21 replies to this topic

[manofsan]

read this:


http://www.betterhum...14/Default.aspx

The protein Klotho has been found to extend the lifespan of mice, and seems to cause insulin resistance.

It's interesting that it might cause diabetes. I thought diabetes is associated with decreased lifespan and not increased lifespan.

[cesium]

Hormone Identified That Extends Life of Mice

Discovery May Lead to Drugs to Increase Human Longevity

By Rob Stein
Washington Post Staff Writer
Thursday, August 25, 2005; 3:48 PM



Scientists have identified a hormone that significantly extends the life span of mice, a discovery that could mark a crucial step toward developing drugs that boost longevity in people.

The hormone is the first substance ever identified that is produced naturally in mammals, including humans, and can extend lifespan -- a long-sought goal in the intense effort to help people live longer.

Much more work is needed to study the substance and investigate whether the hormone or a similar compound would be effective and safe in people, experts cautioned. But the discovery opens highly promising avenues for research and provides tantalizing new clues towards deciphering the basic biology of aging.

"This is a significant discovery. It's an exciting paper," said Anna McCormick of the National Institute on Aging, which helped fund the new research, published online today by the journal Science. "It's definitely the way you would go about designing molecules that would promote healthy aging and longevity in people."

Makoto Kuro-o of the University of Texas Southwestern Medical Center in Dallas, who led the research, said, "This could provide a key to understanding the molecular mechanisms of aging and opens up new areas to the potential therapy for multiple age-related diseases in humans."

The discovery was triggered by a study Kuro-o and his colleagues published in 1997, which identified a gene in mice that, when damaged, caused the animals to experience all the hallmarks of aging in humans -- hardening of the arteries, thinning bones, withered skin, weak lungs -- and to die prematurely. They dubbed the gene Klotho for the Greek goddess who spins the thread of life.

Suspecting the gene may play a role in regulating lifespan, Kuro-o and his colleagues genetically engineered mice with overactive Klotho genes. In the latest experiments, they found that these animals lived an average of 20 percent to 30 percent longer than normal -- 2.4 to 2.6 years versus a normal lifespan of about two years -- without any signs of ill effects, according to the new report.

"The extension of lifespan is widely accepted as a reliable marker for the suppression of aging," Kuro-o said. "This shows the Klotho gene regulates aging."

The researchers then identified a small protein, called a peptide, that the gene produces and found it circulating in the animals' blood at double normal levels.

After isolating and purifying the substance and reproducing it through genetic engineering techniques, the researchers injected the substance into normal mice. Tests on those animals, combined with experiments involving cells in the laboratory, indicate that the substance modulates a crucial biological pathway involved in a panoply of basic metabolic functions that has become the focus of aging research in recent years.

"It's a pathway that has been conserved by evolution that has been found to play a key role in regulating lifespan for flies, worms, mice and probably humans," Kuro-o said.

Studies, for example, suggest that damping down this pathway -- known as the insulin/insulin-like growth factor-1 signaling pathway -- may be the mechanism that extends longevity in animals that are fed an ultra low calorie diet.

The Klotho hormone appears to have a similar effect, Kuro-o said.

"Our work shows that the Klotho gene is an aging-suppressor gene," he said.

Other researchers said the findings were remarkable because no one had previously found a naturally occurring hormone capable of extending the lifespan of a mammal.

"You have lots of ways to shorten the life of an animal, but it's hard to get an animal to live longer," said George Martin of the University of Washington, who serves as the president of the American Federation for Aging Research. "You can kick a radio to make it not work so well, but it's hard to make it work better. It's quite a wonderful discovery."

Kuro-o and his colleagues plan to inject the substance into normal mice to see if it extends their life spans, and to measure the substance in humans to determine whether levels of the protein are correlated with longevity. Previous research has shown that humans have the protein in their blood and that people with a certain variation of the gene are prone to age-related diseases like heart attacks, strokes and osteoporosis.

Scientists will have to determine whether the protein can be produced in sufficient quantities to use it as a drug. It may turn out that other substances that mimic the protein's effects would also work or be safer, Kuro-o said. "That might be more practical," he said.

Kuro-o others cautioned, however, that agents that appear effective and safe in mice often produce complications in humans. The hormone, for example, appears to decrease the effectiveness of insulin, which could limit its usefulness.

"It appears to play a role in the same pathway in people, but that doesn't necessarily mean it's going to be as straightforward to extend lifespan in people as it is in mice," said Valter Longo of the University of Southern California. "But this adds a new component to our picture and perhaps a component that could extend lifespan with few ill effects."

Beyond the possible clinical applications, other researchers said the finding underscores the growing understanding of the basic biology of aging.

"Papers like this are filling in the pieces of the puzzle that will explain the evolutionary biology of aging," said L. Stephen Coles of the UCLA School of Medicine.

http://www.washingto...5082501224.html

[123456]

Good stuff as always; Progress!

[123456]

Good job Manofsan:) , keep the breaking news coming when they happen. [thumb]

[reason]

Abstract here:

http://www.sciencema...tract/1112766v1

Suppression of Aging in Mice by the Hormone Klotho

Hiroshi Kurosu et al.

A defect in Klotho gene expression in mice accelerates the degeneration
of multiple age-sensitive traits. Here we show that overexpression of
Klotho in mice extends life span. Klotho protein functions as a
circulating hormone that binds to a cell-surface receptor and represses
intracellular signals of insulin and insulin-like growth factor-1
(IGF1), an evolutionarily conserved mechanism for extending life span.
Alleviation of aging-like phenotypes in Klotho-deficient mice was
observed by perturbing insulin/IGF1 signaling, suggesting that
Klotho-mediated inhibition of insulin/IGF1 signaling contributes to its
anti-aging properties. Klotho protein may function as an anti-aging
hormone in mammals.

Commentary and links here:

http://www.fightagin...ives/000586.php

and here:

http://www.healthext..._antiaging.html

Klotho stub on Wikipedia, expansion encouraged:

http://en.wikipedia....iki/Klotho_Gene

Reason
Founder, Longevity Meme
reason@longevitymeme.org
http://www.longevitymeme.org

[John Schloendorn]

The hormone is the first substance ever identified that is produced naturally in mammals, including humans, and can extend lifespan

At least the second actually. The catalase story was a few months earlier. Is there really no other one?

[Lazarus Long]

http://news.bbc.co.u...ure/4186324.stm

Now researchers have shown that by boosting the activity of the gene, they can extend the natural lives of male mice from two to three years.

The effect is not quite so strong in female mice.


Downsides

"It could be one of the significant steps for developing anti-ageing therapy," Dr Makoto Kuro-o, assistant professor of pathology at the University of Texas' Southwestern Medical Center and senior author of the study, told Science magazine.

Klotho seems to delay many of the effects of old age, like the weakening of bones, clogging of the arteries and loss of muscle fitness.

Well if the effects are infertility and primarily in the male then maybe the benefits could be tied to the creation of a male pill providing a direct reward for the voluntary use of male contraception that also extends the life of the user.

That is assuming aside from the already recognized side effects that there is not a problem with libido suppression and the infertility is reversible.

The use of contraception is also itself going to be controversial as many types are being linked with breast cancer incidence in women and I think there is going to be 'more' pressure for the creation of a male pill and this could be one avenue.

[John Schloendorn]

The effect is not quite so strong in female mice

Strange, life-extension due to impaired IGF-1 signaling is normally more pronounced in females. Any ideas how come? Could this be pointing to partially independent pathways of life-extension by Klotho and reduced IGF-1 signaling that might synergize when combined?

[Michael]

This (1) is what I have come to term "the usual nonsense." The text states that "Mice carrying the EFmKL46 or EFmKL48 transgenic alleles, fed ad libitum, outlived wild-type controls by 20.0 and 30.8%, respectively, in males and by 18.8 and 19.0%, respectively, in females." Specifically, "The averagelife span of male wild-type, EFmKL46, and EFmKL48 mice was 715 ± 44 days,858 ±40 days and 936 ± 47days (means ±SEM), respectively. The average life span of female wild-type, EFmKL46, and EFmKL48 mice was 697 ± 45 days, 829 ± 32 days and 830± 29 days, respectively."

However, there was only a MEAN LS "extension" in either strain, and the "extension" only constituted an incomplete NORMALIZATION of the shortened LS of the animals in question. The control strain in this experiment was C3H, which is a short-lived strain of mouse; see mortality and pathology info here:

http://www.informati.../docs/C3H.shtml

A normal, healthy, non-genetically-fucked-up mouse should on average live ~900 d, and ~1200 max (2); these animals clearly do not constitute healthy controls, tho' Kuro-o's group seem to have done an unusually good job of raising them, to their credit. IAC, one can normalize the survivorship of such animals by simply interfering with the built-in disease vulnerability that cuts short their lives. This tells us nothing at all about aging, and in no way helps us to develop anti-aging interventions for humans.


They don't formally report max LS (tenth-decile survivorship), but eyeballing the curves (Fig 1, A & B) shows that the last mouse in each group died at the age of roughly:

Wild-type C3H males:990 days
Wild-type C3H females: 1010 days
EFmKL46 transgenic males: 1110 days
EFmKL48 transgenic males: 1160 d
EFmKL46 transgenic females: 1080 d
EFmKL48 transgenic females: 1080 d

All that the extra klotho dose did was move the 2 transgenics closer to -- and in no case fully! -- the average and maximum lifespan expected of mice that aren't genetically disfavored or in poor husbandry conditions. In the case of the females, the effect is nearly negligible; since the data were never formally reported, I'm guessing that the difference was statistically nonsignificant, as I suggest it was also "clinically" and scientifically.

Of course, a zillion things -- melatonin, cysteine, hydroxylamine, alpha-tocopherol, ethoxyquin, 2-mercaptoethylamine, etc etc -- do this. This tells us something about how antioxidants can counter the abuse of poor animal husbandry or bad genes, but it doesn't tell us anything about basically healthy animals -- and even less about aging per se.

It's really too bad that they didn't do this on a longevous background, not only because it would have given meaningful results in general, but light of recent surprising data suggesting that it is the low levels of thyroid hormones, and not IGF1, that slows aging in dwarf rodents (3,4); other GH/IGF1 or insulin signaling disruptions have not been clearly demonstrated to slow down aging (8). A clearer result, positive or negative, with klotho as an IGF1/insulin signal disrupter would have added significantly to our understanding.

IAC, this was not going to lead to a truly useful result, as Aubrey de Grey has ably shown (5-7), attempting to "clean up" the deleterious effects of normal metabolism is an ineffective strategy for the development of anti-aging biomedicine: what is needed is interventions which directly target aging damage per se.

-Michael

1. Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I, Takayama Y, Herz J, Kahn CR, Rosenblatt KP, Kuro-O M.
Suppression of Aging in Mice by the Hormone Klotho.
Science. 2005 Aug 25; [Epub ahead of print]
PMID: 16123266 [PubMed - as supplied by publisher]


2. Miller RA, Harper JM, Dysko RC, Durkee SJ, Austad SN.
Longer life spans and delayed maturation in wild-derived mice.
Exp Biol Med (Maywood). 2002 Jul;227(7):500-8.
PMID: 12094015

3. Vergara M, Smith-Wheelock M, Harper JM, Sigler R, Miller RA.
Hormone-treated snell dwarf mice regain fertility but remain long lived and disease resistant.
J Gerontol A Biol Sci Med Sci. 2004 Dec;59(12):1244-50.
PMID: 15699523 [PubMed - indexed for MEDLINE]

4. Sonntag WE, Carter CS, Ikeno Y, Ekenstedt K, Carlson CS, Loeser RF,
Chakrabarty S, Lee S, Bennett C, Ingram R, Moore T, Ramsey M.
Adult-onset growth hormone and insulin-like growth factor I deficiency reduces neoplastic disease, modifies age-related pathology, and increases life span.
Endocrinology. 2005 Jul;146(7):2920-32. Epub 2005 Mar 24.
PMID: 15790724 [PubMed - indexed for MEDLINE]

5. de Grey AD.
An engineer's approach to the development of real anti-aging medicine.
Sci Aging Knowledge Environ. 2003 Jan 8;2003(1):VP1. Review.
PMID: 12844502 [PubMed - indexed for MEDLINE]
http://www.gen.cam.a...ens/focusPP.pdf

6. de Grey AD.
Challenging but essential targets for genuine anti-ageing drugs.
Expert Opin Ther Targets. 2003 Feb;7(1):1-5.
PMID: 12556198 [PubMed - as supplied by publisher]
http://www.gen.cam.a...sens/manu21.pdf

7. de Grey AD, Ames BN, Andersen JK, Bartke A, Campisi J, Heward CB, McCarter RJ, Stock G.
Time to talk SENS: critiquing the immutability of human aging.
Ann N Y Acad Sci. 2002 Apr;959:452-62; discussion 463-5.
PMID: 11976218 [PubMed - indexed for MEDLINE]
http://www.gen.cam.a...sens/manu12.pdf

8. Barger JL, Walford RL, Weindruch R.
The retardation of aging by caloric restriction: its significance in the transgenic era.
Exp Gerontol. 2003 Nov-Dec;38(11-12):1343-51. Review.
PMID: 14698815 [PubMed - indexed for MEDLINE]

[jaydfox]

Did anyone else find it ironic/counterintuitive that this LS extension effect was found correlated with increased insulin production and decreased insulin sensitivity?

[manofsan]

Well, decreased response to the insulin might force the body to produce more of it to obtain the same effect, meaning that more will show up in the bloodstream.

[manofsan]

Hi Prometheus, well, just as how Anti-Lock Braking System might preserve the lifespan of your brakepads by preventing you from sharply hitting your brakes, or how automatic transmission might preserve your transmission lifespan by preventing you from accelerating too sharply, similarly I would think this decreased insulin response from Klotho seems to preserve cellular lifespan by reducing their ability to sharply increase their metabolism in response to insulin.

A better metabolic dampening system might give a more even, middle-of-the-road metabolism that translates into the greater longevity, don't you think? In a way, that's working along the same lines as Caloric Intake Restriction, which economizes on your metabolism.

[John Schloendorn]

I'd tend to agree with Prometheus that this is still good science... Even in this mouse model of not-so-well-being (Thanks to Michael for pointing this out!), such a protective effect is remarkable and might lead to future discoverys of considerable academic interest. But I strongly agree with Michael that it is bad rejuvenation medicine for two simple and overriding reasons:

- The intervention is congenital, its adult-onset effectivity is completely unclear and methods of administration in wild-type adults are not straightforward.
- Testing it in humans would seem to involve the death of the experimenter by aging before a result is obtained and even the most radically altruistic immortalists don't have that time, because others are dying, too.

It worries me a little that the discussion of interventions for which both of these hold takes as much time and space at imminst, rather than sustainable, "repair vs replace" methods. It's easy to shout "life-extension", but it's kinda harder to analyze just which fundamental discoveries will support the development of bona fide SENS interventions. Everyone, please do make that effort more often.

Btw, this is just the same problem we're having in the biogerontology community!

[Santos]

...I remember I'd read about some humans that become adult and old before they have ten years, so they died before become adults; these humans have problems with a specify hormone so some people think these hormones could control aged. What about these point?

Respect to the research about Klotho, I think the most important point could be the related to caloric restriction how is pointed in some other forums and it is coherent with the catalase story pointed here by John, so we can look for chemicals that work in this way... and eat less?

[caver]

This is interesting: http://www.scienceda...51104085003.htm

http://www.scienceda...50826073745.htm

Edited by caver, 26 November 2005 - 05:37 AM.

[spiritus]

Interesting, now where can I score some, heh

[manofsan]

The Klotho gene, associated with anti-aging, has been found to reduce blood pressure:

http://www.physorg.c...s169920058.html

[tunt01]

The Klotho gene, associated with anti-aging, has been found to reduce blood pressure:

http://www.physorg.c...s169920058.html

pretty sure this gene also regulates your circadian rhythm and sleep pattern

[HealthologisT]

I dont trust these LONGEVITY experiments using MICE for HUMANS a whole lot. Them little critters have the NERVOUS SYSTEM of a cat in a room full of rocking chairs! It dont take much to EXTEND their lifespan. Same with FLIES.

The results can be misleading. Not saying some of it dont apply. However, to me, a better ANIMAL for longevity studies would be those ORANGUTAN MONKEYS they are using now. Most of ya PRIMATES got VEINS like you and me near bout. And a METABOLIC RATE close too. They dang near humans! lol!

[Nate-2004]

Rodents are completely different than humans and I wish science would drop the rodent dependency. 

 

Here are my thoughts on klotho. As mentioned earlier, increased klotho downregulates insulin, which in rats might be fine but in humans, that might result in increased glucosepane and crosslinking. Increased insulin also upregulates klotho, which means low carb diets are out if you want more klotho.

 

Vitamin D also down regulates klotho but apparently only the active form and so far only in dialysis patients. Vitamin D is hugely important for retaining bone with age, preventing skin cancer and other types of DNA damage over the long term. This may trump klotho.

 

I have the TT homozygous allele for Klotho expression which is the norm for most people, (GT is the overexpressed allele). It seems like the best way to achieve increased klotho expression is CRISPR, just modify this allele, change it to GT.