Aging eyes and the immune system – Science Magazine

A central promise of regenerative medicine is the ability to repair aged or diseased organs using stem cells (SCs). This approach will likely become an effective strategy for organ rejuvenation, holding the potential to increase human health by delaying age-related diseases (1). The successful translation of this scientific knowledge into clinical practice will require a better understanding of the basic mechanisms of aging, along with an integrated view of the process of tissue repair (1).

The advent of SC therapies, now progressing into clinical trials, has made clear the many challenges limiting the application of SCs to treat disease. Our duty, as scientists, is to anticipate such limitations and propose solutions to effectively deliver on the promise of regenerative medicine.

Degenerating tissues have difficulty engaging a regulated repair response that can support efficient cell engraftment and restoration of tissue function (2). This problem, which I encountered when trying to apply SC-based interventions to treat retinal disease, will likely be an important roadblock to the clinical application of regenerative medicine approaches in elderly patients, those most likely to benefit from such interventions. I therefore hypothesized that the inflammatory environment present in aged and diseased tissues would be a major roadblock for efficient repair and that finding immune modulators with the ability to resolve chronic inflammation and promote a prorepair environment would be an efficient approach to improve the success of SC-based therapies (2, 3).

Immune cells, as sources and targets of inflammatory signals, emerged naturally as an ideal target for intervention. I chose to focus on macrophages, which are immune cells of myeloid origin that exist in virtually every tissue of the human body and which are able to reversibly polarize into specific phenotypes, a property that is essential to coordinate tissue repair (3, 4).

If there is an integral immune modulatory component to the process of tissue repair that has evolved to support the healing of damaged tissues, then it should be possible to find strategies to harness this endogenous mechanism and improve regenerative therapies. Anchored in the idea that tissue damage responses are evolutionarily conserved (5), I started my research on this topic using the fruit fly Drosophila as a discovery system.

The fruit fly is equipped with an innate immune system, which is an important player in the process of tissue repair. Using a well-established model of tissue damage, I sought to determine which genes in immune cells are responsible for their prorepair activity. MANF (mesencephalic astrocyte-derived neurotrophic factor), a poorly characterized protein initially identified as a neurotrophic factor, emerged as a potential candidate (6). A series of genetic manipulations involving the silencing and overexpression of MANF and known interacting partners led me to the surprising discovery that, instead of behaving as a neurotrophic factor, MANF was operating as an autocrine immune modulator and that this activity was essential for its prorepair effects (2). Using a model of acute retinal damage in mice and in vitro models, I went on to show that this was an evolutionarily conserved mechanism and that MANF function could be harnessed to limit retinal damage elicited by multiple triggers, highlighting its potential for clinical application in the treatment of retinal disease (2).

Having discovered a new immune modulator that sustained endogenous tissue repair, I set out to test my initial hypothesis that this factor might be used to improve the success of SC-based therapies applied to a degenerating retina. Indeed, the low integration efficiency of replacement photoreceptors transplanted into congenitally blind mice could be fully restored to match the efficiency obtained in nondiseased mice by supplying MANF as a co-adjuvant with the transplants (2). This intervention improved restoration of visual function in treated mice, supporting the utility of this approach in the clinic (7).

Next, my colleagues and I decided to address the question of whether the immune modulatory mechanism described above was relevant for aging biology and whether we could harness its potential to extend health span. We found that MANF levels are systemically decreased in aged flies, mice, and humans. Genetic manipulation of MANF expression in flies and mice revealed that MANF is necessary to limit age-related inflammation and maintain tissue homeostasis in young organisms. Using heterochronic parabiosis, an experimental paradigm that involves the surgical joining of the circulatory systems of young and old mice, we established that MANF is one of the circulatory factors responsible for the rejuvenating effects of young blood. Finally, we showed that pharmacologic interventions involving systemic delivery of MANF protein to old mice are effective therapeutic approaches to reverse several hallmarks of tissue aging (8).

A confocal fluorescence microscope image of a giant macrophage shows MANF (mesencephalic astrocyte-derived neurotrophic factor) expression in red.

The biological process of aging is multifactorial, necessitating combined and integrated interventions that can simultaneously target several of the underlying problems (9). The potential of immune modulatory interventions as rejuvenating strategies is emerging and requires a deeper understanding of its underlying molecular and cellular mechanisms.

One expected outcome of reestablishing a regulated inflammatory response is the optimization of tissue repair capacity that naturally decreases during aging (3). Combining these interventions with SCbased therapeutics holds potential to deliver on the promise of regenerative medicine as a path to rejuvenation (1).

PHOTO: COURTESY OF J. NEVES

GRAND PRIZE WINNER

Joana Neves

Joana Neves received undergraduate degrees from NOVA University in Lisbon and a Ph.D. from the Pompeu Fabra University in Barcelona. After completing her postdoctoral fellowship at the Buck Institute for Research on Aging in California, Neves started her lab in the Instituto de Medicina Molecular (iMM) at the Faculty of Medicine, University of Lisbon in 2019. Her research uses fly and mouse models to understand the immune modulatory component of tissue repair and develop stem cellbased therapies for age-related disease.

PHOTO: COURTESY OF A. SHARMA

FINALIST

Arun Sharma

Arun Sharma received his undergraduate degree from Duke University and a Ph.D. from Stanford University. Having completed a postdoctoral fellowship at the Harvard Medical School, Sharma is now a senior research fellow jointly appointed at the Smidt Heart Institute and Board of Governors Regenerative Medicine Institute at the Cedars-Sinai Medical Center in Los Angeles. His research seeks to develop in vitro platforms for cardiovascular disease modeling and drug cardiotoxicity assessment. http://www.sciencemag.org/content/367/6483/1206.1

FINALIST

Adam C. Wilkinson

Adam C. Wilkinson received his undergraduate degree from the University of Oxford and a Ph.D. from the University of Cambridge. He is currently completing his postdoctoral fellowship at the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University, where he is studying normal and malignant hematopoietic stem cell biology with the aim of identifying new biological mechanisms underlying hematological diseases and improving the diagnosis and treatment of these disorders. http://www.sciencemag.org/content/367/6483/1206.2

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Aging eyes and the immune system - Science Magazine