The new research provides the first systemic understanding of aging gut - albeit in fruit flies - and links alterations to the symbiotic, or commensal, relationship between bacteria and the absorptive cells lining the intestine to health and lifespan.
According to lead researcher Dr Heinrich Jasper, while recent research in humans has linked the composition of gut flora with diet and health in the elderly - with the list of age-related diseases associated with changes in gut bacteria including cancer, diabetes, and inflammatory bowel disease - there is no systematic understanding of how we go from having a young, healthy gut to one that is old and decrepit.
Writing in Cell, Jasper and his team provide a model for studying many of the dysfunctions that are characteristic of the aging gut - and gives credence to the growing belief that having the right balance of gut bacteria may be key to enjoying a long healthy life.
"Our study explores age-related changes in the gut that include increased oxidative stress, inflammation, impaired efficiency of the immune response, and the over-proliferation of stem cells," explained Jasper - of the Buck Institute for Research on Aging in the US. "It puts these changes into a hierarchical, causal relationship and highlights the points where we can intervene to rescue the negative results of microbial imbalance."
Microbial imbalance
Jasper and his team's research revealed that the bacterial load in fruit fly intestines increases dramatically with age, resulting in an inflammatory condition.
This imbalance is driven by chronic activation of the stress response gene FOXO (something that happens with age), which in turn suppresses the activity of a class of molecules (PGRP-SCs, homologues of PGLYRPs in humans) that regulate the immune response to bacteria.
Suppression of this immune response also deregulates signalling molecules such as Rel and NFkB, which are important to mount an effective immune response to gut bacteria.
According to Jasper, the resulting immune imbalance allows bacterial numbers to expand, triggering an inflammatory response that includes the production of free radicals, and leads to an over-proliferation of stem cells in the gut, resulting in epithelial dysplasia, a pre-cancerous state.
Jasper said the most exciting result of their study occurred when his group increased the expression of PGRP-SC in epithelial cells of the gut, which restored the microbial balance and limited stem cell proliferation. This enhancement of PGRP-SC function was sufficient to increase lifespan of flies.
"If we can understand how aging affects our commensal population – first in the fly and then in humans – our data suggest that we should be able to impact health span and life span quite strongly, because it is the management of the commensal population that is critical to the health of the organism," he said.
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Source: Cell
Volume 156, Issue 1, Pages 109-122, , doi: 10.1016/j.cell.2013.12.018
"PGRP-SC2 Promotes Gut Immune Homeostasis to Limit Commensal Dysbiosis and Extend Lifespan"
Authors: Linlin Guo, Jason Karpac, Susan L. Tran, Heinrich Jasper