The Great Beyond

Is it surprising that the Mail and the Express pushed the sensationalism on this story? The press release certainly talks about it as if it could be an anti-aging pill...

Quote from U of Texas release: "I never thought we would find an anti-aging pill for people in my lifetime; however, rapamycin shows a great deal of promise to do just that."

Are there any human rapamycin producing intestinal microbiome bacteria that would extend human life? Or is there any plasmid that can be shared among a population of bacteria (the presence of a single species is not stable in human gut microflora)?

Just for the sake of clarity the Nature Press Release mentions mice in the headline and first sentence and quotes the News and Views for further context:

Longevity: Drug extends lifespan of mice (AOP)

A drug used by transplant recipients to stop them rejecting their new organ can significantly extend the lifespan of mice, finds a paper published online this week in Nature.

Rapamycin is a bacterial product originally found in a soil sample from Rapa Nui, or Easter Island. It targets TOR, a kinase that regulates protein translation, cell growth and cell metabolism in response to environmental cues. Reducing TOR function has already been shown to extend the life of yeast, nematode worms and flies, but now David Harrison and colleagues report the effect for the first time in mammals.

The team fed rapamycin to mice late in their life — 600 days of age — and showed that the median and maximal lifespan of treated animals was extended by 9–14%. Currently, the only way to extend the life of a rodent is by severely restricting its diet, so this marks the first report of a pharmacological intervention that lengthens the life of mammals.

In a related News & Views article, Matt Kaeberlein and Brian Kennedy warn that "healthy individuals should not consider taking rapamycin to slow ageing — the potential immunosuppressive effects of this compound alone are sufficient to caution against this." But it's hoped that the finding will lead to the development of interventions for the treatment and prevention of age-related diseases.

Title-: what is Mechanism of action of Rapamycin for prolonging the age?

Rapamycin was originally isolated from a bacterium found on Rapa Nui, the indigenous name for Easter Island. Rapamycin (Rapamune®, Wyeth Ayerst, sirolimus) is a specific inhibitor of the target of rapamycin (TOR). Rapamycin is also a powerful suppressor of the human immune system, as cell anti proliferating drug, so commonly given to organ[Kidney] transplant patients[6mg as soon as after transplant, then 2mg daily for 2-3months as maintenance dose] to help to prevent the rejection of transplanted organs, used with cardiac drug eluting stents[to prevent proliferation of endothelial cells after stent] and may be used as a cancer adjuvant therapy, and also in autosomal dominent polycystic kidney disease. The drug is very costly approximately costs Rs12000/=, in Indian currency a month. Orthologue (mTOR), is also referred to as FKBP12-rapamycin associated protein (FRAP), rapamycin and FKBP12 target (RAFT), rapamycin target (RAPT), or sirolimus effector protein (SEP). mTOR lies downstream of IGF and has been implicated in several pathways that contribute to tumorigenesis, such as translation initiation and cap-dependent translation. The protein kinase TOR genes (TOR1 and TOR2) were first identified in the early 1990s in a screen for rapamycin-resistant yeast mutants[1] . Rapamycin forms a complex with the immunophilin FK506 binding protein-12 (FKBP12), which binds to the FKBP12-rapamycin binding (FRB) domain of mTOR and inhibits its kinase activity. Rapamycin thus can inhibit the growth of a broad spectrum of cancers including rhabdomyosarcoma, neuroblastoma, glioblastoma, small cell lung carcinoma, osteosarcoma, pancreatic cancer, leukaemia, B-cell lymphoma, and breast and colon cancer-derived cells[2]The rapamycin analogues, CCI-779 (Wyeth-Ayerst, PA, USA), RAD001 (Novartis, Switzerland), and AP23573 (Ariad Pharmaceuticals, MA, USA) have shown promise in clinical trials[3] .mTOR functions by integrating extracellular signals (growth factors and hormones), with amino-acid availability and intracellular energy status to control translation rates and additional metabolic processes[4] .mTOR enhances translation initiation in part by phosphorylating two major targets, the eIF4E binding proteins (4E-BPs) and the ribosomal protein S6 kinases (S6K1 and S6K2) that cooperate to regulate translation initiation rates.[5] In Peutz Jeghers syndrome, Tuberous Sclerosis, and other diseases where PTEN is inactivated, the use of rapamycin as a clinical means to reverse the effect of elevated mTOR activity is an attractive option[5]. These diseases are distinct from other hamartoma-associated disorders (such as VHL syndrome) since they have an established molecular link to mTOR. Earlier studies demonstrated that PTEN-inactivated tumour cells exhibit enhanced sensitivity to the rapamycin analog CCI-779[6] More recently, several studies have shown that rapamycin treatment, in combination with other chemotherapeutic drugs, can lead to enhanced selective killing of cancer cells. In particular, the protein tyrosine kinase (PTK) inhibitor, Imatinib (Gleevec, STI571) synergises with rapamycin to inhibit BCR/ABL transformed cells[7] . The effect of rapamycin may be enhanced as a result of Imatinib-induced Akt/mTOR signaling, a complication that is thought to lead to Imatinib resistance. Rapamycin can also synergise with paclitaxel, carboplatin, and vinorelbine to induce apoptosis in breast cancer cells[8] Cisplatin-induced apoptosis of A549 lung cancer cells is also significantly enhanced when combined with RAD001[9] . This could be in part due to reduced translation of p53-activated p21 mRNA in A549 and MCF7 cells treated with RAD001, thereby allowing the dosage of cisplatin to be reduced Also, the use of the EGFR/VEGFR inhibitor, AEE788, in combination with RAD001 greatly decreased tumour growth in glioma xenografts (Goudar et al, 2005). Furthermore, targeting the glycolytic pathway in combination with mTOR inhibition may also be useful in cases where DNA-damaging agents are less efficient in inhibiting growth and promoting apoptosis of cancer cells[10] .
Aging is the progressive, universal decline first in functional reserve and then in function that occurs in organisms over time. Aging is heterogeneous. It varies widely in different individuals and in different organs within a particular individual. Aging is not a disease; however, the risk of developing disease is increased, often dramatically, as a function of age. The biochemical composition of tissues changes with age; physiologic capacity decreases, the ability to maintain homeostasis in adapting to stressors declines, and vulnerability to disease processes increases with age. After maturation, mortality rate increases exponentially with age
Some Theories of Aging[11]

Hypothesis How It May Work
Genetic Aging is a genetic program activated in post-reproductive life when an individual's evolutionary mission is accomplished
Oxidative stressAccumulation of oxidative damage to DNA, proteins, and lipids interferes with normal function and produces a decrease in stress responses
Mitochondrial dysfunction A common deletion in mitochondrial DNA with age compromises function and alters cell metabolic processes and adaptability to environmental change
Hormonal changes The decline and loss of circadian rhythm in secretion of some hormones produces a functional hormone deficiency state
Telomere shortening Aging is related to a decline in the ability of cells to replicate
Defective host defenses The failure of the immune system to respond to infectious agents and the over activity of natural immunity create vulnerability to environmental stresses
Accumulation of senescent cells Renewing tissues become dysfunctional through loss of ability to renew

So it is not well understood how rapamycin actually prolongs life affecting the ageing process and how its connected to calorie restriction and ageing? Through sirolimus effectors protein (SEP)? Then ageing process can be slowed by a drug therapy starting at an advanced age? should healthy individuals over age 50 consider taking rapamycin to slow his/her ageing?. However it is too costly therapy then. Moreover there are many adverse drug reactions of rapamycin like opportunistic infections, lynmhocele lymphoedema, sepsis, tachycardia hepatotoxicity susceptibilities to lymhoma and other malignancies, exfoliative dermatities azospermia to name a few. Mice are known to live longer if fed a calorie-restricted diet that is close to starvation levels, but this would be very difficult for a person to maintain. what should be the dose?

References
[1] Heitman J, Movva NR, Hall MN Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science1991; 253: 905–909 |
[2]Huang S, Houghton PJ Inhibitors of mammalian target of rapamycin as novel antitumor agents: from bench to clinic. Curr Opin Investig Drugs 2002;3: 295–304 |
[3] Panwalkar A, Verstovsek S, Giles FJ Mammalian target of rapamycin inhibition as therapy for hematologic malignancies. Cancer2004; 100: 657–666 |
[4] Hay N, Sonenberg N Upstream and downstream of mTOR. Genes Dev2004; 18: 1926–1945
[5]E Petroulakis, Y Mamane, O Le Bacquer, D Shahbazian and N Sonenberg mTOR signaling: implications for cancer and anticancer therapy British Journal of Cancer 2006; 94, 195–199. doi:10.1038/sj.bjc.6602902 http://www.bjcancer.com/Published online 13 December 2005
[6] Guertin DA, Sabatini DM An expanding role for mTOR in cancer. Trends Mol Med 2005;11: 353–361
[7] Mohi MG, Boulton C, Gu TL, Sternberg DW, Neuberg D, Griffin JD, Gilliland DG, Neel BG Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc Natl Acad Sci USA2004; 101: 3130–3135
[8] Mondesire WH, Jian W, Zhang H, Ensor J, Hung MC, Mills GB, Meric-Bernstam F Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells. Clin Cancer Res2004; 10: 7031–7042
[9] Beuvink I, Boulay A, Fumagalli S, Zilbermann F, Ruetz S, O'Reilly T, Natt F, Hall J, Lane HA, Thomas G The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell 2005;120: 747–759
[10] Xu RH, Pelicano H, Zhang H, Giles FJ, Keating MJ, Huang P () Synergistic effect of targeting mTOR by rapamycin and depleting ATP by inhibition of glycolysis in lymphoma and leukemia cells. Leukemia2005; 19: 2153–2158
[11] Lisa B. Caruso; Aging; Chapter 9. Geriatric Medicine page at Harrison's Internal Medicine17th ed edited by

© To Prof Pranab Kumar Bhattacharya as per IPR Copy Right Rules

Authors_ :Professor Pranab kumar Bhattacharya MD(cal), FIC path(Ind.) , Professor of Pathology, In charge of Histopathology Unit, in charge Blood Bank &VCCTC, in charge of Cytogenetics. Institute of Post Graduate Medical Education & Research, 244a AJC Bose Road, Kolkta-20, West Bengal, India; Mr. Rupak Bhattacharya BSc(Cal)MSc(JU) of 7/51 purbapalli, Sodepur Dist 24 parganas(North) Kol-110, West Bengal, India; Dr.Avisnata Das MBBS(cal), ex House Physician, Medical College, Kolkata; Miss upasana Bhattacharya of Mahamyatala, Garia kol-86 Dr. Tridib Mandal MD( Biochem) cal. Assistant Professor, dept. of Biochemistry, Dr. Hriday Das MD(cal) DTM&H(cal) Medical officer, Dept .of nephrology IPGMER, Dr. Jayanta Das Gupta MD(cal) DM(cal) Asssociate professor, Dept. Gastroenterology Institute of Post Graduate Medical Education & Research, 244a AJC Bose Road, Kolkta-20, West Bengal, India

Is there any documentation regarding the circumstances surrounding the discovery of rapamycin? Why were soil samples obatined from Rapa Nui in 1965? What organization or individual obtained these samples?

Thanks for any information.