Review
Disentangling the Complexity of Nutrition, Frailty and Gut
Microbial Pathways during Aging: A Focus on Hippuric Acid
Andrea Ticinesi 1,2,3,* , Angela Guerra 1,2, Antonio Nouvenne 2,3, Tiziana Meschi 1,2,3 and Stefania Maggi 4
1 Department of Medicine and Surgery, University of Parma, Via Antonio Gramsci 14, 43126 Parma, Italy
2 Geriatric-Rehabilitation Department, Azienda Ospedaliero-Universitaria di Parma, Via Antonio Gramsci 14,
43126 Parma, Italy
3 Microbiome Research Hub, University of Parma, Via delle Scienze 7, 43124 Parma, Italy
4 National Research Council, Neuroscience Institute, Via Giustiniani 2, 35128 Padova, Italy
* Correspondence: andrea.ticinesi@unipr.it
Abstract: Hippuric acid (HA) is a metabolite resulting from the hepatic glycine conjugation of benzoic
acid (BA) or from the gut bacterial metabolism of phenylalanine. BA is generally produced by gut
microbial metabolic pathways after the ingestion of foods of vegetal origin rich in polyphenolic
compounds, namely, chlorogenic acids or epicatechins. It can also be present in foods, either naturally
or artificially added as a preservative. The plasma and urine HA levels have been used in nutritional
research for estimating the habitual fruit and vegetable intake, especially in children and in patients
with metabolic diseases. HA has also been proposed as a biomarker of aging, since its levels in the
plasma and urine can be influenced by the presence of several age-related conditions, including
frailty, sarcopenia and cognitive impairment. Subjects with physical frailty generally exhibit reduced
plasma and urine levels of HA, despite the fact that HA excretion tends to increase with aging.
Conversely, subjects with chronic kidney disease exhibit reduced HA clearance, with HA retention
that may exert toxic effects on the circulation, brain and kidneys. With regard to older patients with
frailty and multimorbidity, interpreting the HA levels in the plasma and urine may result particularly
challenging because HA is at the crossroads between diet, gut microbiota, liver and kidney function.
Although these considerations may not make HA the ideal biomarker of aging trajectories, the study
of its metabolism and clearance in older subjects may provide valuable information for disentangling
the complex interaction between diet, gut microbiota, frailty and multimorbidity.
Keywords: polyphenol; gut microbiota; frailty; sarcopenia; cognition; benzoic acid; diet
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