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 genes not passed on Deleterious genes passed on Later Generations

And then I realized this in 1977 . . . Over many generations of postponed reproduction
Reproduction DeleteriousM utations

= Longer, more robust lifespan

B

Here is what I started to do in 1977: Breed fruit flies with postponed reproduction
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 metabolism Increased resistance to environmental stress Greater total reproductive output

100

Per-cent Surviving

Long Lived Females
50

Normal Females
0
0 20 40 60 80 100

Fruit Fly Age (days)

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  Let evolution do the job Evolution by

Natural Selection supply us with the answer to the question of how to build a longer-lived mammal And then reverseengineer 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 longerlived 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