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.

CNS Ageing in Health and Neurodegenerative Disorders

“…Mutagens, such as chemicals and radiation, can cause large chromosomal rearrangements or point mutations, which accumulate with time rendering cells more prone to genetic instability which is linked to age-related disorders [ 18 ]. Notably, genomic instability has been associated with the normal as well as the pathogenic ageing of the human brain and it may be a factor for the development of neurodegenerative diseases such as AD [ 19 ] and PD [ 20 ]. Epigenetic alterations, which are acquired modifications in gene expression including DNA histone modifications and gene silencing via non-coding RNAs, such as microRNAs [ 21 ] and methylation, mainly in CpG islands that had been associated with a shorter lifespan [ 22 ] appear more frequently in the elderly [ 23 , 24 ].…”

Natural Variation in Age-Related Dopamine Neuron Degeneration is Glutathione-Dependent and Linked to Life Span

“…The movement disorder in Parkinson’s disease (PD) results from a progressive degeneration and loss of dopamine neurons in the substantia nigra. The single biggest risk factor for developing PD is age, suggesting that aging promotes a loss of dopamine neuron health and viability (1, 2). Aging leads to a decline in molecular, cellular and physiological function that impacts brain health and homeostasis (3).…”

The influence of accelerated brain aging on coactivation pattern dynamics in Parkinson's disease

“…While the etiology and pathogenesis of PD remain elusive, aging is widely recognized as the predominant risk factor for brain degeneration (Collier et al., 2011; Phillipson, 2014). Several major contributors to PD development, including mitochondrial dysfunction, oxidative stress, neuroinflammation, and protein homeostasis disruption, overlap with molecular hallmarks in the normal brain aging process (Coleman & Martin, 2022). In addition, the extensive branching and high energy demands of dopaminergic neurons render them particularly susceptible to age‐related metabolic dysfunction (Mamelak, 2018), potentially initiating the neurodegenerative cascade in PD.…”