T cell activation. Nat Immunol 15:1046-54
Cuervo, Ana Maria; Macian, Fernando (2014) Autophagy and the immune function in aging. Curr Opin Immunol 29:97-104
Quintavalle, Cristina; Di Costanzo, Stefania; Zanca, Ciro et al. (2014) Phosphorylation-regulated degradation of the tumor-suppressor form of PED by chaperone-mediated autophagy in lung cancer cells. J Cell Physiol 229:1359-68
Morimoto, Richard I; Cuervo, Ana Maria (2014) Proteostasis and the aging proteome in health and disease. J Gerontol A Biol Sci Med Sci 69 Suppl 1:S33-8
Bejarano, Eloy; Yuste, Andrea; Patel, Bindi et al. (2014) Connexins modulate autophagosome biogenesis. Nat Cell Biol 16:401-14
Schneider, Jaime L; Cuervo, Ana Maria (2014) Autophagy and human disease: emerging themes. Curr Opin Genet Dev 26:16-23
Schneider, Jaime L; Cuervo, Ana Maria (2014) Liver autophagy: much more than just taking out the trash. Nat Rev Gastroenterol Hepatol 11:187-200
Cuervo, Ana Maria; Wong, Esther (2014) Chaperone-mediated autophagy: roles in disease and aging. Cell Res 24:92-104
Balch, William E; Sznajder, Jacob I; Budinger, Scott et al. (2014) Malfolded protein structure and proteostasis in lung diseases. Am J Respir Crit Care Med 189:96-103
Schneider, Jaime L; Suh, Yousin; Cuervo, Ana Maria (2014) Deficient chaperone-mediated autophagy in liver leads to metabolic dysregulation. Cell Metab 20:417-32

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