Posted 23 August 2006

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Live Discussion led by Leigh Ann Henricksen and Howard J. Federoff on 17 August 2004.

Participants: Craig Atwood, University of Wisconsin; Richard Bowen, Voyager Pharmaceutical Corporation.; Paul Coleman, University of Rochester; Keith Crutcher, University of Cincinnati; Della David, University of Zurich; Tom Fagan, Alzheimer Research Forum; Howard Federoff, University of Rochester; Leigh Ann Henricksen, University of Rochester; Emory Hill, Screen, Inc.; Tiffany F. Hughes, University of South Florida; Ruth Perez, University of Pittsburgh; Malcolm Ritter, Associated Press; Wang Danling, Tongji Medical College, Wuhan, China; Daniel Ward, Sterling Health, Akamai; Naomi Yamada, Wayne State University.

Note: The transcript has been edited for clarity and accuracy.

Richard Bowen is executive vice president of Voyager Pharmaceutical Corporation, which is currently conducting clinical trials of the leutinizing hormone suppressor leuprolide for the ability to improve cognitive function and slow the progression of Alzheimer disease (AD).

Howard Federoff
Greetings to all.

Tom Fagan
Hi Craig, Hi Howard.

Howard Federoff
Good day, Craig.

Craig Atwood
Hi Howard, all good at Rochester?

Howard Federoff
All is well and moving forward.

Craig Atwood
Hi Richard.

Keith Crutcher
Hi all...

Tom Fagan
Okay, we seem to have a quorum now and it is five past the hour, so I think we should get started. I'm Tom Fagan, filling in for Gabrielle Strobel who is on leave until next January. Maybe Leigh Ann and Howard would like to get the ball rolling by reiterating some of the premises of the chat.

Howard Federoff
We are gathered to discuss the implications of recent research in the area of caloric restriction (CR) with respect to several issues. These include the nexus between insulin and SIR2 dependent pathways, impact on cytoprotection, and AD.

Leigh Ann
There are new intersections between these pathways hitting the press almost daily.

Howard Federoff
Perhaps we should begin with a brief chat about the work that integrates NAD dependent SIR2 to FOXO. Let me be more direct: Do we have a detailed understanding of the biochemistry of CR to be able to envision therapeutic applications? Any takers?

Craig Atwood
Is it caloric restriction that we need to focus on per se or the effects that CR has on hormones?

Howard Federoff
Great question: Clearly, spanning phylogeny, we must account for the yeast mechanisms when explaining studies in higher animal.

Richard Bowen
A new theory of aging that will be published tomorrow in Gerontology puts forth a mechanism.

Howard Federoff
Richard, please share the highlights with us.

Tom Fagan
Yes, Richard, sounds interesting, do tell.

Craig Atwood
This is from Richard: We believe that aging and reproduction are regulated primarily by the hormones of the hypothalamus-pituitary-gonad (HPG) axis. The reason caloric restriction increases longevity is because it represents a hostile reproductive environment. In the study mentioned above (see Bowen and Atwood, 2004), the animals also perceived an inconsistent food supply as a hostile reproductive environment. In such an environment the HPG axis is downregulated, allowing the organism to slow its rate of aging and preserve its fertility, thereby increasing the likelihood of encountering a reproductive-friendly environment at some time in the future. There are already numerous drugs on the market that are able to accomplish this and clinical trials using one of these compounds are currently underway for the treatment of Alzheimer disease.

Richard Bowen
I can't type as fast as Craig. The title of the paper is Living and Dying for Sex.

Tom Fagan
I thought we were supposed to be discussing "clean" living.

Craig Atwood
There is evidence that it is not caloric restriction per se that increases longevity. A study done where animals were fed ad libitum every other day lived longer but their overall food intake was no different than that of the animals fed ad libitum every day (see Anson et al., 2003).

Howard Federoff
Let's explore the evidence for the HPG axis as the gate. The QOD (every other day) regimen does result in alternate physiology that is in part reflecting hormonal changes. Do you believe this is it?

Leigh Ann
These animals still maintained the benefits of CR such as reduced cholesterol. What about hormone levels? What do we know about hormones in these mice?

Craig Atwood
The organism perceives the environment (internally and externally) via the HPG axis and therefore determines when it is appropriate to reproduce. No food, not much point reproducing….

Richard Bowen
Yes, the duration of caloric restriction that causes an increase in longevity may differ between species, but studies have shown that fasting has beneficial effects on age-related parameters.

Howard Federoff
The Mark Mattson PNAS paper (see Anson et al., 2003) does make clear that some features of traditional CR are mimicked by QOD, but not all characteristics are similar. The benefit of this QOD regimen appears to be useful for cytoprotection.

Richard Bowen
It may be that an optimum duration of fasting was not reached in the Mattson study.

Craig Atwood
Mice have similar HPG hormonal changes with CR, and following menopause, as humans. There is a suppression of gonadotrophin-releasing hormone (GNRH) release, gonadotropins and sex steroids with CR, in much the same way as when an elite cyclist stops cycling.

Howard Federoff
Craig and Richard, do you know whether gonadectomized animals benefit from CR?

Craig Atwood
No, but I would assume so, given that we believe gonadotropins are signaling via the IGF-1 pathway, and hence regulate longevity.

Richard Bowen
The effect of CR on castrated animals would likely depend on whether or not the animal was castrated before or after puberty.

Howard Federoff
Explain. There is evidence that in flies, CR can still provide benefit when started much later in life.

Richard Bowen
Salmon that are castrated before "puberty" live twice as long but still developed the gnarly features of spawning salmon, but at a much slower rate.

Howard Federoff
You raise an interesting point: Do women with hypothalamic amenorrhea have any physiological changes that we would consider CR-like?

Craig Atwood
Howard, again I would assume yes but don't know of any studies/data.

Richard Bowen
That's a great question about thyroid. But I would say that if it reduces fertility, it would extend longevity unless, of course, the hyperthyroidism was so severe that it was the primary reason for death, such as arrhythmia.

Craig Atwood
Howard, what physiological changes were you thinking of regarding CR?

Howard Federoff
Lowered insulin signaling, variable but lowered thyroglobulin (TG). Thyroid status is an interesting point. One wonders whether the relationship of T3/T4 and mitochondrial uncoupling should be given greater attention.

Craig Atwood
Lowered insulin/insulin-like growth factor (IGF) signaling should slow cell division via Forkhead phosphorylation and inhibition of nuclear translocation, thereby increasing longevity.

Richard Bowen
One thing in the paper is a possible explanation for why birds and turtles live so long. Flight is a great benefit regarding predator evasion, but it comes at a significant metabolic cost, i.e., the bird might have to expend 90 calories in order to obtain 100 calories. Therefore, the bird is always somewhat calorically restricted. Only when there is an abundance of food does its HPG axis become activated and usually produce small clutches.

Tom Fagan
All, has anyone ever correlated longevity with serum hormone levels?

Howard Federoff
I'm unaware of such data—good question.

Richard Bowen
Which hormone levels? I am aware of unpublished data where rats exposed to six months of leuprolide (a suppressor of leutinizing hormone) lived 18 percent longer than did controls.

Tom Fagan
Thanks, Richard, that's interesting. Presumably, these were all fed the same diet. I wonder if leuprolide suppresses appetite?

Richard Bowen
Tom, no, at least not in the mouse. We saw increased longevity but increased weight in mice exposed to leuprolide. This was presented at the Society for Neuroscience meeting.

Craig Atwood
Tom, I think the data is mentioned in the theory paper (see Bowen and Atwood, 2004).

Howard Federoff
If we could get back to neurodegenerative disease: Do we have enough evidence to implicate dysregulation of the HPG as a goal for producing cytoprotection? Do STACs (sirtuin activators) achieve this when chronically administered? Conversely, do you buy in to the hypothesis that hyperinsulinemia without overt diabetes mellitus (DM) is a contributing risk for AD or other neurodegenerative diseases?

Richard Bowen
We believe that AD is caused by neurons reentering the cell cycle. We think that leutinizing hormone (LH) is a mitogen important for brain development early in life, but when LH increases later in life in an attempt to maintain fertility, the neurons are perceiving a fetal environment and try to divide.

Craig Atwood
And that this dysregulation of the HPG axis alters signaling to neurons (as well as all cells of the body) to promote the aberrant reentry of neurons into cell death. Maintenance of the axis at reproductive adult hormone levels (i.e., preventing the increase in gonadotropins, decrease in sex steroids, increase in activins and decrease in inhibins) would slow degeneration, since we believe these hormonal changes are driving senescence in an active manner to remove non-fertile members of the species out of the gene pool (good for the species, not for the individual!).

Howard Federoff
If this were true, then women on hormone replacement therapy (HRT) would have follicle stimulating hormone (FSH)/LH suppression and reduced AD (independent of E2 effects).

Craig Atwood
HRT, yes. The conjugated equine estrogen studies are difficult to interpret for reasons I can go into if you're interested. However, trials using 17β-estrdiol (by Sanjay Asthana) have shown a decreased incidence of AD on this hormone. Estradiol acts back negatively to suppress GNRH release and gonadotropin secretion, and therefore, sex steroid production.

Howard Federoff
The GNRH antagonist data are more relevant as the HRT involves E2 responses.

Craig Atwood
The conjugated equine estrogens (CEE) are primarily made up of estrone sulfate, which binds the estrogen receptor (ER) but acts more like a selective estrogen receptor modulator (SERM) to block signaling of the small amount of 17β-estradiol still present in the women's blood. This is why in the Women's Health Initiative (WHI) studies, they are seeing less breast cancer with the CEE and slightly more neurological problems.

Howard Federoff
Richard, are you suggesting that stem cell renewal or capacity to produce committed pools of derivatives are impaired by gonadotropins?

Richard Bowen
Pluripotent stem cells are quite able to respond appropriately to LH, but neurons permanently differentiated due to NGF are not. This results in cell dysfunction or death.

Leigh Ann
I'm not sure I follow the cell reentry argument because cell cycle arrest targets of FOXO are upregulated by SIRT1.

Richard Bowen
Leigh Ann, one of Forkhead's main functions is the regulation of the cell cycle. When phosphorylated by intermediates of the IGF pathway, it is not able to enter the nucleus. If Forkhead remains in the cytoplasm, it allows for cell division. This makes sense because a cell should not divide if there are not enough available nutrients.

Howard Federoff
Agree. What about this abortive mitosis idea in postmitotic neurons? Remember that AD begins far earlier with synaptic dysfunction than overt death. Your model must explain this feature, as well.

Craig Atwood
Howard, I am a proponent of the abortive mitosis idea, and hormone changes begin much earlier than clinical presentation of the disease.

Howard Federoff
Craig, what are the available data on the subject?

Craig Atwood
For abortive mitosis?

Howard Federoff
No, for the assertion of defined hormonal changes as causative antecedents?

Craig Atwood
Howard, I can send you a review! (This review is in press. Alzforum will post a link when it becomes available).

Leigh Ann
Richard, what are the data that neurogenic signals lead to death in a postmitotic neuron?

Craig Atwood
With regard to the abortive mitosis hypothesis, AD neurons display all the features of a cell trying to divide: polyploidy, increased mitochondria, growth hormone signaling pathways are upregulated, tau is phosphorylated, APP processing changes—all occur with cell division, during fetal brain development and during AD!

Richard Bowen
We have renamed this "dyosis" for dysfunctional mitosis.

Craig Atwood
There is a tremendous amount of evidence that hormones are linked to AD, including correlations with hormone levels, HRT decreasing the incidence and delaying the onset of the disease (see Bowen et al., 2004).

Emory Hill
HRT decreasing the incidence and delaying the onset of AD?

Craig Atwood
Emory, see my comments on CEE vs estradiol, i.e., unnatural vs. natural sex steroids.

Tom Fagan
All, what about therapeutics and lifestyle choices as a means of mimicking or attaining a CR state? Must we eat like birds? What can we do to promote longevity and prevent neurodegenerative disease?

Craig Atwood
Tom, no, we don't have to eat like birds, we just have to suppress our HPG axis hormones!

Howard Federoff
Do women with PCO (polycystic ovarian syndrome) have increased risk? After all, they have remarkably altered HPG and have increased IGF1 levels.

Richard Bowen
Howard, women with PCO have early onset of numerous age-related health problems. I doubt if they live long enough to get AD. Was that your question?

Howard Federoff
Many of them, including those I've followed, do live long enough for us to collect data.

Craig Atwood
Howard, what are your data?

Howard Federoff
Craig, I don't have a citation for you but will search.

Craig Atwood
Okay, thanks.

Howard Federoff
On therapeutics: Do sirtuin activators (STACs, e.g., resveratrol) make sense? Are we putting ourselves in a chronic low stress-response state that may make us more vulnerable over a protracted period?

Richard Bowen
Howard, on therapeutics, unfortunately I have no idea what STACs are.

Howard Federoff
Richard, these are agents that increase the activity of SIR2. What should the STACs do regarding abortive mitosis?

Richard Bowen
That is a deacetylase inhibitor, right?

Leigh Ann
The recent data indicating that p65 deacetylation of SIRT1 leads to increased death by TNFα cause one to pause and wonder if we should be so eager to modulate upregulation of SIRT1 either directly or by some other pathway.

Craig Atwood
What happens in the absence of TNFα? Does the suppression of the HPG axis in terms of inducing the same longevity benefits as CR make sense to everyone? Not all at once, now….

Richard Bowen
It makes sense to me.

Craig Atwood
Thank you, Richard.

Richard Bowen
We'll have to collaborate some time.

Howard Federoff
Your hypothesis needs to explain the other features, hormonally, cellularly and molecularly, for starters.

Craig Atwood
Have you read the theory paper? It's all in there, but I'll try to give a summary….

Howard Federoff
Given that I did not receive it until recently, no.

Tom Fagan
Craig, on HPG axis making sense, it seems that someone would have correlated HPG hormone levels with longevity (not just in mice) by now. Is that hard to do for some reason? Too costly, time-consuming, etc.?

Richard Bowen
Tom, you are correct: It has been done and the levels correlate extremely well with aging. That is, depending on your definition of aging. See the abstract Craig just pasted.

Craig Atwood
Here goes: A mechanistic understanding of aging has yet to be described; this paper puts forth a new theory that has the potential to explain aging in all sexually reproductive life forms. The theory also puts forth a new definition of aging—any change in an organism over time. This definition includes not only the changes associated with the loss of function (i.e., senescence, the commonly accepted definition of aging), but also the changes associated with the gain of function (growth and development). Using this definition, the rate of aging would be synonymous with the rate of change. The rate of change/aging is most rapid during the fetal period when organisms develop from a single cell at conception to a multicellular organism at birth. Therefore, "fetal aging" would be determined by factors regulating the rate of mitogenesis, differentiation, and cell death. We suggest that these factors also are responsible for regulating aging throughout life. Thus, whatever controls mitogenesis, differentiation. Hormones are known to regulate mitogenesis and differentiation; we propose that aging is primarily regulated by the hormones that control reproduction (hence, the Reproductive-Cell Cycle Theory of Aging). In mammals, reproduction is controlled by the hypothalamic-pituitary-gonadal (HPG) axis hormones. Longevity-inducing interventions, including caloric restriction, decrease fertility by suppressing HPG axis hormones and HPG hormones are known to affect signaling through the well-documented longevity regulating GH/IGF-1/PI3K/ Akt/Forkhead pathway. This is exemplified by genetic alterations in Caenorhabditis elegans, where homologues of the HPG axis pathways, as well as the daf-2 and daf-9 pathways, all converge on daf-16, the homologue of human Forkhead that functions in the regulation of cell cycle events. In summary, we propose that the hormones that regulate reproduction act in an antagonistic pleiotrophic manner to control aging via cell cycle signaling; promoting growth and development early.

Tom Fagan
Do you have the four-line version handy?

Craig Atwood
Here it is: In summary, we propose that the hormones that regulate reproduction act in an antagonistic pleiotrophic manner to control aging via cell cycle signaling, promoting growth and development early in life in order to achieve reproduction, but later in life, in a futile attempt to maintain reproduction, become dysregulated and drive senescence.

Howard Federoff
In your collective opinions, what critical study needs to be done to directly test the hypothesis?

Craig Atwood
They have already been done. Referenced in the theory.

Howard Federoff
All, with no alternative interpretations?

Richard Bowen
Craig, modesty is your greatest attribute.

Tom Fagan
Craig, well, I guess we can all go home, then.

Craig Atwood
Okay.

Richard Bowen
No, no, I'm having too much fun.

Howard Federoff
What about people with precocious puberty? What do you predict?

Craig Atwood
Live shorter. Puberty is very correlated with longevity.

Richard Bowen
Of course, that would not be the case if they are treated with leuprolide.

Howard Federoff
Is this borne out by data? I'm sorry, I do not know of the data—can you refer me to these papers?

Craig Atwood
…which makes sense, evolutionarily, of course. Yes, much data; staring at some now on my desk for 12 different animal species, puberty and longevity correlation of about 0.8 (see Thomas et al., 2001 and Nelson, 1988). For precocious puberty, I'd have to look, for exact references, but this is well-established in animals.

Richard Bowen
The theory also explains what regulates the onset of puberty.

Craig Atwood
Probably depends on whether they go through puberty, like the Dwarf mice which live longer, or don't go through puberty.

Tom Fagan
What about rapid aging? Has the HPG run amok in those unfortunate folks?

Howard Federoff
Progeria Werner's?

Tom Fagan
Yes, Werner's.

Richard Bowen
Isn't Werner's a problem of maintaining accurate DNA? If this is screwed up, I would think it would have an effect on cell division and vice versa. If caloric restriction works in Werner's, then the theory should hold.

Howard Federoff
Sorry, we did not have a chance to discuss STACs, SIR2, PPARγ, among others. Will have to sign off. Thanks for a stimulating lunch time—we have all, I assume, adhered to our CR!

Craig Atwood
Regulation of the HPG hormones won't stop aging, since there is still signaling through the metabolic IGF-1 pathway, but it will greatly influence longevity.

Ruth Perez
Are there differences in the effects of puberty on longevity in males and females?

Craig Atwood
Females go through puberty earlier and live longer (generally), but this is complicated.

Richard Bowen
There is a complicated answer. Females do not live longer than males if you control for height.

Leigh Ann
Thanks, all!