A recent study published in the PLOS Biology Journal discussed the recent advances in understanding how the microbiome influences aging and associated diseases.
Study: Forging the microbiome to help us live long and prosper. Image Credit: fizkes/Shutterstock.com
Background
In high-income countries, age is the primary risk factor for several diseases. Microbes colonize different sites in and on the human body, with the maximum colonization along the gastrointestinal (GI) tract. Prior research has underscored the vital role of gut microbiota in health and disease.
The effects of the microbiome on the aging process and the potential to manipulate the microbiome for promoting healthy aging remain unclear.
In the present study, the authors discussed the emerging evidence on the effects/role of the microbiome in aging and age-related diseases.
Aging and microbiome
Centenarians exhibit an increased bacterial diversity relative to younger people and are enriched for Clostridium, Parabacteroides, and Alistipes.
In line with this, many microbial metabolites are elevated in centenarians. Frailty has been linked to inter-individual differences in the gut microbiome. Older frail adults have a lower gut microbial diversity than less frail adults.
However, the causal role of microbiota in frailty is yet to be established. Aging is accompanied by an impaired immune system, leading to the expansion of microbes formerly suppressed by the immune system.
Microbiome effects on host lifespan
Studies in germ-free (GF) animal models have supported the causal role of the microbiome in determining hosts’ lifespan. Research in model systems suggests that microbiome exposure in early life is beneficial to increase lifespan.
Evidence suggests that bacterial colonization during the embryonic development of Drosophila melanogaster increases lifespan.
Nonetheless, this conflicts with the findings from GF mice, rats, or Caenorhabditis elegans that outlive conventionally raised control animals. Therefore, the detrimental effects of microbiota in late life might outweigh the potential benefits of colonization in early life.
The microbiome can reduce the lifespan of older animals. For instance, Escherichia coli accumulation in the GI of Caenorhabditis elegans can lead to age-associated death.
A study showed that antibiotic-treated mid-aged (9.5 weeks) killifish outlived untreated killifish. Interestingly, inoculating microbiota from a six-week-old killifish increased the lifespan of mid-aged groups.
Moreover, research on mouse models of progeria has shown the potential to extend lifespan through microbiome-based interventions.
Role of the microbiome in age-associated diseases
The prevalence of cancer increases with age, from less than 25 cases per 100,000 in individuals under 20 to more than 1,000 cases per 100,000 in people over 60. This trend is also observed in the prostate, colorectal, or breast cancer.
Comparisons of malignant tumors in colorectal cancer to adjacent non-malignant mucosa revealed that Fusobacterium nucleatum was significantly enriched.
Studies in mice have provided evidence of the causal role of this bacterium in colon cancer, wherein it activates the expression of oncogenic and pro-inflammatory genes and pathways promoting myeloid cell infiltration.
Further, fecal microbiota transplantation (FMT) from melanoma patients responding to immunotherapy into others led to a reduction in tumor size. The microbiome can also metabolize anti-cancer drugs to downstream metabolites with increased/decreased activity.
A study has highlighted several pathways through which the microbiome can influence type 2 diabetes or obesity phenotypes. The microbiome contributes to caloric intake by helping digest otherwise inaccessible dietary components.
It can also influence host energy expenditure by modifying host enzymatic activity and gene expression. Most cases (>95%) of Parkinson’s disease occur in adults over 50, and emerging evidence has implicated the GI tract in this disease.
Research in mice revealed the mechanisms through which the gut microbiome and brain communicate to impact the pathogenesis of Parkinson’s disease. An altered microbiota is observed in a mouse model of Parkinson’s disease with α-synuclein overexpression (ASO model).
Colonizing GF ASO mice with the gut microbiota of affected mice/humans has aggravated motor dysfunction and brain pathology.
Sex, aging, and the microbiome
Aging is distinct in males and females, with differences in lifespan, age-related diseases, and frailty. Most age-related diseases show sexual dimorphism; cancer incidence/survival is higher in females, and the incidence of several non-reproductive cancers is highly sex-biased.
Moreover, females have a higher obesity risk than males, whereas the risk of type 2 diabetes is comparable between males and females.
Males have an increased risk of Parkinson’s, but females experience severe illness. Recent studies have indicated that sex and microbiome are linked in humans. Preliminary results implicate sex hormones as mediators of this association.
Sex hormone levels are altered in GF mice compared to conventionally raised mice. In addition, circulating levels of sex hormones are associated with gut microbiota composition and diversity.
Concluding remarks
The authors summarized the existing evidence on the role of the microbiome in aging and related diseases.
Future research on aging or age-related diseases should focus on the role of the microbiome by using GF models, microbiome profiling, and controlling for associated variables.
Moreover, it will be critical to delineate how sex alters the microbiome and the downstream outcomes of age-related diseases. Overall, this emerging interdisciplinary research domain could address prevailing questions on host-microbiome interactions across the lifespan.
