Aging and Age Associated Diseases

Aging and Age Associated Diseases


The Conti Group

1.Cloning Interleukin 18 (IL-18) and characterization of its role as neuro-immunomodulator.

In 1997, the Conti lab cloned interferon-gamma inducing factor, subsequently named interleukin 18 (IL-18), from the adrenal gland and demonstrated its expression in the central nervous system. Over several years, the lab demonstrated that IL-18 is a cytokine that can be produced in the central nervous system either during inflammation or stress. The distribution of its receptors in neurons throughout the brain indicates that this molecule can affect neuronal function, a hypothesis at least in part demonstrated by the Conti lab for the ability of IL-18 to regulate feeling and sickness behavior by acting on neurons of the bed nucleus of the stria terminalis. In addition, IL-18 also appears to be able to modulate neuroinflammation contributing to neuronal damage.

2.The neuroimmunology of interleukin 13 (IL-13) and its role in Parkinson’s Disease.

The Conti lab identified IL-13 and its receptor alpha 1 (IL-13R1) as factors that contribute to the onset and/or progression of Parkinson’s Disease (PD). The group demonstrated that in the brain IL-13Rα1 was exclusively expressed in dopaminergic neurons that are lost in PD and that IL-13 could be induced locally by neurons and glial cells. It was found that activation of IL-13Rα1 signaling could potentiate cellular susceptibility to otherwise non-toxic levels of reactive oxidates species. This data provided evidence that IL-13 and IL-13Rα1 can affect survival of dopaminergic neurons that are lost in PD and prompted the lab to investigate the possible implications and application of these findings. In vitro, the ability of IL-13 to potentiate oxidative-mediated damage can be inhibited by blocking either the Jak-State or the PI3 kinase-mTOR signaling activated by IL-13Rα1. Two FDA approved drugs that may be capable of this include rapamycin and ruxolitinib. Findings in the Conti lab provide a rationale for testing the effects of ruxolitinib in slowing the progression of PD. Results also indicate that future regenerative medicines for PD may need to consider developing iPSC derived neurons depleted of IL-13Rα1 which would otherwise serve as a death signal re-exposing the transplanted cells to the same vulnerability of the parental ones.

3.Central Regulation of Temperature Homeostasis and the Biology of Aging.

Age is the main risk factor for the development of neurodegenerative diseases and, as such, investigating its biology is one step towards deciphering the mechanisms of neurodegeneration. To date, the only intervention shown to slow aging is a balanced reduction of calorie intake (now known as calorie restriction, CR). CR causes a reduction in core body temperature (Tb). The Conti lab has demonstrated that lowered Tb contributes to the beneficial effects of CR. They also identified some of the molecules and neuronal circuitry that regulated Tb reduction during CR. These include hypothalamic insulin-like growth factor (IGF-1R) and the kappa opioid receptor. Ongoing investigation is aimed at identifying the genetic and the biochemical pathways that mediate the effects of temperature on longevity. We hope that these will represent targets for generating “temperature mimetics” to treat age-associated diseases including neurodegeneration.

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Select Publications

Conti, B., Sanchez-Alavez, M., Winsky-Sommerer, R., Morale, M. C., Lucero, J., Brownell, S., Fabre, V., Huitron, Resendiz, S., Henriksen, S., Zorrilla, E. P., de Lecea, L. & Bartfai, T. Transgenic mice with a reduced core body temperature have an increased life span. Science 314, 825-828 (2006).

Morrison, B. E., Marcondes, M. C., Nomura, D. K., Sanchez-Alavez, M., Sanchez-Gonzalez, A., Saar, I., Kim, K. S., Bartfai, T., Maher, P., Sugama, S. & Conti, B. Cutting Edge: IL-13Ralpha1 Expression in Dopaminergic Neurons Contributes to Their Oxidative Stress-Mediated Loss following Chronic Peripheral Treatment with Lipopolysaccharide. J Immunol 189, 5498-5502 (2012).

Conti, B. & Hansen, M. A Cool Way to Live Long. Cell 152, 671-672 (2013).

Cintron-Colon, R., Sanchez-Alavez, M., Nguyen, W., Mori, S., Gonzalez-Rivera, R., Lien, T., Bartfai, T., Aid, S., Francois, J. C., Holzenberger, M. & Conti, B. Insulin-like growth factor 1 receptor regulates hypothermia during calorie restriction. Proc Natl Acad Sci U S A 114, 9731-9736 (2017).

Aguirre, C. A., Morale, M. C., Peng, Q., Sanchez-Alavez, M., Cintrón-Colón, R., Feng, K., Fazelpour, S., Maher, P. & Conti, B. Two single nucleotide polymorphisms in IL13 and IL13RA1 from individuals with idiopathic Parkinson’s disease increase cellular susceptibility to oxidative stress. Brain Behav Immun Available online 7 April 2020 (2020).

Conti, B. Hot news about temperature and lifespan. Nature Metabolism (2022) (In press)

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Our research programs are funded primarily by grants from the National Institutes of Health (NIH). Private donations help to accelerate the progress of research through the purchase of laboratory supplies and equipment or the recruitment of additional laboratory personnel. Thank you!

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