What Do These Rodents Have in Common?

Meeting Summary: Comparative Biology of Aging v0.5 “We are confronted with insurmountable opportunities” -- Walt Kelly

The Program The basic problem A recommended new mind set Stuff we don’t know yet Stuff we don’t know how to do yet What to do with $2M - $20M 8 untested hypotheses 2 missing dimensions 2 hunches 2 appraisals, one giddy, one sober A closing Pogo quote

The Basic Problem Why do disease, disability and death go up in old age? Why does this happen fast in mice, fairly fast in dogs, slower in horses, and real slow in people?

The Basic Problem (In Other Words) How does aging cause the signs of old age? What times aging?

Old Mind Set “The most important single risk factor for cancer is age.”

Recommended New Mind Set “The most important single risk factor for cancer is whether your parents were mice, dogs, or people.”

Some Stuff We Don’t Know Yet Are IMR and MRTD (and maybe “offset”) under distinct genetic regulation?

Some Stuff We Don’t Know Yet Are the factors that modulate aging rate within a species (of mammals) also involved in the much larger inter-species variations?

Some Stuff We Don’t Know Yet Are there deep evolutionary roots for the "switch" from growth to endurance?

Some Stuff We Don’t Know Yet Are there important things about aging (not diseases) that can only be learned by looking at very long lived animals? [Does Nature have to cheat to make humans?]

Some Stuff We Don’t Know How To Do Yet What do we do after we have a well analyzed zoo blot? Can we do anything intelligent with vast lists of inter-species variants? (This will soon get much worse as array data hits the fan.)

Some Stuff We Don’t Know How To Do Yet What’s the best way to test, in mammals, the hints bequeathed us from the unmammals? –The IGF and thyroid hormone stories –The hints about multi-stress resistance switches –What is daf-16 doing?

Some Strategic Questions on Which NIA May or May Not Want Free Advice We have standard species (M musculus; C elegans, D melanogaster). Do we also need standard pairs or triplets of sister species selected for differences in life history patterns? If we wanted to spend $1M/year on each of two new models for aging (not for Alzheimer's or bone or menopause or cancer or immunity or …), which two would we pick? If NIA sets $20M - $100M aside for "comparative biology", what % should go to (a) new single species studies; (b) comparisons of races and subspecies; (c) work that compares species of mammals; (d) work that compares species of unmammals.

Untested Hypotheses: “There are Age-Rate- Coherent Differences Among Mammals in... …stem cell turnover rates …cell replacement rates …repair of DNA adducts …repair of DNA breakage …removal of misfolded proteins …resistance to heavy metals, ROS damage …levels of inducible heat shock protein(s) …protein dwell time

Two Missing Dimensions (I): Not Just “How Much of It Is There?” but “Where?”

Two Missing Dimensions (II): Not Just “How Much of It Is There?” but “When?”

Two not very original Hunches The important genes evolved to switch from “Sex, now” to “hang-out,” and they still channel development either to “quick” or else to “tough” in newer phyla The important genes encode “when” rather than “what.” –(Ref: SJ Gould, Ontogeny and Phylogeny)

Current Records (Place Your Bets) Diets: 50% Single genes: 50% Dog breeding: 100% Mammalian radiation: 3000%

An Optimistic Prediction: 200 years from now, this meeting will be seen as the critical turning point in modern medicine, the first step in the exploitation of biogerontological ideas towards the development of effective preventive medicines.

A more pessimistic appraisal: “We have met the enemy and he is us*” [ - Walt Kelly] * I don’t mean “us” - I mean “them,” the legislators, peer reviewers, and scientific administrators (ret.) who now spend less than 0.01% of the NIH budget on comparative biology of aging.