Re: Radicals may not be that important in CR-effect

[Guest guest]

Hi ,

I have no opinions about de Grey, et al, and I don't mind you saying he's a quack, BUT it does make me wonder why you think he's a quack?

I believe ROS is a necessary evil, and oxidation a fact.

But "inhibition of apoptosis may instead be one of the key mechanisms by which caloric restriction retards aging" ????

Isn't apoptosis the killing of cancer cells? Is this saying apoptosis kills good cells too? (As I might expect).

Regards.

----- Original Message -----

From: T

Sent: Sunday, July 17, 2005 12:39 AM

Subject: [ ] Radicals may not be that "important" in CR-effect

I think many of you guys have probably already read this, but I think this work is very important, as it is essential that we all "put the 90s behind us" and relegate "free radicals" to their appropriate place in a "larger matrix" of more substantial biological processes.

For too long, individuals that have overemhasized a "chemistry" perspective have ruled the debate. But, the 21st century is the golden age of molecular biology, and so it is fitting that the research community is beginning to see that the various chemicals once thought to hold primacy in the mechanisms of aging are actually the product of a larger, more integrative biological framework.

(Yes, and de Grey is a quack.)

=-=-=-=-=-=-=-=

http://www.the-scientist.com/news/20050715/02

=-=-=-=-=-=-=

"Mitochondrial DNA mutations appear to lead to aging by induced apoptosis and not by increased production of free radicals that lead to cellular damage as previously thought, scientists report in this week's Science. Tomas Prolla at the University of Wisconsin-Madison and colleagues found a rise in mtDNA mutations led to premature aging but not to increased levels of reactive oxygen species.

The researchers measured several markers of oxidative stress, including hydrogen peroxide, protein carbonyls, F2-isoprostanes, and oxidative damage to DNA and RNA, in liver and skeletal muscle. None of these markers showed any sign of increased oxidative stress."

Prolla noted that the main mechanism of action of caloric restriction, the only nutritional intervention that retards aging, "was thought to be a suppression of free radical production." Prior research had found that caloric restriction also delayed mtDNA mutation accumulation and reduced mitochondria-linked apoptotic pathways. "So our findings and those of others suggest inhibition of apoptosis may instead be one of the key mechanisms by which caloric restriction retards aging," he said."

=-=-=-=-=-=-==-

T. pct35768@...

[Guest guest]

> Hi , > I have no opinions about de Grey, et al, and I don't mind you saying he's a quack, BUT it does make me wonder why you think he's a quack?

Look, it has been said many times, many ways, but the guy is just an enthusiast, and little else. A mere dilettante with that golden gift for circumlocution that had hold the ears of the ignorant captive with a whimsical mix of fantasy and half-truth. I

I was looking for Guarente's specic quote on this guy, but I think Science mag may have it stuffed back in its archive. I think this article may be somewhat old, but it encapsulates what I feel about him. He may actually have been "labeled" a professor of Genetics by Cambridge, but this is something akin to a "honorary degree".

Also understand that the UK research community features a little bit more "activist research", and their take on many on many issues of scientific substance is a little different than other scientific communities.

For instance, they are "rabidly" pro-radical, as is most of Europe. I think something about radicals really appeals to the European sense of "inevitable death and decay" that is heightened by the rather cynical outlook Europeans have on social hierarchies and the inequality inherent in class stratification. Look at the often unsustainable social safety nets they gravitate to. What they don't "accept" as a "philosophically" valid notion is that the "rough and tumble" experiences of life can make you stronger, which is a principle that some Americans feel is somewhat valid, and hence you see our more "unforgiving" social safety net.

However, the Europeans are probably not going to be right about radicals, but de Grey got suckered into all that b.s. just like the rest of the 'em.

A good old fashioned American team, led by Prolla at the University of Wisconsin-Madison, is going to have set these Europeans straight, and get them on the same page so the entire community can move forward from the radical hype.

Basically, de Grey embodies everything I hate about the British. So full of eloquence, yet simultaneously often devoid of substance. I don't lilke people that walk up to podiums, use 30-letter words about Gompertz curves, and then go out to lunch, and think that you have changed the world for people other than insurance company actuaries.

http://66.102.7.104/search?q=cache:nK5yqMjkMUkJ:www.popsci.com/popsci/print/0,21553,929447,00.html+Guarente+%22de+Grey%22+%22not%22 & hl=en

\

\

\

V

"I slide in behind a venerable wooden table at the Eagle and take my first measure of the man. De Grey, 41, is lanky and favors the classic combination of T-shirt, old jeans and sneakers. He has a Rasputin-length beard that he strokes incessantly. He’s a confirmed drinker of fine English ales, and when he makes a strong point, which is often, he raps his pint glass on the table like a judge bringing his court to order. The pronouncements are delivered in a moderately posh English drawl, with a touch of a lisp. “Cambridge is so full of eccentrics,” he says, “nothing surprises anybody over here. And there are plenty of people with beards my size. But some in the university do find it hard to get used to the idea that someone would actually be doing seriously significant academic work in his spare time.” De Grey, you see, is not, as he is sometimes mistaken to be, a professor of genetics at Cambridge but a half-time research associate with a day job managing a genetics database. "

=-=-=-=-=-=-=-=-=

T.

pct35768@...

Start your day with - make it your home page

[Guest guest]

I have long held the personal opinion that deGray is way out in outer space somewhere - his ideas seem more based on " science fiction " than science.

on 7/17/2005 2:14 PM, T at pct35768@... wrote:

Look, it has been said many times, many ways, but the guy is just an enthusiast, and little else. A mere dilettante with that golden gift for circumlocution that had hold the ears of the ignorant captive with a whimsical mix of fantasy and half-truth. I

[Guest guest]

OK, you were asked but so much of the science around CR is conjecture at this point. I wouldn't be

overly reliant upon using the measure of a man to credit or discredit theories. There has surely been

good science generated by total assholes, and vice versa.

It's tough enough keeping the data straight, lets not waste too much effort on ad hominum pursuits.

There is already pretty healthy skepticism around here.

Be well

JR

-----Original Message-----From: [mailto: ]On Behalf Of TSent: Sunday, July 17, 2005 1:15 PM Subject: [ ] Re: Radicals may not be that "important" in CR-effect

> Hi , > I have no opinions about de Grey, et al, and I don't mind you saying he's a quack, BUT it does make me wonder why you think he's a quack?

[Guest guest]

But, ,

Getting 's opinions as well as others is what I do. The total data input is what I look at, what I must do to understand the systems. The systems are not well defined, and are too complex for humans to model, maybe too large to put all into any computer.

So I must rely on chaotic data as well as formalized, which is not nearly all that is known by the practicing doctor, eg. Most who have the knowledge do not bother to write articles.

So case in point, de grey make not have ANY ideas of his own at all, but just reiterates what he hears from the "high and mighty" that surround him and don't care about exposure.

Regards.

----- Original Message -----

From:

Sent: Sunday, July 17, 2005 2:02 PM

Subject: RE: [ ] Re: Radicals may not be that "important" in CR-effect

OK, you were asked but so much of the science around CR is conjecture at this point. I wouldn't be

overly reliant upon using the measure of a man to credit or discredit theories. There has surely been

good science generated by total assholes, and vice versa.

It's tough enough keeping the data straight, lets not waste too much effort on ad hominum pursuits.

There is already pretty healthy skepticism around here.

Be well

JR

-----Original Message-----From: [mailto: ]On Behalf Of TSent: Sunday, July 17, 2005 1:15 PM Subject: [ ] Re: Radicals may not be that "important" in CR-effect

> Hi , > I have no opinions about de Grey, et al, and I don't mind you saying he's a quack, BUT it does make me wonder why you think he's a quack?

[Guest guest]

Hi All,

See the definition of apoptosis:

Programmed cell death as signalled by the nuclei in normally functioning human

and

animal cells when age or state of cell health and condition dictates. An active

process requiring metabolic activity by the dying cell, often characterised by

cleavage of the DNA into fragments that give a so called laddering pattern on

gels.

Cells that die by apoptosis do not usually elicit the inflammatory responses

that

are associated with necrosis, though the reasons are not clear. Cancerous cells,

however, are unable to experience the normal cell transduction or

apoptosis-driven

natural cell death process.

--- jwwright <jwwright@...> wrote:

> Isn't apoptosis the killing of cancer cells? Is this saying apoptosis kills

good

> cells too? (As I might expect).

Al Pater, PhD; email: old542000@...

__________________________________________________

[Guest guest]

Thanks for that clarification.

So things that kill cancers do so by making the cancer cell incur apoptosis, right?

Except maybe ROS?

Regards.

----- Original Message -----

From: Al Pater

Sent: Sunday, July 17, 2005 3:15 PM

Subject: Re: [ ] Radicals may not be that "important" in CR-effect

Hi All,See the definition of apoptosis:Programmed cell death as signalled by the nuclei in normally functioning human andanimal cells when age or state of cell health and condition dictates. An activeprocess requiring metabolic activity by the dying cell, often characterised bycleavage of the DNA into fragments that give a so called laddering pattern on gels.Cells that die by apoptosis do not usually elicit the inflammatory responses thatare associated with necrosis, though the reasons are not clear. Cancerous cells,however, are unable to experience the normal cell transduction or apoptosis-drivennatural cell death process. --- jwwright <jwwright@...> wrote:> Isn't apoptosis the killing of cancer cells? Is this saying apoptosis kills good> cells too? (As I might expect).Al Pater, PhD; email: old542000@...

[Guest guest]

--- jwwright <jwwright@...> wrote:

> So things that kill cancers do so by making the cancer cell incur apoptosis,

> right?

Yes, such as apotosis induced by chemotherapy or radiation therapy, which affect

cancer cells much more than normal cells, since cancer cells are dividing cells.

> Except maybe ROS?

Reactive oxygen species are generally involved, it seems to me.

Al Pater, PhD; email: old542000@...

__________________________________________________

[Guest guest]

I wonder what this implies vis a vis longevity for someone who has

undergone chemotherapy...?

>

> > So things that kill cancers do so by making the cancer cell incur

apoptosis,

> > right?

>

> Yes, such as apotosis induced by chemotherapy or radiation therapy,

which affect

> cancer cells much more than normal cells, since cancer cells are

dividing cells.

>

> > Except maybe ROS?

>

> Reactive oxygen species are generally involved, it seems to me.

>

> Al Pater, PhD; email: old542000@y...

>

> __________________________________________________

>

[Guest guest]

>I wonder what this implies vis a vis longevity for someone who has>undergone chemotherapy...?

My own personal suspicion is that longevity in such individuals will be compromised to the degree that the chemotherapy outstripped their body's ability to invoke compensatory "reparative" mechanisms, both "short-term" (ROS interception) and "long-term" (actual DNA repair). There will be a loss of genomic integrity most likely with each bout of severe chemotherapy that will affect both normal and cancerous cells.

The Prolla research in particular specifically examined the effects of mitochondrial mutations on "aging", and they found that mutations in the mitochondrial genome sensitize the cell to apoptosis. There is a smattering of research indicating that cancer cells figure out a way to "cheat this system", and may feature mutations that render them invincible to this "natural" process. There are some groups even contending that some cancers actually "rid" themselves of all significant mitochondrial mutations to obtain the "immortality" they are going after. This is not that implausible, however, as many of the same genes thought to promote aging are through to be anti-cancer.

Many chemotherapy agents are rather non-specific DNA lesioning agents, and so it would not be unthinkable that one important mechanism to always consider in assessing their efficacy is that capacity to lesion the mitochondrial genome and induce apoptosis. One of the "classics" in this regard is doxorubicin, whose mitochondrial toxicity has been well-characterized.

Some of these agents will undoubtedly lesion "stem cells" and other cells that need to be preserved, but, such cells often proliferate, and it is not unconceivable that they may "shed" or be "crowded out" by more "well-functioning" stem cells. The exact "particulars" involved in longitudinal stem cells dynamics is something that future research needs to address in order to understand the exact significance of many therapeutics in use today.

I honestly think Prolla probably overstepped his finding just a little bit by emphasizing how "radicals don't matter". I think in some contexts, they "could" matter, but only as little packets of information (that also tend to "cook" things, but "cooking" things is a manner of transmitting information as well). However, the research is very interesting in that you can produce a phenotypic progression that parallels normative aging all in the context of *decreasing* radical burden. This highlights the importance of apoptosis in the phenomenonology of aging.

=-=-=-=-=-=-=-

FEMS Yeast Res. 2004 Nov;5(2):127-32.

Related Articles,

Links

Mitochondria damage checkpoint in apoptosis and genome stability.Singh KK.Department of Cancer

Genetics, Cell and Virus Building, Room 247, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. keshav.singh@...Mitochondria perform multiple cellular functions including energy production, cell proliferation and apoptosis. Studies described in this paper suggest a role for mitochondria in maintaining genomic stability. Genomic stability appears to be dependent on mitochondrial functions involved in maintenance of proper intracellular redox status, ATP-dependent transcription, DNA replication, DNA repair and DNA recombination. To further elucidate the role of mitochondria in genomic stability, I propose a mitochondria damage checkpoint (mitocheckpoint) that monitors and responds to damaged mitochondria. Mitocheckpoint can coordinate and maintain proper balance between apoptotic and anti-apoptotic signals. When mitochondria are damaged, mitocheckpoint can be activated to help cells repair damaged mitochondria, to restore normal

mitochondrial function and avoid production of mitochondria-defective cells. If mitochondria are severely damaged, mitocheckpoint may not be able to repair the damage and protect cells. Such an event triggers apoptosis. If damage to mitochondria is continuous or persistent such as damage to mitochondrial DNA resulting in mutations, mitocheckpoint may fail which can lead to genomic instability and increased cell survival in yeast. In human it can cause cancer. In support of this proposal we provide evidence that mitochondrial genetic defects in both yeast and mammalian systems lead to impaired DNA repair, increased genomic instability and increased cell survival. This study reveals molecular genetic mechanisms underlying a role for mitochondria in carcinogenesis in humans.Publication Types:

Review Review, Tutorial

PMID: 15489195 [PubMed - indexed for MEDLINE]

=-=-=-=-==-=-=-

Am J Physiol Heart Circ Physiol. 2005 Aug;289(2):H722-31. Epub 2005 Mar 25.

Related Articles,

Links

Moderate endurance training prevents doxorubicin-induced in vivo mitochondriopathy and reduces the development of cardiac apoptosis.Ascensao A, Magalhaes J, Soares JM, Ferreira R, Neuparth MJ, Marques F, Oliveira PJ, Duarte JA.Dept. of Sport Biology, Faculty of Sport Sciences, Univ. of Porto, Rua Dr. Placido Costa, 91, 4200-450 Porto, Portugal. aascensao@...).The objective of this work was to test the hypothesis that endurance training may be protective against in vivo doxorubicin (DOX)-induced cardiomyopathy through mitochondria-mediated mechanisms. Forty adult (6-8 wk old) male Wistar rats were randomly divided into four groups (n = 10/group): nontrained,

nontrained + DOX treatment (20 mg/kg), trained (14 wk of endurance treadmill running, 60-90 min/day), and trained + DOX treatment. Mitochondrial respiration, calcium tolerance, oxidative damage, heat shock proteins (HSPs), antioxidant enzyme activity, and apoptosis markers were evaluated. DOX induces mitochondrial respiratory dysfunction, oxidative damage, and histopathological lesions and triggers apoptosis (P < 0.05, n = 10). However, training limited the decrease in state 3 respiration, respiratory control ratio (RCR), uncoupled respiration, aconitase activity, and protein sulfhydryl content caused by DOX treatment and prevented the increased sensitivity to calcium in nontrained + DOX-treated rats (P < 0.05, n = 10). Moreover, training inhibited the DOX-induced increase in mitochondrial protein carbonyl groups, malondialdehyde, Bax, Bax-to-Bcl-2 ratio, and tissue caspase-3 activity (P < 0.05, n = 10). Training also increased by approximately 2-fold the expression of

mitochondrial HSP-60 and tissue HSP-70 (P < 0.05, n = 10) and by approximately 1.5-fold the activity of mitochondrial and cytosolic forms of SOD (P < 0.05, n = 10). We conclude that endurance training protects heart mitochondrial respiratory function from the toxic effects of DOX, probably by improving mitochondrial and cell defense systems and reducing cell oxidative stress. In addition, endurance training limited the DOX-triggered apoptosis.PMID: 15792986 [PubMed - in process]

=-=-=-=-=-=-=

T. pct35768@...

__________________________________________________