Microbiome and Longevity: Gut Microbes Send Signals to Host Mitochondria

The microbiome has emerged as a major determinant of the functioning of host organisms, affecting both health and disease. Here, Han et al. use the workhorse of aging research, C. elegans, to identify specific mechanisms by which gut bacteria influence mitochondrial dynamics and aging, a first step toward analogous manipulations to modulate human aging. The microbiome has emerged as a major determinant of the functioning of host organisms, affecting both health and disease. Here, Han et al. use the workhorse of aging research, C. elegans, to identify specific mechanisms by which gut bacteria influence mitochondrial dynamics and aging, a first step toward analogous manipulations to modulate human aging. Aging research has made great strides, yielding a number of possible interventional strategies aimed at extending human lifespan and healthspan—the disease-free and highly functional period of life (Kennedy et al., 2014Kennedy B.K. Berger S.L. Brunet A. Campisi J. Cuervo A.M. Epel E.S. Franceschi C. Lithgow G.J. Morimoto R.I. Pessin J.E. et al.Cell. 2014; 159: 709-713Abstract Full Text Full Text PDF PubMed Scopus (1200) Google Scholar). Yet, the path to human testing is complicated, since any strategy that involves giving drugs to healthy people is justifiably limited by a low tolerance for side effects and toxicity. Another burgeoning field in recent years is that of the gut microbiome, where a series of breakthrough studies have pointed to the complex interplay between gut residents and host biology. One reason for excitement is the possibility that the microbiome might be manipulated in ways to prevent or treat disease. Invertebrate models have proven essential for aging research, leading to the identification of many of the pathways now thought to mediate mammalian aging. Fortuitously, the C. elegans microbiome is as simple as the human microbiome is complex. Its primary constituent is its bacterial food source, which in the laboratory is generally a strain of E. coli. A few studies have implicated resident gut bacteria in the control of worm aging (Heintz and Mair, 2014Heintz C. Mair W. Cell. 2014; 156: 408-411Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar), but the range and extent of these interactions is largely unknown. In one interesting example, a diabetes drug linked to aging, metformin, has been reported to extend worm lifespan through modulation of bacterial folate metabolism (Cabreiro et al., 2013Cabreiro F. Au C. Leung K.Y. Vergara-Irigaray N. Cochemé H.M. Noori T. Weinkove D. Schuster E. Greene N.D. Gems D. Cell. 2013; 153: 228-239Abstract Full Text Full Text PDF PubMed Scopus (641) Google Scholar). In this issue of Cell, Han et al., 2017Han B. Sivaramakrishnan P. Chih-Chun J.L. Neve I.A.A. He J. Tay L.W.R. Sowa J.N. Sizovs A. Du G. Wang J. et al.Cell. 2017; 169 (this issue): 1249-1262Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar expose the interconnectedness of worms and their gut microbiota with respect to aging, screen for bacterial mutants that alter worm aging, discover that they impact a wide range of conserved worm-aging pathways, and identify a specific link between a bacterial polysaccharide and worm mitochondrial dynamics. Using a premade library of E.coli lacking individual non-essential genes, Han et al., 2017Han B. Sivaramakrishnan P. Chih-Chun J.L. Neve I.A.A. He J. Tay L.W.R. Sowa J.N. Sizovs A. Du G. Wang J. et al.Cell. 2017; 169 (this issue): 1249-1262Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar developed a screening strategy to identify specific E.coli strains that extend worm lifespan. Through this screen and a follow-up validation approach, they ultimately identify 29 bacterial mutants out of nearly 4,000 that lead to long-lived worms. Given that the goal is to extend healthspan, as well as lifespan, the mutants were also tested for their ability to prevent age-associated pathology in worm models, with nearly half prolonging the lifespan or delaying phenotypic consequences in short-lived Amyloid-β transgenic worms and more than half preventing lethality associated with a germline tumor model. Surprisingly, these mutants decorate several E. coli metabolic pathways, and epistasis analysis indicates that they can affect aging through several established longevity pathways, including mTOR, JNK, and Insulin/IGF signaling, as well as caloric restriction. Two of the bacterial mutants (Δlon and Δhns), which suppress production of the polysaccharide colanic acid (CA), were chosen for further study because they acted independently of the pathways described above. These mutants secrete high levels of CA, and supplementation of CA accompanied by wild-type bacteria is indeed sufficient to replicate their lifespan benefits (Figure 1). By analyzing a wider range of worm mutants linked to lifespan, Han et al., 2017Han B. Sivaramakrishnan P. Chih-Chun J.L. Neve I.A.A. He J. Tay L.W.R. Sowa J.N. Sizovs A. Du G. Wang J. et al.Cell. 2017; 169 (this issue): 1249-1262Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar discover that these effects are lost when the worm electron transport chain is impaired. Although CA supplementation does not significantly impact mitochondrial number or energy levels in young animals, it does promote mitochondrial fission and enhances the mitochondrial unfolded protein response under stress conditions. Both drp-1, the gene required for mitochondrial fission, and components of the mitochondrial UPR are required for lifespan extension by increased CA, leading the authors to conclude that its effects are mediated through improved mitochondrial homeostasis. Why increased mitochondrial fission in this context results in improved mitochondrial homeostasis and extended lifespan remains to be explored. However, these effects are likely evolutionarily ancient and conserved in other aging model organisms, since yeast mutants associated with extension of replication lifespan have been reported to confer increased mitochondrial fission (Yao et al., 2015Yao Y. Tsuchiyama S. Yang C. Bulteau A.L. He C. Robison B. Tsuchiya M. Miller D. Briones V. Tar K. et al.PLoS Genet. 2015; 11: e1004968Crossref PubMed Scopus (35) Google Scholar). Moreover, CA supplementation is sufficient to extend fruit fly lifespan and confer increased mitochondrial fragmentation in mammalian cells (Han et al., 2017Han B. Sivaramakrishnan P. Chih-Chun J.L. Neve I.A.A. He J. Tay L.W.R. Sowa J.N. Sizovs A. Du G. Wang J. et al.Cell. 2017; 169 (this issue): 1249-1262Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar). Among the many implications of this study, two stand out. First, since CA is produced in response to stress on the part of the bacteria, worms may have evolved response pathways that read bacterial stress in the gut and initiate response pathways as a means to offset impending adverse conditions. Intriguingly, the organelle most responsive to these signals, the mitochondria, evolved from bacteria (Andersson et al., 1998Andersson S.G. Zomorodipour A. Andersson J.O. Sicheritz-Pontén T. Alsmark U.C. Podowski R.M. Näslund A.K. Eriksson A.S. Winkler H.H. Kurland C.G. Nature. 1998; 396: 133-140Crossref PubMed Scopus (1330) Google Scholar). This case of microbiota-host co-evolution may portend findings in similar studies of mammals. Second, and of more immediate importance to aging, the findings of Han et al., 2017Han B. Sivaramakrishnan P. Chih-Chun J.L. Neve I.A.A. He J. Tay L.W.R. Sowa J.N. Sizovs A. Du G. Wang J. et al.Cell. 2017; 169 (this issue): 1249-1262Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar clearly establish that the makeup of the bacterial microbiota can influence aging in the host organism. Therefore, by identifying and seeding bacterial variants associated with healthy aging, it may be possible to enhance human longevity. In addition, the identification of small molecules like CA makes it possible to consider direct supplementation as a means to target human aging, and CA is a possible candidate already. Alongside lifestyle modification, supplements, and pharmacologic agents, Han et al., 2017Han B. Sivaramakrishnan P. Chih-Chun J.L. Neve I.A.A. He J. Tay L.W.R. Sowa J.N. Sizovs A. Du G. Wang J. et al.Cell. 2017; 169 (this issue): 1249-1262Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar place microbiome manipulation firmly in the armamentarium of strategies to target human aging, raising further exciting possibilities for improving human healthspan and lifespan. Microbial Genetic Composition Tunes Host LongevityHan et al.CellJune 15, 2017In BriefThe genetic composition of gut microbes controls the production of metabolites that impact host longevity. Full-Text PDF Open Archive