Download - More SENSE talk for LA - Michael Rose
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8/14/2019 More SENSE talk for LA - Michael Rose
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Reverse EngineeringSENSE, Strategies for
Engineering NegligibleSenescence Evolutionarily
Michael R. Rose,
University of California, Irvine
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Goals for this talk
Show that you can use evolution to
deliberately slow aging in model organisms:
the scientific problem
Some discussion of the means by which this
evolutionary finding can be applied to human
patients: the evolutionary engineering
problem, or SENSE issue Today I am going to focus on the Reverse
Engineering and Genomic aspects of SENSE
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Good engineering has to be basedon correct science, such as the
correct cause of aging:
Rose and Mueller 2000
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Reproduction
Deleterious
genes not
passed on
Deleterious
genes passed
on
Later Generations
Early Life
The Timing of Reproduction Controls the Evolution of
Aging
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Reproduction
DeleteriousM
utations
= Longer, more robust lifespan
And then I realized this in 1977 . . .
Over many generations of postponed
reproduction
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Here is what I started to do in1977: Breed fruit flies with
postponed reproductionBB
OO
larval rearing
larval rearing Day 14
Day 14
Day 28, . . . , 70
Egg collectionEgg collection
Egg collectionEgg collection
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Methuselah Flies Live Longer,Better Our flies have
longer life withnormalmetabolism
Increasedresistance toenvironmentalstress
Greater totalreproductiveoutput Fruit Fly Age (days)
0 20 40 60 80 100
Per-centSurviving
Long Lived Females
NormalFemales
0
50
100
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Evolutionary Route toMethuselah
So it was natural for
New Scientist to ask for
an article about how to
go from fruit flies tohumans: 1984s The
Evolutionary Route to
Methuselah
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Proposed Methuselah Mouse I:Delayed breeding to let
evolution do the job Let Evolution byNatural Selectionsupply us with theanswer to the question
of how to build alonger-lived mammal
And then reverse-engineer its answer to
develop anti-agingtherapies for geneticallyunaltered humans
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Reverse Engineering is theKey Step So what is the evidence that we can go from a
Methuselah organism of any type backward to
figure out how to intervene more directly?
This is answered in detail in the bookMethuselah Flies
Here I will give an example to illustrate the
method
But vastly more detail is in fact already available
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Going Down One Level
Evolutionary biologists like
to focus on life-history if not
fitness itself
For almost 20 years, in our
laboratory we have chosento look inside the fly
& not just do the genes,
either
E.g. longer lived flies haveincreased starvation
resistance
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Direct Selection onPhysiology
To check theevolutionary physiologyof starvation resistance,we selected specifically
for increased starvationresistance in multiplelines, multiple times
Increasing starvation
resistance moderatelytends to increaselongevity by itself
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Going Down Another Level
With Phil Service, TimBradley, & others, we havesought the physiologicalmechanism(s) thatunderlies increased
starvation resistance inlonger-lived flies
Answer: lipid content Reverse engineering: we
can control fly lipid contentby controlling their diet
And we know that doing justthis will increase theirlongevity.
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This illustrates the generalpoint . . Starting with organisms that are evolutionary
solutions to the problem of building a longer-
lived animal, we can work out the physiology
of how to do this withoutevolution Thus we could do exactly this with a SENSE
Methuselah Mouse
Note also that a SENSE Methuselah Mousesupplies NEW information about the
pathways to tweak
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BUT THERE IS ANOTHER OPTION:GENOMIC SENSE About 75% of fly genes are also in humans,
with recognizable sequences and often
similar functions
As we already have Methuselah Flies, wehave 30-70% of what a Methuselah Mouse
would offer, and we now have genomic
bridging technologies that can take you froma fly to a mouse and on to a human
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OVERVIEW of SENSE
1. Use genomics to extend results from flies
to humans, obtaining first generation
therapies
2. At the same time, start selecting forSENSE Methuselah Mice
3. When SENSE Methuselah Mice are
available, make use of the fly-human partialsolutions and their vicissitudes to develop still
better interventions with the Methuselah Mice