Abstract
Background
Parkinson's disease (PD) results from complex interactions among environmental, genetic, and aging factors. Telomeres, which ensure chromosome stability, naturally shorten with cell division, contributing to aging and cellular senescence. However, studies investigating telomere length (TL) in PD have produced inconsistent results.
Objective
This study aims to explore the relationship between TL and PD using a unique PD‐discordant monozygotic twin design, which minimizes confounding factors such as age, gender, and genetic background. We also examined the impact of PD‐related genetic mutations on TL.
Methods
We analyzed relative telomere length (RTL) in blood samples from 29 pairs of monozygotic twins discordant for PD. Data was stratified by disease duration, and we investigated the influence of genetic variants (GBA1 and LRRK2) on RTL.
Results
No significant difference in RTL was observed between PD‐affected twins and their healthy co‐twins overall. However, twins with longer disease duration (≥8 years) showed a significant decline in RTL (0.90 ± 0.18 vs. 1.07 ± 0.24; P = 0.046), which was more pronounced with a 10‐year disease duration cutoff (0.85 ± 0.18 vs. 1.06 ± 0.22; P = 0.015). GBA1‐mutated PD twins exhibited significantly longer RTL than non‐mutated twins, a result replicated in non‐twin GBA1 carriers and extended to LRRK2 carriers.
Conclusions
Our findings suggest that aging and cellular senescence primarily drive sporadic PD, whereas genetic forms are linked to disruptions in cellular pathways, such as lysosomal or mitochondrial functions. These insights highlight the role of genetics in telomere dynamics in PD. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Keywords: aging, GBA1, LRRK2, monozygotic twins, Parkinson's disease, telomeres
Parkinson's disease (PD) is the neurodegenerative disorder‐affecting millions of people worldwide‐with the fastest growing rate (in terms of age‐standardized prevalence, disability, and deaths). 1 Although the exact cause of PD is still not fully understood, it is clear that a combination of demographic, genetic, and environmental components contributes to its development. Among these, aging is considered the most significant risk factor: incidence and prevalence increase with age, and the risk of developing PD is estimated to double every 5 to 10 years after the age of 60. 2
The relationship between aging and neurodegeneration is intricate and interconnected. Aging is the primary determinant affecting the clinical course and progression of PD, with normal aging often presenting with mild parkinsonian signs that differ from the distinctive clinical picture of PD. 3 PD arises from a lack of cellular compensatory mechanisms in vulnerable brain regions, and age‐related vulnerability is amplified by genetic susceptibility and environmental factors. Although the precise mechanisms responsible for the link between aging and PD remain unclear, it has been suggested that the gradual build‐up of cellular damage because of factors such as oxidative stress, mitochondrial dysfunction, and protein misfolding may contribute to disease pathogenesis. 4
Beside these processes, another hallmark of cell senescence is telomere shortening. Telomeres are nucleoprotein structures formed by hexameric (TTAGGG) tandem repeats and associated proteins that cap the end of each chromosome, therefore, contributing to maintain chromosome stability and genome integrity. 5 The average length of human telomeres ranges from 5 to 10 kb in somatic cells to 10 to 20 kb in germ cells. 6 , 7 , 8 However, telomere length (TL) gradually and physiologically shortens with each cell division, ultimately leading to cellular senescence and aging. 9 Indeed, TL is considered a complex trait, influenced on one hand by chromosomal loci, age, gender, and paternal age at conception, and on the other by various accelerating stressors—such as oxidative stress and inflammation—that can in turn contribute to the development of age‐related disorders (eg, cancer, cardiovascular disease, and neurodegenerative conditions, including Alzheimer's disease and PD). 10 , 11 , 12 , 13
As for PD, studies on TL have provided inconclusive, or even contradictory, results: (1) two studies, involving a low number of patients, found shorter telomeres 14 , 15 ; (2) a larger number of small studies found no significant changes in TL 13 ; and (3) the largest study so far, including 408 cases and 809 controls, found longer TL in PD patients. 16 However, this last study was recently questioned by a massive Mendelian randomization analysis based on 37 688 PD patients and 449 056 controls. 17
We report a study on monozygotic twin pairs discordant for PD, aimed at investigating the possible association of TL with PD in absence of confounding factors related to age, gender, and genetics.
Subjects and Methods
This study was approved by the local Ethics Committee (protocol code 483/18) and conducted according to the Declaration of Helsinki and the European legislation on sensitive personal data recording. All participants signed an informed consent.
Sample Collection, Clinical Assessment, and Genetic Analyses
We included 29 monozygotic twin pairs discordant for PD. Disease diagnosis was performed using the United Kingdom Brain Bank criteria 18 by neurologists expert in movement disorders at the Parkinson's Institute of Milan (https://www.parkinson.it). Collected data included sex, age at blood sample collection, age at onset (ie, when the first motor symptom was noticed by the patient), and disease duration. Clinical data accounting for the severity of symptoms (the Unified Parkinson's Disease Rating Scale [UPDRS], parts I, II, and III) and disease stage (Hoehn and Yahr [HY] stage) were collected by trained movement disorder specialists in the best on‐ and off‐therapy state (Table 1).
TABLE 1.
Demographic and clinical data of analyzed cohorts
| Variable | Healthy controls (n = 29) | Healthy co‐twins (n = 29) | PD twins (n = 29) | GBA1 PD patients (n = 30) | LRRK2 PD patients (n = 30) |
|---|---|---|---|---|---|
| Male gender, n (%) | 20 (69.0) | 20 (69.0) | 20 (69.0) | 18 (60.0) | 9 (30.0) |
| Age at sample collection, y [mean (SD)] | 62.7 ± 10.9 | 62.5 ± 10.8 | 62.5 ± 10.8 | 62.3 ± 9.1 | 62.0 ± 10.6 |
| Age at PD onset, y [mean (SD)] | – | – | 55.2 ± 10.7 | 53.0 ± 10.6 | 53.2 ± 10.8 |
| Disease duration, y [mean (SD)] | – | – | 7.3 ± 5.7 | 9.3 ± 5.6 | 8.8 ± 5.5 |
| UPDRS‐part II (score), mean (SD) | – | – | 6.8 ± 4.0 | 10.3 ± 7.5 | 9.5 ± 5.0 |
| UPDRS‐part III (score), mean (SD) | – | – | 15.3 ± 10 | 19.8 ± 9.3 | 20.1 ± 10.5 |
| Hoehn and Yahr stage, mean (SD) | – | – | 1.8 ± 0.77 | 2.3 ± 0.6 | 2.3 ± 0.5 |
Abbreviations: y, years, PD, Parkinson's disease, SD, standard deviation; UPDRS, Unified Parkinson's Disease Rating Scale.
DNA was extracted from peripheral blood using the automated Chemagic Star workstation (Hamilton, Reno, NV, USA). Zygosity was confirmed by quantitative‐fluorescent polymerase chain reaction (PCR) using the Devyser Compact v3 kit (Devyser, Hägersten, Sweden).
Whole‐exome sequencing (WES) and relative data analysis are detailed in the Supplementary Materials (Data S1). Sanger‐sequencing validation was performed only for variants identified in PD‐associated genes. Primer sequences and PCR conditions are available on request.
We included different control groups in the analysis. These groups, which closely match the twin pairs in sample size, comprised: (1) 60 non‐twin PD patients (30 with a GBA1 and 30 with a LRRK2 variant); and (2) 29 neurologically healthy subjects, all recruited at the Parkinson's Institute of Milan. 19 Their demographic and clinical characteristics are summarized in Table 1.
Relative TL Measurement
Relative TL (RTL) was measured by real‐time semi‐quantitative PCR using two assays: one specific for telomeres and the second for a single‐copy gene (human β‐globin [HBB]), as described. 20 Briefly, we used 1.6 ng of genomic DNA for each sample and performed amplifications using the SYBR Premix Ex Taq (Takara, Kusatsu, Japan) on a LightCycler 480 (Roche, Basel, Switzerland), following a touchdown thermal protocol. Assays were performed in triplicate and data were analyzed using the same threshold value. In each plate, we included the same control DNA sample as an internal reference. Average cycle threshold (Ct) and standard deviation were calculated for each amplicon in each sample. ΔCt values were determined by subtracting the average Ct of telomere from the average Ct of HBB. Control DNA ΔCt values were also calculated. RTL values were determined using the formula ΔΔCt = (sample average HBB Ct − sample average telomere Ct) − (control DNA average HBB Ct − control DNA average telomere Ct). The RTL assay was validated using a cohort of 87 individuals spanning ages from 4 months to 104 years (Data S1).
Statistical Analysis
Statistical analyses were conducted to investigate differences within and between groups. For two‐group comparisons, parametric or non‐parametric tests for paired (specifically for twins) or unpaired data were used as appropriate. General linear or regression models were built to adjust for major potential confounders (age, sex, and disease duration). Tests were 2‐tailed, and the P < 0.05 threshold was adopted to determine statistical significance. All the analyses were conducted using the R software (https://www.r-project.org/).
Results
Disease Duration Impacts on TL
To address the potential role of TL in PD, 29 monozygotic twin pairs discordant for PD diagnosis were included in the study. Table 1 shows their demographic and clinical characteristics. For all, RTL was measured in DNA extracted from total blood.
We first compared PD patients versus their healthy twins and versus a control group of age‐ and sex‐matched healthy subjects. No significant difference (0.03 [95% CI, −0.01 to 0.06]; P = 0.17) in RTL was observed between the two groups of twins. However, on average, the group of non‐twin controls exhibited a significantly higher RTL when compared to both the affected and the healthy twins (0.73 ± 0.18 vs. 0.48 ± 0.22, P < 0.001; 0.73 ± 0.18 vs. 0.51 ± 0.24, P < 0.001, respectively) (Fig. 1A).
FIG. 1.
Disease duration influences telomere length (TL) in monozygotic twins. Relative telomere length (RTL) was quantified by real‐time semi‐quantitative polymerase chain reaction (PCR) on genomic DNA extracted from total blood of Parkinson's disease (PD) and healthy twins using the SYBR Green chemistry. (A,B) Boxplots show RTL values according to the disease status or the disease duration group. Results are shown as normalized rescaled values. (C,D) Boxplots show the mean RTL ratios (calculated between the PD and the healthy twin within each pair), stratifying couples according to the disease duration of the affected twin. In all cases, boxes define the interquartile range; the central line refers to the median. *P < 0.05; ***P < 0.001; n, number of analyzed subjects. [Color figure can be viewed at wileyonlinelibrary.com]
We categorized twin cases according to median disease duration and we observed a marginal decline in RTL in patients with longer history of PD (≥8 years; for interaction, P = 0.059) (Fig. 1B). We, then, calculated the RTL ratio within each twin pair (RTL PD twin/ RTL healthy twin), to control for age, sex, genetics, and (at least partially) shared environmental factors. After stratifying pairs by median disease duration, we observed a significant reduction in the average RTL ratio in the group of patients with longer disease duration (1.07 ± 0.24 vs. 0.90 ± 0.18; P = 0.046). This result was even more significant when using a 10‐year disease duration cutoff (1.06 ± 0.22 vs. 0.85 ± 0.18; P = 0.015) (Fig. 1C,D).
RTL Is Associated with Genetic PD
We evaluated the possible impact of PD‐associated gene variations on RTL differences in our twin population. Twins were screened using WES; the variants identified in PD‐associated genes are reported in Data S1. We found clearly pathogenic variants (as defined in the ClinVar database) only in the GBA1 gene: two pairs were carriers of the p.L483P and a third one of the p.N409S variant (all at the heterozygous state).
We stratified PD twins for the presence of a GBA1 variant, and we surprisingly observed that the group of patients with a lysosomal genetic defect had a significantly longer RTL (1.64 fold‐increase) than non‐mutated cases (mean difference for paired data by GBA1 status, +0.30 [95% CI, 0.14–0.46]; P = 0.028) (Fig. 2A), suggesting an independent effect of the GBA1 status.
FIG. 2.
Pathogenic variants in Parkinson's disease (PD) genes impact on relative telomere length (RTL). Boxplots show RTL according to the mutation status (A) considering only PD twins, or (B) PD twins with additional GBA1/LRRK2 PD patients. Boxes define the interquartile range; the central line refers to the median. *P < 0.05; **P < 0.005; n, number of analyzed subjects. [Color figure can be viewed at wileyonlinelibrary.com]
To confirm this observation and mitigate sample size disparities, we measured RTL in additional 30 non‐twin PD patients carrying GBA1 variants (10 carrying p.N409S, 8 p.E365K, 5 p.L483P, 2 p.T408M, 2 p.E388K, and the remaining having p.W420C, c.IVS2+1G>A, and the RECN allele). Their inclusion in the analysis yielded consistent findings, ie mean sex‐ and age‐adjusted difference in RTL (+0.16 [95% CI, 0.06–0.26]; P = 0.002) (Fig. 2B). After accounting also for disease duration, the RTL difference between GBA1 carriers and non‐carriers remained significant (+0.14 [95% CI, 0.05–0.23]; P = 0.006).
Finally, to test the possibility that RTL is specifically associated with GBA1 variants, we measured RTL in 30 non‐twin PD patients carrying the p.G2019S variant in the LRRK2 gene, another major genetic risk factor for PD. 21 Again, we observed a significantly higher RTL (fully adjusted mean difference, +0.15 [95% CI, 0.04–0.27]; P = 0.012), therefore, suggesting that it is associated with genetic PD, independently from the defective gene (Fig. 2B).
RTL Is Not Associated with Clinical Parameters
Finally, we explored the association between RTL and clinical data accounting for the severity of symptoms and disease. In regression analysis adjusted for age, sex, disease duration, and genetic status no significant association was found with UPDRS part I, II, and III, and HY stage (data not shown).
Discussion
In this study, we investigated a cohort of monozygotic twin pairs discordant for PD, an ideal design to explore the contribution of risk factors to the disease onset, which is typical of adulthood. Such approach is advantageous as it is independent from cohort effects and allows controlling for genetics, age, sex, and most early‐life environmental exposures. 22 This is especially important when studying telomeres, given the high heritability of TL 23 , 24 and considering that telomere shortening mostly occurs during the first two decades of life, when cells rapidly divide and differentiate because of growth and development. 25 , 26
The first and obvious comparison we performed—between PD patients versus their healthy twins—revealed a substantial invariance of TL, but both groups, interestingly, displayed a significantly lower RTL compared to controls. This could indicate that healthy twins may exhibit molecular signs of PD despite the absence of clinical symptoms, consistently with findings from other twin studies. 27 , 28 Further experiments will need to confirm this quite surprising and interesting observation. We also investigated the relationship between PD duration and TL, by calculating the RTL ratio within each twin pair. In this case, we found a significant reduction in the average RTL ratio in twins with a longer disease duration, particularly in those greater than 10 years, indicating that TL might be influenced by the progression and severity of the disease.
In our endeavor to explore potential correlations of TL with other characteristics of our cohort, we stratified twin pairs based on sex, UPDRS, HY scale, smoking status, coffee consumption, presence of anxiety symptoms, and pathogenic variants in PD genes. No statistically significant associations were observed (data not shown), the only exception being the GBA1 status. Indeed, we surprisingly found that the GBA1‐mutated PD twins exhibited significantly longer RTLs compared to non‐mutated ones. We replicated this result even after the inclusion of additional non‐twin PD patients in the analysis, further supporting this finding.
Although it is well known that telomere maintenance is interconnected with autophagy 29 , 30 , 31 , 32 and possibly influenced by other compensatory telomerase activity mechanisms, we could suggest that in GBA1‐mutated PD patients the disease is primarily due to defects in the lysosomal pathway rather than cellular senescence (reflected by telomere shortening).
Our observation of a relationship between LRRK2 variants and RTL provides additional support for this hypothesis. As aging stands out as the primary risk factor for PD, it is conceivable that the sporadic form of the condition, lacking identifiable genetic defects, is predominantly influenced by cellular senescence. In contrast, genetic forms of PD may be primarily attributed to disruptions in one or more key cellular pathways, such as those involving lysosomes or mitochondria. This theory aligns with the observation that genetic PD is less affected by age, and notably, GBA1‐PD is characterized by an earlier onset compared to sporadic PD.
The evidence that PD‐related variants are associated with longer telomeres in PD adds complexity to the interpretation of the TL role in the disorder. GBA1 and LRRK2 variants are known to be significant genetic risk factors for PD, hence their presence in a substantial proportion of PD cases (up to 15% for GBA1, 1%–2%, for LRKK2) can potentially and significantly bias TL evaluation. 19 , 21 , 33 Our findings suggest that TL may not serve as a strong biomarker for PD symptoms. However, the observation on GBA1/LRRK2 mutation carriers, along with the detected telomere shortening over disease duration, shed light in the inconsistencies in the literature regarding TL and PD. 13 , 14 , 15 , 16 , 17
It is essential to recognize that our study is constrained by some limitations: (1) our twin cohort, while notably unique, is relatively small, nevertheless this is probably one of the largest studies on monozygotic twins discordant for PD reported in literature; (2) TL dynamics may differ among tissues, and blood TL, used in this study, may not fully reflect telomere changes in the brain, which is the primary disease site. However, leucocytes are easily accessible and many studies demonstrate that TL within individuals is generally strongly correlated across tissues. 34 , 35 , 36
In conclusion, we provided novel insights into the TL‐PD relationship, showing an association between disease duration and TL, nevertheless the complex interplay between genetic predisposition and environmental influences cannot be overlooked. Future studies with longitudinal sampling will be crucial to disentangle these contributing factors and clarify whether telomere dynamics directly influence disease progression or reflect broader cellular aging processes in PD.
Moreover, we highlighted, for the first time, differences between familial (genetic) and sporadic PD patients suggesting that this could mirror dissimilarities in the pathogenic mechanisms underlying the two forms of the disorder. The observation that PD‐related variants are associated with longer RTL in PD patients raises intriguing questions regarding the molecular players involved. Further investigations are warranted from one hand to elucidate the mechanisms linking these mutations, TL, and PD pathogenesis, and on the other to focus on novel therapeutic targets for this devastating disease, possibly including anti‐aging treatments already described in the literature and available on the market. 37
Author Roles
(1) Review Article: A. Conception, B. Design, C. Execution, D. Analysis; (2) Manuscript Preparation: A. Writing of the First Draft, B. Editing of the Final Version.
L.S.: 1A, 1B, 1D, 2A.
V.R.: 1B, 1C, 2A.
E.C.: 1D, 2A.
G.S.: 2B.
D.C.: 1C, 2B.
S.D.: 1A, 2A.
S.M.: 2B.
G.C.: 2B.
I.U.I.: 1C, 2B.
G.P.: 1A, 2B.
R.A.: 1A, 1B, 2A, 2B.
Financial Disclosures
I.U.I. received grants, speaking, and consultant honoraria from Medtronic, Newronika, and speaking honoraria from AbbVie. The other authors declare that there are no additional disclosures to report.
Supporting information
Data S1. Supporting Information.
Acknowledgments
We express our gratitude to all the patients and healthy control subjects who gave their consent to be part of the Genetic Biobank and, therefore, contributed to this work. This study was supported by PRIN (Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale, Grant no. 2017228L3J, coordinators S.D. and R.A.) and by the generous contribution of the “Fondazione Pezzoli per la Malattia di Parkinson,” Milan (Italy), a charitable association linked to AIP (the “Italian Association of Parkinsonians,” https://www.parkinson.it/fondazione-pezzoli.html). The “Fondazione Pezzoli per la Malattia di Parkinson” paid part of lab expenses and the salary of L.S. DNA samples belong to the “Parkinson Institute Biobank,” member of the Telethon Network of Genetic Biobanks (http://biobanknetwork.telethon.it).
Gianni Pezzoli and Rosanna Asselta contributed equally to this work.
Relevant conflicts of interest/financial disclosures: I.U.I. received grants, speaking, and consultant honoraria from Medtronic, Newronika, and speaking honoraria from AbbVie. The other authors declare that there are no additional disclosures to report.
Data Availability Statement
Data available on reasonable request from the authors.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1. Supporting Information.
Data Availability Statement
Data available on reasonable request from the authors.