Long-term fasting-induced parasympathetic and sympathetic autonomic nervous system modulation in a subgroup of the GENESIS study

Before the start of fasting, the group of 16 individuals (8 males and 8 females) had a mean age of 45 ± 11 years and a mean body mass index (BMI) of 26 ± 4 kg/m². After 11 days of fasting, participants experienced a significant reduction in body weight (75.9 ± 10.3 kg to 70.2 ± 9.4 kg; −5.7 ± 1.3 kg, p < 0.001). Systolic blood pressure decreased from 121.3 ± 15.7 mmHg to 114.4 ± 10.8 mmHg (−6.9 ± 13.4 mmHg, p = 0.04), and diastolic blood pressure did not significantly change, from 79.6 ± 8.8 mmHg to 76.1 ± 9.9 mmHg. Heart rate, as measured by electronic sphygmomanometer, increased slightly but not significantly from 67.2 ± 10.6 bpm to 69.2 ± 13.4 bpm (p = 0.52). Mental well-being improved significantly, with scores increasing from 53.4 ± 6.7 to 57.6 ± 8.5 (+4.2 ± 6.9, p = 0.029). Sleep quality, as measured by the Pittsburgh Sleep Quality Index, remained statistically unchanged (5.2 ± 2.0 to 4.9 ± 2.8; p = 0.700).

HRV recordings demonstrated high fidelity, with artifact rates consistently below 5%. We first aggregated HRV daily measurements into three broad periods (before, during, and after fasting) to reduce experimental noise (Table 1). Parasympathetic activity measured by RMSSD significantly increased from 27.16 ± 10.5 to 32.92 ± 17.65 ms after fasting compared to before (p = 0.01), suggesting enhanced vagal tone post-fasting. Sympathetic activity, reflected by the sympathetic nervous system (SNS) index, significantly decreased after fasting (p = 0.00007) indicating reduced sympathetic drive. Measures of overall heart rate variability, such as the standard deviation of NN intervals (SDNN) and the standard deviation along the line of identity of NN intervals (SD2), were not significantly modified by fasting. These findings suggest that fasting induces a pronounced shift toward parasympathetic dominance.

Table 1 HRV parameters reflecting ANS regulation during long-term fasting.

We also analysed these findings on a day-by-day basis to uncover the temporal pattern of autonomic shifts during the fasting period (Fig. 1). This detailed analysis highlights a nuanced response, with the early days of fasting marked by an increase in sympathetic cardiac activity. Additionally, the day-by-day evaluation confirms the sustained enhancement of parasympathetic control during the food reintroduction phase following fasting.

Fig. 1: Effects of long-term fasting on clinical parameters of cardiovascular function and heart rate variability as a measure of autonomic nervous system tone.figure 1

A Study design. B Changes in body weight (kg), systolic and diastolic blood pressure (mmHg), pulse (bpm), mental well-being (Warwick-Edinburgh Mental Wellbeing Scale), and sleep quality (Pittsburgh Sleep Quality Index) from baseline (D0) to the end of fasting (D11). Data are presented as boxplots showing the median and interquartile range. C The two indices PNSindex (parasympathetic nervous system index) and SNSindex (sympathetic nervous system index) evaluate parasympathetic and sympathetic cardiac activity, and the stress index (SI) cardiovascular stress. Statistical significance is from a linear-mixed model using the subject unique ID as a random effect and the timepoint as a fixed effect using R package lmerTest (*p < 0.05; **p < 0.01; ***p < 0.001). The blue area represents the fasting period, where day 1 is the first fasting day.

Mental well-being documented by the Warwick-Edinburgh Mental WellBeing Scale increased during the study from 53.4 ± 6.7 at baseline to 57.6 ± 8.5 at the end of the fasting period (p = 0.02). Quality of sleep as measured by the Pittsburgh Sleep Quality Index was statistically unchanged.

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