CR4 - Steven Spindler:
Identification of Longevity Therapeutics Using Gene-Expression Biomarkers

Tumor-associated Mortality:

• 90% of mice were dying of cancer overall.
• CR possibly reduced incidence of tumors (their growth rate and/or their growth rate) but certainly decreased mortality, and it did so rapidly in the test group.
• Older mice responded robustly (!)

Studies with Drosophila:

• short term mortality quickly responds to calorie restriction

[diversion for explanation of Hybridized Microarray Measurements of Gene Expression: I would not do this subject justice, but it involves growing single-stranded DNA using a silicon wafer to determine level of gene expression]

“Is CR-related gene expression linked to lifespan extension?” (get this slide!)

• comparison of groups of old mice (33 months) for various types of CR & various durations
• some genes took more than 8 weeks to fully change to “cancer protecting expression”, but the majority changed early on (1 or 2 weeks) for the better – a good sign
• a lifetime of CR with “control diet” for 8 weeks at the end reversed all cancer-protecting gene expression back to baseline levels (!). (so, no donuts on your deathbed)
• LIST of effects: general promotion of apotosis (anti-cancer); reduced inflammation; promotion of cardiovascular health; enhancement of protein turnover and replacement

Relationship between gene expression and CR:

• rapid gene expression changes seen with CR
• implies reciprocal relationship between gene expression changes and life/health extension and CR

Effects on Heart in Old Mice: (Dhahbi et al., J. Geront, in press)

• vascular collagen is reduced by CR in mice (why good? More collagen implies stiffness in the tissues and heart must work harder, increasing blood pressure)
• this is a slow effect, more than 8 weeks in mice

CR May “Work” in Humans:

• Vallejo nursing home study
• Kagawa Okinawan study
• Walford Biosphere CR study
• Roth Baltimore Longitudinal Study of Aging Analysis
• Ravussin study of 6 mo of CR
• Fontana-Holloszy study of human CR practicioners
• Mayo Clinic Health Letters study (5-10% weight loss reduced many markers of disease and risk factors)

CR May NOT work in Humans:

• We are not nematodes/flies/mice/dogs, etc
• CR group in NIA rhesus study showed higher mortality (CR group malnourished? Controls eating too much? Caging, depression?)
• Human demographic studies do not support an increase in longevity with BMIs below “normal” (M. Sunder, Economics & Human Biology 3, 271-295, 2005)

Is the Answer a CR Diet?

• Human CR has down sides: immune suppression, increased risk of non-cancer and non-CVD mortality, less muscle mass, subjective cold, irritability, depression, preoccupation with food, hoarding behaviors…. (first bunch from Ravussin, rest of info from book below….)
• (check out book of ‘pyschology of conscientious objectors’ – hard to find)

Longevity pharms may be efficacious even if CR does not work

• bowhead’s longevity…

How to look for drugs that mimic CR?

• Mouse studies show that supplements did nothing, only CR did.
• 86% dies of lymphoma or hematoma
• More rapid discovery of mimetics is needed without death as the endpoint
• Surrogate assay: needed, similar to anti-cancer therapies, possibly gene-expression biomarkers?

Hypothesis that gene expression biomarkers can identify CR mimetics:

• 8 weeks (begun at 22 months) of CR vs long-term CR: 70% of gene expression effects were seen in short term group
• Metformin reproduced 80% of CR effects
• 8 week CR vs Metformin – Metformin seems to be even better in results (lower risk of cancer in diabetics, extends lifespan in all subjects, reduces tumor incidence

Should we take Metformin? NO. Similar study with Rosiglidazone shows that the effects could be limited to diabetics, and late-life effects could be dismal.

GET THESE SLIDES….. very detailed and info-dense