## 2 Materials and Methods
### Metabolomics Analyses  
NMR sample preparation was performed following standard procedures [24; 27; 28]. NMR spectra were acquired for all samples using a Bruker 600 MHz (5 mm PATXI \({}^{1}\)H-\({}^{13}\)C-\({}^{15}\)N and \({}^{2}\)H-decoupling probe including a z-axis gradient coil) equipped with an automatic refrigerated sample changer (SampleJet, Bruker BioSpin, Billerica, MA, USA). Temperature  
\begin{table}
\begin{tabular}{c c c c c c} \hline \hline \multirow{2}{*}{**Cohort**} & \multirow{2}{*}{**Tot**} & \multirow{2}{*}{**N\({}^{\circ}\)**} & \multirow{2}{*}{**F/Tot**} & **Mean Age F** & **Mean Age M** \\  & & & & **(Max Mix)** & **(Max Min)** \\ \hline \multirow{2}{*}{Hs} & \multirow{2}{*}{118} & UNIBO (39) & \multirow{2}{*}{54/118} & \multirow{2}{*}{66.7 (82.5; 52)} & \multirow{2}{*}{68.2 (85; 49)} \\  & & UMG-GOE (79) & & & \\ \multirow{2}{*}{Cent} & \multirow{2}{*}{57} & UNIBO (39) & \multirow{2}{*}{39/57} & \multirow{2}{*}{105.2 (112.3; 100)} & \multirow{2}{*}{102.9 (106.3; 100)} \\  & & UNIBO (39) & & & \\ \multirow{2}{*}{Sib} & \multirow{2}{*}{199} & AUSL-ISNB (93) & \multirow{2}{*}{115/199} & \multirow{2}{*}{59.8 (90; 23)} & \multirow{2}{*}{59.2 (84; 23)} \\  & & SAS (106) & & & \\ \multirow{2}{*}{dn\({}^{2}\)PD} & \multirow{2}{*}{233} & UMG-GOE (228) & \multirow{2}{*}{109/233} & \multirow{2}{*}{65.1 (84; 29)} & \multirow{2}{*}{64.8 (87; 39)} \\  & & SAS (5) & & & \\ \multirow{2}{*}{advPD} & \multirow{2}{*}{22} & UMG-GOE (22) & \multirow{2}{*}{7/22} & \multirow{2}{*}{66.7 (77; 52)} & \multirow{2}{*}{70.0 (84; 59)} \\ \hline \hline \end{tabular}  
* HS: healthy subjects; Cent: centenarians; CentOs: centenarians’ offspring; Sib: siblings; dn2 PD: de novo drug-naive PD patients; advPD: advanced PD patients under dopaminergic treatment; UNIBO: Alma Mater Studiorum, Universita di Bologna (IT); UMG-GOE: Universitaetsmedizin Goettingen, Georg-August-Universitaet Goettingen, Stiftung Oeferfellichen Rechts (DE); AUSL-ISNB: Azizenda Unita’ Sanitaria Locale Di Bologna (IT); SAS: Servicio Andaluz De Salud (ES); N\({}^{\circ}\): number of subjects per cohort; F: females; M: males.  
\end{table}
Table 1: Design and characteristics of the cohorts included in the study.  
\begin{table}
\begin{tabular}{c c c c c c} \hline \hline  & \multicolumn{2}{c}{**dn\({}^{2}\)PD**} & \multicolumn{2}{c}{**advPD**} & \\  & **Mean** & **sd** & **Mean** & **sd** & \(\mathbf{p}\)**-Value** \\ \hline age & 65.24 & 10.09 & 68.95 & 7.33 & 0.11 \\ Hoehn and Yahr Scale & 1.51 & 1.07 & 3.13 & 0.60 & 4.52 \(\times\)\(10^{-10}\) \\ UPDRS I & 1.63 & 1.76 & 5.05 & 3.10 & 2.74 \(\times\)\(10^{-10}\) \\ UPDRS II & 6.83 & 5.80 & 19.45 & 6.66 & 1.98 \(\times\)\(10^{-15}\) \\ UPDRS III & 17.42 & 13.92 & 34.41 & 15.77 & 1.11 \(\times\)\(10^{-5}\) \\ UPDRS IV & 0.62 & 1.39 & 5.15 & 4.22 & 2.89 \(\times\)\(10^{-18}\) \\ UPDRS sum & 25.57 & 20.28 & 62.10 & 22.08 & 2.75 \(\times\)\(10^{-11}\) \\ Duration of the disease (years) & RD & RD & 9.32 & 2.78 & / \\ BMI & 27.18 & 4.79 & 25.95 & 3.72 & 0.28 \\ \hline \hline \end{tabular}  
* RD: Recently diagnosed.  
\end{table}
Table 2: Characteristics of PD patients and severity scores. Total UPDRS score includes various items contributing to four subscales: (I) mutation, behavior, and mood; (II) activities of daily living; (III) motor symptoms; and (IV) complications of therapy.  
was equilibrated using a BTO 2000 thermocouple at 310 K keeping each serum sample for 5 min inside the probe before the measurement.  
Each serum sample was analyzed using a NOESY 1D presat (noeysgppr1d.comp; Bruker BioSpin) pulse sequence using 32 scans, 98,304 data points, a spectral width of 18,028 Hz, an acquisition time of 2.7 s, a relaxation delay of 4 s, and a mixing time of 0.01 s and suppressing the water peak at 4.702 ppm.