Monday, December 18, 2017

BacterioFiles 321 - Escherichia Extends elegans Existence

Caenorhabditis elegans
By Bob Goldstein, UNC Chapel Hill
CC BY-SA 3.0
This episode: Bacteria with various gene knockouts help roundworms live longer and with less disease!

Download Episode (9.9 MB, 10.75 minutes)

Show notes:
News item

Journal Paper:
Han B, Sivaramakrishnan P, Lin C-CJ, Neve IAA, He J, Tay LWR, Sowa JN, Sizovs A, Du G, Wang J, Herman C, Wang MC. 2017. Microbial Genetic Composition Tunes Host Longevity. Cell 169:1249–1262.e13.

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    Episode outline:

    • Background: What more sought than elixir of youth? Or fountain
      • As old as history, epic of Gilgamesh
    • Modern science many advances in extending life expectancy
      • Sanitation, medicine, agriculture/food security
    • More promising findings to come sometime
      • Telomeres, mental health, etc
    • But low-hanging fruit has been picked
    • What’s new: Now, scientists publishing in Cell have created strains of gut bacteria that extend the healthy life of tiny roundworms!
    • Methods: Pretty hard to study in mammals
      • Bigger and more complex and longer lifespans
    • So chose nematode Caenorhabditis elegans
      • Well-understood lifespan and microbiota
      • In lab often contain only E. coli, on which they feed
    • Used set of E. coli strains with each gene knocked out one at a time (except essential genes)
      • Keio collection, resistance marker insertions
      • Grew roundworms on each of these strains to see effects, 3983 mutants
    • To avoid confusion of worms reproducing and making more worms, used mutant strain
      • Grows and reproduces normally, but embryos die at 25C
      • Look at only the desired generation and see how long it survives
    • With 68 of the mutant bacterial strains, nematodes lived longer
      • 23-35 (depending on microbe genetic background) extended by >10%
      • No common function for these genes, various different functional groups
      • 21 also extended life even when encountered as adult worms, not even exposed early
    • But how? Tested worm strains with specific age-related problems
      • In worms prone to tumors, 16 bacterial strains increased survival rate
      • In worms producing human Alzheimer’s-associated protein (amyloid beta)
        • 14 strains increase lifespan, and 12 delay loss of function
      • Overall, 13 protect against both problems
    • Some mechanisms known for longer roundworm life
      • Insulin-like growth factor, caloric restriction
      • Used worm strains with knockouts of genes related to these pathways
        • Many helpful bacteria were then unable to extend lifespan of these worms
        • Confirms relevance of mechanisms
      • Except for caloric restriction, which seemed unrelated to bacterial effects
    • Found 2 mutants that worked independently of all tested mechanisms
      • Both mutants in genes related to production of metabolite colanic acid
      • Polysaccharide secreted by some enterobacteria
      • Both mutants produced more colanic acid than usual
      • Deleting colanic acid production in these mutants removed life extension effect
        • Fully or partially, depending on strain
      • So colanic acid seems part of effect but not whole
      • Seems to help preserve mitochondrial function, works in other species too
    • Also tried colanic acid directly, independent from bacteria
      • Works just as well
      • Also helps fruit flies too
      • Doesn’t work by inhibiting bacterial growth or pathogens; actually sorta helps them
    • Applications and implications: Worth exploring for health effects beyond nematodes
      • Helpful for understanding mechanisms of aging and longevity
      • Possible clue toward probiotics or helpful chemicals
    • Clarifications if necessary: Do not try at home, bacteria or chemical
      • Not at all worked out for anything but tiny animals
      • Dose, effectiveness, timing, side effects
    • How does being in lab affect effect?
      • No comparison here of lab worms vs. wild-caught, or wild microbiota
      • Might not work the same in the wild
    • What do I think: Seems counterintuitive that knocking out genes in bacteria makes them helpful in extending life
      • Implies that bacteria were being harmful before, and then lost that ability?
      • Not quite; removing regulatory proteins that inhibit processes can give bacteria new powers
        • Like producing more colanic acid
    • Interesting interaction between bacteria and mitochondria
      • Mitochondria derived from intracellular bacteria long time ago
      • Possible that colanic acid plays some role between bacteria independent from host?
    • Lots of interesting questions to study

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