Speaker 10: Konrad Howitz - Lifespan Extension by Plant Polyphenol Sirtuin Activators: A Case of "Xenohormesis"?

BIOMOL International - biotech research company. Investigating resveratrol and other mammalian signal transducers and assay systems. Looking for trends in basic and pharmaceutical research to find and make compounds researchers will want to work with.

SIRT-1 is closest human analog to Sir2 - which has been shown to extend lifespan in yeast.

I'm going to abbreviate resveratrol as 'R' and Sirtuin (SIRT) as 'S' in the notes below.

There is a whole bunch of different S's in humans.

Acetylation - wrapping of Histone "Tails". Controls whether DNA is expressed. The "histone code hypothesis". S's tend to keep DNA "wrapped up" - and therefore silent.

Acetylation also involved with transcription factors like p53. Wide effects...

When p53 becomes deacetylated it gets destroyed more easily, or at least becomes less active. S's seem to suppress deacetylation, improving cancer fighting ability?

Konrad shared lots of info and details on challenge is company has faced on overcome in finding compounds that measure and influence the S pathway.

Resveratrol is S activator

• R is produced by plants in response to stress (drought, heat, UV)
• R is abundant in red wine
• R suppresses tomorigenesis in mice
• R is suspected (based on French paradox and others) to have cardioprotective and neuroprotective effects.

In other words, R keeps genes "hunkered down" via S, a concrete implementation of the shift we sometimes think that CR brings about - namely shifting of resources from growth and reproduction to maintenance and repair...

Yeast results:

The equivalent of "lifespan" in yeast is number of times it can divide before crapping out.

In yeast, less food (glucose) -> more replications (= longer lifespan).

This CR lifespan extension depends on S pathway.

In presence of R, yeast divide more before crapping out (= live longer, greater max lifespan).

When give yeast R and add CR on top of that, yeast don't live any longer than just R alone, or just CR alone. Suggests CR is equivalent to S activation in yeast...

Results also show resveratrol increases lifespan in flies. CR doesn't create much further lifespan gains in flies in the presence of R in their diet.

But in flies, R seems to only result in average lifespan gains. Also, CR impacts reproductive fitness of female flies, while R doesn't. Suggest R and CR aren't exactly equivalent - R is probably not an exact CR mimetic...

Nematodes lifespan also extended by resveratrol.

Resveratrol seems to deplete fats from adipocytes

R seems to delay axon degeneration - good for brain?

R effects transcription factor - PPAR-gamma, p53, NF-Beta

CR seems to elevate SIRT1 protein expression in rat liver, brain, kidney, skeletal muscle.

SIRT1 connects to the Insulin/IGF-1 pathway via FOXOs transcription factors.

Konrad worked w/ Meredith and Paul to measure SIRT-1 expression while they were on Resveratrol. VERY preliminary data, but direct measurement in them seem to show R supplementation results in increased SIRT-1 gene expression. Looks pretty dramatic, but only one data point.

Start of VERY speculative part of talk - why have SIRT-1 pathway?

How does CR Work? Two types of models:

Passive models:

• reduce oxidative stress
• modulate glycemia and insulinemia
• Endocrine changes

• Hormesis: CR is low-intensity stressor, which activate bodies defense responses.

Resveratrol, like isoflavones, is stress response compound in plants - which go up when plant get exposed to too much UV, caterpillar attacks, temperature extremes, etc.

These polyphenol compounds could have originally been signaling molecule for stress within the plant.

Perhaps we mammals have retained ability to respond to these signals too, since we evolved from plants long back in our lineage...

Xenohormesis Hypothesis: Molecules such as plant polyphenols, produced in plants, may have effect in consumers of plant (i.e. us mammals).

Why would this be adaptive?

Speculatively: if plants you are eating are under stress, their increased polyphenol content may signal forthcoming famine conditions. It could be advantageous for you to begin to react - i.e. hunker down to prepare for the lean times to come. The effects researchers have observed from R may be just such a response...

Luigi said herbs grown w/o pesticides and in "wild conditions" (i.e. more stress) have higher polyphenol content.

Conclusions:

• S activators lead to increased lifespan in lower organisms.
• R is most potent of S activators we've found.
• Plant polyphenols like R seem to provide health benefits.
• Xenohormesis may be mechanism by which these polyphenols have their effect.