Summary

Leigh Ann Henricksen and Howard J. Federoff led this live discussion on 17 August 2004. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

Transcript:

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!

 

Background

Background Text

 

By Leigh Ann Henricksen and Howard J. Federoff
University of Rochester School of Medicine & Dentistry, Dept. of Neurology, Center for Aging and Developmental Biology, 601 Elmwood Ave., Rochester, NY 14624, USA.

For many, growing old seems inevitable. Aging is the result of a lifetime of accumulated use and attendant damage. To a great extent our genomes direct the longevity cinema, casting the molecular characters, their interactions, and orchestrated response to extrinsic stress. Those fortunate enough to have inherited a good endowment would appear to have a higher probability of attaining a functional long life. Yet this analysis does not suggest that we should be resigned to simply let it play out as written. Rather, our important task is to modulate the genomic direction to improve on an otherwise preordained outcome. How can this be achieved and through what means? Expanding research on the phenomenon of caloric restriction and its molecular underpinnings is pointing the way. Our growing understanding portends novel strategies to address age-related disorders.

A breakthrough in aging research was the observation that caloric restriction extends life span. It is well documented that a nutritional diet with a reduced total caloric intake will increase the life span of organisms as diverse as yeast, worms, fruit flies and mice (Koubova and Guarente, 2003). The evolutionary conservation of the effects of caloric restriction (CR) suggests that these genetically tractable organisms may provide the models necessary to define the mechanisms and molecules required to understand and define aging in higher eukaryotes. In worms and flies, CR leads to a reduction in body fat, temperature, fecundity and an increased sensitivity to insulin (Clancy et al., 2001; Dillin et al., 2002). In mammals, the levels of insulin and insulin growth factor (IGF) also are reduced, illustrating the importance of insulin and IGF-1 on aging. Molecular genetics in both C. elegans and Drosophila have proven that a reduction in insulin and IGF-like peptides leads to an increased life span (Clancy et al., 2001; Tatar et al., 2001; Tu et al., 2002).

In yeast, screens for genetic determinants of aging uncovered that mutation of the NAD+-dependent protein deacetylase SIR2 (herein called SIRT1), results in a reduction in life span (Anderson et al., 2003; Lin and Guarente, 2003). Overexpression of SIRT1 in both yeast and worms leads to an increase in life span. Further, it has been shown that manipulation of nuclear NAD+ levels also contribute to longevity in a SIRT1-dependent manner (Rongvaux et al., 2003). Finally, several types of low-level stress also lead to increased longevity, potentially through either insulin-like signaling, SIRT1, and other stress-induced pathways (Tissenbaum and Guarente, 2002). These data underscore the importance of these proteins and their downstream effects, and suggest possible prospects for therapeutics development. The current excitement in our understanding of the molecular mechanism of aging arises from the realization that these pathways are interconnected and may ultimately converge.

The importance of insulin signaling on life expectancy is well established, as loss of either the insulin receptor or its substrate slows aging. Even so, it was not known if this was the direct or indirect result of insulin-like peptides. In worms, stimulation of the insulin receptor leads to the activation of a kinase cascade leading to the phosphorylation of members of the forkhead (FOXO) transcription family (Tissenbaum and Guarente, 2002). When phosphorylated, FOXO is sequestered within the cytoplasm. Translocation of FOXO to the nucleus through a reduction in the insulin-like signaling, or over-expression of FOXO within adipose tissue or neurons, leads to an increase in life expectancy.

Two recent reports (Giannakou et al., 2004; Hwangbo et al., 2004) show that the ability of Drosophila FOXO (dFOXO) to modulate life span is conserved in Drosophila. Constitutive over-expression of FOXO in a number of specific tissues is lethal in the fly. However, controlled expression of dFOXO within fat bodies, particularly those in the brain, result in a long life span. Interestingly, increased expression of dFOXO within neurons failed to increase life span. However, dFOXO expression in the head fat body altered the levels of insulin-like peptide within the adult brain, suggesting that insulin signaling within a limited number of cells may have a paracrine effect on other cells within the CNS. In addition, the expression of dFOXO within fat bodies provides cytoprotection against the oxidative stress caused by the drug paraquat.

It will be of great interest to determine if regulation of FOXO and its downstream targets will attenuate the oxidative damage thought to participate in neurodegenerative diseases such Alzheimer's and Parkinson's diseases. These data continue to illustrate that one's fate can be altered by modulating the balance of various cellular signals. Moderating insulin levels by diet or developing compounds that trigger the appropriate downstream event may lead to lifelong benefits.

All of these data indicate that CR alters longevity by ultimately regulating gene expression through the transcription factor FOXO. Yet, in yeast, SIRT1 also is clearly involved in mediating effects of CR. How does it fit in? Recent studies (Brunet et al., 2004; Motta et al., 2004) of SIRT1 in C. elegans provide the bridge linking the insulin pathway and SIRT1. The data showed that FOXO activity is required for SIRT1-mediated longevity and established that SIRT1 interacts and deacetylates FOXO, altering transcription of its targets. Further, deacetylation of FOXO appears to upregulate stress-resistance genes and downregulate proapoptotic targets. This led the authors to speculate that SIRT1, through FOXO, regulates the cell's response to favor stress resistance over death.

The ability of insulin signaling to affect life expectancy is documented not only in worms and flies, but also in mammals, as mice lacking the insulin receptor in adipose tissue are long-lived (Bluher et al., 2003; see ARF related news story). However, it has remained a question if SIRT1 would promote cytoprotection within mammals in response to CR. As reported most recently by David Sinclair's group, (Cohen et al., 2004; see ARF related news story), SIRT1 expression is increased in multiple tissues in response to CR in part due to a response mediated by insulin signaling. These authors further identify a new target for SIRT1, the DNA repair protein Ku70. When deacetylated, Ku70 forms a complex with the proapoptotic factor Bax, preventing Bax from entering the mitochondria and mediating cell death. Interestingly, sera from mice maintained on a CR diet were able to induce SIRT1 and protect against oxidative stress. Again, specific changes in gene expression are shown to provide cytoprotection and link SIRT1 action to apoptosis regulation.

Although understanding the multiple effects of CR on survival may seem daunting, these studies collectively illustrate a relationship between the insulin signaling cascade and SIRT1. What remains to be seen is how NAD+ metabolism will affect these pathways. SIRT1 and other DNA stress response enzymes require NAD+ as a co-substrate. Manipulation of the synthesis of NAD+ through the NAD+ salvage enzymes PNC1 and NPT1 increases the life span of yeast in a SIRT1 dependent manner (Anderson et al., 2003; Gallo et al., 2004). It is possible that CR also may alter NAD+ synthesis enzymes.

Evidence is growing that dietary habits may play a role in determining the risk for brain diseases. Alterations in glucose metabolism due to insulin resistance and hyperinsulinemia are observed in patients with affective disorders, depression, and AD (Rasgon and Jarvik, 2004). It has been proposed that the failure to properly utilize glucose in the brain may cause neuronal injury leading to neurodegeneration. There is growing concern within developed countries regarding the dangers associated with overeating and its link to disorders such as diabetes (Mattson, 2003). A high caloric intake also is correlated with an increased occurrence of Alzheimer's disease (Gustafson et al., 2003). Of interest is the protection that CR affords in models of these disorders (Prolla and Mattson, 2001). Animal models demonstrate that CR protects against neuronal damage in the hippocampus triggered by the toxin kainic acid, and that CR leads to a reduction in age-related neuronal loss in Alzheimer's disease. Further, animals maintained on CR are resistant to oxidative damage caused by neurotoxicants such MPTP. Thus, understanding the molecular mechanisms of CR may lead to new targets for therapeutics development for neurodegenerative diseases. Pharmaceuticals that mimic the positive effects of CR may also confer its neuroprotective benefits. In fact, one agonist of SIRT1, resveratrol , reduces BAX-mediated apoptosis in cell culture (Cohen et al., 2004).

This rapidly growing body of data suggests that aging, at least at the cellular level, will be defined as the alteration and cross talk of different signaling pathways. CR not only increases life span, but also provides neuroprotection in a number of neurodegenerative models including Alzheimer's and Parkinson's disease.

However, is CR a viable lifestyle? Only those people with steely determination and self-control will adhere to such a strict dietary regime. Although CR offers protection during the mid-life of model organisms, it remains to be seen if humans will benefit. Also, for those patients diagnosed with a neurodegenerative disorders, will simply changing your diet be sufficient to soften the course of the disease? Unraveling how CR alters cellular physiology will enable the identification of novel cytoprotective targets. This knowledge might lead to the discovery of new classes of therapeutics. When targeted to the afflicted region of disease, these compounds may promote neuronal survival. Although these compounds will not prevent the final curtain call, they may rewrite the last act of life with increased intelligence and wit, and ultimately adulation by the cognescenti.

Let's discuss these questions during the discussion:

1. On willing mind but weaker flesh: Most people can't adhere to caloric restriction. Are there other ways of activating the pathway short of living on the edge of starvation?

2. For those considering trying CR: what are the side effects? How about fertility?

3. Could one design a diet that turns on CR signaling but leaves one feeling reasonably sated?

4. Short of CR, are there other dietary means to reduce insulin signaling?

5. What deleterious effects could activating these pathways have? They are, after all, a stress response of sorts.

6. What are the next steps scientifically to flesh out this hypothesis?

7. It's early days, but what might be some of the therapeutic strategies to exploit CR signaling? Gene therapy? Small molecule inhibitors? Against which targets?

8. Have AD mouse models been put on CR? Does it improve behavioral phenotype? Synaptic damage? Would this even be a good experiment?

9. NAD is a common and widely studied molecule. Are there NAD-based therapeutic approaches from other diseases that could be adapted to AD?

10. Does CR prolong an animals lifespan mainly by acting as a neuroprotectant? If so, could a neuroprotective drug mimic the effect of CR?

11. What new classes of therapeutics do we need? E.g., the biotech company Renovis has an oxygen radical scavenger that is in a phase 3 trial against stroke. Could such a drug, in the final outcome, have a similar effect as the signaling pathways triggered by CR?

References:

Anderson RM, Bitterman KJ, Wood JG, Medvedik O, Sinclair DA (2003) Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae. Nature 423:181-185. Abstract

Bluher M, Kahn BB, Kahn CR (2003) Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299:572-574. Abstract

Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY, Hu LS, Cheng HL, Jedrychowski MP, Gygi SP, Sinclair DA, Alt FW, Greenberg ME (2004) Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303:2011-2015. Abstract

Clancy DJ, Gems D, Harshman LG, Oldham S, Stocker H, Hafen E, Leevers SJ, Partridge L (2001) Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science 292:104-106. Abstract

Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, De Cabo R, Sinclair DA (2004) Calorie Restriction Promotes Mammalian Cell Survival by Inducing the SIRT1 Deacetylase. Science. 2004 Jun 17 [Epub ahead of print] Abstract

Dillin A, Crawford DK, Kenyon C (2002) Timing requirements for insulin/IGF-1 signaling in C. elegans. Science 298:830-834. Abstract

Gallo CM, Smith DL, Jr., Smith JS (2004) Nicotinamide clearance by Pnc1 directly regulates Sir2-mediated silencing and longevity. Mol Cell Biol 24:1301-1312. Abstract

Giannakou ME, Goss M, Junger MA, Hafen E, Leevers SJ, Partridge L (2004) Long-lived Drosophila with Overexpressed dFOXO in Adult Fat Body. Science. 2004 Jun 10 [Epub ahead of print] Abstract

Gustafson D, Rothenberg E, Blennow K, Steen B, Skoog I (2003) An 18-year follow-up of overweight and risk of Alzheimer disease. Arch Intern Med 163:1524-1528. Abstract

Hwangbo DS, Gersham B, Tu MP, Palmer M, Tatar M (2004) Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature. 2004 Jun 3;429(6991):562-6. Abstract

Koubova J, Guarente L (2003) How does calorie restriction work? Genes Dev 17:313-321. Abstract

Lin SJ, Guarente L (2003) Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity and disease. Curr Opin Cell Biol 15:241-246. Abstract

Mattson MP (2003) Will caloric restriction and folate protect against AD and PD? Neurology 60:690-695. Abstract

Motta MC, Divecha N, Lemieux M, Kamel C, Chen D, Gu W, Bultsma Y, McBurney M, Guarente L (2004) Mammalian SIRT1 represses forkhead transcription factors. Cell 116:551-563. Abstract

Prolla TA, Mattson MP (2001) Molecular mechanisms of brain aging and neurodegenerative disorders: lessons from dietary restriction. Trends Neurosci 24:S21-31. Abstract

Rasgon N, Jarvik L (2004) Insulin resistance, affective disorders, and Alzheimer's disease: review and hypothesis. J Gerontol A Biol Sci Med Sci. 2004 Feb;59(2):178-83; discussion 184-92. Review. Abstract

Rongvaux A, Andris F, Van Gool F, Leo O (2003) Reconstructing eukaryotic NAD metabolism. Bioessays 25:683-690. Abstract

Tatar M, Kopelman A, Epstein D, Tu MP, Yin CM, Garofalo RS (2001) A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292:107-110. Abstract

Tissenbaum HA, Guarente L (2002) Model organisms as a guide to mammalian aging. Dev Cell 2:9-19. Abstract

Tu MP, Epstein D, Tatar M (2002) The demography of slow aging in male and female Drosophila mutant for the insulin-receptor substrate homologue chico. Aging Cell 1:75-80. Abstract

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References

News Citations

  1. Lean Mice Live Longer: Does Insulin in Fat Hasten Aging?
  2. Who Says Chivalry is Dead?—Sir2 Fights Against Aging in Mammals

Webinar Citations

  1. Cast Call for Players: Healthy Aging Through Lean Living

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  18. . Will caloric restriction and folate protect against AD and PD?. Neurology. 2003 Feb 25;60(4):690-5. PubMed.
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Further Reading

Papers

  1. . Brain energy metabolism in Alzheimer's disease: 99mTc-HMPAO SPECT imaging during verbal fluency and role of astrocytes in the cellular mechanism of 99mTc-HMPAO retention. Brain Res Brain Res Rev. 2001 Oct;36(2-3):230-40. PubMed.
  2. . Dual modes of aging in Mediterranean fruit fly females. Science. 1998 Aug 14;281(5379):996-8. PubMed.