Impact of aging on animal models of Parkinson's disease

Abstract

Aging is the biggest risk factor for developing Parkinson's disease (PD), the second most common neurodegenerative disorder. Several animal models have been developed to explore the pathophysiology underlying neurodegeneration and the initiation and spread of alpha-synuclein-related PD pathology, and to investigate biomarkers and therapeutic strategies. However, bench-to-bedside translation of preclinical findings remains suboptimal and successful disease-modifying treatments remain to be discovered. Despite aging being the main risk factor for developing idiopathic PD, most studies employ young animals in their experimental set-up, hereby ignoring age-related cellular and molecular mechanisms at play. Consequently, studies in young animals may not be an accurate reflection of human PD, limiting translational outcomes. Recently, it has been shown that aged animals in PD research demonstrate a higher susceptibility to developing pathology and neurodegeneration, and present with a more disseminated and accelerated disease course, compared to young animals. Here we review recent advances in the investigation of the role of aging in preclinical PD research, including challenges related to aged animal models that are limiting widespread use. Overall, current findings indicate that the use of aged animals may be required to account for age-related interactions in PD pathophysiology. Thus, although the use of older animals has disadvantages, a model that better represents clinical disease within the elderly would be more beneficial in the long run, as it will increase translational value and minimize the risk of therapies failing during clinical studies. Furthermore, we provide recommendations to manage the challenges related to aged animal models.

Distinct patterns of gene expression changes in the colon and striatum of young mice overexpressing alpha-synuclein support Parkinson Disease as a multi-system process

“…Agingrelated changes in mitochondrial and lysosomal pathways may contribute to increased disease susceptibility in aged animal models of disease. [2,69,70] While differences in the mitochondrial mass of enteric neurons from PD patients, and differences in expression of mitochondrial genes in PD colon biopsies have been previously reported [71,72], we see evidence for alterations in epithelial cells both from gene expression pro ling and respirometry in freshly isolated colon crypts. One possible functional consequence of these alterations is impaired intestinal homeostasis [73][74][75][76] resulting in reduced barrier integrity, which is seen in PD [57][58][59]61,63].…”

Age and sex differentially shape brain networks in Parkinson's disease

“…Our findings have important implications in both preclinical and clinical conditions. Most of previous studies used young animals to establish PD models, however, young animals are more resistant to PD‐related pathophysiology than old animals 45 . Therefore, animal models that better characterize clinical disease within the elderly would be more beneficial, as it will increase the translational value and attenuate the risk of failures in clinical trials 45 .…”

“…Most of previous studies used young animals to establish PD models, however, young animals are more resistant to PD‐related pathophysiology than old animals. 45 Therefore, animal models that better characterize clinical disease within the elderly would be more beneficial, as it will increase the translational value and attenuate the risk of failures in clinical trials. 45 In fact, Miller et al 46 have ever found both aging and genetic susceptibility were required for the occurrence of disease phenotypes, such as loss of tyrosine hydroxylase (TH) expression and enlarged mitochondria or Lewy‐body‐precursor inclusions using a premature aging model by expressing progerin, a truncated form of lamin A.…”

“… 45 Therefore, animal models that better characterize clinical disease within the elderly would be more beneficial, as it will increase the translational value and attenuate the risk of failures in clinical trials. 45 In fact, Miller et al 46 have ever found both aging and genetic susceptibility were required for the occurrence of disease phenotypes, such as loss of tyrosine hydroxylase (TH) expression and enlarged mitochondria or Lewy‐body‐precursor inclusions using a premature aging model by expressing progerin, a truncated form of lamin A. Because aging plays an essential role in the pathogenesis of PD, anti‐aging therapies would provide new opportunities for the development of disease‐modifying treatments for PD.…”

LRRK2-G2019S Synergizes With Ageing and Low-Grade Inflammation to Promote Gut and Peripheral Immune Cell Activation That Precede Nigrostriatal Degeneration

“…Ageing and inflammation are among the key factors that may promote neuronal dysfunction and degeneration. 2,[22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]46,102 Notably, ageing, as a multistep chronic physiological process affecting central and peripheral organ and tissue homeostasis relies on highly integrated interactions, especially neuroendocrine-immune crosstalks, both at central and peripheral levels, that may turn into a pathological setting, as a result of dysfunctional genetic/epigenetic regulatory networks, as observed in PD 46,[102][103][104] .…”