LIFE EXTENSION - Senior Years Prolongued

Wednesday, 8 July 2009 00:00 UK

Tests raise life extension hopes

A drug discovered in the soil of a South Pacific island may help to fight the ageing process, research suggests.

When US scientists treated old mice with rapamycin it extended their expected lifespan by up to 38%.

The findings, published in the journal Nature, raise the prospect of being able to slow down the ageing process in older people.

However, a UK expert warned against using the drug to try to extend lifespan, as it can suppress immunity.

Rapamycin was first discovered on Easter Island in the 1970s.

It is already used to prevent organ rejection in transplant patients, and in stents implanted into patients to keep their coronary arteries open. It is also being tested as a possible treatment for cancer.

Researchers at three centres in Texas, Michigan and Maine gave the drug to mice at an age equivalent to 60 in humans.

The mice were bred to mimic the genetic diversity and susceptibility to disease of humans as closely as possible.

Rapamycin extended the animals' expected lifespan by between 28% and 38%.

The researchers estimated that in human terms this would be greater than the predicted increase in extra years of life, if both cancer and heart disease were prevented and cured.

Researcher Dr Arlan Richardson, of the Barshop Institute, said: "I've been in ageing research for 35 years and there have been many so-called 'anti-ageing' interventions over those years that were never successful.

"I never thought we would find an anti-ageing pill for people in my lifetime; however, rapamycin shows a great deal of promise to do just that."

Professor Randy Strong, of the University of Texas Health Science Center, said: "We believe this is the first convincing evidence that the ageing process can be slowed and lifespan can be extended by a drug therapy starting at an advanced age."

Calorie restriction

Rapamycin appears to have a similar effect to restricting food intake, which has also been shown to boost longevity.

It targets a protein in cells called mTOR, which controls many processes involved in metabolism and response to stress.

The researchers had to find a way to re-formulate the drug so that it was stable enough to make it to the mice's intestines before beginning to break down.

The original aim was to begin feeding the mice at four months of age, but the delay caused by developing the new formulation meant that feeding did not start until the animals were 20 months old.

The researchers thought the animals would be too old for the drug to have any effect - and were surprised when it did.

Professor Strong said: "This study has clearly identified a potential therapeutic target for the development of drugs aimed at preventing age-related diseases and extending healthy lifespan.

"If rapamycin, or drugs like rapamycin, works as envisioned, the potential reduction in health cost will be enormous."

'Don't try it now'

Dr Lynne Cox, an expert in ageing at the University of Oxford, described the study as "exciting".

She said: "It is especially interesting that the drug was effective even when given to older mice, as it would be much better to treat ageing in older people rather than using drugs long-term through life."

However, she added: "In no way should anyone consider using this particular drug to try to extend their own lifespan, as rapamycin suppresses immunity.

"While the lab mice were protected from infection, that's simply impossible in the human population.

"What the study does is to highlight an important molecular pathway that new, more specific drugs might be designed to work on.

"Whether it's a sensible thing to try to increase lifespan this way is another matter; perhaps increasing health span rather than overall lifespan might be a better goal."

Sirolimus (INN/USAN), also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. A macrolide, Sirolimus was first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Easter Island . an island also known as "Rapa Nui", hence the name.

It is marketed under the trade name Rapamune by Wyeth.

Sirolimus was originally developed as an antifungal agent. However, this was abandoned when it was discovered that it had potent immunosuppressive and antiproliferative properties.

A 2009 study indicated that rapamycin can prolong the life of mice. If this increase in lifespan were translated to human years, it might allow humans to live more than a hundred years.

Unlike the similarly-named tacrolimus, sirolimus is not a calcineurin inhibitor. However, it has a similar suppressive effect on the immune system. Sirolimus inhibits the response to interleukin-2 (IL-2) and thereby blocks activation of T- and B-cells. In contrast, tacrolimus inhibits the production of IL-2.

The mode of action of Sirolimus is to bind the cytosolic protein FK-binding protein 12 (FKBP12) in a manner similar to tacrolimus. However, unlike the tacrolimus-FKBP12 complex which inhibits calcineurin (PP2B), the sirolimus-FKBP12 complex inhibits the mammalian target of rapamycin (mTOR) pathway by directly binding the mTOR Complex1 (mTORC1). mTOR is also called FRAP (FKBP-rapamycin associated protein) or RAFT (rapamycin and FKBP target). FRAP and RAFT are actually more accurate names since they reflect the fact that rapamycin must bind FKBP12 first, and only the FKBP12-rapamycin complex can bind FRAP/RAFT/mTOR.

The chief advantage sirolimus has over calcineurin inhibitors is that it is not toxic to kidneys. Transplant patients maintained on calcineurin inhibitors long-term tend to develop impaired kidney function or even chronic renal failure; this can be avoided by using sirolimus instead. It is particularly advantageous in patients with kidney transplants for hemolytic-uremic syndrome, as this disease is likely to recur in the transplanted kidney if a calcineurin-inhibitor is used. However, on October 7 2008, the FDA approved safety labeling revisions for sirolimus to warn of the risk for decreased renal function associated with its use.

Sirolimus can also be used alone, or in conjunction with calcineurin inhibitors and/or mycophenolate mofetil, so as to provide steroid-free immunosuppression regimes. However, impaired wound healing and thrombocytopenia is a possible side effect of sirolimus; therefore, some transplant centres prefer not to use it immediately after the transplant operation, instead administering it only after a period of weeks or months. Its optimal role in immunosuppression has not yet been determined, and is the subject of a number of ongoing clinical trials.

The anti-proliferative effect of sirolimus has also been used in conjunction with coronary stents to prevent restenosis in coronary arteries following balloon angioplasty. The sirolimus is formulated in a polymer coating that affords controlled release through the healing period following coronary intervention. Several large clinical studies have demonstrated lower restenosis rates in patients treated with sirolimus eluting stents when compared to bare metal stents, resulting in fewer repeat procedures. A sirolimus-eluting coronary stent is marketed by Cordis, a division of Johnson & Johnson, under the tradename Cypher

It has been proposed, however, that such stents may increase the risk of vascular thrombosis.

Additionally sirolimus is currently being assessed as a theraputic option for autosomal dominant polycystic kidney disease (ADPKD). Case reports indicate that sirolimus can reduce kidney volume and delay the loss of renal function in patients with ADPKD.

Sirolimus also shows promise in treating tuberous sclerosis complex (TSC), a congenital disorder that leaves sufferers prone to benign tumor growth in the brain, heart, kidneys, skin and other organs. The drug is approved by the USFDA for use in children and adults who develop subependymal giant cell astrocytomas, or SEGAs, a brain tumor that appears in up to 30 percent of TSC patients. Phase III clinical trials have linked the drug to SEGA remission, although the tumors often re-grew once treatment stopped. Sirolimus has also been shown to shrink kidney tumors in adults with TSC. Anecdotal reports that the drug ameliorates TSC symptoms such as facial angiofibromas, ADHD, and autism remain unproven.

The anti-proliferative effects of sirolimus may have a role in treating cancer. Recently, it was shown that sirolimus inhibited the progression of dermal Kaposi's sarcoma in patients with renal transplants. Other mTOR inhibitors such as temsirolimus (CCI-779) or everolimus (RAD001) are being tested for use in cancers such as glioblastoma multiforme and mantle cell lymphoma.

Combination therapy of doxorubicin and sirolimus has been shown to drive AKT-positive lymphomas into remission in mice. Akt signalling promotes cell survival in Akt-positive lymphomas and acts to prevent the cytotoxic effects of chemotherapy drugs like doxorubicin or cyclophosphamide. Sirolimus blocks Akt signalling and the cells lose their resistance to the chemotherapy. Bcl-2-positive lymphomas were completely resistant to the therapy; nor are eIF4E expressing lymphomas sensitive to sirolimus.

Rapamycin showed no effect on its own

As with all immunosuppressive medications, rapamycin decreases the body's inherent anti-cancer activity and allows some cancers which would have been naturally destroyed to proliferate. Patients on immunosuppressive medications have a 10- to 100-fold increased risk of cancer compared to the general population. Furthermore, people who currently have or have already been treated for cancer have a higher rate of tumor progression and recurrence than patients with an intact immune system

In a study of Sirolimus as a treatment for TSC, researchers observed a major improvement regarding retardation related to autism. The researchers discovered Sirolimus regulates one of the same proteins that the TSC gene does, but in different parts of the body. They decided to treat mice three to six months old (adulthood in mice life-spans); this increased the autistic mice's intellect to about that of normal mice in as little as three days.

Rapamycin is a macrocyclic polyketide isolated from Streptomyces hygroscopicus that has been shown to exhibit antifungal, antitumor, and immunosuppressant properties.

The biosynthesis of the rapamycin core is accomplished by a type I polyketide synthase (PKS) in conjunction with a nonribosomal peptide synthetase (NRPS). The domains responsible for the biosynthesis of the linear polyketide of rapamycin are organized into three multienzymes, RapA, RapB and RapC which contain a total of 14 modules (See figure 1). The three multienzymes are organized such that the first four modules of polyketide chain elongation are in RapA, the following six modules for continued elongation are in RapB, and the final four modules to complete the biosynthesis of the linear polyketide are in RapC.

Then the linear polyketide is modified by the NRPS, RapP, which attaches L-pipecolate to the terminal end of the polyketide and then cyclizes the molecule yielding the unbound product, prerapamycin

The core macrocycle, prerapamycin is then modified (See figure 3) by an additional five enzymes which lead to the final product, rapamycin. First the core macrocycle is modified by RapI, SAM-dependant O-methyltransferase (MTase), which O-methylates at C39. Next, a carbonyl is installed at C9 by RapJ, a cytochrome P-450 monooxygenases (P-450). Then, RapM, another MTase, O-methylates at C16. Finally, RapN, another P-450 installs a hydroxyl at C27 immediately followed by O-methylation by Rap Q, a distinct MTase, at C27 to yield rapamycin

Rapamycin plaque on Easter Island: A plaque reminding of the discovery of rapamycin (sirolimus) on Rapa Nui (Easter Island), near Rano Kau. The plaque is written in Brazilian Portuguese, and reads: In this location were obtained, in January 1965, soil samples that allowed for the obtainment of rapamycin, a substance that inaugurated a new era for organ transplant patients. An homage from the Brazilian investigators, November 2000.

Neste locam foram obtidas em janeiro de 1965 as amostras de solo que permitiram obter a rapamicina substancia que inaugurou uma nova era para os pacientes submetidos a transplantes do orgaos. Homenagem dos investigadores brasileiros - novembro de 2000 WYETH BRASIL

january 1965 rapamicina