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, age-related disease in humans.

Keywords: GPCR; age-related macular degeneration; eye; photoreceptors; retina.

Fig. 1.

Death rates for men and women in the United States based on data from the US Social Security Administration. Probability of death begins to increase exponentially after the sixth decade of life (https://www.ssa.gov/).

Fig. 2.

Frequencies and changes of human debilitating conditions with age. Graphs show data for (A) cancer (1), (B) bone mass (2), (C) cardiovascular disease (3), (D) dementia (4), (E) diabetes (5), and (F) vision impairment (6). These changes are representative of physiological decline occurring in the latter decades of life.

Fig. 3.

Age-dependent changes in endocrine homeostasis. Human data were compiled for (A) prevalence of thyroid failure (16), (B) testosterone/estrogen production (17, 18), (C) melatonin production (19), and (D) human growth hormone production (20). Thyroid dysfunction increases with age alongside decreased production of testosterone, estrogen, melatonin, and growth hormone.

Fig. 4.

Prevalence of age-associated eye disorders in the US population according to age, sex, and race (6). Age is the primary risk factor for developing (A) cataracts, (B) glaucoma, (C) diabetic retinopathy, and (D) AMD.

Fig. 5.

Cellular signaling networks. Cellular signaling receptors differ in their mechanisms of activation and signal transmission, subcellular localization, and ligand binding (37). Interconnected signaling pathways converge on common effector molecules, which modulate gene expression, mitochondrial functionality, and cytoskeletal structure. Adapted with permission from ref. .

Fig. 6.

GPCR signalosome: components and actions. GPCRs constitute a large family of transmembrane proteins that transduce extracellular stimuli into intracellular signaling responses. Ligand binding to GPCRs leads to activation of heterotrimeric G alpha (G_α) proteins, which have various downstream effects on intracellular processes. Drug action on GPCRs was reviewed extensively in ref. .