more sense talk for la - michael rose

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

more sense talk for la - michael rose

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