Multifactorial microbial networks shape aging and neurodegeneration

The gut microbiome, composed of trillions of microorganisms residing in the gastrointestinal tract, has emerged in the last decade as a central modifier of human health and disease. It is implicated in nutrient sensing and metabolism, immune regulation, protection against pathogens, and modulation of the nervous system. With an ever-increasing aging population, understanding the microbial regulation of host physiology is vital to promoting healthy longevity. Here we highlight key microbiome changes in aging, their associations with age-related physiological properties, and potential mechanisms of work. We discuss means of microbiome manipulation to reverse or slow down the more harmful consequences of aging, such as frailty, metabolic alterations, chronic systemic inflammation, cognitive decline, and memory loss. A special focus is dedicated to microbiome-associated metabolites such as sort-chain fatty acids and nicotinamide adenine dinucleotide+ as major drivers of microbiome-gut-brain communication. Finally, we cover key discoveries on epigenetic regulation by the gut microbiome, including DNA methylation and acetylation, histone modification, and noncoding RNA modulation, and portray the paths by which it shapes host physiology in aging. By integrating the current knowledge on microbial regulation of aging, a better understanding of the gut-brain network is being built up to propagate the development of new pro-longevity therapies.