Human aging and disease: Lessons from age-related macular degeneration

Abstract

Aging is the most significant risk factor associated with chronic disease in humans. The accumulation of genetic damage throughout life leads to a variety of biological aberrations, including disrupted protein homeostasis, metabolic dysfunction, and altered cellular signaling. Such changes ultimately result in cellular senescence, death, or transformation to uncontrolled proliferation, thereby compromising human health. Events contributing to age-dependent physiological decline also occur in the context of hormonal and metabolic changes, affecting interconnected cellular networks. This complexity often confounds the development of effective treatments for aging and age-related diseases. In contrast to monotherapy and polypharmacology, an innovative systems pharmacology approach can identify synergistic combinations of drugs that modulate distinct mechanistic nodes within a network, minimizing off-target side effects and enabling better therapeutic outcomes. G protein-coupled receptors (GPCRs) are particularly good targets for the application of systems pharmacology, because they activate different signal transduction pathways that can culminate in a common response. Here, we describe a systems pharmacology strategy for the treatment of age-related macular degeneration (AMD), a multifactorial chronic disease of the eye. By considering the retina as part of a large, interconnected network, systems pharmacology will enable the identification of combination therapies targeting GPCRs to help restore genomic, proteomic, and endocrine homeostasis. Such an approach can be advantageous in providing drug regimens for the treatment of AMD, while also having broader ramifications for ameliorating adverse effects of chronic, agerelated disease in humans.