Citation: Zeppa, S.D.; Agostini, D.; Ferrini, F.; Gervasi, M.; Barbieri, E.; Bartolacci, A.; Piccoli, G.; Saltarelli, R.; Sestili, P.; Stocchi, V. Interventions on Gut Microbiota for Healthy Aging. Cells 2023, 12, 34. https://doi.org/ 10.3390/cells12010034 Academic Editors: Pengfei Xu and Walter Wahli Received: 24 November 2022 Revised: 15 December 2022 Accepted: 17 December 2022 Published: 22 December 2022 Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). cells Review Interventions on Gut Microbiota for Healthy Aging Sabrina Donati Zeppa 1 , Deborah Agostini 1 , Fabio Ferrini 1, * , Marco Gervasi 1, * , Elena Barbieri 1 , Alessia Bartolacci 1 , Giovanni Piccoli 1 , Roberta Saltarelli 1 , Piero Sestili 1 and Vilberto Stocchi 2 1 Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy 2 Department of Human Science for Promotion of Quality of Life, Univerity San Raffaele, 00166 Rome, Italy * Correspondence: f.ferrini2@campus.uniurb.it (F.F.); marco.gervasi@uniurb.it (M.G.) Abstract: In recent years, the improvement in health and social conditions has led to an increase in the average lifespan. Since aging is the most important risk factor for the majority of chronic human diseases, the development of therapies and intervention to stop, lessen or even reverse various age-related morbidities is an important target to ameliorate the quality of life of the elderly. The gut microbiota, that is, the complex ecosystem of microorganisms living in the gastrointestinal tract, plays an important role, not yet fully understood, in maintaining the host’s health and homeostasis, influencing metabolic, oxidative and cognitive status; for this reason, it is also named “the forgotten endocrine organ” or “the second brain”. On the other hand, the gut microbiota diversity and richness are affected by unmodifiable factors, such as aging and sex, and modifiable ones, such as diet, pharmacological therapies and lifestyle. In this review, we discuss the changes, mostly disadvantageous, for human health, induced by aging, in microbiota composition and the effects of dietary intervention, of supplementation with probiotics, prebiotics, synbiotics, psychobiotics and antioxidants and of physical exercise. The development of an integrated strategy to implement microbiota health will help in the goal of healthy aging. Keywords: gut microbiome; aging; diet; supplements; physical activity; longevity; lifestyle 1. Introduction Aging is an inevitable biochemical process that results from the body’s limited capacity to regenerate itself. In Western civilizations, the length of life is continually increasing, but aging is frequently accompanied with an elevated risk of chronic illnesses, including cancer and cardiovascular and neurodegenerative disorders [1]. The cellular and molecular indicators for aging are genomic instability, decreased telomere length, epigenetic changes, defective nutrition sensing, loss of proteostasis, cellu- lar senescence, exhaustion of stem cells and altered intercellular communication. These hallmarks of old-age should be taken into account to set anti-aging therapies [2]. Many preventive anti-aging interventions measures, including calorie restriction, dietary inter- vention, exercise, pharmacological therapies and genetic alterations, have been proposed in several organisms [3,4]. In animal models, the reduction of mammalian targets of rapamycin (mTOR) ex- pression and the increase in sirtuin (SIR) levels through genetic engineering has been demonstrated to prolong lifespan [5]. However, its applicability in human society is hampered by difficulty in managing gene alterations. Thus, the focus of current anti-aging research is on nongenetic therapies. In humans, the most promising strategies for improving health and lifespan by lower- ing the risk of age-related diseases include a correct diet, regular exercise, secure living and working conditions and pharmacological therapy [3,4]. Cells 2023, 12, 34. https://doi.org/10.3390/cells12010034 https://www.mdpi.com/journal/cells