Unraveling Parkinson's Disease Neurodegeneration: Does Aging Hold the Clues?

Abstract

Aging is the greatest risk factor for Parkinson's disease (PD), suggesting that mechanisms driving the aging process promote PD neurodegeneration. Several lines of evidence support a role for aging in PD. First, hallmarks of brain aging such as mitochondrial dysfunction and oxidative stress, loss of protein homeostasis, and neuroinflammation are centrally implicated in PD development. Second, mutations that cause monogenic PD are present from conception, yet typically only cause disease following a period of aging. Third, lifespan-extending genetic, dietary, or pharmacological interventions frequently attenuate PD-related neurodegeneration. These observations support a central role for aging in disease development and suggest that new discoveries in the biology of aging could be leveraged to elucidate novel mechanisms of PD pathophysiology. A recent rapid growth in our understanding of conserved molecular pathways that govern model organism lifespan and healthspan has highlighted a key role for metabolism and nutrient sensing pathways. Uncovering how metabolic pathways involving NAD+ consumption, insulin, and mTOR signaling link to the development of PD is underway and implicates metabolism in disease etiology. Here, we assess areas of convergence between nervous system aging and PD, evaluate the link between metabolism, aging, and PD and address the potential of metabolic interventions to slow or halt the onset of PD-related neurodegeneration drawing on evidence from cellular and animal models.

Keywords: Aging; Parkinson’s disease; metabolism; mitochondria.

Fig. 1

Convergent effects of aging and Parkinson’s disease development on key biological functions. Major overlapping effects of aging and PD on mitochondrial homeostasis, protein homeostasis and inflammation are described. See text for additional details. ROS, reactive oxygen species.

Fig. 2

Similar impact of insulin/IGF-1 and mTOR pathway manipulations on aging and PD-related neurodegeneration. Impact of dietary and genetic manipulations on several key nodes throughout the insulin/IGF-1 and connected mTOR signaling pathway on aging and PD-related neurodegeneration are shown. Green boxes denote beneficial effects (i.e., delayed/attenuated aging or PD neurodegeneration) and orange boxes denote deleterious effects (i.e., accelerated aging or PD neurodegeneration). Figure was created on BioRender.com.