Reverse Engineering

SENSE, Strategies for

Engineering Negligible
Senescence Evolutionarily

Michael R. Rose,
University of California, Irvine
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
Good engineering has to be based
on correct science, such as the
correct cause of aging:

Rose and Mueller 2000
The Timing of Reproduction Controls the Evolution of
Aging

Early Life
Reproduction

X
Deleterious Deleterious
genes not genes passed
passed on on

Later Generations
And then I realized this in 1977 . . .
Over many generations of postponed
reproduction
Reproduction

DeleteriousM
utations

= Longer, more robust lifespan

 Here is what I started to do in
1977: Breed fruit flies with
postponed reproduction
B larval rearing Day 14

Egg collection

O larval rearing Day 14 Day 28, . . . , 70

Egg collection
Methuselah Flies Live Longer,
Better
 Our flies have
longer life with
normal 100

metabolism

Per-cent Surviving
Long Lived Females
 Increased
resistance to 50

environmental Normal
stress Females

 Greater total 0
reproductive 0 20 40 60 80 100
Fruit Fly Age (days)
output
Evolutionary Route to
Methuselah
 So it was natural for
New Scientist to ask for
an article about how to
go from fruit flies to
humans: 1984’s “The
Evolutionary Route to
Methuselah”
Proposed Methuselah Mouse I:
Delayed breeding to let
evolution do the job
 Let Evolution by
Natural Selection
supply us with the
answer to the question
of how to build a
longer-lived mammal
 And then reverse-
engineer its answer to
develop anti-aging
therapies for genetically
unaltered humans
Reverse Engineering is the
Key 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 book
“Methuselah Flies”
 Here I will give an example to illustrate the
method
 But vastly more detail is in fact already available
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 chosen
to look “inside” the fly
 & not just do the genes,
either
 E.g. longer lived flies have
increased starvation
resistance
Direct Selection on
Physiology
 To check the
evolutionary physiology
of starvation resistance,
we selected specifically
for increased starvation
resistance in multiple
lines, multiple times
 Increasing starvation
resistance moderately
tends to increase
longevity by itself
Going Down Another Level
 With Phil Service, Tim
Bradley, & others, we have
sought the physiological
mechanism(s) that
underlies increased
starvation resistance in
longer-lived flies
 Answer: lipid content
 Reverse engineering: we
can control fly lipid content
by controlling their diet
 And we know that doing just
this will increase their
longevity.
This illustrates the general
point . .
 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 without evolution
 Thus we could do exactly this with a SENSE
Methuselah Mouse
 Note also that a SENSE Methuselah Mouse
supplies NEW information about the
pathways to tweak
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, we
have 30-70% of what a Methuselah Mouse
would offer, and we now have genomic
bridging technologies that can take you from
a fly to a mouse and on to a human
OVERVIEW of SENSE

 1. Use genomics to extend results from flies

to humans, obtaining first generation
therapies
 2. At the same time, start selecting for
SENSE Methuselah Mice
 3. When SENSE Methuselah Mice are
available, make use of the fly-human partial
solutions and their vicissitudes to develop still
better interventions with the Methuselah Mice